Polycyclic compound, pharmaceutical composition possessing property of h3 receptor antagonist and method for treatment by its using

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel polycyclic compounds of the formula (I): wherein radicals and symbols have values given in the invention claim. Compounds of the formula (I) possess properties of H3 receptors antagonist. Also, invention relates to a pharmaceutical composition containing compounds of the formula (I). Also, invention relates to a method for treatment of disease of group comprising difficulty in nasal breath, obesity, somnolence, narcolepsy, attention deficiency with hyperactivity, Alzheimer's disease and schizophrenia that involves using compounds of the formula (I) and, optionally, in combination of H receptor antagonist.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

39 cl, 3 tbl, 31 ex

 

Prior art

In WO 95/14007, published may 26, 1995, described antagonists types of antifungals for receptor N3.

In WO 99/24405, published may 20, 1999, described ligands of type imidazole for receptor N3.

In U.S. patent US 5869479, issued February 9, 1999, describes a composition for the symptomatic treatment of allergic rhinitis using a combination of at least one antagonist of histamine receptor H1and at least one antagonist of histamine receptor H3.

Due manifested in the art of interest to compounds that act on the receptors of N3new compounds such as antagonists of the receptor N3would provide a valuable contribution in this area of technology. The present invention makes such a contribution.

Brief description of the invention

The present invention relates to new compounds of the structure

or their pharmaceutically acceptable salts or MES, in which

(1) R1selected from the group including:

(a) aryl;

(b) heteroaryl;

(c) heteroseksualci;

(d) alkyl;W

(e) cycloalkyl and

(f) alkylaryl,

where these groups of R1optionally contain from 1 to 4 substituents, independently selected from the group including:

(1) halogen (e.g., Br, F or Cl, n is edocfile F or Cl);

(2) hydroxyl, (i.e. HE);

(3) the lowest alkoxy (for example, (C1-C6-alkoxy, preferably (C1-C4-alkoxy, more preferably (C1-C2-alkoxy, more preferably methoxy);

(4) -CF3;

(5) CF3O-;

(6) -NR4R5;

(7) phenyl;

(8) -NO2;

(9) -CO2R4;

(10) -CON(R4)2where all R4are the same or different;

(11) -S(O)mN(R20)2where all R20are identical or different and denote H or alkyl group, preferably (C1-C4)-alkyl, more preferably (C1-C2)-alkyl and more preferably methyl;

(12) -CN and

(13) alkyl, or

(2) R1and X together form a group selected from:

(3) X is selected from =O, =C(NOR3), =C(NNR4R5),

(4) M1means a carbon atom;

(5) M2selected from the group comprising C and N;

(6) M3and M4independently selected from the group comprising C and N;

(7) Y is selected from the group comprising-CH2-, =C(O) =C(NOR20) (where R20is the same as defined above) and =C(S);

(8) Z means (C1-C6)-alkyl group;

(9) R2means a five - or six-membered heteroaryl cycle, specified six-membered hetero is Riley cycle contains 1 or 2 nitrogen atom, and the remaining atoms of the cycle are carbon atoms, and the said five-membered heteroaryl cycle contains 1 or 2 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, and the remaining atoms of the cycle are carbon atoms; the specified five - or six-membered heteroaryl cycle optionally containing from 1 to 3 substituents independently selected from the group comprising halogen, hydroxyl, lower alkyl, lower alkoxy, -CF3, CF3O-, -NR4R5, phenyl, -NO2, -CO2R4, -CON(R4)2where all R4are the same or different, -CH2NR4R5, -(N)C(NR4R5)2or-CN;

(10) R3selected from the group including:

(a) hydrogen;

(b) (C1-C6)-alkyl;

(c) aryl;

(d) heteroaryl;

(e) heteroseksualci;

(f) arylalkyl (for example, aryl-(C1-C4)-alkyl, for example, -(CH2)w-aryl, where w is from 1 to 4, preferably from 1 to 2, most preferably 1, such as, for example, -CH2-phenyl or-CH2-(substituted phenyl));

(g) -(CH2)e-C(O)N(R4)2where all R4are the same or different;

(h) -(CH2)e-C(O)OR4;

(i) -(CH2)e-C(O)R30where R30means geterotsyklicescoe group, such as, for example, morpholinyl, piperidinyl, piperazinyl the Yu or pyrrolidinyloxy, including

(j) -CF3and

(k) -CH2CF3,

where these aryl, heteroaryl, heterocyclyl and aryl fragment specified arylalkyl optionally contain from 1 to 3 (preferably 1) substituents independently selected from the group comprising halogen (such as F or Cl), -OH, -OCF3, -CF3, -CN, -N(R45)2, -CO2R45and-C(O)N(R45)2where all R45independently selected from the group comprising H, alkyl, alkylaryl or alkylaryl where specified aryl fragment contains from 1 to 3 substituents independently selected from the group comprising-CF3HE, halogen, alkyl, -NO2or-CN;

(11) R4selected from the group comprising hydrogen, (C1-C6)-alkyl, aryl, alkylaryl mentioned aryl and arylalkyl group optionally contain from 1 to 3 substituents selected from the group comprising halogen, -CF3, -OCF3, -OH, -N(R45)2, -CO2R45or-C(O)N(R45)2or-CN, where R45are as defined above;

(12) R5selected from the group comprising hydrogen, (C1-C6)-alkyl, -C(O)R4, -C(O)2R4and-C(O)N(R4)2where all R4chosen independently and R4are the same as defined above;

(13) or R4and R5together with the nitrogen atom to which they St is explained, form a five - or six-membered geteroseksualnoe ring (e.g., morpholine);

(14) R6selected from the group comprising alkyl, aryl, alkylaryl, halogen, hydroxyl, lower alkoxy, -CF3, CF3O-, -NR4R5, phenyl, -NO2, -CO2R4, -CON(R4)2where all R4are the same or different, or-CN;

(15) R12selected from the group comprising alkyl, hydroxyl, alkoxy or fluorine;

(16) R13selected from the group comprising alkyl, hydroxyl, alkoxy or fluorine;

(17) and (subscript u R12is from 0 to 2;

(18) b (subscript u R13is from 0 to 2;

(19) with (subscript u R6is from 0 to 2;

(20) e is from 0 to 5;

(21) m is from 1 to 2;

(22) n is 1, 2 or 3 and

(23) p is 1, 2 or 3, provided that, if M3and M4mean nitrogen, p is 2 or 3 (i.e., if M3and M4mean nitrogen, then R is not equal to 1).

The present invention also relates to pharmaceutical compositions containing an effective amount of the compounds of formula I and a pharmaceutically acceptable carrier.

The present invention also relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract (e.g., upper airway), stagnation (e.g., swelling of the mucous membrane of the nose), hypotension, cardiovascular disease, disease the gastrointestinal tract, Hyper - and hypokinesia and secretion of acid in the gastrointestinal tract, obesity, sleeping disorders (e.g., hypersomnia, sleepiness and narcolepsy), disorders of the Central nervous system, attention deficit hyperactivity disorder (DVGA), Hypo - and hyperactivity of the Central nervous system (for example, agitation and depression) and other Central nervous system diseases (such as Alzheimer's disease, schizophrenia, and migraine)comprising assigning a patient in need of such treatment (e.g., a mammal such as a human), an effective amount of the compounds of formula I.

The present invention also relates to a method of Allergy treatment, comprising the administration to a patient in need of such treatment (e.g., a mammal such as a human), an effective amount of the compounds of formula I.

The present invention also relates to a method of treatment caused by allergic lesions of the respiratory tract (e.g., upper respiratory tract, including the introduction of a patient in need of such treatment (e.g., a mammal such as a human), an effective amount of the compounds of formula I.

The present invention also relates to a method of treatment of congestion (for example, swelling of the mucous membrane of the nose), involving the introduction of a patient in need of such treatment (e.g., a mammal, so the mu as a man), effective amounts of compounds of formula I.

The present invention also relates to pharmaceutical compositions containing an effective amount of the compounds of formula I and an effective amount of a receptor antagonist H1in combination with a pharmaceutically acceptable carrier.

The present invention also relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract (e.g., upper airway) and stagnation (e.g., swelling of the mucous membrane of the nose), involving the introduction of a patient in need of such treatment (e.g., a mammal such as a human), an effective amount of the compounds of formula I in combination with an effective amount of a receptor antagonist H1.

The present invention also relates to a method of Allergy treatment, comprising the administration to a patient in need of such treatment (e.g., a mammal such as a human), an effective amount of the compounds of formula I in combination with an effective amount of a receptor antagonist H1.

The present invention also relates to a method of treatment caused by allergic lesions of the respiratory tract (e.g., upper respiratory tract), which includes keeping the patient in need of such treatment (e.g., a mammal such as a human), the effective number of the value of the formula I in combination with an effective amount of a receptor antagonist H 1.

The present invention also relates to a method of treatment of congestion (for example, swelling of the mucous membrane of the nose), involving the introduction of a patient in need of such treatment (e.g., a mammal such as a human), an effective amount of the compounds of formula I in combination with an effective amount of a receptor antagonist H1.

Detailed description of the invention

In the present invention, the following terms, unless otherwise indicated, use the following values:

alkyl (including the alkyl fragments alkoxyl and alkylaryl) means a linear or branched carbon chains and contains from one to twenty carbon atoms, preferably from one to six carbon atoms;

alkylaryl means an alkyl group as defined above, associated with an aryl group, as defined below, such that said aryl group is linked to the rest of the molecule;

aryl (including the aryl fragment of alkylaryl) means a carbocyclic group containing from 6 to 15 carbon atoms and including at least one aromatic ring (e.g., aryl is a benzene ring), with all available capable of substitution of the carbon atom of the carbocyclic group being considered as possible of the provisions of the merger;

arylalkyl means aryl group, ODA is defined above, associated with the alkyl group defined above, such that said alkyl group is linked to the rest of the molecule;

cycloalkyl means a saturated carbocyclic ring containing from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms;

halogen means fluorine, chlorine bromine or iodine;

heteroaryl means a cyclic group containing at least one heteroatom selected from the group comprising O, S or N, which is carbocyclic ring structure and having a number of delocalized PI-electrons, sufficient to impart aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms; examples include (without restrictions) isothiazole, isoxazole, furazane, triazolyl, thiazolyl, thienyl, furanyl (furyl), pyrrolyl, pyrazolyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridyl (e.g. 2-, 3 - or 4-pyridyl), pyridyl-N-oxide (for example, 2-, 3 - or 4-pyridyl-N-oxide), triazinyl, pteridinyl, indolyl (benzopyrrole), perioperative, ethenolysis, chinoline, honokalani, naphthyridines where specified pyridyl-N-oxide can be represented in the form

heteroseksualci means a saturated carbocyclic ring containing from 3 to 15 carbon atoms, preferably from 4 to carbon atoms, and it carbocyclic ring included from 1 to 3 heteroatomic groups selected from the group comprising-O-, -S - and-NR40where R40means (C1-C6)-alkyl, alkylaryl, -C(O)R4, -C(O)OR4or-C(O)N(R45)2(where R45is the same as defined above, and all R45chosen independently); examples include (without restrictions) 2 -, or 3-tetrahydrofuranyl, 2 - or 3-tetrahydrofuryl, 2-, 3 - or 4-piperidinyl, 2 - or 3-pyrrolidinyl, 2 - or 3-piperazinil, 2 - or 4-dioxane, 1,3-dioxolane, 1,3,5-tritional, pentamethylbenzene, perhydrosqualene, decahydroquinoline, trimethylene, azetidine, 1-azacyclopenta, 1,3-ditional, 1,3,5-trioxane, morpholinyl, thiomorpholine, 1,4-dioxane and 1,3,5-hexahydrotriazine, diazolidinyl, tetrahydropyranyl;

lower alkyl means an alkyl group as defined above, which contains from 1 to 6 carbon atoms, preferably 1-4 carbon atoms;

lowest alkoxyl means CNS group, the alkyl part of which contains from 1 to 6 carbon, preferably 1-4 carbon atoms;

=C(O) means

=C(NOR3means

where (1) means a mixture of isomers of oxime; (2) means one geometrical isomer of the oxime in which a group-OR3located on the same side from the far Eastern branch of the telecommunication, as the group left from carbon atoms; (3) means one geometrical isomer of the oxime in which a group-OR3located on the same side of the double bond, and the right group from the carbon atom; (1) can also be represented in the form

=C(NNR4R5means

and is a mixture of isomers

-(N)C(NR4R5)2means

in the structure

means a nitrogen atom, which is located in one of the 4 positions outside the area of the condensing cycle, i.e. in positions 1, 2, 3 or 4 below:

Asón means acetic acid;

BOC means tert-butoxycarbonyl;

CBZ means carbonylations (-C(O)och2With6H5);

CSA means camphorsulfonic acid;

DBU means 1,8-diazabicylo[5.4.0]undec-7-ene;

DBN means 1,5-diazabicylo[4.3.0]non-5-ene;

DCC means dicyclohexylcarbodiimide;

DEC means 2-diethylaminoethylmethacrylate;

DIBAL-H means diisobutylaluminium;

DIPEA means N,N-diisopropylethylamine;

DIBAL means diisobutylaluminium;

DMAP means of 4-(dimethyl what Mino)pyridine;

DMF means dimethylformamide;

DMSO means dimethylsulfoxide;

EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide;

EtOA means ethyl acetate;

EtOH means ethanol;

FMOC means 9-fluorenylmethoxycarbonyl;

NOT means 1-hydroxybenzotriazole;

'lah means alumoweld lithium;

LDA means diisopropylamide lithium;

m-CPBA means m-chloroperbenzoic acid;

Meon means methanol;

NaBH(SLA)3means triacetoxyborohydride sodium;

NaBH4means borohydride sodium;

NaBH3CN means cyanoborohydride sodium;

NaHDMS means hexamethyldisilazide sodium;

NBS means of N-bromosuccinimide;

RCC means pyridineboronic;

PG denotes a protective group;

Rumor means benzotriazol-1-electropermeabilization;

t-BOC means tert-butoxycarbonyl;

TEMPO means 2,2,6,6-tetramethyl-1-piperidinomethyl free radical;

TFA means triperoxonane acid;

THF means tetrahydrofuran;

TMAD means N,N,N, N'-tetramethyldisiloxane;

TMEDA means tetramethylethylenediamine;

Tr triphenylmethyl;

Tris - Tris(hydroxymethyl)aminomethane;

p-TsOH is p-toluensulfonate acid;

CI/mmol means Curie/mmol (specific measure of radioactivity);

Ki means the inhibition constant for the complex substr the t/receptor;

RA2means logEC50in accordance with the definition given in J. Hey, Eur. J. Pharmacol., (1995), Vol.294, 329-335;

The Belarusian library Association means of mass spectroscopy with fast atom bombardment;

HPLC means high performance liquid chromatography;

IHMS means of liquid chromatography - mass spectroscopy;

MS means mass spectrum;

Msvr means of mass spectroscopy, high-resolution;

ICSD means of mass spectroscopy low-resolution;

TLC means thin layer chromatography.

In addition, when used in the present invention "upper respiratory tract" usually means the upper part of the respiratory system, i.e. the nose, throat and associated structures.

In addition, when used in the present invention an "effective amount" generally means effective therapeutic point of view the number.

Segments held inside of cyclic systems, show that this connection can be established with any capable of substitution of the carbon atoms of the cycle.

Some compounds corresponding to the present invention may exist in different isomeric (e.g., enantiomeric, diastereoisomeric and geometric) forms. It is assumed that the present invention covers all such isomers, as well as mixtures, including racemic see the si. Also covered enol form.

Compounds corresponding to the present invention are ligands for histamine receptor H3. Compounds corresponding to the present invention can also be described as antagonists of the receptor N3or as antagonists at the N3.

Compounds corresponding to the present invention, are the main form acceptable from a pharmaceutical point of view salts with organic and inorganic acids. Examples of acids suitable for the formation of such salts are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methansulfonate and other inorganic and carboxylic acids well known to specialists in this field of technology. Salt is produced by the interaction of the free base with a sufficient amount of the desired acid with the formation of salts occurring in the normal way. Free base can be distinguished by treating the salt with a suitable dilute aqueous solution of a base, such as dilute aqueous solution of sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. Free base differ from the corresponding salts by some physical characteristics, such as rastvorimost is in polar solvents, however, for the objectives of the present invention for other characteristics, salts of acids and bases equivalent to the corresponding free bases.

The compounds of formula I can be in resolutiony, as well as in solvated forms, including hydrated forms, such as polyhydrate. Usually solvated forms, created with acceptable from a pharmaceutical point of view solvents, such as water, ethanol and the like, the present invention is equivalent to the nonsolvated forms.

Compounds corresponding to the present invention, it is possible to combine with a receptor antagonist H1(i.e. compounds corresponding to the present invention, it is possible to combine with a receptor antagonist H1in the pharmaceutical compositions or compounds corresponding to the present invention, can be administered with receptor antagonist H1).

