Aza-ring bridged compound

FIELD: pharmacology.

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

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

14 cl, 60 tbl, 15 ex

 

The technical field

The present invention relates to Aza-ring connection with an internal bridge, which is used as active ingredient in pharmaceutical compositions, in particular pharmaceutical compositions for the treatment of inflammatory diseases.

Background of invention

Acetylcholine released from cholinergic nerve in the peripheral and Central nervous system, causing various biological responses by binding to two types of acetylcholine receptors, nicotinic receptors and muscarinic receptors, respectively. Of them muscarinic receptor belongs to the superfamily transmembrane channel conjugated to G protein receptors, and currently there are five subtypes of these receptors, M1, M2, M3, M4and M5each of which are encoded by different gene sequences. These five types of receptors are widely distributed in every tissue of the body of vertebrates. It is known that muscarinic receptor has both excitatory and inhibitory effects, depending on its subtype. In particular, the functional role of different muscarinic receptors, for example the part of the receptor M3present in the smooth muscle of the Airways in reaction sacramentally muscles or other roles, were described in the General Overview of Caulfield, et al. (Non-patent document 1).

As for lungs, muscarinic receptor is present in the smooth muscle of the trachea and bronchial submucosal glands and parasympathetic site. It is established that the greatest density distribution of muscarinic receptors in the parasympathetic node, and then into the submucosal glands and smooth muscles of the trachea, in the specified order, and the lowest in the smooth muscles of the bronchi (non-Patent document 2).

As a muscarinic receptor, which plays an important role in the lung tissue, you can specify three types of M1, M2and M3. The receptor for M3that is present in the smooth muscle of the respiratory tract, involved in the reduction of smooth muscle, which causes obstruction of the Airways. If the receptor M3activated phospholipase C in the cytoplasm is activated through the activation of the stimulatory G-protein, further causes dissociation of phosphatidylinositol 3-phosphate into phosphatidylinositol 4,5-bisphosphate and, finally, phosphorylation of contractile protein. The receptor for M3present in submucosal glands, and smooth muscle, which is present in the lung tissue. If this type of receptor M3is activated, is the mucus.

Receptors M2approximately 50-80% of cholinergic receptors, which are present diately ways smooth muscles. Details regarding the role of this receptor subtype, is still not clear, but believe that reducing the amount of cAMP produced in the cytoplasm inhibits the relaxation of smooth muscles of the respiratory tract due to sympathetic innervation. Central receptors M2common in postganglionarnyh parasympathetic fibers. In physiological conditions the Central receptor M2plays a role in negative regulation of release of acetylcholine from parasympathetic tissue. The receptor for M2is expressed in heart muscle that occurs as a result of regulation chronotropic actions. The receptor for M1found in the parasympathetic ganglia of the lung tissue, and it performs the function of facilitating neurotransmission. Receptors M1common not only in ganglia, but also in the peripheral lung parenchymal tissue, but their function is not clear.

In lung tissue, the abnormal function of muscarinic receptor felt in the formation of many pathological conditions. In particular, for inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma and the like, a prolonged inflammatory response leads to the dysfunction of the inhibitory receptor M2that is present in the parasympathetic nerve, and increases the release is of atilhan by stimulation of the vagus nerve (non-Patent document 3). Thus, dysfunction of this receptor determines the relative advantage of the functions mediated by the receptor M3that leads to the induction of hyperactivity of the Airways. In this regard, consider that a drug that selectively antagonisitic function, mediated by the receptor M3, with no effect on function, receptor-mediated M2is an effective therapeutic tool.

COPD, which is the restriction of the airway, usually as a result of organic changes due to long-term inflammation in peripheral Airways and, above all, the alveoli, which leads to the appearance of symptoms of cough, sputum, shortness of breath and such, ranks fourth among the leading causes of mortality in 2005 and is the leading cause of death worldwide. In addition, it is expected that by 2020 it will be the third leading cause of death. Smoking is a major risk factor for COPD, and recently, in addition, air pollution due to dust or similar factors also indicated as risk factors, among others. The cost of medical treatment of COPD is very high and is expected to increase the number of patients in the future.

Therapy with anticholinergic agent for inhalation is considered as a medicament the military tool, first of all, we choose to treat the above diseases (non-Patent document 4), and in recent years, in each region in the West and in Asia long acting anticholinergic agent, Tiotropium (Spiriva (registered trademark)), began to enter the market. However, taking into account the status of treatment, none of the usual anticholinergics, including Spiriva (registered trademark), are not valuable from the point of view of convenience and safety, and, thus, at the moment there is space for improvement. Thus, it is highly desirable the creation of anticholinergic agents for oral administration or inhalation, enhanced with any of the above points of view.