It is known that many chemical substances have antagonistic activity against receptor H1. Many of applicable compounds can be classified as ethanolamines, ethylendiamine, alkylamines followed, fenotiazinas or piperidino. Examples of antagonists of receptor H1include (without limit): astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, Klamath is h, cyclizine, carebastine, cyproheptadine at, carbinoxamine, descarboethoxyloratadine (also known as SCH-34117), diphenhydramine, doxylamine, dimethindene, Bastin, epinastine, efletirizine, Fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, doberstyn, erastamisel, ecumest, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine. Many connections can easily be examined to determine activity against receptors Hiusing known methods, including specific blocking the contractile response to the effects of histamine for the isolated ileum of the Guinea pig. See, for example, WO 98/06395, published February 19, 1998

Thus, in the methods of the present invention, in which the compound of formula I is combined with an effective amount of a receptor antagonist H1specified receptor antagonist H1selected from the group including astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine at, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, Bastin, epinastine, efletirizine, Fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, IU is lysine, mizolastine, mequitazine, mianserin, doberstyn, erastamisel, ecumest, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine.

In addition, in the methods of the present invention, in which the compound of formula I is combined with an effective amount of a receptor antagonist H1specified receptor antagonist H1selected from the group including astemizole, azatadine, azelastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, carebastine, descarboethoxyloratadine, diphenhydramine, doxylamine, Bastin, Fexofenadine, loratadine, levocabastine, mizolastine, erastamisel and terfenadine.

In addition, in the methods of the present invention, in which the compound of formula I is combined with an effective amount of a receptor antagonist H1specified receptor antagonist H1selected from the group comprising: azatadine, brompheniramine, cetirizine, chlorpheniramine, carebastine, descarboethoxyloratadine (also known under the designation SCH-34117), diphenhydramine, Bastin, Fexofenadine, loratadine and erastamisel.

In addition, in the methods of the present invention, in which the compound of formula I is combined with an effective amount of a receptor antagonist H1specified receptor antagonist H1is the battle loratadine.

In addition, in the methods of the present invention, in which the compound of formula I is combined with an effective amount of a receptor antagonist H1specified receptor antagonist H1is descarboethoxyloratadine.

In addition, in the methods of the present invention, in which the compound of formula I is combined with an effective amount of a receptor antagonist H1specified receptor antagonist H1represents fexofenadin.

In addition, in the methods of the present invention, in which the compound of formula I is combined with an effective amount of a receptor antagonist H1specified receptor antagonist H1is cetirizine.

Preferably, when using the above methods were subjected to treatment caused by allergic lesions of the respiratory tract.

Also preferably, when using the above methods were subjected to the treatment of allergies.

Also preferably, when using the above methods were subjected to the treatment of edema of the mucous membrane of the nose.

Preferably, in the above methods using combinations of the compounds of formula I (antagonist H3) and antagonist of H1antagonist of H1selected from a group is s, including loratadine, descarboethoxyloratadine, Fexofenadine and cetirizine. More preferably, the antagonist of H1was loratadine or descarboethoxyloratadine.

In the methods of the present invention, in which the antagonist of N3corresponding to the present invention (compound of formula (I), is administered in combination with an antagonist of H1these antagonists can be administered simultaneously, sequentially (i.e. one after another in a relatively short period of time) and sequentially (first one and then the other, after a certain period of time). Usually, when the antagonist is administered sequentially or alternately, an antagonist of N3corresponding to the present invention (compound of formula (I), appoint the first.

Thus, one way of implementing the present invention relates to pharmaceutical compositions containing an effective amount of compounds 32 and a pharmaceutically acceptable carrier.

Another variant of implementation of the present invention relates to pharmaceutical compositions containing an effective amount of compound 54 and a pharmaceutically acceptable carrier.

Another variant of implementation of the present invention relates to pharmaceutical compositions containing an effective amount of the compounds 55 and pharmaceutically PR is acceptable carrier.

Another variant of implementation of the present invention relates to pharmaceutical compositions containing an effective amount of a compound A and a pharmaceutically acceptable carrier.

Another variant of implementation of the present invention relates to pharmaceutical compositions containing an effective amount of a compound 287 and a pharmaceutically acceptable carrier.

Another variant of implementation of the present invention relates to pharmaceutical compositions containing an effective amount of a compound 320, and a pharmaceutically acceptable carrier.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract, congestion, hypotension, cardiovascular disease, diseases of the gastrointestinal tract, Hyper and hypokinesia and secretion of acid in the gastrointestinal tract, obesity, sleeping disorders, disorders of the Central nervous system, attention deficit hyperactivity disorder, Hypo - and hyperactivity of the Central nervous system, Alzheimer's disease, schizophrenia and migraine, comprising the administration to a patient in need of such treatment, an effective amount of compound 32.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergies porazeni the respiratory tract, congestion, hypotension, cardiovascular disease, diseases of the gastrointestinal tract, Hyper and hypokinesia and secretion of acid in the gastrointestinal tract, obesity, sleeping disorders, disorders of the Central nervous system, attention deficit hyperactivity disorder, Hypo - and hyperactivity of the Central nervous system, Alzheimer's disease, schizophrenia and migraine, comprising the administration to a patient in need of such treatment, an effective amount of compound 54.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract, congestion, hypotension, cardiovascular disease, diseases of the gastrointestinal tract, Hyper and hypokinesia and secretion of acid in the gastrointestinal tract, obesity, sleeping disorders, disorders of the Central nervous system, attention deficit hyperactivity disorder, Hypo - and hyperactivity of the Central nervous system, Alzheimer's disease, schizophrenia and migraine, comprising the administration to a patient in need of such treatment, an effective amount of compound 55.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract, congestion, hypotension, cardiovascular disease, diseases of the gastro-to the muscle path, Hyper - and hypokinesia and secretion of acid in the gastrointestinal tract, obesity, sleeping disorders, disorders of the Central nervous system, attention deficit hyperactivity disorder, Hypo - and hyperactivity of the Central nervous system, Alzheimer's disease, schizophrenia and migraine, comprising the administration to a patient in need of such treatment, an effective amount of a compound A.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract, congestion, hypotension, cardiovascular disease, diseases of the gastrointestinal tract, Hyper and hypokinesia and secretion of acid in the gastrointestinal tract, obesity, sleeping disorders, disorders of the Central nervous system, attention deficit hyperactivity disorder, Hypo - and hyperactivity of the Central nervous system, Alzheimer's disease, schizophrenia and migraine, comprising the administration to a patient in need of such treatment, an effective amount of compound 287.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract, congestion, hypotension, cardiovascular disease, diseases of the gastrointestinal tract, Hyper and hypokinesia and secretion of acid in the gastrointestinal tract, airini is, sleep disorders, disorders of the Central nervous system, attention deficit hyperactivity disorder, Hypo - and hyperactivity of the Central nervous system, Alzheimer's disease, schizophrenia and migraine, comprising the administration to a patient in need of such treatment, an effective amount of compound 320.

Another variant of implementation of the present invention relates to a method of treatment caused by allergic lesions of the respiratory tract comprising the administration to a patient in need of such treatment, an effective amount of compound 32.

Another variant of implementation of the present invention relates to a method of treatment caused by allergic lesions of the respiratory tract comprising the administration to a patient in need of such treatment, an effective amount of compound 54.

Another variant of implementation of the present invention relates to a method of treatment caused by allergic lesions of the respiratory tract comprising the administration to a patient in need of such treatment, an effective amount of compound 55.

Another variant of implementation of the present invention relates to a method of treatment caused by allergic lesions of the respiratory tract, including the appointment of a patient in need of such treatment, an effective amount of a compound A.

Another variant of implementation of the present invention from OSISA to method of treatment caused by allergic lesions of the respiratory tract, includes introduction to the patient in need of such treatment, an effective amount of compound 287.

Another variant of implementation of the present invention relates to a method of treatment caused by allergic lesions of the respiratory tract comprising the administration to a patient in need of such treatment, an effective amount of compound 320.

Another variant of implementation of the present invention relates to a method for treatment of allergies or edema of the nasal mucosa, including the introduction of a patient in need of such treatment, an effective amount of compound 32.

Another variant of implementation of the present invention relates to a method for treatment of allergies or edema of the nasal mucosa, including the introduction of a patient in need of such treatment, an effective amount of compound 54.

Another variant of implementation of the present invention relates to a method for treatment of allergies or edema of the nasal mucosa, including the introduction of a patient in need of such treatment, an effective amount of compound 55.

Another variant of implementation of the present invention relates to a method for treatment of allergies or edema of the nasal mucosa, including the introduction of a patient in need of such treatment, an effective amount of a compound A.

Another option is the implementation of this is about the invention relates to a method for treatment of allergies or edema of the nasal mucosa, includes introduction to the patient in need of such treatment, an effective amount of compound 287.

Another variant of implementation of the present invention relates to a method for treatment of allergies or edema of the nasal mucosa, including the introduction of a patient in need of such treatment, an effective amount of compound 320.

Another variant of implementation of the present invention relates to pharmaceutical compositions containing an effective amount of compounds 32 and an effective amount of a receptor antagonist H1and a pharmaceutically effective carrier.

Another variant of implementation of the present invention relates to pharmaceutical compositions containing an effective amount of compound 54 and an effective amount of a receptor antagonist H1and a pharmaceutically effective carrier.

Another variant of implementation of the present invention relates to pharmaceutical compositions containing an effective amount of the compounds 55 and an effective amount of a receptor antagonist H1and a pharmaceutically effective carrier.

Another variant of implementation of the present invention relates to pharmaceutical compositions containing an effective amount of a compound I and an effective amount of a receptor antagonist H1and pharmaceutically effective the first carrier.

Another variant of implementation of the present invention relates to pharmaceutical compositions containing an effective amount of a compound 287 and an effective amount of a receptor antagonist H1and a pharmaceutically effective carrier.

Another variant of implementation of the present invention relates to pharmaceutical compositions containing an effective amount of a compound 320 and an effective amount of a receptor antagonist N1and a pharmaceutically effective carrier.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 32 in combination with an effective amount of a receptor antagonist H1.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 54 in combination with an effective amount of a receptor antagonist H1.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the surrounding the introduction of the patient, in need of such treatment, an effective amount of compound 55 in combination with an effective amount of a receptor antagonist H1.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of a compound A in combination with an effective amount of a receptor antagonist H1.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 287 in combination with an effective amount of a receptor antagonist H1.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 320 in combination with an effective amount of a receptor antagonist H1.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient who, in need of such treatment, an effective amount of compound 32 in combination with an effective amount of a receptor antagonist H1selected from the group including astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine at, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, Bastin, epinastine, efletirizine, Fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, doberstyn, erastamisel, ecumest, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 54 in combination with an effective amount of a receptor antagonist H1selected from the group including astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine at, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, Bastin, epinastine, efletirizine, Fexofenadine, hydroxyzine, ketotifen, loratadine, evocable, meclizine, mizolastine, mequitazine, mianserin, doberstyn, erastamisel, ecumest, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 55 in combination with an effective amount of a receptor antagonist H1selected from the group including astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine at, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, Bastin, epinastine, efletirizine, Fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, doberstyn, erastamisel, ecumest, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of a compound A in combination with an effective amount and is of agonist receptor H 1selected from the group including astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine at, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, Bastin, epinastine, efletirizine, Fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, doberstyn, erastamisel, ecumest, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 287 in combination with an effective amount of a receptor antagonist H1selected from the group including astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine at, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, Bastin, epinastine, efletirizine, Fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, doberstyn, erastamisel, ecumest, pyrilamine, promethazine, terfenadine, three is alinamin, temelastine, trimeprazine and triprolidine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 320 in combination with an effective amount of a receptor antagonist H1selected from the group including astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine at, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, Bastin, epinastine, efletirizine, Fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, doberstyn, erastamisel, ecumest, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 32 in combination with an effective amount of a receptor antagonist N1selected from the group comprising loratadine, descarboethoxyloratadine, Fexofenadine and cetirizine.

D. the natives option of implementing the present invention relates to a method of Allergy treatment, caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 54 in combination with an effective amount of a receptor antagonist H1selected from the group comprising loratadine, descarboethoxyloratadine, Fexofenadine and cetirizine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the appointment of a patient in need of such treatment, an effective amount of compound 55 in combination with an effective amount of a receptor antagonist H1selected from the group comprising loratadine, descarboethoxyloratadine, Fexofenadine and cetirizine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the appointment of a patient in need of such treatment, an effective amount of a compound A in combination with an effective amount of a receptor antagonist H1selected from the group comprising loratadine, descarboethoxyloratadine, Fexofenadine and cetirizine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the stomach is positive ways and stagnation, includes introduction to the patient in need of such treatment, an effective amount of compound 287 in combination with an effective amount of a receptor antagonist H1selected from the group comprising loratadine, descarboethoxyloratadine, Fexofenadine and cetirizine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 320 in combination with an effective amount of a receptor antagonist H1selected from the group comprising loratadine, descarboethoxyloratadine, Fexofenadine and cetirizine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 32 in combination with an effective amount of a receptor antagonist H1selected from the group comprising loratadine and descarboethoxyloratadine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, eff the active number of connections 54 in combination with an effective amount of a receptor antagonist H 1selected from the group comprising loratadine and descarboethoxyloratadine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the appointment of a patient in need of such treatment, an effective amount of compound 55 in combination with an effective amount of a receptor antagonist H1selected from the group comprising loratadine and descarboethoxyloratadine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the appointment of a patient in need of such treatment, an effective amount of a compound A in combination with an effective amount of a receptor antagonist H1selected from the group comprising loratadine and descarboethoxyloratadine.

Another variant of implementation of the present invention relates to a method for treatment of allergies caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 287 in combination with an effective amount of a receptor antagonist N1selected from the group comprising loratadine and descarboethoxyloratadine.

Another option domestic the present invention relates to a method of Allergy treatment, caused by allergic lesions of the respiratory tract and stagnation, including the introduction of a patient in need of such treatment, an effective amount of compound 320 in combination with an effective amount of a receptor antagonist H1selected from the group comprising loratadine and descarboethoxyloratadine.

Preferably, R1was selected from a group including

(A) aryl (more preferably phenyl);

(B) substituted aryl (e.g., substituted phenyl), and most preferably, substituents for the specified substituted aryl are selected from the group including (1) halogen (e.g., monohalogen or dihalogen), more preferably chlorine or fluorine, more preferably monochloro, dichloro, monitor or debtor, and (2) alkyl, more preferably unbranched alkyl (i.e., a linear chain, for example, methyl), more preferably a substituted alkyl, more preferably alkyl, containing as substituents halogen (for example, 1, 2 or 3 halogen atom such as Cl or F), more preferably alkyl, containing as substituents fluorine atoms, and still more preferably trifluoromethyl;

(C) heteroaryl, most preferably five - or six-membered heteroaryl cycle, more preferably six-membered heteroaryl cycle, and even more preferably pyridyl examples of heteroaryl cycles include pyridyl, thienyl, pyrimidyl, thiazolyl and pyridyl-N-oxide, and examples of the most preferred heteroaryl rings are

where is preferred

(D) substituted heteroaryl, most preferably halogen or alkyl substituted heteroaryl (for example, haloperidol (for example, perperidis) and alkylaryl), more preferably substituted heteroaryl, in which the substituents are independently selected from the group comprising the same or different alkyl group (more preferred is an alkyl group with a linear chain, for example, methyl), more preferably alkyl substituted thiazolyl, and even more preferably

and even more preferably

(E) if R1and X form a group together, the fragment is

where it is most preferable that was equal to 0 or 1 and, if equal to 1, most preferably, R6meant halogen and, if equal to 1, most preferably, R6meant fluorine.

Preferably, X has mean =C(NOR3), where most preferably, R3was selected from the group comprising H, alkyl and halogen-substituted alkyl (e.g. the measures fluoro-substituted alkyl, such as-CH2CF3), most preferably alkyl, more preferably methyl and ethyl, more preferably methyl.

Preferably, M2meant nitrogen.

It is preferable that n was equal to 2.

Preferably, and was equal to 0 or 1, and most preferably 0.

Preferably, b is 0 or 1, and most preferably 0.

Preferably, to 0 or 1, and most preferably 0, and if C is 1, then preferably, R6meant halogen, and, if equal to 1, most preferably, R6meant fluorine.

Preferably, e is equal to 1-5.

Preferably, Y has mean =C(O) (i.e. =C=O).

Preferably, M3and M4were selected such that (1) one of them is meant the carbon, and the other is nitrogen or (2) both meant nitrogen, and most preferably, M3meant carbon.

Preferably, R was equal to 2. Preferably, Z is meant (C1-C3)-alkyl, and most preferably

Preferably, R2meant six-membered heteroaryl cycle, most preferably pyridyl, substituted pyridyl, pyrimidyl or substituted pyrimidyl, more preferably pyridyl, pyridyl, as the Deputy is Deputy containing-NR 4R5pyrimidyl and pyrimidyl, as Deputy containing-NR4R5even more preferably pyridyl, pyridyl, as Deputy containing-NH2(i.e. R4and R5mean N), pyrimidyl and pyrimidyl, as Deputy containing-NH2(i.e. R4and R5mean N), and even more preferably

and even more preferably

Preferably, R3meant H or alkyl, more preferably H or methyl.

Preferably, R4meant H or lower alkyl, more preferably H or methyl, and more preferably N.

Preferably, R5meant N, (C1-C6)-alkyl or-C(O)R4most preferably H or methyl, and more preferably N.

Preferably, R12meant alkyl, hydroxyl or fluorine, and most preferably N.

Preferably, R13meant alkyl, hydroxyl or fluorine, and most preferably N.

Typical compounds corresponding to the present invention include (without limit) connection 23, 30, 31, 32, 33, 41, 44, 45, 49, 50, 52, 53, 54, 55, 56, 57A, 59, 65, 75, 76, 80, 82, 83, 88, 92, 99, 104, 105, 110, 111, 117, 121, 123, 127, 128, 200-241, 244-273, 275 and 278-282, 287, 296, 301-439 and 446.

Thus, typical compounds correspond to the s to the present invention, include (without limit) connection 23, 30, 31, 32, 33, 44, 45, 49, 50, 53, 54, 55, 59, 75, 76, 83, 88, 92, 99, 104, 110, 117, 128, 200, 201, 203-215, 217-241, 244-246, A, 247-253, A, 254-273, 275, 278 and 280-282, 317, 334 403.

Preferred compounds corresponding to the present invention, selected from the group comprising compounds 23, 30, 31, 32, 33, 50, 53, 54, 55, 56, 57A, 59, 92, 212, 215, 218, 219, 220, 224, 225, 226, 227, 229, 233, 235, 237, 238, 246, A, 247, 248, 251, 253, A, 268-273, 275, 278-281, 287, 296, 301, 304-307, 309, 312, 314-318, 320-356 and 358-376.

The most preferred compounds corresponding to the present invention, selected from the group comprising compounds 30, 31, 32, 33, 54, 55, 56, 57A, 225, 237, A, A, 273, 280, 287, 296, 301, 304-307, 309, 312, 314-318, 320-348, 350-356, 359-372 and 374-376.

Thus, one way of implementing the present invention relates to the connection 32.

Another variant of implementation of the present invention relates to the connection 54. Another variant of implementation of the present invention relates to the connection 55. Another variant of implementation of the present invention relates to the connection A. Another variant of implementation of the present invention relates to the compound 287. Another variant of implementation of the present invention relates to the connection 320.

Structures of the above compounds are presented in the examples below and in the following tables 1-3.

The most preferred compound corresponding to this is the invention, is a compound of the formula

The present invention also relates to the compound of the formula

The present invention also relates to the compound of the formula

Connections 32A and 32V can also be used in pharmaceutical compositions and methods of the present invention.

To obtain the compounds of the present invention, it is possible to use the following methods.

One way of synthesis includes a linear sequence of reactions to obtain the desired compounds, ie,

A+b→AB+→ABC+D→ABCD.

This linear sequence of reactions for the synthesis of compounds of the present invention, as discussed below. In the presented method R1means aryl, heteroaryl or alkyl; X= ketone, oxime or substituted oxime; M1=M3= carbon; M2=M4= nitrogen; Y represents C=O; Z=CHR; R2means heteroaryl and n and m equal to 2 (according to this method it is also possible to obtain compounds with n and m equal to 1).

Stage 1: synthesis of ketone 8

In the above equations PG denotes a protective group, and M stands for Li or MgX1(where X1means Cl, Br or I).

In equations (1) and (2) a Grignard reagent 2 is introduced into the reaction e is ectropion, such as aldehyde 1 or nitrile 4, in a suitable aprotic solvent such as THF or ether. PG denotes a protective group. Suitable protective groups include, for example, methyl and benzyl. In the case of nitrile 4 treatment with acid gives directly the ketone 8. Alcohol 3 using a number of different reagents can oxidize and get 8. Alternatively, the amide 7 you can enter into reaction with the ORGANOMETALLIC compound and directly get the ketone 8. Appropriate for this stage protective groups include urethane, amide, etc. Thus, examples of protective groups for the equation (3) include t-Boc, CBZ and FMOC.

Stage 2: removal of protective groups from 8

If the protective group PG is methyl group, then the specified methyl group can be removed by using a reagent, such as charformat; if PG denotes a urethane group, such as group t-Boc, it can be removed with a dilute acid, such as HCl.

Stage 3: synthesis of 11

Amin 9 can be introduced into the reaction mix with acid 10 by using a number of methods well known in the art, such as methods using DCC or PyBOP. Alternatively, the acid 10 can be activated by conversion into the acid chloride or a mixed acid anhydride and then enter it into reacts the Yu with amine 9 and get 11. Suitable protective groups for 10 include, for example, t-Boc.

Stage 4: synthesis of amine 12

The connection 11, in which the protecting group is t-Boc protective group can be removed with acid, such as HCl in dioxane or TFA in CH2Cl2and get Amin 12.

Stage 5: synthesis of compound 14

13 R3means alkyl group. E. means useplease group, halogen or E means a carbonyl group.

Compound 14 can be obtained by the reaction of the amine with 12 to 13. If F denotes a carbonyl group (C=O), 12 and 13 is introduced into the reaction in a solvent such as CH2Cl2in the presence of molecular sieves. After completion of the reaction (for example, through the period of time from 1 to 10 h) add recovery agent, such as NaBH(SLA)3. Alternatively, if E denotes a halogen atom such as Cl or Br, 12 and 13 is introduced into the reaction in a solvent such as DMF, in the presence of a tertiary amine and get the product 14. Suitable protective groups include, for example, t-Boc, phthaloyl.

Step 6: synthesis of compound 16

Compound 14 can be converted into the oxime by 15 introduction 14 in the reaction with H2NOR3·HCl in pyridine at a temperature equal to 40-60°C. Alternative, 14 you can enter into reaction with H2 NOR3·HCl in alcohol as solvent in the presence of bases such as NaOAc, and get 15.

An alternative approach to the synthesis of compounds of formula I includes a synthesis of the two halves of the molecule with subsequent combination of these two fragments, i.e

A+b→AB

With+D→CD

AB+CD→ABCD.

In this case, the synthesis of fragment AB carried out as described above. Synthesis of fragment CD described below.

Stage 1: synthesis of compound 17

R30is as defined above (i.e. alkyl). R35means methyl or ethyl.

Connection 17 are synthesized in the same manner as described for synthesis of compound 14.

Stage 2: synthesis of compound 18

M stands for Li, Na or K.

Connection 17 omelet in a mixture of solvents, such as, for example: (1) EtOH or Meon and water, or (2) THF, water and Meon, using alkali metal base, such as LiOH or NaOH, at a temperature of from 50 to 100°and receive salt 18.

Compound 18 can enter into reaction with the compound 9 as described above, and get 14. The remaining stages are the same.

Compounds used in the present invention are presented as examples in the following examples, which should not be construed as limiting the present invention. For JV is expert in the art should be clear alternative ways of synthesis and similar structures, included in the scope of the present invention.

Example 1

Stage 1

To a solution of 10,81 g (100 mmol) 2-amino-4-methylpyridine in 250 ml of tert-butanol are added 26,19 g (120 mmol) BOC-anhydride. The reaction mixture was stirred at room temperature overnight, concentrated, served on silica gel and subjected to flash chromatography (30% hexane/CH2Cl2up to 0-2% acetone/CH2Cl2and get 15,25 g (73,32 mmol; 73%) of compound 1A as a white solid.

Stage 2

At -78°to a solution of 1A (35,96 g, 173 mmol) in THF (1.4 l) for 30 min portions was added a 1.4 M solution of BuLi (272 ml, 381 mmol) in hexano. The reaction mixture is allowed to warm and stirred for 2 h at room temperature, which leads to the formation of an orange precipitate. The mixture was re-cooled to -78°and for 6 h, keeping the temperature equal to -78°C, bubbled through the suspension pre-dried oxygen (passed through a column of Drierite). During this time the color of the reaction mixture turns orange. At -78°the reaction is stopped by adding 51,4 ml (700 mmol) Me2S, and then 22 ml (384 mmol) Asón. The reaction mixture is allowed to warm and stirred for 48 h at room temperature. Diluted with water and extracted with CH2Cl2and ZAT is concentrated and subjected to flash chromatography (0-15% acetone/CH 2Cl2and get 20,15 g (90 mmol; 52%) of the alcohol 2A as a pale yellow solid.

Stage 3

To a solution of 19,15 g (of 85.5 mmol) of the alcohol 2A in 640 ml of CH2Cl2add saturated aqueous solution to 8.62 g (103 mmol) of NaHCO3and 444 mg (4.3 mmol) of NaBr. The reaction mixture was cooled to 0°and added 140 mg (0.90 mmol) of TEMPO. With vigorous stirring portions over 40 min add 122 ml of 0.7 M (85,4 mmol) selling bleach solution containing 5.25 percent NaOCl). After another 20 min of incubation at 0°With the reaction stopped with a saturated aqueous solution of Na2S2O3and the reaction mixture allowed to warm to room temperature. Diluted with water and extracted with CH2Cl2and then concentrated and subjected to flash chromatography (30% hexane/CH2Cl2up to 0-2% acetone/CH2Cl2and get 15,97 g (71,9 mmol; 84%) of aldehyde 3A in the form of an almost white solid.

Stage 4

To a solution of 11.87 per g (of 53.5 mmol) of aldehyde 3A in 370 ml of CH2Cl2add 9,07 ml (58.8 mmol) of utilisedictated, and then four drops of Asón. Then the reaction mixture was stirred at 40 min at room temperature, then add 22,68 g (107 mmol) NaBH(SLA)3. The reaction mixture was stirred at room themes is the temperature value during the night, neutralized with a saturated aqueous solution of NaHCO3, diluted with water and extracted with CH2Cl2. Concentration and flash chromatography (0-4% saturated solution of NH3in MeOH/CH2Cl2gives KZT 19.09 g (52,6 mmol, 98%) of compound 4A in the form of an almost white solid.

Stage 5

To a solution of 1.57 g (4,33 mmol) of ester 4A in 10 ml of a mixture of THF - water - methanol composition 3:1:1 was added 0.125 g (to 5.21 mmol) LiOH. The reaction mixture was stirred at room temperature over night, concentrated and subjected to drying in high vacuum, getting to 1.59 g of the crude acid 5A in the form of a yellowish solid, which is used without purification.

Example 2

A solution of compound 6A (42 mmol), NBS (126 mmol) and Bz2O2(4.2 mmol) in CCl4(400 ml) 5 h refluxed at 80°C, cooled and stirred at room temperature overnight. The reaction mixture is filtered and concentrated and the residue purified on a flash column (30% EtOAc/hexane) and obtain the desired compound 7A (3.1 g, 23%).

Example 3

Stage 1

To a solution of 8A (10 g, 79,4 mmol) and DMAP (0,029 g, 0.24 mmol) in methylene chloride (150 ml) at 0°With added dropwise tuloldalarol (16,1 g, 79,4 mmol). The reaction mixture was stirred at anatoy temperature during the night. After stirring over night the reaction mixture was washed with saturated aqueous NaHCO3with water , dried and concentrated, obtaining compound 9A as a yellow solid (20 g, 99.8 per cent), which is used without further purification.

Stage 2

In a manner similar to described in Example 2, compound 9A (20 g, 79.3 mmol) is converted into a compound 10A.

Stage 3

Compound 10A (0.5 g, 1.5 mmol) and hydrazine (0.5 M solution in ethanol, 5 ml, 2.5 mmol) are mixed and stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer is dried, concentrated and the residue purified on a flash column (3% solution of methanol in ethyl acetate) and get a connection 11A (0.2 g, 66%).

Example 4

Stage 1

Compound 12A (2 g, and 18.3 mmol) and 13A (3.5 g, 22 mmol) dissolved in methylene chloride and stirred for 1 h at room temperature. Added NaBH(SLA)3(5,4 g, 25.6 mmol) and the reaction mixture is stirred for 5 h at room temperature. The reaction mixture was washed with saturated aqueous NaHCO3with water , dried, concentrated and the residue purified on a flash column (2% solution of methanol in ethyl acetate). Get the connection 14A (4.5 g, 99%).

Stage 2

In a manner similar to described in Example 1, step 5, compound 14A (0.35 g, 1.4 mmol) is converted into a compound 15A (0.31 g, 100%).

Example 5

Stage 1

To a solution of 2,4-diferentialglea (16A, 28.1 mmol) in THF (10 ml) was added the Grignard reagent 17A (1,33 M solution in THF, 30 ml) and the mixture is stirred at room temperature overnight. The reaction is stopped with saturated solution of NH4Cl (150 ml), extracted three times with EtOAc (100 ml), dried, filtered and concentrated. Flash chromatography (20% Meon/EtOAc) gives the desired compound 18A (1.8 g,27%).

Stage 2

Compound 18A (1.6 g, 6.7 mmol), H2NHOH·HCl (0.95 g, 6.7 mmol) and pyridine (7 ml) are mixed and during the night is heated at 60°C. the Pyridine is removed in vacuo and the residue is treated with methylene chloride and saturated aqueous NaHCO3. The organic layer is separated, dried and concentrated and the residue purified using flash chromatography, obtaining compound 19A (1.4 g, 82%).

Stage 3

To a suspension of NaH (0,41 g, 10.2 mmol) in THF (10 ml) was slowly added dropwise a solution of 19A (1.3 g, 5,11 mmol) in DMF (5 ml) and the reaction mixture was stirred over night at 70-75°C. the Mixture was twice extracted with EtOAc three times and using H2O (30 ml), dried over MgSO4and conc the Ute, receiving the crude compound 20A, which is used without further purification (1.04 g, 87%).

Stage 4

To a solution of compound 20A (4.3 mmol) in dichloromethane (20 ml) at 0°add 2-chloroethylphosphonic (6.2 mmol) and triethylamine (7.2 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent is evaporated, to the residue was added Et2O and unreacted starting material is removed by filtration. The filtrate is concentrated and the residue re-dissolved in Meon and 30 min refluxed. Remove methanol gives the product 21 (0.3 g), used without further purification.

Stage 5

To a mixture of compound 21 (1,64 mmol), compound 5A (1,64 mmol) and PyBOP (1,64 mmol) was added DIPEA (4,92 mmol) and CH2Cl2(10 ml) and the reaction mixture was stirred at room temperature over a weekend. Add a saturated solution of NaHCO3(100 ml) and the reaction mixture is extracted twice with CH2Cl2(100 ml), dried over solid MgSO4, concentrated and subjected to flash chromatography (70% EtOAc/hexane) and get a connection 22 (1.04 mmol, 64%).

Stage 6

Compound 22 (0.2 g, and 0.37 mmol) was dissolved in CF3CO2N (3 ml) and methylene chloride (3 ml)and stirred at room temperature overnight. The solvent is removed by evaporation, add a saturated solution of NaHCO3and the mixture is extracted with methylene chloride. The organic layer is dried (MgSO4), filtered and concentrated and the residue purified using flash chromatography, receiving the connection 23 (0.11 g, 68%).

Example 6

Stage 1

A solution of 24 (50 g, 387 mmol) and triethylamine (110 ml) in dioxane (400 ml) and water (400 ml) at 4°treated with Boc2O (9.3 g, 426 mmol). The cooling bath removed and the solution is allowed to warm to room temperature. After 21 h with vacuum volume reduce by two-thirds. The residue was poured into ethyl acetate (250 ml) and water (250 ml). Add saturated aqueous solution of NaHCO3and the organic phase is separated and discarded. The aqueous phase is acidified with 10% HCl solution and extracted with ethyl acetate. The combined organic phases are washed with water, brine, dried (Na2SO4and concentrate, getting 25 in the form of a white powder (82 g, 94%).

Stage 2

To a solution of compound 25 (40 g, 175 mmol) in DMF (250 ml) at 4°With added N,O-dimethylhydroxylamine (34 g), EDCl (44 g, 0,228 mol), NAWT (2.4 g) and DIPEA (120 ml). The reaction mixture is heated to room temperature and stirred over night. Then the reaction mixture was concentrated in vacuo to half volume and howled who live in a mixture of ethyl acetate: water composition 1:1. The organic layer is separated and the aqueous layer was extracted with additional ethyl acetate. The combined organic phases are washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, water and brine and dried. Concentration gives 26 in the form of a light yellow oil (46,7 g, 99%).

Stage 3

To a solution of 2-bromopyridine (17.6 ml, 0,184 mol) in THF (600 ml) at -78°C for 15 min added dropwise n-BuLi (115 ml of 1.6 M solution in hexano, 0,184 mol). After stirring at this temperature for another 30 min dropwise within 15 min was added a solution of 26 (25 mg, 91,9 mmol) in THF (500 ml). The reaction vessel is removed from the cooling bath, put on an oil bath, and 1.5 h heated at 60°C. Then the reaction mixture is cooled to 4°C, diluted with ether (500 ml) and treated with saturated aqueous Na2SO4, (approximately 5 ml). The mixture is transferred into a conical flask and diluted with additional ether (700 ml). Add an additional amount of saturated aqueous solution of Na2SO4, then a solid Na2SO4. The mixture is filtered through a layer of solid Na2SO4and concentrated in vacuo. The chromatography was carried out on a flash column (0-20% solution of ethyl acetate in hexano) gives compound 27 as a yellow oil (16,85 g, 63%).

Stage 4

<>

A solution of 27 (3.3 grams, or 11.4 mmol) in methanol (50 ml) is treated with 4 M HCl solution in dioxane (50 ml) and stirred for 1.5 h at room temperature. Removal of solvent in vacuo gives 28 in the form of a brownish-yellow powder (3 g, 100%).