For example, it is known urethane compound, which has an antagonistic activity against receptor M3and has an inhibitory effect on the reduction of the respiratory tract, in which the ring And the following formula is an unsubstituted benzene or unsubstituted pyridine (Patent document 1). In this patent document is not disclosed and are not offered the compound of the present invention.

Chemical formula 1

[the meaning of the symbols in the formula you can see in this publication]

Galesville urethane compound, presented below, which has an antagonistic activity against receptor M3and has an inhibitory effect on the reduction of the respiratory tract (Patent document 2). However, in this patent document is not disclosed and are not offered the compound of the present invention.

Chemical formula 2

[the meaning of the symbols in the formula you can see in this publication]

[Patent document 1] Publication international publication no WO 95/21820

[Patent document 2] Publication international publication no WO 95/06635

[Non-patent document 1] Pharmacology and Therapeutics, 1993, vol. 58, pp. 319-379

[Non-patent document 2] American Journal Respiratory and Critical Care Medicine, 1998, 158, pp. 154S-160S

[Non-patent document 3] Life Science, 1999, vol. 64(6-7), pp. 449-455

[Non-patent document 4] American Journal Respiratory and Critical Care Medicine, 2001, 163, pp. 1256-1276

Disclosure of invention

The problem solved by the present invention

Presents the connection, which is useful as an active ingredient of pharmaceutical compositions, in particular pharmaceutical compositions for the treatment of inflammatory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and the like.

Means of solving the problem

The authors of the present invention have conducted extensive studies of compounds with ant is geneticheskim action on muscarinic receptor M 3and in the result it was found that Aza-ring connection to the internal bridge is useful for antagonistic action on muscarinic receptor M3thus was established the present invention.

In particular, the present invention relates to the compound of formula (I) or salts thereof and pharmaceutical composition comprising the compound of formula (I) or its salt and excipient.

Chemical formula 3

R1represents-H or C1-6alkyl;

R2is an Aza-ring with an internal bridge selected from the group comprising formulas (a), (b), (c) and (d):

Chemical formula 4

where the ring carbon atom in Aza-ring with an internal bridge may be substituted by one or more groups R22;

m, n and p have the meanings, respectively, 1 or 2;

r is 0 or 1;

R21represents a C1-6alkyl, -C1-6alkyl-O-aryl or-C1-6alkyl-aryl;

R22represents a C1-6alkyl-cycloalkyl or-C1-6alkyl-aryl;

R3is thienyl, phenyl, pyridyl, pyrazinyl, thiazolyl or pyrazolyl, each of which may be substituted by one or more R31;

where R31represents a halogen, -OH, -CN, -CF3C1-6 alkyl or-O-C1-6alkyl;

ring a represents an aromatic hydrocarbon ring, heteroclite or cycloalkane,

each of which may be substituted by a group RA;

where RArepresents a halogen, -CN, -NH2C1-6alkyl, -O-C1-6alkyl, -CONH2, -NH-C1-6alkyl, -NH-C1-6alkyl-O-C1-6alkyl-aryl, -NH-C1-6alkyl-aryl or-NH-C1-6alkyl-OH,

where C1-6the alkyl may be substituted by one or more halogen atoms;

V represents-NH - or-O-;

W represents -(CH2)q- or -(CH2)s-CH = ;

q is 0, 1 or 2;

s has a value of 1 or 2;

X-is protivoiadie; and

represents a simple bond or double bond;

provided that when ring a is a substituted benzene, R3represents phenyl, pyridyl, pyrazinyl, thiazolyl or pyrazolyl, each of which may be substituted by one or more R31; and

in the case where the ring a is an unsubstituted benzene, q has a value of 1 or 2; and

when ring a represents cycloalkyl, R3represents phenyl which may be substituted by one or more R31.

Moreover, unless otherwise stated, in the case when Moly in any formulas in the present description is also used in other formulas, the same symbols have the same value.

The present invention relates to pharmaceutical compositions for the treatment of inflammatory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and the like, which comprises a compound of formula (I) or its salt, i.e. therapeutic tool for the treatment of inflammatory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and the like, which comprises a compound of formula (I) or its salt.