Stage 5

To a suspension of compound 5A (17,4 g, 50 mmol), compound 28 (11 g, 42 mmol) and diisopropylethylamine (34,6 ml, 199 mmol) in DMF (125 ml) was added NOWT (7,83 g, 58 mmol), EDC (18,54 g, 96.7 mmol) and molecular sieves with a pore size equal to 4 Å. The mixture is stirred for 40 h at room temperature, diluted with methylene chloride (600 ml) and 0.5 N. NaOH solution (400 ml) and filtered. The precipitate is thoroughly washed with an additional amount of 0.5 n NaOH solution and methylene chloride. The combined organic phases are concentrated and twice chromatographic on silica gel (from a mixture of hexane : methylene chloride composition of 1:1 to 6% solution of a saturated solution of NH3in methanol in methylene chloride), get 29 in the form of a yellowish-brown solid (22,3 g), which is used in the next stage without additional processing.

Stage 6

A solution of 29 (22,3 g, 44 mmol) in methylene chloride (120 ml) and triperoxonane acid (60 ml) was stirred at room temperature for 7 hours, the Reaction mixture was concentrated, subjected to 3 h impacts the view of a high vacuum, dissolved in toluene, concentrated and re-exposed to high vacuum. Thus obtained crude brown oil is used in the next stage without additional purification.

Stage 7

Compound 30 (approximately 17.9 g, 44 mmol) is dissolved in pyridine (420 ml), treated with N2NOCH3·HCl (21,78 g, 264 mmol) and 14 h heated at 90°C. Then the reaction mixture was concentrated and the residue dissolved in a mixture of methylene chloride (500 ml) with 2 N. NaOH solution (500 ml). The organic phase is separated and the aqueous phase extracted with more methylene chloride (300 ml). The organic phase is dried, concentrated and the residue chromatographic on SiO2(0-13% NH3/MeOH in CH2Cl2and receives a yellow solid (9,26 g). Mixed fractions obtained by column chromatographic again and get more of 3.23 g of the desired substance. The total yield 12,49 g (overall yield for last two stages is equal to 65%).

Stage 8

Compound 31 (1 g) in ethanol (15 ml) is divided into two pure isomers using column Chiralcel AD (20 mm × 500 mm) (eluent: 75:25, hexane : isopropanol with addition of 0.5% N,N-diethylamine; flow rate 50 ml/min; UV detection wavelength 254 nm) and get a connection 32 (0.6 g) and compound 33 (0.4 g). [M+H] +437 32 and 33.

Alternatively, the connection 32 can be obtained from compound 5A in a manner analogous to that described for obtaining compounds 287 in stage 3 of Example 28.

Example 7

Stage 1

To a solution of 34 (2.4 g, 13.5 mmol) in THF (15 ml) was added compound 35 (26 ml of a 1.3 M solution) and the reaction mixture was stirred at room temperature overnight. Add 2 HCl solution until the pH value will not be less than 2, and the THF removed under reduced pressure. The reaction mixture was neutralized by adding 1 n NaOH solution and the aqueous phase is extracted with 5% solution Meon in EtOAc. The organic phase is dried, concentrated and the residue chromatographic (20% solution Meon in EtOAc)to give 36 (1,03 g, 28%).

Stage 2

To a solution of 36 (1,03 g of 3.78 mmol) in 1,2-dichloroethane (30 ml) was added 1-chloroethylphosphonic (0,76 ml, 7.6 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent is removed in vacuum and the residue is washed with ether. The solid residue is removed by filtration, the ether is removed by evaporation and receive the oil which is dissolved in the Meon (15 ml) and 2 h refluxed. Removal of solvent gives 37, which is used in the next stage without additional purification (1.4 g).

Stage 3

Compound 37 (0,98 g of 3.78 mmol), N-BOC-isonipecotic acid (0.87 g, of 3.78 mmol), DEC (1,11 g, 5.7 mmol), NOT (0.68 g, 4,91 mmol) and DIPEA (3 ml) are mixed in CH2Cl2(40 ml) and stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2and washed with saturated aqueous NaHCO3. The organic layer is dried, concentrated and the residue chromatographic (10% solution of hexane in EtOAc)to give 38 (1,61 g, 91%).

Stage 4

Compound 38 (1,61 g of 3.43 mmol) in CH2Cl2(15 ml) is treated with 1 N. HCl solution in dioxane (5.2 ml) and stirred at room temperature overnight. The solvent is removed in vacuum and get 39 (1.65 g), which is used without further purification.

Stage 5

Compound 39 (1.65 g, 4,01 mmol), 7 (1.29 g, of 3.07 mmol) and Et3N (1.7 ml) are mixed in DMF (40 ml) and stirred at room temperature overnight. The reaction mixture was dissolved in EtOAc and washed 4 times with water. The organic layer is dried and concentrated and the residue purified via chromatography (5% solution Meon in EtOAc)to give 40 (0.6 g, 47%).

Stage 6

A solution of 40 (0.31 g, 0.51 mmol) in pyridine (5 ml) is treated with H2NOMe·HCl (0,092 g at 1.08 mmol) and heated at 60°With during the night. actionnow mixture is diluted with a 10% solution of the Meon in CH 2Cl2, washed with saturated aqueous NaHCO3, dried and concentrated and the residue purified via chromatography (10-15% solution Meon in EtOAc)to give 41 (0.09 g).

Example 8

Stage 1

In a manner similar to described in Example 7, stage 3-4, compound 42 is converted into a connection 43.

Stage 2

To a solution of 43 (2.3 g, 6.3 mmol) in CH2Cl2(60 ml) was added molecular sieves with a pore size equal to 4Åand 4-formylpyridine (0.68 ml to 6.9 mmol) and the mixture stirred for 3 h at room temperature. Then added NaBH(OAc)3(2.7 g, 12.7 mmol) and the reaction mixture was stirred 1 h the Reaction is stopped by addition of NH4Cl, and then add saturated aqueous solution of NaHCO3. Then the reaction mixture was extracted with EtOAc and the combined organic layers are dried and concentrated, obtaining a residue that chromatographic (20% solution Meon in EtOAc). Get a connection 44 (2.3 g, 87%).

Stage 3

In a manner similar to described in Example 7, step 6, compound 44 is converted into a connection 45.

Example 9

Stage 1

In a manner similar to described in Example 8, step 2, compound 46 (1.13 g, 6 mmol) is converted into a compound 47 (1.7 g, 100%).

Stage 2

In a manner similar to described in Example 7, step 4, compound 47 (1.7 g, 6,13 mmol) is converted into a compound 48 (1.9 g, 100%).

Stage 3

To a mixture of compound 48 (or 0.57 g, 2 mmol) and compound 42 (0.52 g, 2 mmol) in CH2Cl2(20 ml) was added Et3N (1,95 ml) and the reaction mixture is cooled to -40°C. Add triphosgene (0.2 g) and the reaction mixture was stirred 2 h at -40°C and 48 h at room temperature. Then the reaction mixture was washed with 1 N. NaOH solution, brine and the organic layer dried. Concentration gives a residue which is purified by chromatography on a column (10% solution Meon in EtOAc.) and get 49 (0.14 g, 55%).

Stage 4

In a manner similar to described in Example 7, step 6, compound 49 (0.09 g, 0.21 mmol) make the connection 50.

Example 10

Stage 1

In a manner similar to described in Example 7, stage 3-4, compound 28 (2.6 g, 9.9 mmol) is converted into a compound 51 (1.1 g).

Stage 2

In a manner similar to described in Example 7, step 5, compound 51 (1.1 g, to 2.94 mmol) is transformed into compound 11 (0,59 g, to 2.94 mmol) and get a connection 52 (0,53 g).

Stage 3

In a manner similar to described in Example 6, stage 7, the connection 52 (0,53 g, 126 mmol) is converted into a compound 53 (0,48 g).

Stage 4

In a manner similar to described in Example 6, step 8, 4 diastereoisomer connection 53 can be obtained using column Chiralcel AD (75:25, hexane : EtOAc with the addition of 0.5% Et2NH). Two more quickly eluruumina connection (54 and 55) are E-isomers of the oxime, and slower eluruumina connection (56 and 57A) represent the Z-isomers of the oxime.

Isomer And540.12 g
Isomer550.11 g
Isomer560.08 g
The D isomer57A0.06 g

Example 11

Stage 1

A solution of n-BuLi (4,2 ml of 1.6 M solution in hexane) in THF (25 ml) at -25°treated with (i-Pr)2NH (0,69 g, 6.8 mmol). The reaction mixture was stirred for 1 h at 0°S, and then cooled to -70°C. are added dropwise compound 4A (0,82 g of 2.26 mmol) in THF (5 ml) and the reaction mixture was stirred 2 h at -70°C and 2 h at -50°C. the Reaction mixture was re-cooled to -70°and added (1S)-(+)-(10-camphorsulfonic)oxaziridine (1.04 g, to 4.52 mmol) in THF (5 ml). Reactionary see the camping 2 hours and stirred at -70° And during the night slowly warmed to room temperature. The reaction is stopped with saturated solution of NH4Cl and extracted with EtOAc. The organic layer is dried and concentrated and the residue purified via chromatography on a column (1:1, hexane : EtOAc) and get 57 (0,44 g, 51%).

Stage 2

In a manner similar to described in Example 1, step 5, compound 57 (0,42 g, 1.1 mmol) is converted into a compound 58 (0.4 g).

Stage 3

In a manner similar to described in Example 6, stage 5-8, compound 58 (0.25 g, 0.7 mmol) is converted into a compound 59 (0.1 g).

Example 12

Stage 1

A solution of compound 60 (10 g, at 50.7 mmol) in ether (150 ml) at -78°sequentially treated with TMEDA (11,8 g of 101.4 mmol) and n-BuLi (58.5 ml of 1.3 M solution in hexano, 76 mmol) and at this temperature the reaction mixture is stirred for 6 hours Then add undiluted CH3SO4CH3(12.8 g, 101,4 mmol) and the reaction mixture during the night slowly cooled down to room temperature. Add saturated aqueous NaCl solution and the organic layer separated. The aqueous layer was extracted three times with ether and the combined organic layers are dried, concentrated and the residue chromatographic (5% solution of EtOAc in hexane) and get 61 (8.0 g, 75%).

Stage 2

A solution of 61 (8 g of 37.9 mmol) in THF (40 ml) at 0°treated dropwise with a solution NR3·THF (45,4 ml of 1.0 M solution in THF, to 45.4 mmol) and the reaction mixture during the night give to slowly warm to room temperature. The reaction mixture was re-cooled to 0°and added EtOH (17 ml), buffer solution with pH=7 (25 ml) and H2O2(25 ml) and the reaction mixture was stirred at room temperature overnight. Then the solvent is removed in vacuo and the residue poured into water and CH2Cl2. Added 10% aqueous NaOH solution (10 ml) and the organic layer separated. The aqueous layer was extracted with additional CH2Cl2and the combined organic layers dried and concentrated. The remainder chromatographic (40% solution of EtOAc in hexane) and receive 62 (3 g).

Stage 3

A solution of 62 (2.8 g, 12.2 mmol) in EtOAc (30 ml) and NaBr (1.26 g, 0.12 mmol) in a saturated aqueous solution of NaHCO3(30 ml) cooled to 0°and treated with TEMPO (0.02 g, 0.12 mmol). After 15 minutes add NaOCl (17,44 ml) and the mixture stirred for 3 h. Add saturated aqueous solution of Na2S2O2and by adding 1 n HCl solution pH was adjusted to 5-6. The mixture is extracted with EtOAc and the organic layers dried and concentrated. The remainder chromatographic (10-20% solution EtOA in hexane) and get a connection 63 (2.1 g, 76%).

Stage 4

To a suspension of PCC (0.95 g, 4.4 mmol) in CH2Cl2(5 ml) under cooling (0° (C) added dropwise a solution of 63 (0.5 g, 2.2 mmol). The mixture is stirred at room temperature overnight. Add the additional number of RCC (1 EQ.) and the mixture is boiled for 2 h under reflux. The reaction mixture is cooled, filtered through celite and concentrated, obtaining the crude compound 64 (1.5 g), which is used without further purification.

Stage 5

In a manner similar to described in Example 5, stage 5, Example 7, step 4, Example 1, step 4 and Example 6, stage 6 and 7, 64 (0.73 g, 3 mmol) turn 65 (0.1 g).

Example 13

Stage 1

When 0°With the salt solution of Vilsmeier obtained is carried out within 15 min dropwise addition of phosphorus oxychloride (150,0 ml of 1.61 mol) to DMF (310,4 ml, 4,01 mol) followed by cooling in a bath of iced portions over 45 min was added malonic acid (40.1 per g of 0.39 mol). Then the reaction mixture is heated to 100°and stirring is continued for 48 hours After the reaction mixture is allowed to cool to room temperature and the reaction stopped, slowly pouring the reaction mixture into a slurry NaHCO3(808 g, 9,62 mol) in water. The solution is drained from the excess is and NaHCO 3and concentrate to dryness in a vacuum. After drying in high vacuum for 2 days solid residue repeatedly washed with CH2Cl2until TLC confirms the complete removal of the product. The combined organic extracts concentrated in vacuo and get 41,0 g of dark brown oil, which was directly used in the next stage.

Stage 2

To a solution of 32.5 g (256 mmol) of the crude malondialdehyde 66 650 ml of absolute ethanol was added 24.5 g (256 mmol) of guanidine hydrochloride and 17.4 g (256 mmol) of ethoxide sodium. The reaction mixture for 4 h refluxed, cooled to room temperature, concentrate and dry in vacuo to make of the silica gel. Flash chromatography (0-10% Meon/20% acetone/CH2Cl2gives 11,0 g (89,4 mmol; 23% (based on malonic acid (2-stage)) pyrimidine 67 in the form of a light yellow solid.

Stage 3

To a mixture of 166 mg (1.35 mmol) aminopyridine 67, 17 mg (0.14 mmol) and DMAP 418 ml (3.00 mmol) Et3N in 10 ml of THF was added 589 mg (2.7 mmol) of (BOC)2O. the Mixture is stirred for 5 h at room temperature, concentrated to dryness, making silica gel and subjected to flash chromatography (1-3% acetone/CH2Cl2and obtain 117 mg (0.36 mmol, 27%) of compound 68 in the form of transparent is the asle.

Stage 4

To a solution of 117 mg (0.36 mmol) of the aldehyde 68 in 7 ml of CH2Cl2add 67 μl (0.43 mmol) of utilisedictated and 5 µl of acetic acid. After 30 min was added 153 mg (0,72 mmol) NaBH(SLA)3. The mixture is stirred at room temperature overnight, diluted with CH2Cl2, washed with aqueous solution of NaHCO3, dried and concentrated, the crude residue is subjected to flash chromatography (1-4% saturated solution of NH3in MeOH/CH2Cl2and get 133 mg (0.29 mmol, 81%) of compound 69 in the form of transparencies.

Stage 5

To a solution of ester 69 in 5 ml of a mixture of THF-water-methanol composition 3:1:1 was added 11 mg (0.44 mmol) LiOH. The reaction mixture was stirred at room temperature overnight, concentrated to dryness and dried in high vacuum, getting 134 mg of the crude acid 70 in the form of a yellowish solid, which is used without purification.

Example 14

Stage 1

At -78°to a solution of 2.36 g to (11.4 mmol) of picoline 1A in 70 ml of THF for 10 min servings gain of 16.3 ml of a 1.4 M solution of BuLi (of 22.8 mmol) in hexano. The reaction mixture is allowed to warm and stirred for 2 h at room temperature, which leads to the formation of an orange precipitate. The mixture was re-cooled to -78° C and for 1 min bubbled through a solution of ethylene oxide, and then stirred for 5 minutes This two-stage sequence is repeated eight times. The mixture is allowed to warm to -50°C, stirred at this temperature for 40 min, the reaction is stopped with the help of 1.34 ml (23 mmol) Asón and the reaction mixture allowed to warm to room temperature. Dilution with water followed by extraction with Asón, the concentration of the organic phase and flash chromatography of the crude residue (10-15% acetone/CH2Cl2give 1.50 g (5,95 mmol, 53%) of compound 71 as a white solid.

Stage 2

At -60°to a solution of 628 ml (7.2 mmol) of oxalicacid in 20 ml of CH2Cl2added dropwise to 1.03 ml (14.5 mmol) of DMSO. After stirring the mixture for 15 min at -55°C for 15 min was added a solution of 1.50 g (5,95 mmol) of alcohol 71 in 20 ml of CH2Cl2. After completion of addition, the mixture stirred for 30 min at -55°and then add 4,18 ml (30.0 mmol) Et3N and stirred for further 15 minutes and Then the reaction mixture is heated to room temperature and diluted with water. Extraction using Asón, the concentration of the organic phase and flash chromatography (1-15% acetone/CH2Cl2give 1,00 g (4.00 mmol, 67%) of compound 72 in the form of an almost white solid.

Stage 3

To a solution of 1.00 g (4.0 mmol) of aldehyde 72 in 25 ml of CH2Cl2add 617 μl (4.8 mmol) of utilisedictated, and then one drop of the Asón. Then the reaction mixture was stirred at 40 min at room temperature, after which was added 1.70 g (8.0 mmol) NaBH(SLA)3. The reaction mixture was stirred at room temperature overnight, neutralized with a saturated aqueous solution of NaHCO3, diluted with water and extracted with CH2Cl2. Concentration and flash chromatography (0-4% saturated solution of NH3in MeOH/CH2Cl2give 1,41 g (3.6 mmol, 90%) of compound 73 as a white solid.

Stage 4

To a solution of 534 mg (1,47 mmol) of ester 73 in 4 ml of a mixture of THF - water - methanol composition 3:1:1 was added 60 mg (2,50 mmol) LiOH. The reaction mixture was stirred at room temperature overnight, concentrated to dryness and dried in high vacuum, getting 540 mg of the crude acid 74 in the form of a white solid which is used without purification.

Example 15

In a manner similar to described in Example 6, stage 5, 6 and 7, 70 turn 75.

Example 16

In a manner similar to described in Example 6, stage 5, 6 and 7, turn 74, 76.

Example 17

With the adiya 1

To a solution of 77 (0.73 g, is 3.82 mmol) in CH2Cl2(10 ml) was added (COCl)2(0,41 ml, 4,58 mmol)and then DMF (0.1 ml) and the reaction mixture is 3 hours and maintained at 40°C. the Reaction mixture was concentrated and get a brown solid, which was dissolved in CH2Cl2(10 ml). Add N,O-dimethylhydroxylamine (0.56 g, 5,73 mmol) and DIPEA (1,33 ml) and the reaction mixture was stirred at room temperature overnight. The reaction is stopped by adding a saturated aqueous solution of NaHCO3and extracted with EtOAc. The combined organic layers are dried and concentrated and the residue purified using chromatography and receive 78 (3.2 g, 84%).

Stage 2

In a manner similar to described in Example 5, stage 1 and 4, 78 (0,57 g, is 2.41 mmol) turn 79 (0,59 g).

Stage 3

In a manner similar to described in Example 6, stage 5, 6 and 7, 79 (0,38 g, 1,49 mmol) turn 80 (0.24 g).

Example 18

Stage 1

In a manner similar to described in Example 6, stage 7, 81 (0.36 g, of 0.53 mmol; synthesized in the same manner as compound 30) turn 82 (0.34 g).

Stage 2

To a solution of 82 (0,115 g, 0.25 mmol) in DMF (4 ml) was added NaH (60% dispersion in mineral the om oil, 0.03 g, from 0.76 mmol). After 5 min at room temperature add CF3CH2OSO2CF3(0,069 g, 0.3 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and to remove DMF is shaken out three times with water. The organic layer is dried and concentrated, obtaining a residue, which is purified using chromatography (10% Meon/NH3in EtOAc) and receive 83 (0.08 g, 30%).

Example 19

Stage 1

To a solution of 17 (0.21 mol, 100 ml THF, -10°C) for 15 min add 84 (0.14 mol) and the reaction mixture becomes very viscous. Add an additional amount of THF (100 ml) and approximately 2.5 h, the yellow suspension is heated from -10 to 10°C. the Reaction is stopped by adding 100 ml of a saturated solution of NH4Cl and 100 ml of H2O. Extracted once with EtOAc (300 ml) and eight times with CH2Cl2(150 ml). Dried over solid MgSO4and filtered. Concentrated and purified using flash chromatography on silica gel (3 to 10% Meon (NH3)/CH2Cl2and receive 85 (11 g, yield 38%).

Stage 2

To a mixture of 85 (9.2 grams) and MnO2(42 g) was added 200 ml of CH2Cl2and the mixture is stirred at room temperature overnight. Add an additional amount of MnO (20 g) and the reaction mixture stirred for further 24 h MnO2filtered off, the reaction mixture was concentrated and purified using flash chromatography on silica gel (5 and 10% Meon (NH3)/CH2Cl2get 86 (3.1 g, yield 33%).

Stage 3

In a manner similar to described in Example 7, step 2, 86 (3.1 g) turn 87 (2.0 g, yield 68%).

Stage 4

In a manner similar to described in Example 7, stage 3, 4, 5 and 6, turn 87 and 88.

Example 20

Stage 1

To a solution of compound 89 in CH2Cl2(20 ml) at 0°add m-SRV (0.54 g) and the reaction mixture is stirred at 25 min 0°and then 2 h at room temperature. Add 40% of NH4OH (12 ml) and the mixture is stirred for 30 minutes the Aqueous layer was separated and extracted with CH2Cl2(10 ml). Dried (MgSO4), filtered and concentrated in vacuo. Flash chromatography (5% Meon (NH3)/CH2Cl2gives 90 (0,67 g, 80%).

Stage 2

To a solution of compound 90 (0.65 g) in CH2Cl2(6 ml) at -10°With added TFA (6 ml) and the reaction mixture over 1 h and stirred at a temperature of -10 to 0°C. Concentrate and twice subjected to azeotropic distillation with toluene (20 ml), concentrated to dryness, recip what I 91 in the form of a resinous oil, which is used without additional processing.

Stage 3

In a manner similar to described in Example 7, steps 5 and 6, turn 91 of 92.

Example 21

Stage 1

To a solution of 93 (of 5.17 g, 22.7 mmol) in THF (100 ml) at -50°With added dropwise n-BuLi (38,4 ml of 1.3 M solution in hexane. After keeping at -40°within hours, the reaction mixture was again cooled to -50°and add 95 (4,84 g, 22.7 mmol) in THF (20 ml). After keeping at -50°With over 2,75 h add glacial acetic acid and then a saturated aqueous solution of NH4Cl. The mixture is heated to room temperature and the layers separated. The aqueous layer was extracted with EtOAc. The combined organic layers are dried (MgSO4), filtered and concentrated, obtaining a residue, which is purified using flash chromatography (1 to 3% Meon/NH3in CH2Cl2), receiving 95 (6,35 g, 63%).

Stage 2

Way similar to that described in Example 12, step 3, 95 (5.34 g, 12,11 mmol) turn 96 (4.71 g, 75%).

Stage 3

In a manner similar to described in Example 6, stage 4, 96 (3.7 g, 8,43 mmol) turn 97 (is 3.08 g, > 100%), which is used in the next stage without additional processing.

Stage 4

Compound 97 (0.7 g, 2.25 mmol), N2NOCH3·HCl (0,94 g, 11,23 mmol) and NaOAc (1.47 g, 17,97 mmol) are mixed in a 1-pentanol (20 ml) and water (2 ml) and 2 days refluxed. The reaction mixture is cooled to room temperature and added with 0.5 n NaOH solution. EtOH is removed under vacuum, add additional water (15 ml) and the reaction mixture extracted with 10% solution in EtOH CH2Cl2(full volume 180 ml). The combined organic extracts are dried and concentrated, gaining 98 (0.55 g, 92%).

Stage 5

In a manner similar to described in Example 6, stage 5, 6 and 7, 98 turn 99.

Example 22

Stage 1

Obtained according to the method described in J. Org. Chem., 1968, 33 (6), 2388.

A solution of 2.2 g (9.5 mmol) 100 75 ml of glacial acetic acid for 5 h hydronaut in the presence of 0.5 g of 10 wt.% platinum-on-charcoal. The reaction mixture was filtered to remove catalyst and the filtrate is concentrated by evaporation under reduced pressure, obtaining a solid residue, which is alkalinized with a 0.5 n NaOH solution and extracted with methylene chloride (CH2Cl2). The methylene chloride extracts are dried over anhydrous MgSO4and concentrate. The residue is purified using flash chromatography elwira a mixture of 10-30% 7 N. NH3- Meon in CH2Cl 2and get 0,82 g of compound 101 (melting point 158-163°). IHMS m/z 240 (MH+).

Stage 2

A mixture of 0.12 g (0.52 mmol) 101, 0.2 g (0.52 mmol) of 5A, of 0.67 g (0.5 mmol) of 1-hydroxybenzotriazole (NOVT) and 0.11 g (or 0.57 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (DEC) in 7 ml of anhydrous dimethylformamide (DMF) was stirred at ambient temperature for 18 hours the Mixture is diluted with water and the resulting precipitate is filtered off, getting 0.26 g 102, in the form of a white solid (melting point 110-115°). IHMS m/z 557 (MH+).

Stage 3

To a solution of 0.34 g (2.7 mmol) of oxalicacid in 3 ml of anhydrous CH2Cl2at -70°and with stirring add to 0.44 g (5.7 mmol) of anhydrous methylsulfoxide in 2 ml of CH2Cl2. After stirring at -70°C for 10 min to the reaction mixture was added 1.2 g (2,15 mmol) 102 in 10 ml of CH2Cl2. Stir the mixture was kept at -70°C for 0.5 h, then mixed with 1.8 ml (13 mmol) of triethylamine and the mixture is allowed to warm to room temperature. The mixture is diluted with water and extracted with CH2Cl2. The organic extracts washed with brine, dried over anhydrous MgSO4and concentrate, receiving 1.18 g 103 in the form of glass. IHMS m/z 555 (MH+).

Stage 4

A solution of 0.8 g (1.44 mmol) 103 and 0.6 g (7.2 mmol) of methoxyamphetamine in 40 ml of ethanol and 40 ml of pyridine for 18 h refluxed. The mixture is concentrated and the residue is dissolved in a mixture of ethyl acetate/ether and washed with water. The organic solution is dried over anhydrous MgSO4and concentrate, receiving 0.65 g of a viscous residue which is dissolved in 8 ml triperoxonane acid and 8 ml of CH2Cl2and stirred for 18 h at ambient temperature. The solution is concentrated and the residue is alkalinized 1 N. solution of NaHCO3and extracted with ethyl acetate. The organic extracts washed with brine, dried over anhydrous MgSO4and concentrate, receiving resinous residue. Purification of the residue via flash chromatography using 5-8% 7 N. NH3- Meon in CH2Cl2gives 0,151 g 104 in the form of resin, IHMS m/z 484 (MH+), and 0,146 g 105 in the form of glass, IHMS m/z 556 (MH+).

The mixing of the solution 0,056 g free base 104 in ethyl acetate with a solution of 0.04 g of maleic acid in ethyl acetate leads to the formation of sludge, which is marked by filtration and obtain 0.06 g of Dimineata 104 (the melting temperature of 155-160°).

Example 23

Stage 1

2.4 g (10 mmol) 106 restore method similar to that described in Example 22, step 1, and get 1.5 g 107 in the form of semi-liquid substances. IHMS m/z 240 (the H+).

Stage 2

1.5 g (of 6.31 mmol) 107 is introduced into the reaction mix with the connection 3 way similar to that described in Example 22, step 2, and get 3 g 108 in the form of a solid (melting point 104-106°). IHMS m/z 557 (MH+).

Stage 3

1,17 g (2.1 mmol) 108 oxidize manner similar to that described in Example 22, step 3, and obtain 0.7 g 109 in the form of glass, IHMS m/z 557 (MH+).

Stage 4

0.32 g (of 0.58 mmol) 109 is introduced into reaction with 0.6 g (7.2 mmol) of methoxyamphetamine in the same way as described in Example 22, step 4, and get 0,065 g 110 in the form of resin, IHMS m/z 484 (MH+), and 0.12 g 111 in the form of glass, IHMS m/z 556 (MH+).

Example 24

Stage 1

A mixture of 18 g (74 mmol) 112, 7.2 g (74 mmol) of N,O-dimethylhydroxylamine, and 19.4 g (15 mmol N,N-diisopropylethylamine, 1.1 g (8 mmol) NOWT and 14.2 g (74 mmol) of DEC in 80 ml of anhydrous DMF for 18 h and stirred at ambient temperature. The mixture is diluted with water and extracted with ethyl acetate. The organic extracts are washed with 1% solution of NaHCO3and brine, dried over MgSO4and concentrate, getting 15.5 g 113 in the form of oil. IHMS m/z 287 (MH+).

Stage 2

To a solution of 2.9 g (18 mmol) of 2-bromopyridine in 30 ml anhydrous THF PR is -78° C and under stirring for 0.5 h added dropwise to 7.5 ml of 2.5 M solution of n-BuLi in hexane. After stirring at -78°C for 1 h to the reaction mixture was added a solution of 5.1 g (17.8 mmol) 113 in 15 ml of THF. The mixture is stirred for 48 h at ambient temperature, mixed with saturated aqueous NH4Cl and extracted with ether. The organic extracts washed with brine, dried over anhydrous MgSO4and concentrated, gaining 5.7 g 114 in the form of oil. IHMS m/z 305 (MH+).

Stage 3

A solution of 3.15 g (10.4 mmol) 114 and 3,47 g (to 41.6 mmol) methoxyamphetamine in 30 ml of ethanol and 30 ml of pyridine for 18 h refluxed. The mixture is concentrated and the residue is dissolved in ether and washed with water. The organic solution is dried over anhydrous MgSO4and concentrate, receiving 2.5 g 115 in the form of oil. IHMS m/z 334 (MH+).

Stage 4

A solution of 2.4 g (7.2 mmol) of 22 in 20 ml of CH2Cl2and 20 ml triperoxonane acid 1 h and stirred at ambient temperature. The solution concentrate. The residue is alkalinized saturated aqueous NaHCO3and extracted with CH2Cl2. The organic extracts washed with brine, dried over anhydrous MgSO4and concentrate, receiving 1,41 g 23 in the form of glass. IHMS m/z 234 (MH+).

Stage 5

The mixture 0,466 g (2 mmol) 116, 0,517 g (2.2 mmol) of 5A, 0,276 g (2 mmol) NOWT and 0.46 g (2.4 mmol) DEC 20 ml of anhydrous DMF for 18 h and stirred at ambient temperature. The mixture is concentrated by evaporation under reduced pressure at a bath temperature of 25-45°and the remainder chromatographic using 4% (7 N. NH3/CH3IT) in CH2Cl2getting to 0.48 g of a syrup which is dissolved in 15 ml EtOAc-EtOH (3:1, by vol.) and mixed with a solution of 0.26 g of maleic acid in 10 ml EtOAc-EtOH (1:1). The precipitate is filtered off and obtain 0.35 g of the maleate 117 (melting point 160-163°). IHMS m/z 451 (MH+).

Example 25

Stage 1

To a solution of 4.16 g (20 mmol) of 1A in 80 ml of anhydrous THF at -78°C for 25 min with stirring, added dropwise a 2.5 M solution of n-BuLi in hexane. After stirring for 1 h at a temperature of from -78°With up to the room to the reaction mixture was added a solution of 6 g (22 mmol) of 26 in 100 ml of anhydrous THF and 18 h incubated at room temperature. The mixture is mixed with saturated aqueous NH4Cl and extracted with EtOAc. The organic extracts washed with brine, dried over anhydrous MgSO4and concentrate, receiving 6,1 g 118 (melting point 146-149°). IHMS m/z 420 (MH+).

Stage 2

The solution 3,71 g (8,8 mmol) 118 and 3.7 g (44 m is ol) methoxyamphetamine in 40 ml of pyridine and 40 ml of ethanol for 2 days refluxed. The mixture is concentrated and the residue dissolved in CH2Cl2and washed with saturated aqueous NaCl. The organic solution is dried over anhydrous MgSO4and concentrated, obtaining 2.6 g 119 in the form of glass. IHMS m/z 421 (MH+).

Stage 3

A solution of 0.9 g (2.14 mmol) 119 in 10 ml of CH2Cl2and 10 ml triperoxonane acid 2 h and stirred at ambient temperature. The solution concentrate. The residue is dissolved in CH2Cl2, washed with saturated aqueous NaHCO3and brine, dried over anhydrous MgSO4and concentrate, getting a solid residue which is triturated with CH3CN and filtered, obtaining 0.29 grams 120 (the melting temperature of 200-205°). IHMS m/z 321 (MH+).

Stage 4

0.1 g (0.31 mmol) 120 and 0,83 g (0.35 mmol) of 5A is introduced into the reaction mix in the same way as described in Example 24, step 5, and obtain 0.12 g of the maleate 121 (melting point 170-173°). IHMS m/z 538 (MH+).

Example 26

Stage 1

In a manner similar to described in Example 6, stage 7, 122 (0.26 g, 0.41 mmol) turn 123 (0.08 g, 40%).

Example 27

Stage 1

To a suspension of LAH (0,83 g, 22 mmol) in ether (20 ml) at 0°With added dropwise 124 (3.2 g, 17.5 mmol) in THF (15 ml). The reaction mixture was stirred for 1.5 h Ave the 0° And the reaction is stopped by adding water (0.8 ml), 20% aqueous solution of NaOH (0.8 ml) and water (2.4 ml). The mixture is stirred for 15 min, filtered and the filter cake is washed with CH2Cl2. The filtrate is concentrated and receive the oil which is dissolved in ether (30 ml), washed with brine and dried (MgSO4). Filtration and concentration in vacuo gives 125 (2.5 g), which is used without further purification.

Stage 2

Stage 3

Analogously to example 1, stages 4 and 5, turn 125 and 126.

Stage 4

In a manner similar to described in Example 6, step 5, turn 126 and 127.

Stage 5

In a manner similar to described in Example 6, stage 7, 127 turn to 128.

The compounds listed in table 1 (first column), obtained from the compounds listed in the last column of table 1, using essentially the same techniques as used in the examples described above.

TABLE 1
Connection # STRUCTUREThe mass spectrum of the [M+N]+The original connection
200470.1
201456.1
202456.1
203531.1
204499.1
205497.1
206517.1
207549.1
208599.1
209568.1
210565.1
211483
212484.1
213583.1
214552.1
215471
216512
217512
218504
219454
220470
221 456
222456
223495
224470
225470
226504
227484
228472
229486
230572
231 505
232452
233518
234450
235442
236423
237423
238436
239451
240423
241423
244435
245519
246451
247421
248438
249452
250487
251543
252501
253457
254471
255465
256465
257422
258406
259455
260484
261443
262440
263441
264 427
265427
266518
267490
268455
269439
270407
271421
272407
273455
275425
278425
279439
280470
281469
282504

The following isomers A and A can be separated from the above 246 and 253, respectively, using techniques well known to specialists in this field of technology.