Further, the present invention relates to the use of compounds of formula (I) or its salt to obtain a pharmaceutical composition for the treatment of inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma and the like, and to a method of treatment of inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma and the like, comprising an introduction to the patient an effective amount of the compounds of formula (I) or its salt.

The effect of the present invention

The compound of formula (I) or its salt has an antagonistic effect on the binding of the muscarinic receptor M3and, therefore, can be used as a prophylactic and/or therapeutic agent for the treatment of inflammatory diseases such as chronic the E. obstructive pulmonary disease (COPD), asthma and the like.

Best mode for carrying out the present invention

Hereinafter in this application, the present invention will be described in detail.

In this description of “halogen” refers to F, Cl, Br or I.

In the present description, “C1-6alkyl” refers to alkyl straight or branched chain containing 1-6 carbon atoms, for example, stands, ethyl, n-propylene, isopropyl, n-butile isobutyl, sec-butile, tert-butile, n-pentile, n-hexyl or the like. In another variant embodiment it represents a C1-4alkyl. In the following variant embodiment it represents methyl, ethyl or isopropyl.

In the present description, “- C1-6alkyl-” refers to, when he has the prefix and suffix with a hyphen, C1-6alkylene straight or branched chain, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethane, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene or similar. In the following variant embodiment it represents a C1-4alkylen and in another variant embodiment is methylene, ethylene or trimethylene.

In this description of the “aromatic hydrocarbon ring” means an aromatic hydrocarbon ring containing 6-14 carbon atoms. In one embodiment, the embodiment of his examples include benzo is, naphthalene and the like, and in the next version of the incarnation - benzene.

In the present description “heteroclite” means a 5-6-membered aromatic heterokonta containing one or more heteroatoms that are the same or different from each other, selected from the group comprising nitrogen, oxygen and sulfur, which may be condensed with cycloalkenyl ring or benzene ring. In particular, its examples include pyridine, pyrazin, pyrimidine, pyridazine, pyrazole, imidazole, oxazole, thiazole, thiophene, furan, oxadiazol, isothiazol, isooctanol, thiadiazole, quinoline, isoquinoline, benzothiazole, benzothiophene, benzoxazole, indole, indazole, cyclopentadiene and the like. In the following variant embodiment heterokonta represents a 5-membered heterokonta, and in another variant of embodiment of his examples include oxazole, thiophene, thiazole, thiadiazole and cyclopentadiene. In another variant of embodiment of his examples include thiophene and thiazole.

In the present description “cycloalkyl” means C3-9non-aromatic carbon ring, which may contain partially unsaturated bond and may be condensed with a benzene ring. In addition, it also includes a ring with an internal bridge. Therefore, its specific examples include cyclopropane, CYCLOBUTANE, cyclohexane, Cycloheptane, cyclooctane, C is loboutin, cyclohexen, cyclooctadiene, norburn, Borden, indan, tetrahydronaphthalene and the like, and in another variant embodiment of the cyclohexane.

Next, examples of protovoulia “X-include a halide ion, triftorbyenzola, para-toluensulfonate, methanesulfonate and the like, as in the following variant embodiment it is preferably a halide ion (e.g. chloride ion, brainy ion and ideny ion), but is not limited to this. Then, in the next version of the embodiment of his examples also include inorganic anions such as ion, nitric acid ion, phosphoric acid ion carboxylic acid and the like, carboxylates, such as formate (HCOO-), acetate (CH3COO-), propionate, oxalate and the like, and anions of amino acids such as glutamic acid, etc.

“Aminoalkenes” refers to another connection “X-”.

In the present description, the expression “may be substituted” means that the group is unsubstituted or has from 1 to 5 substituents. Moreover, in the case of multiple substituents, these substituents can be identical or different from each other.

In the present description, the Deputy for which acceptable “may be substituted” or “substituted”can be any Deputy, which is usually used as C is the election agent for each group.

For example, examples of the substituent in ring A, for which acceptable “may be substituted” or “substituted”include halogen, -CN, -NH2C1-6alkyl, -O-C1-6alkyl, -CONH2, -NH-C1-6alkyl, -NH-C1-6alkyl-O-C1-6alkyl-aryl, -NH-C1-6alkyl-aryl, and-NH-C1-6alkyl-OH.