Example 28

Stage 1

To a solution of 1.00 g (8,13 mmol) of pyrimidine aldehyde 67 (stage 2 of Example 13) in 40 ml of CH2Cl2gain of 1.36 ml (of 10.58 mmol) utilisedictated and 2 drops of acetic acid. Mix 40 min mix at room temperature, and then added 2.58 g (12,17 mmol) NaBH(SLA)3. The mixture is then stirred for 20 h at room temperature, diluted with water Rast is a PR NaOH (pH adjusted to 11) and extracted with CH 2Cl2. The organic phase is dried and concentrated, the residue is subjected to flash chromatography (4-8% to about 3 N. a solution of NH3in MeOH/CH2Cl2and obtain 1.55 g (by 5.87 mmol, 72%) amine 285 in the form of a yellowish solid.

Stage 2

To a solution of a 3.83 g (14,51 mmol) of ester 285 60 ml of a mixture of THF - H2O - Meon composition 3:1:1 was added 1.22 g (29,02 mmol) of LiOH monohydrate. The reaction mixture was stirred at room temperature over night, concentrated and subjected to drying in high vacuum, receiving of 3.84 g of the crude lithium salt of the acid 286 in the form of a yellow solid. The substance can be used directly or can be cleared by passing through a layer of silica gel and elwira using about 3 N. solution of NH3in the Meon.

Stage 3

To a mixture of 3.32 g (14,05 mmol) acid 286 and 4,07 g (14,05 mmol) 4-[(E)-(methoxyimino)-2-pyridinylmethyl]piperidinemethanol (see below connection 447) in 40 ml of DMF are added to 8.94 ml (70,25 mmol) 4-ethylmorpholine and 14.0 ml (23,52 mmol) of a solution of the cyclic anhydride 1-papapostolou acid in ethyl acetate to a concentration of 50 wt.%. The reaction mixture is stirred for 4.5 hours at 50°and then 14 h at room temperature. The mixture is concentrated, and then for 24 h and dried in high vacuum to remove any remaining DMF. Will ottokodalacy distribution between aqueous NaOH solution and CH 2Cl2, the organic phase is separated, dried and concentrated, the residue is subjected to flash chromatography (5-15% to about 3 N. a solution of NH3in MeOH/CH2Cl2and get 4,60 g (10,51 mmol, 75%) of amide 287 in the form of light yellowish-brown foamy substance. MS 438 (M+1).

Example 29

Stage 1

Literature: J. Heterocyclic Chem., 1966. 3, 252.

3,4-Pyridinedicarboxylic 288 (10.0 g, of 67.5 mmol) dissolved in 162 g of 10% aqueous NaOH solution and in the bath with ice salt, the solution is cooled to a temperature of 7°C. are added dropwise bromine (3.6 ml, 70 mmol). After addition of a solution of 45 min is heated on the steam bath with a temperature equal to 80-85°C. Then the yellow solution is cooled to a temperature equal to 37°With, then added dropwise 17 ml of glacial acetic acid until the pH value becomes equal to 5.5. The resulting mixture overnight store in the refrigerator. The formed solid is filtered off and washed with 5 ml water and 5 ml of methanol. The reaction gives 6,35 g 289 product, which melts at 280-285°C (decomposition).

Stage 2

Solid compound 289 (9.5 g, 69 mmol) is carefully added to the three aliquot of a suspension of lithium aluminum hydride (9.5 g, 250 mmol) in 200 ml of dry tetrahydrofuran. Received a hot mixture of two days was stirred at room temperature. PEFC is cooling in the bath with ice, the reaction is stopped consistently cautiously dropwise adding 10 ml of water, then 10 ml of 15% aqueous NaOH, then water (30 ml). The formed solid is filtered through a layer of celite and washed several times with THF. The oil obtained after evaporation of the solvent during curing hardens. The reaction mixture was purified using flash chromatography on silica gel, using as eluent a mixture of 5% Meon (NH3)/EtOAc, and get 6,21 g (72%) of compound 290. JHMS: m/z 125 (M+1).

Stage 3

Manganese dioxide (29 g, 334 mmol) at room temperature and the effective mixing one portion was added to a suspension of 3-amino-4-hydroxymethylbenzene 290 (5.0 g, of 40.3 mmol) in 500 ml of chloroform. Two days later, the solid is filtered through a layer of celite and washed with chloroform. Removal of the solvent under reduced pressure yields of 4.2 g (85%) of compound 291 in the form of a yellow solid.

Stage 4

The solution utilisedictated (12.5 g, 79.5 mmol) and 3-aminopyridine-4-carboxaldehyde 291 (3.33 g, 27,3 mmol) in dry dichloromethane (400 ml), stirred for 1 h at room temperature, then added 60 g of activated molecular sieves with a pore size equal to 3 Å. The mixture is stirred for another 90 min, then at room temperature in one portion was added 20 g (96,mmol) triacetoxyborohydride sodium. After stirring for three days solid is filtered off through a layer of celite and washed with dichloromethane. The solution is stirred for 15 min with 100 ml saturated aqueous sodium bicarbonate solution, then the organic layer is separated from the water. The organic layer twice washed with saturated aqueous sodium bicarbonate, then brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting oil is purified using flash chromatography on silica gel, using as eluent a mixture of EtOAc : hexane : Meon (NH3). This procedure gives 6.8 g (94%) of compound 292. MS-the Belarusian library Association: m/z=264 (M+1).

Stage 5

Ethyl-1-[(3-amino-4-pyridinyl)methyl]-4-piperidinecarboxylate 292 and 4.75 g, 18,04 mmol) stirred for 24 h at room temperature with 1.51 g (36 mmol) of the monohydrate of lithium hydroxide in 75 ml of methanol. Removal of the solvent under reduced pressure gives compound 293 in the form of a white solid.

Stage 6

4-(2-Pyridylcarbonyl)piperidine 28 (stage 4 in Example 6) (0.3 g, was 1.58 mmol), lithium-1-[(3-amino-4-pyridinyl)methyl]-4-piperidinecarboxylate 293 (0.34 g, 1.4 mmol), DEC (0,38 g, 2.0 mmol) and NOT (0.27 g, 2.0 mmol) at room temperature for two days is stirred in 10 ml of dry DMF. The reaction is stopped with 50 ml of 0.5 N. aqueous NaOH solution, and C is the solution extracted with dichloromethane. The combined extracts washed with brine and dried over anhydrous sodium sulfate. Product 295 allocate using flash chromatography on silica gel, using as eluent a mixture of EtOAc : hexane : Meon (NH3) (50:45:5). Yield 0.27 g (47%). MS-the Belarusian library Association: m/z=408 (M+1).

Stage 7

1-[[[1-[(3-Amino-4-pyridinyl)methyl]-4-piperidinyl]carbonyl]-4-(2-pyridylcarbonyl)]piperidine 295 (0,196 g, 0.48 mmol) and methoxynicotinate (0,401 g, 4.8 mmol) in 6.0 ml of dry pyridine for 24 h in an atmosphere of N2heated at a bath temperature of 70°C. After removal of the pyridine by using reduced pressure, the residue treated with saturated aqueous sodium bicarbonate. The resulting mixture was extracted several times with dichloromethane. The combined extracts washed with brine and dried over anhydrous sodium sulfate. The reaction mixture was purified using preparative thin layer chromatography on silica gel. Plate elute with a mixture of EtOAc : hexane : Meon (NH3) (60:35:5) and 296 product is extracted with a mixture of 10% Meon (NH3)/EtOAc. Yield 0.15 g (71%). MS-the Belarusian library Association: m/z=437 (M+1).

Example 30

Stage 1

A mixture of 297 (1 g, 10 mmol) with a solution of water - dioxane composition of 1:1 (50 ml) is treated with Et3N (4 ml, 13 mmol) and BOC2O (2.8 g, 13 mmol) in 4°C and allowed to warm to 20°during the underwater day. Then the solvent is removed in vacuum. The residue is treated with a mixture of water-ethyl acetate composition 1:1 and the organic layer discarded. The aqueous layer was acidified with 1 N. aqueous solution of HCl and extracted three times with ethyl acetate. The combined organic phases are washed with water and brine, dried (Na2SO4and concentrate, getting 298 in the form of a white solid (1.8 g, 90%).

Stage 2

A mixture of 298 (1.8 g, 9 mmol), N,O-dimethylhydroxylamine (2.6 g, 27 mmol), EDCl (5 g, 27 mmol), NAWT (0.1 g, 1 mmol) and DIPEA (12.5 ml, 72 mmol) in DMF (30 ml) is stirred overnight at 20°C. Then the reaction mixture was concentrated in vacuo to half volume, poured into water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, water and brine, dried (Na2SO4and concentrate, getting 299 in the form of a clear oil (2.1 g, 98%).

Stage 3

To a solution of 2-bromopyridine (1.2 ml, 12 mmol) in THF (60 ml) at -78°C for 15 min added dropwise n-BuLi (8 ml, 1.6 M solution in hexano, 12 mmol). After stirring at this temperature for another 30 min dropwise within 15 min was added a solution of 299 (1 g, 4 mmol) in THF (20 ml). Then the reaction mixture for 1 h, heated at 60°the. After cooling to 20°the reaction mixture is diluted with ether, the reaction is stopped saturated aqueous Na2SO4and dried over solid Na2SO4. The mixture is then filtered through a layer of solid Na2SO4and concentrated in vacuo. The chromatography was carried out on a flash column (0-20% ethyl acetate-hexane) gives 300 in the form of a yellow oil (0.12 g, 11%).

Stage 4

By the method similar to that used at stages 4 to 7 of Example 6, get a connection 301. MS 409 (M+1).

By methods similar to those described in the above examples, get connections, are shown in table 2.

TABLE 2
ConnectionSTRUCTUREMC (M+1)
302430
303421
304505
305505
306471
307426
308img src="https://img.russianpatents.com/845/8456846-s.jpg" height="28" width="85" > 408
309442
310437
311437
312458
313402
314487
315438
316467
317424
318451
319430
320523
21453
322453
323410
324 413
325439
326466
327453
328453
329424
330453
331438
332488
333437
334437
335479
336452
337466
338438
339465
340 465
341513
342452
343550
344499
345451
346451
347451
348451
349452
350455
351455
352422
353422
354492
355438
356 437
357424
358510
359539
360453
361409
362438
363426
364422
365483
366483
367497
368465
369479
370479
371493
372 564
373517
374568
375426
376455
377456
378452
379427

Using techniques similar to those described in the above examples, using the starting compounds shown in table 3, get the connection specified in the column "Structure" of table 3. Each connection specified in table 3, is a mixture of isomers Akimov that are marked with the symbolcommunication between the nitrogen atom of the oxime and the fragment HE or OCH3.

TABLE 3
CONNECTIONStructureThe original substance
380
381
382
383
384
385
386

CONNECTIONStructureThe original substance
387
388
389
390
391
392
393

AEGINETIAStructureThe original substance
394
395
396
397
398
399
400

CONNECTIONStructureThe original substance/td>
401
402
403
404
405
406
407

CONNECTIONStructureThe original substance
408
409
410
411
412
413
414

CONNECTIONStructureThe original substance
415
416
417
418
419
420
421
CONNECTIONStructureThe original substance
422
423
424
425
426
427
428

CONNECTIONStructureThe original substance
429
430
431
432
433
434
435

CONNECTIONStructureThe original substance
436
437
438
439

Example 31

Stage 1

To a solution of LDA (233 ml, 2.0 M solution in a mixture of THF/heptane/ethylbenzene, 0,466 mol) in THF (300 ml) at 0°C for 1.0 h added dropwise a solution of compounds 440 (100 g, 0,mol) in THF (approximately 400 ml). Red-orange solution stirred for 30 min at 0°and then using the cannula transferred into a pre-cooled (0° (C) a solution of N-forbindelseshastighed (153 g, 0,485 mol) in dry THF (about 600 ml). The reaction mixture was stirred for 30 min at 0°and then 18 h at room temperature. The total volume of solvent is reduced by about one third and add EtOAc (approximately 1 liter). The solution is successively washed with water, 0.1 G. HCl solution, saturated aqueous NaHCO3and brine. The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure, obtaining the crude liquid. Separation using flash chromatography (mixture of 6:1 hexane - EtOAc) gives compound 441 (93,5 g, 87%).

Stage 2

In a manner similar to described in Example 6, stage 4, the connection 441 turn in connection 442.

Stage 3

In a manner similar to described in Example 1, stage 4, the connection 442 make in connection 443.

Stage 4

In a manner similar to described in Example 1, stage 5, 443 connection make the connection 444.

Stage 5

In a manner similar to described in Example 6, step 5, compound 5 is converted into a compound 445.

Stage 6

In a manner similar to described in Example 6, stage 6, the connection 445 transform in connection 446.

In the above examples, the compound 4-[(E)-(methoxyimino)-2-pyridinylmethyl]piperidinemethanol

you can use to obtain the compounds of the present invention, see, e.g., Examples 6 and 28. Connection 447 preferably be obtained from the compounds of formula

and from the compounds of formula 449

R50means alkyl or aryl group, f is from 0 to 4, R51means alkyl group, and Q means halide group, where these alkyl, aryl and halide groups are as defined above.

Connection 447 can be obtained from 448 and 449

(a) the conversion of compounds of formula 449 in the appropriate Grignard reagent (A)

(b) introducing the compounds of formula 448 in the reaction with the compound of the formula A with obtaining the compounds of formula 450

(C) introducing the compounds of formula 450 reaction with a suitable alkylchlorosilanes formula 451

obtaining the compounds of formula 452

(d) obtaining salt (formula 453)

(e) introducing the compounds of formula 453 reaction with alkoxyamine (NH2OR51) or its hydrochloride with getting oxime of the formula 454

(f) the isomerization of the compounds of formula 454 by processing a strong acid and conversion to the desired salt of the acid of formula 454 with a high content of E-isomer, when the content of the E-isomer greater than the contents of the Z-isomer in accordance with a ratio of 90:10. If f=0, R51means methyl, and the acid used in the isomerization of compounds 454, represents HCl and the final product is a compound of formula 447.

Thus, the receipt can be represented as follows:

By the above method, the compound 447 can be obtained as follows:

The transformation of compounds 461 in connection 447 leads mainly to the E-isomer of compound 447 with high stereochemical purity and high yield. Isomerization of the mixture of phenolic compounds with acidic catalysts discussed in the work .Zsuzsanna et al., Hung. Magy. Km. Foly., 74 (3) (1968), 116-119.

The above method is to start with the connection 449. In stage 1 4-halogen-1-alkylpiperidines (or 4-halogen-1-arylpiperazine) by reaction with magnesium converted into the corresponding Grignard reagent (A). The reaction is usually p is avodat at temperatures approximately -10°C to the boiling point. Usually for this reaction are suitable hydrocarbon solvent, such as, for example, toluene, xylene, chlorobenzene, dichlorobenzene and the like, or mixtures of the above hydrocarbons with simple ether, such as, for example, (C5-C12)-simple alkyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme (diethyl ether diethylenglycol), 1,4-dioxane, tetrahydrofuran and the like, the Solution is cooled to a temperature of from about -10°With up to about 10°and then conducting the reaction with a suitable 2-cyanopyridine (448) for about 10-120 minutes Examples of suitable 2-cyanopyridines are 2-cyanopyridine, 4-methyl-2-cyanopyridine, 4-ethyl-2-cyanopyridine, 4-phenyl-2-cyanopyridine, etc. Preferred are 2-cyanopyridine and 4-methyl-2-cyanopyridine. The Grignard reagent is usually used in a quantity equal to 1-4 molar equivalents relative to the compound of formula 448, preferably about 1-3 molar equivalents and typically in about 1.5 to 2.5 molar equivalents. Product formulas 450 can be distinguished using techniques well known in the art, such as, for example, treatment with an acid (such as HCl), preferably in a suitable solvent (e.g. tetrahydrofuran or ethyl acetate).

Then the product formula 450 at the next stage, you can type in d is the Ktsia with alkylchlorosilanes. Suitable alkylaromatic are, for example, methylchloroform, ethylchloride, propylchloride and the like, and preferable are methylchloroform and ethylchloride. Usually for this reaction are suitable hydrocarbon solvent, such as, for example, toluene, xylene, chlorobenzene, dichlorobenzene and the like, or mixtures of the above hydrocarbons with simple ether, such as, for example, (C5-C12)-simple alkyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, 1,4-dioxane, tetrahydrofuran and the like, the Reaction is usually conducted at temperatures of approximately 25-100°C, preferably about 40-90°and usually about 50-80°C for about 1-5 hours

After completion of the reaction the formed acid is usually washed off and the product formula 452 can be distinguished by extraction with organic solvents.

The compound of formula 452 then can be converted into a salt by treatment with acid, such as sulfuric acid, hydrochloric acid, triperoxonane acid and the like, usually in a solvent at temperatures from ambient temperature up to the boiling point of the solvent. Suitable solvents include hydrocarbons, such as, for example, toluene, xylene, chlorobenzene, dichlorobenzene and the like, As in the compound of formula 452 has two nitrogen atom, ordinary salt which contains 2 mol of acid per 1 mol of compound 452.

The compound of formula 453 then you can turn in alkyloxy formula 454 by its introduction into the reaction with alkoxyamino (or its hydrochloride) is usually in the form of an aqueous solution. Suitable alkoxyamine are, for example, methoxyamine, amoxilin, etc. is Preferred methoxyamine. Alkoxyamine (or its hydrochloride) is usually used in a quantity of from about 1 to about 4 molar equivalents, preferably from about 1 to about 3 molar equivalents, and usually from about 1 to about 2 molar equivalents. Usually catalyze the reaction of a weak acid, such as, for example, acetic acid, formic acid, etc. or mixtures thereof. You can add an auxiliary solvent, such as for example, methanol, ethanol, isopropanol, n-butanol and the like or mixtures thereof. The product of formula 454 after treatment is a mixture of Z - and E-isomers, the ratio between which is necessary for their stereochemical processing, can be installed using methods well known in the art, such as, for example, HPLC.

Treatment of compounds of formula 454 strong acid in the reaction conditions described below, leads to isomerization of a mixture of Z - and E-isomers education mostly E-isomer. Typically, the compound of formula 454 can be dissolved in a solvent such as, for example, meta is ol, ethanol, isopropanol, n-butanol and the like, ether such as methyl tert-butyl ether, tetrahydrofuran and the like, hydrocarbons such as, for example, heptane, hexane, toluene and the like, nitrile, such as acetonitrile, benzonitrile, etc. or mixtures of such solvents. The dissolved compound is then treated with a strong acid, such as, for example, HCl, HBr, H2SO4and the like, at temperatures in the range from 20 to 100°C for about 1-20 hours the Acid is usually used in a quantity of from about 1 to about 8 molar equivalents, preferably from about 1 to about 6 molar equivalents, and usually from about 2 to about 4 molar equivalents. Treatment usually leads to the formation of salt mainly E-isomer of compounds of formula 454, which represents a compound of formula 447 if 454 R51- methyl, n=0 and the acid is HCl.

As is well known to specialists in this field of technology, the products obtained at various stages of the above-described method, can be extracted and cleaned using conventional methods, such as, for example, filtration, recrystallization, solvent extraction, distillation, precipitation, sublimation, etc. Products you can analyze or verify their purity using conventional methods, such as, for example, thin-layer chromatogra the Oia, NMR, HPLC, melting point, mass spectrum analysis, elemental analysis and the like, well known to specialists in this field of technology.

Analysis of the binding of H3receptor

In this experiment, the source receptor H3is the brain of the Guinea pig. Animals have a mass equal to 400-600 g of Brain tissue is homogenized with a solution of 50 mm Tris, pH=7,5. The final concentration of tissue in gomogenizirovannom buffer solution is 10% (wt./vol.). For removal of lumps of tissue and debris homogenizate centrifuged at 1000 g for 10 min and the resulting supernatant centrifuged at 50000 g for 20 min to precipitate membranes, which are then washed three times in homogenizing buffer solution (each time 50000 g for 20 min). Membrane frozen and stored at -70°C.

All the compounds are dissolved in DMSO and then diluted in binding buffer solution (50 mm Tris, pH=7,5) so that the final concentration was 2 μg/ml with 0.1% of DMSO. Then membranes (400 μg protein) was placed in a test tube for the reaction. The reaction begins by the addition of 3 nm [3H]R-α-methylhistamine (8,8 CI/mmol) or 3 nm [3H]Nα-methylhistamine (80 CI/mmol) and continue incubation at 30°C for 30 minutes a Bound ligand is separated from unbound is about ligand by filtration and the amount of radioactive ligand, associated with membranes was determined by liquid scintillation spectrometry. Incubation is always performed twice and the standard error is always less than 10%. Compounds that inhibit more than 70% of specific binding of the radioactive ligand to the receptor, to determine the Ki values (nm) subjected to serial dilution.

Connection 23, 30, 31, 32, 33, 44, 45, 49, 50, 53, 54, 55, 56, 57A, 59, 75, 76, 83, 88, 92, 99, 104, 110, 117, 128, 200, 201, 203-215, 217-241, 244-246, A, 247-253, A, 254-273, 275, 278, 280-282, 287, 296, 301-310 and 312-379 have Ki values in the range from about 0.25 to about 370 nm.

The preferred connection 23, 30, 31, 32, 33, 50, 53, 54, 55, 56, 57A, 59, 92, 212, 215, 218, 219, 220, 224, 225, 226, 227, 229, 233, 235, 237, 238, 246, A, 247, 248, 251, 253, A, 268-273, 275, 278-281, 287, 296, 301, 304-307, 309, 312, 314, 318, 320-356 and 358-376 have Ki values that are in the range of from about 0.25 to about 33 nm.

The most preferred compounds 30, 31, 32, 33, 54, 55, 56, 56A, 225, 237, A, A, 273, 280, 287, 296, 301, 304-307, 309, 312, 314-318, 320-348, 350-356, 359-372 and 374-376 have Ki values in the range from about 0.25 to about 16 nm.

A more preferred compound 32 has a value of Ki is equal to or 0.83 nm.

More preferred compounds 54, 55, A, 287, 320 have Ki values in the range from about of 1.05 to about 9,75 nm.

In the manufacture of pharmaceutical compositions described in the present izopet the Institute, 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 and include, for example, magnesium carbonate, magnesium stearate, talc, sugar and lactose. Tablets, powders, pills and 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 work A.Gennato (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.

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

Aerosol compositions 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 the gas, for example nitrogen.

In the scope of the present invention also includes a solid form compositions which are intended for conversion into liquid form compositions 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 composition can be creams, lotions, aerosols and/or emulsions and can be included in the matrix patch percutaneous exposure or patch reservoir type that is commonly used in the art for such purpose.

Preferably the oral connection.

Preferably, the pharmaceutical composition is contained in a single dosage form. In this form, the composition is divided into single doses of appropriate size containing appropriate quantities of the active components, such as quantity sufficient to achieve the required targets.

The number of active compounds contained in one dose of a medicinal product, in accordance with the specific case of application is usually can be changed or adjusted in the range from about 1 to about 150 mg, preferably from about 1 to about 75 mg, b is more preferably from about 1 to about 50 mg

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 holds a specialist in this field of technology. For convenience, the total daily dose can be split and assign 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 in 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 the symptoms treated. A typical recommended daily dosage regime by oral administration may include the introduction of from about 1 to about 300 mg/day, preferably from 1 to 75 mg/day, administered by two to four divided doses.

The above-described methods, as appropriate for the present invention using the compound of the formula I also include one or more compound of formula I, and the above-described methods, as appropriate for the present invention involving the use of compounds of formula I in combination with a receptor antagonist H1also include use is the use of one or more compound of formula I in combination with one or more antagonists of receptor H 1.

Although the present invention is described with specific variants of implementation of the above, for professionals with a common training in the art will clear many alternatives, modifications, and changes. It is implied that all such alternatives, modifications and changes are included within the scope and essence of the present invention.

1. The compound of the formula

or its pharmaceutically acceptable salt or MES, in which

(1) R1selected from the group including

(a) phenyl;

(b) heteroaryl, selected from the group comprising a pyridyl, thienyl, pyrimidyl, hinely, thiazolyl, pyrazolyl, pirolli, chinadoll, pyridyl-N-oxide and pyrazinyl; and

(e) (C3-C7-cycloalkyl;

where these groups of R1optionally contain from 1 to 4 substituents, independently selected from the group including

(1) halogen;

(2) hydroxyl;

(3) (C1-C6-alkoxyl;

(4) -CF3;

(6) -NR4R5;

(7) phenyl;

(11) -S(O)mN(R20)2where all R20are identical or different and denote H or C1-C6is an alkyl group; and

(13) (C1-C6)-alkyl, unsubstituted or substituted with halogen; or

(2) R1 and X together form a group selected from the

(3) X is selected from =O, =C(NOR3), =C(NNR4R5),

(4) M1means a carbon atom;

(5) M2means N;

(6) M3means C or N and M4means N;

(7) Y mean =C(O);

(8) Z means (C1-C6)-alkyl group;

(9) R2means heteroaryl cycle, selected from the group comprising a pyridyl, pyrimidyl, pyridyl-N-oxide, furanyl, thiazolyl, pyridazinyl, pyrazolyl, oxazolyl, thienyl, pirolli, thiadiazolyl, sensational and oxadiazolyl, and specified heteroaryl cycle optionally containing from 1 to 3 substituents independently selected from the group comprising halogen, (C1-C6)-alkyl, (C1-C6-alkoxy, -NR4R5, -CO2R4, -CH2NR4R5or(N)C(NR4R5)2;

(10) R3selected from the group including

(a) hydrogen;

(b) (C1-C6)-alkyl;

(c) phenyl;

(f) phenyl-(C1-C6)-alkyl;

(h) -(CH2)e-C(O)OR4;

(i) -(CH2)e-C(O)R30where R30means geterotsyklicescoe group selected from the group comprising morpholinyl and pyrrolidinyl; or

2CF3;

where these aryl, heteroaryl, heterocyclyl and aryl fragment specified arylalkyl optionally contain from 1 to 3 substituents independently selected from the group comprising halogen and-CF3;

(11) R4selected from the group comprising hydrogen and (C1-C6)-alkyl;

(12) R5selected from the group comprising hydrogen, (C1-C6)-alkyl and-S(O)2R4;

(13) or R4and R5together with the nitrogen atom to which they are bound, form morpholinyl ring;

(14) R6means halogen;

(15) R12selected from the group comprising hydroxyl and fluorine;

(16) R13selected from the group comprising (C1-C6)-alkyl, hydroxyl and fluorine;

(17) and is 0 or 1;

(18) b is 0 or 1;

(19) is 0 or 1;

(20) e is 1;

(21) m is 2;

(22) n is 2 and

(23) p is 1, 2 or 3 provided that if M3and M4mean nitrogen, p is 2 or 3.

2. The compound according to claim 1, in which R1selected from the group including

(A) phenyl;

(B) substituted phenyl in which the substituents for the specified substituted aryl selected from the group comprising (1) a halogen, (2) C1-C6-alkyl, and (3) substituted by halogen, C1-C6-alkyl;

(C) heteroaryl selected from the gr is PPI, includes pyridyl, thienyl, pyrimidyl, hinely, thiazolyl, pyrazolyl, pirolli, chinadoll, pyridyl-N-oxide and pyrazinyl;

(D) defined in claim 1, heteroaryl, substituted as indicated in claim 1; or

(E) if R1and X form a group together, the fragment is

3. The compound according to claim 2, in which R1selected from the group including

(A) phenyl;

(B) substituted phenyl in which the substituents for the specified substituted phenyl selected from the group comprising (1) a halogen, (2) C1-C6-alkyl, and (3) substituted by halogen, C1-C6-alkyl;

(C) heteroaryl, selected from the group comprising a pyridyl, thienyl, pyrimidyl, thiazolyl and pyridyl-N-oxide;

(D) substituted (C1-C6)-alkyl thiazolyl or

(E) if R1and X form a group together, the fragment is

where C is 0 or 1, and if C is 1, R6means halogen.

4. The compound according to claim 3 in which R1selected from the group including

(A) phenyl;

(B) substituted phenyl in which the substituents for the specified substituted phenyl selected from the group comprising chlorine, fluorine and trifluoromethyl;

(C) heteroaryl selected from the group including

or

(D) substituted heteroaryl formula

or

(E) if R1and X form a group together, the fragment is

where C is 0 or 1, and if C is 1, R6means fluorine.

5. The compound according to claim 1, in which R1selected from the group including

(A) phenyl;

(B) substituted phenyl in which the substituents for the specified substituted phenyl selected from the group comprising chlorine, fluorine and trifluoromethyl;

(C) pyridyl or

(D) substituted heteroaryl formula

or

(E) if R1and X form a group together, the fragment is

where C is 0 or 1, and if C is 1, R6means fluorine.

6. The compound according to claim 5, in which R1means pyridyl.

7. The connection according to claim 6, in which R1means

8. The compound according to claim 1, in which X means =C(NOR3), a R3selected from the group comprising H and (C1-C6)-alkyl.

9. The connection of claim 8, in which R3selected from the group consisting of H and methyl and ethyl.

10. The connection according to claim 9, in which R3means methyl.

11. The compound according to claim 1, in which the ohms

M3mean carbon and M4mean nitrogen;

n = 2;

and is 0 or 1;

b is 0 or 1;

with 0 or 1, and if C is 1, R6means halogen;

e is equal to 1 and

p is 2;

Y means =C(O) and

Z means (C1-C3)-alkyl.

12. The compound according to claim 1, in which Z means

13. The compound according to claim 1, in which R2mean six-membered heteroaryl cycle, selected from the group comprising a pyridyl, pyrimidyl, pyridyl-N-oxide and pyridazinyl.

14. The connection 13, in which R2selected from the group comprising a pyridyl, pyridyl, as Deputy containing-NR4R5pyrimidyl and pyrimidyl, as Deputy containing-NR4R5.

15. The connection 14, in which R2means pyridyl, as Deputy containing-NH2or pyrimidyl, as Deputy containing-NH2.

16. The connection indicated in paragraph 15, in which R2means

17. The compound according to claim 1, in which R4means H or (C1-C6)-alkyl; R5means H or (C1-C6)-alkyl; R12means hydroxyl or fluorine and R13means (C1-C6)-alkyl, hydroxyl or fluorine.

18. The connection 17, which 4means H or methyl; R5means H or methyl; R12means hydroxyl or fluorine and R13means hydroxyl or fluorine.

19. The compound according to claim 1, in which

(1) R1selected from the group including

(A) phenyl;

(B) substituted phenyl in which the substituents for the specified substituted aryl selected from the group comprising(1) a halogen, (2) C1-C6-alkyl, and (3) substituted by halogen, C1-C6-alkyl;

(C) heteroaryl, selected from the group comprising a pyridyl, thienyl, pyrimidyl, hinely, thiazolyl, pyrazolyl, pirolli, chinadoll, pyridyl-N-oxide and pyrazinyl;

(D) defined in claim 1, heteroaryl, substituted as indicated in claim 1; or (E)if R1and X form a group together, the fragment is

(2) X means =C(NOR3);

(3) R3selected from the group comprising H and (C1-C6)-alkyl;

(4) M2mean nitrogen;

(5) Y mean =C(O);

(6) M3means C or N and M4means N;

(7) Z means (C1-C3)-alkyl and

(8) R2mean six-membered heteroaryl cycle, selected from the group comprising a pyridyl, pyrimidyl, pyridyl-N-oxide and pyridazinyl.

20. The connection indicated in paragraph 15, in which

(1) R1selected from the group including

(A) phenyl;

(B) substituted phenyl in which the substituents for the specified substituted phenyl selected from the group comprising (1) a halogen, (2) C1-C6-alkyl, and (3) substituted by halogen, C1-C6-alkyl;

(C) heteroaryl, selected from the group comprising a pyridyl, thienyl, pyrimidyl, thiazolyl and pyridyl-N-oxide; or

(D) substituted (C1-C6)-alkyl thiazolyl; or

(E) if R1and X form a group together, the fragment is

where C is 0 or 1, and if C is 1, R6means halogen.

(2) R3selected from the group consisting of H, methyl and ethyl;

(3) n = 2;

(4) a is 0 or 1;

(5) b is 0 or 1;

(6) with 0 or 1, and if C is 1, R6means halogen;

(7) e is equal to 1 and

(8) p is 2;

(9) R4means H or (C1-C6)-alkyl;

(10) R5means H or (C1-C6)-alkyl;

(11) R12means hydroxyl or fluorine, and

(12) R13means (C1-C6)-alkyl, hydroxyl or fluorine.

21. Connection by claim 20, in which R2means

R1means

M2means nitrogen, M3means at lead and M 4means nitrogen.

22. The compound according to claim 1, selected from the group including

23. The compound according to claim 1, selected from the group including

24. The compound according to claim 1, having the formula

25. The compound according to claim 1, having the formula

26. The compound according to claim 1, having the formula

27. The compound according to claim 1, having the formula:

28. The compound according to claim 1, having the formula:

29. The compound according to claim 1, having the formula:

30. The compound according to claim 1, ladydee formula:

31. The compound according to claim 1, having the formula:

32. Pharmaceutical composition having the properties of a receptor antagonist N3containing the active ingredient and pharmaceutically acceptable carrier, wherein the active substance contains a compound of the formula (I) according to any one of claims 1 to 31 in an effective amount.

33. The pharmaceutical composition according p, characterized in that it further comprises a receptor antagonist H1in an effective amount.

34. The method of treatment of a disease from the group including nasal congestion, obesity, sleepiness, narcolepsy, attention deficit hyperactivity disorder, Alzheimer's disease and schizophrenia, by introducing to a mammal an effective amount of the active substance, characterized in that the active substance is administered a compound of General formula (I) according to any one of claims 1 to 31.

35. The method according to clause 34, wherein the treatment is subjected to a stuffy nose.

36. The method according to clause 34, wherein the treatment is subjected to nasal congestion, while additionally introducing receptor antagonist H1in an effective amount.

37. The method according to p, characterized in that the specified receptor antagonist H1selected from the group including astemizole, azatadine, elastin, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine at, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, Bastin, epinastine, efletirizine, Fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, doberstyn, erastamisel, ecumest, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine.

38. The method according to clause 37, wherein the specified receptor antagonist H1selected from the group including loratadine, descarboethoxyloratadine, Fexofenadine and cetirizine.

39. The method according to § 38, characterized in that the specified receptor antagonist H1selected from the group including loratadine and descarboethoxyloratadine.



 

Same patents:

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and R8 represent hydrogen atom or (C1-C6)-alkyl; T represents oxygen atom; V represents N<; X1 represents phenyl substituted with 1-2 substitutes chosen from group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, halogen atom, cyano-group or trifluoromethyl; X2 represents a bicyclic heteroaryl comprising 7 carbon atoms and 1-2 heteroatoms chosen from oxygen (O), nitrogen (N) and sulfur (S) atoms optionally substituted with (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or phenyl substituted with halogen atom; Y represents monocyclic heteroarylenyl comprising 3-5 carbon atoms and 1-3 heteroatoms chosen from N and O; Z1 and Z2 represent independently (C1-C4)-alkylene. Compounds of the formula (I) are used in preparing a pharmaceutical composition used in treatment of morbid state in mammal that can be relieved using inhibitor of oxidation of aliphatic acids. Also, invention relates to a pharmaceutical composition inhibiting oxidation of aliphatic acids and comprising at least one pharmaceutically acceptable excipient and the therapeutically effective dose of compound of the formula (I). Invention provides using substituted piperazine compounds as inhibitors of oxidation of aliphatic acids.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

19 cl, 22 ex

FIELD: organic chemistry, medicine, hematology, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): in all their stereoisomeric forms and their mixtures taken in any ratio and their physiologically acceptable salts possessing properties of inhibitors of factor Xa and/or factor VIIa, and to a medicinal agent based on thereof. Also, invention relates to a method for synthesis of these compounds and their using for preparing pharmaceutical agents for inhibition of activity of factor Xa and/or factor VIIa or for their effect on blood coagulation or fibrinolysis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 276 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of bipiperidine of the formula (I): , wherein X means a direct bond, -CH2-, -CH2-CH2- or -CHR9-; R1 means optionally R10- and/or R11-substituted phenyl, optionally R10- and/or R11-substituted heteroaryl, N-oxide of optionally R10- and/or R11-substituted heteroaryl or optionally R10- and/or R11-substituted naphthyl; R2 has one of values given for R1, or it means optionally R10-substituted (C1-C6)-alkyl, optionally R10-substituted (C3-C6)-cycloalkyl, optionally R10-substituted adamantyl; R3 has one of values given for R1; each radical among R4, R5, R6 and R7 means hydrogen atom; R8 means hydrogen atom or (C1-C6)-alkyl; R9 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; R10 represents from 1 to 4 substitutes chosen independently from (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C2-C6)-alkoxyalkyl, (C1-C6)-halidealkyl, (C3-C6)-cycloalkyl, phenyl, heteroaryl, heteroaryl N-oxide, fluorine, chlorine, bromine, iodine atoms, hydroxyl, groups -OR9, -CONH2, -CONHR9, -CONR9R9, -COOH, -CF3, -CHF2, -CN, -NH2, -NHR9, -NHC(O)R9, -NR9C(O)R9; R11 represents two adjacent substitutes that form anellated 4-7-membered nonaromatic ring optionally comprising up to two heteroatoms chosen independently from nitrogen oxygen and sulfur atoms; Y means a direct bond, -C(O)-, -S(O2)-, -CH2-. Proposed compounds can be in free form as a salt. Compounds of the formula (I) and their salts possess antagonistic activity with respect to CCR5-receptors and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 6 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nicotine- or isonicotine-benzothiazole of general formulas (IA) and (IB) their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. In compounds of general formula (IA) and (IB) R1 means phenyl, piperidine-1-yl or morpholine; A means -O-; R means -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)n-O-lower alkyl, lower alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R''), -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidinyl or (C4-C6)-cycloalkyl; R'' mean(s) independently of one another hydrogen atom or lower alkyl; n= 1 or 2; A means -N(R')-; R means lower alkyl, (C4-C6)-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R'')2; R' and R'' mean independently of one another hydrogen atom or lower alkyl; n = 1 or 2; or A means -CH2-; R means -N(R'')-(CH2)m-O-lower alkyl, -N(R'')2, S-lower alkyl, or R means azethidinyl, pyrrolidinyl or piperidinyl that are substituted optionally with hydroxy-group or lower alkoxy-group; or R means morpholinyl, -N(R'')-(CH2)m-(C4-C6)-cycloalkyl, -N(R'')-(CH2)m-C(O)-O-lower alkyl, -O-(CH2)m-O-lower alkyl or alkoxy-group; R'' mean(s) independently of one another hydrogen atom or lower alkyl; m = 1, 2 or 3; or A means -S-; R means lower alkyl, or A-R mean in common piperazinyl substituted with alkyl, -C(O)-lower alkyl or oxo-group, or group A-R means piperidinyl substituted with lower alkoxy-group or hydroxy-group, or group A-R means morpholinyl substituted with lower alkyl, or group A-R means (C4-C6)-cycloalkyl, azethidine-1-yl optionally substituted with hydroxy-group or lower alkoxy-group, or group A-R means thiomorpholinyl-1,1-dioxo-group, tetrahydropyrane or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Proposed compounds can be used in treatment of diseases mediated by adenosine A2A-receptors, for example, Alzheimer disease, some depressive states, toxicomania and Parkinson's disease.

EFFECT: valuable medicinal properties of compounds and agent.

37 cl, 10 sch, 109 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to derivatives of benzothiazole of the general formula (I): wherein R means hydrogen atom, -(CH2)n-phenyl optionally substituted with a substitute chosen from the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl or -N(R')-C(O)-(lower)-alkyl, -(CH2)n-pyridinyl optionally substituted with (lower)-alkyl, -(CH2)n-(C3-C6)-cycloalkyl optionally substituted with hydroxy-group, -(CH2)n-benzo[1,3]dioxolyl, -(CR'2)-thiophenyl, -(CR'2)n-thiazolyl optionally substituted with (lower)-alkyl, -(CH2)n-C(O)-thiophenyl optionally substituted with halogen atom, -(CH2)-furanyl optionally substituted with (lower)-alkyl, -(CHR')n-benzofuran-1-yl, -(CH2)n-benzo[b]thiophenyl, -(CH2)n-N(R')-C(O)-phenyl optionally substituted with halogen atom or (lower)-alkoxy-group. -(CH2)n-C(O)-phenyl optionally substituted with (lower)-alkoxy-group, -(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxine-6-yl, -(CH2)n-N(R')-C(O)-pyridinyl, -(CH2)n-tetrahydrofuranyl, -CH-biphenyl, -CH-(phenyl)pyridinyl, -(CH2)n-1-oxo-(CH2)n-CH-(phenyl)tetrahydropyranyl, -(CH2)n-1-oxo-1,2,3,4-tetrahydroquinoline-3-yl or -(CH2)n-S-[1,3,4]thiadiazol-2-yl optionally substituted with amino-group; R' means hydrogen atom or (lower)-alkyl and independently of one another in case R'2; n = 0, 1, 2, 3 or 4. Also, invention relates to a medicament possessing high affinity to adenosine A2A-receptors and high selectivity with respect to A1-receptors and comprising one or more derivatives of benzothiazole of the formula (I) and pharmaceutically acceptable excipients. Invention provides using derivatives of benzothiazole as ligands of adenosine receptors.

EFFECT: valuable medicinal properties of compounds and medicament.

13 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and R8 represent hydrogen atom or (C1-C6)-alkyl; T represents oxygen atom; V represents N<; X1 represents phenyl substituted with 1-2 substitutes chosen from group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, halogen atom, cyano-group or trifluoromethyl; X2 represents a bicyclic heteroaryl comprising 7 carbon atoms and 1-2 heteroatoms chosen from oxygen (O), nitrogen (N) and sulfur (S) atoms optionally substituted with (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or phenyl substituted with halogen atom; Y represents monocyclic heteroarylenyl comprising 3-5 carbon atoms and 1-3 heteroatoms chosen from N and O; Z1 and Z2 represent independently (C1-C4)-alkylene. Compounds of the formula (I) are used in preparing a pharmaceutical composition used in treatment of morbid state in mammal that can be relieved using inhibitor of oxidation of aliphatic acids. Also, invention relates to a pharmaceutical composition inhibiting oxidation of aliphatic acids and comprising at least one pharmaceutically acceptable excipient and the therapeutically effective dose of compound of the formula (I). Invention provides using substituted piperazine compounds as inhibitors of oxidation of aliphatic acids.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

19 cl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, medicine, hematology, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): in all their stereoisomeric forms and their mixtures taken in any ratio and their physiologically acceptable salts possessing properties of inhibitors of factor Xa and/or factor VIIa, and to a medicinal agent based on thereof. Also, invention relates to a method for synthesis of these compounds and their using for preparing pharmaceutical agents for inhibition of activity of factor Xa and/or factor VIIa or for their effect on blood coagulation or fibrinolysis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 276 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinone of the general formula (VI): wherein R1, R2, R3 and R4 are chosen independently from group consisting of hydrogen atom (H) and halogen atom; each R5 means independently (C1-C12)-alkyl; R6 means -NR8-(CH2)mR9, -NR10R11 under condition that from 1 to 4 groups -CH2- can be substituted optionally with -OH; R8 means H; R9 means -NR10R11 wherein R10 and R11 mean (C1-C12)-alkyl, or R10 and R11 in common with nitrogen atom to which they are bound can form a heterocyclic group chosen from morpholinyl, pyrrolidinyl and piperidinyl under condition that the heterocyclic group can be substituted optionally with morpholino-group; J means -NH; L means carbon atom (C), and group -C(O)R6 is bound with L; K and M means -CR5; m = 1, 2, 3 or 4; p = 2. Method for synthesis of these compounds involves the addition reaction of compound of the general formula (III): wherein R* means R with compound of the formula (IV): wherein values R1, R2, R3 and R4 are given above with amine of the general formula (V): HR6 (V) wherein R6 is given above to form indolinone of the general formula (VI). Method provides synthesis of indolinone derivatives with the yield 25-85%.

EFFECT: improved method of synthesis.

20 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I): or its pharmaceutically acceptable salts or esters hydrolyzed in vivo and possessing properties of selective inhibitor of cyclin-dependent kinases, such as CDK-2, and inhibiting proliferation of cells. Compounds can be used in preparing medicinal agents used in treatment of cancer diseases. In compounds of the formula (I) R1 represents halogen atom; p = 0 or 1; R2 represents sulfamoyl or group B-E-; q = 0 or 1 wherein p + q = 1; R3 represents hydrogen atom, (C1-C6)-alkyl wherein R3can be substituted optionally at carbon atom with one or some M; R4 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl wherein R4 can be substituted optionally with one or some M; or R3 and R4 taken with nitrogen atom to which they are bound form heterocyclic ring substituted optionally at carbon atom with one or some M wherein if indicated heterocyclic ring comprises group -NH then nitrogen atom can be substituted optionally with group chosen from Q; B is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein B can be substituted optionally at carbon atom with one or some D and wherein indicated heterocyclic group comprises group -NH- then nitrogen atom can be substituted optionally with group chosen from G; E represents -S(O)r- or -N(Ra)SO2- wherein Ra represents hydrogen atom or (C1-C6)-alkyl and r = 2; D is chosen independently from halogen atom, nitro-, cyano-, hydroxy-, amino-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N-(C1-C6)-alkylamino-, N,N-((-C1-C6)-alkyl)2-amino-, (C1-C6)-alkanoylamino-group, (C1-C6)-alkyl-S(O)a wherein a = 0-2, wherein D can be substituted optionally at carbon atom with one or some V; M is chosen independently from halogen atom, nitro-, cyano-, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N,N-((C1-C6)-alkyl)2-amino-group, (C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl or heterocyclic group wherein M can be substituted optionally at carbon atom with one or some P; P, X and Y are chosen independently from hydroxy-group, methyl, methoxy-, dimethylamino-group; G and Q are chosen independently from (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxycarbonyl wherein Q can be substituted optionally at carbon atom with one or some X. Also, invention relates to methods for synthesis of compounds, preparing pharmaceutical compositions based on thereof and to a method for inhibition of proliferation of cells.

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

15 cl, 2 sch, 133 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel aromatic compounds that can be used in treatment of diseases or pathological states accompanying by inflammation, for example, chronic inflammation diseases. Invention describes compound of the formula (II): wherein G means phenyl, pyridinyl, pyrazolyl and wherein G is substituted with one or some groups R1, R2 or R3; Ar means naphthyl; X means (C5-C8)-cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo-groups, phenyl, furanyl, pyridinyl or pyrazolyl; Y means a bond or saturated either unsaturated branched or unbranched (C1-C4)-carbon chain wherein one or some methylene groups are optionally and independently substituted with oxygen (O) or nitrogen (N) atoms; Y is optionally substituted with oxo-group; Z means phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylenesulfoxidyl wherein each of them is optionally substituted with 1-3 (C1-C6)-alkyls or group -CONH2, (C1-C6)-alkyl, nitrile, hydroxy-group, (C1-C6)-alkoxy-group, secondary or tertiary amine wherein amine nitrogen is bound covalently with (C1-C3)-alkyl or (C1-C5)-alkoxyalkyl, tetrahydrofuranyl-(C1-C3)-alkyl, nitrile-(C1-C3)-alkyl, carboxamide-(C1-C3)-alkyl; R1 means independently in each case (C1-C10)-alkyl which is optionally partially or completely halogenated and optionally substituted with 1-3 hydroxy-groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl wherein each of them is optionally substituted with 1-3 groups -CN, halogen atom, (C3-C6)-alkynyl branched or unbranched carbon chain and one or some methylene groups is optionally replaced for atom O and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R2 means branched or unbranched (C1-C6)-alkyl that is optionally partially or completely halogenated, branched or unbranched (C1-C4)-alkoxy-group that in each case is optionally partially or completely halogenated, halogen atom, (C1-C6)-alkoxy-group, hydroxy-group, mono- or di-(C1-C4)-alkyl-amino-group, group -OR6, nitro-group or group mono- or di-(C1-C4)-alkyl-amino-S(O)2 that is optionally partially or completely halogenated, or group -H2NSO2; R3 in each case means independently phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, (C1-C4)-alkynyl group or branched or unbranched (C1-C6)-alkoxy-group wherein each of them is optionally partially halogenated, -OR18 or (C1-C6)-alkyl optionally substituted with group -OR18, amino-group or mono- either di-(C1-C5)-alkyl-amino-group, (C2-C6)-alkynyl branched or unbranched carbon chain wherein one or some methylene groups are optionally replaced for atom O, and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R6 means (C1-C4)-alkyl that is optionally partially or completely halogenated; in each case R18 means independently hydrogen atom, (C1-C4)-alkyl; W means atom O, and its pharmaceutically acceptable derivatives. Also, invention describes a pharmaceutical composition containing these compounds and a method for treatment of disease mediated by cytokines and based on indicated compounds. Invention provides synthesis of novel compounds possessing valuable biological properties.

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

12 cl, 1 tbl, 38 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention describes compound of the formula (I): wherein B represents oxygen atom (O) or -NR1; J represents 5-membered heteroaromatic ring representing group of the formula (J-1): optionally substituted with 1-2 radicals R5 wherein Q represents -NR5; each X, Y and Z represents independently nitrogen atom (N), -CH or - CR5; B1 represents O; R2 represents hydrogen atom (H) or (C1-C6)-alkyl optionally substituted with one halogen atom, or (C2-C6)-alkynyl; or R1 and R2 taken in common form a binding chain consisting of 2-3 members and comprising at least one carbon atom, optionally comprising one carbon atom as -C(=O), optionally substituted with R3 wherein R3 represents (C1-C2)-alkyl; each R represents independently H, (C1-C6)-alkyl, halogen atom or -CN; each R5 represents independently (C1-C6)-halogenalkyl or halogen atom, or each ring is substituted with one R6; each R6 represents independently halogen atom; n represents a whole number 1 or 2. Also, invention describes a composition used for control of insects and comprising the biologically effective dose of compound of the formula (I) and at least one additional component chosen from group comprising surface-active substances, solid and liquid diluting agents, and methods for control of insects with using compositions based on compounds of the formula (I) and compounds of the formula (I). Proposed compounds of the formula (I) possess insecticide activity and can be used in agriculture.

EFFECT: valuable insecticide properties of compounds and compositions.

11 cl, 26 tbl, 4 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel oxazolidinones of the general formula (I): , their pharmaceutically acceptable salts, hydrates and salt hydrates that inhibit factor Xa selectively and possess anti-thrombosis effect. Also, invention relates to a method for synthesis of these compounds (variants) and using the known substituted oxazolidinones of the general formula (A): as agent inhibiting factor Xa selectively and possessing anti-thrombosis effect, and to a medicinal agent based on at least one compound of the formula (I) or at least one compound of the general formula (A). Values of substitutes R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are given in the invention claim.

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

10 cl, 2 tbl, 252 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, medicine, hematology, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): in all their stereoisomeric forms and their mixtures taken in any ratio and their physiologically acceptable salts possessing properties of inhibitors of factor Xa and/or factor VIIa, and to a medicinal agent based on thereof. Also, invention relates to a method for synthesis of these compounds and their using for preparing pharmaceutical agents for inhibition of activity of factor Xa and/or factor VIIa or for their effect on blood coagulation or fibrinolysis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 276 ex

Up!