Variant of embodiment [1] in accordance with the present invention is the following. In relation to formula (I),

(1) the compound in which R1represents-H,

(2) the compound in which R2is an Aza-ring with an internal bridge selected from the group consisting of formulas (a), (b), (c) and (d):

Chemical formula 5

(3) the compound in which r has the value 0,

(4) a compound in which X represents halogen,

(5) the compound in which R3represents phenyl which may be substituted by one or more R31and

R31represents a halogen, -OH, -CN, -CF3, -C1-6alkyl or-O-C1-6alkyl,

(6) a compound in which ring a represents heterokonta or cycloalkyl,

each of which may be substituted by a group selected from the group consisting of one or more RA,

(7) a compound in which V represents O-,

(8) a compound in which W submitted is a -(CH 2)qand q is 0 or 1,

(9) Unionrepresents a simple bond,

(10) the compound in which m, n and p have the meanings, respectively, 1 or 2, and

(11) the compound, which is a combination of two or more of the above (1)to(10), or its salt.

Another variant of the embodiment [2] of the present invention represents a further.

The compound or its salt according to a variant of embodiment [1], in which

ring And represents heterokonta or cycloalkane,

each of which may be substituted by a group selected from the group consisting of one or more RA1;

where RA1represents a halogen, -CN, -NH2C1-6alkyl, -O-C1-6alkyl, -CONH2, -NH-C1-6alkyl, -NH-C1-6alkyl-O-C1-6alkyl-phenyl, -NH-C1-6alkyl-phenyl or-NH-C1-6alkyl-OH,

where C1-6the alkyl may be substituted with halogen.

Another variant of embodiment [3] of the present invention represents a further.

The compound or its salt according to a variant of embodiment [2], in which

ring And represents a group comprising thiophene, thiazole, isothiazol, thiadiazole, oxazole, isooctanol, cyclohexane, norburn, benzothiophen and 5,6-dihydro-4H-cyclopentadien, each of which may be substituted by a group selected and the group, consisting of one or more RA1.

The following variant of embodiment [4] the present invention represents a further.

The compound or its salt according to a variant of embodiment [3], in which

ring And represents a group comprising thiophene, thiazole and cyclohexane,

each of which may be substituted by a group selected from the group consisting of one or more RA1.

The following variant of embodiment [5] the present invention represents a further.

The compound or its salt according to a variant of embodiment [4], in which R1is a-H.

The following variant of embodiment [6] the present invention represents a further.

The compound or its salt according to a variant of embodiment [5], in which

R3represents phenyl which may be substituted by one or more R31,

and R31represents a halogen, -OH, -CN, -CF3, -C1-6alkyl or-O-C1-6alkyl.

The following variant of embodiment [7] the present invention represents a further.

The compound or its salt according to a variant of embodiment [6], in which

R2is an Aza-ring with an internal bridge selected from the group consisting of formulas (a), (b), (c) and (d)where in the case (a) or (c), (m, n, p) has the value(2, 1, 1), (1, 1, 2) or (2, 1, 2) for each of the sequence.

The following variant of embodiment [8] the present invention represents a further.

The compound or its salt according to a variant of embodiment [7], in which

R2is an Aza-ring with an internal bridge selected from the group consisting of formulas (a) and (b), and

R21represents a C1-6alkyl, -C1-6alkyl-O-phenyl or-C1-6alkyl-phenyl.

Examples of specific compounds included in the present invention include the following compounds or their free base.

(1) 1-azabicyclo[2.2.2]Oct-4-ylmethyl(5-phenyl-1,3-thiazol-4-yl)carbamate, hydrochloride

(2) 1-azabicyclo[3.2.2]non-5-yl(5-phenyl-1,3-thiazol-4-yl)carbamate, hydrochloride

(3) (3R)-1-azabicyclo[2.2.2]Oct-3-yl[(1R,2S)-2-phenylcyclohexyl]carbamate, hydrochloride

(4) 1-azatricyclo[3.3.1.1-3,7-]Dec-4-yl(5-phenyl-1,3-thiazol-4-yl)carbamate, hydrochloride

(5) 1-azabicyclo[2.2.2]Oct-3-ylmethyl(2-phenyl-3-thienyl)carbamate, hydrochloride

(6) 1-azabicyclo[2.2.2]Oct-4-yl[5-(4-forfinal)-1,3-thiazol-4-yl]carbamate, hydrochloride

(7) 1-azabicyclo[3.2.1]Oct-6-ylmethyl(5-phenyl-1,3-thiazol-4-yl)carbamate, hydrochloride or

(8) 1-azabicyclo[2.2.2]Oct-3-ylmethyl[5-(4-forfinal)-1,3-thiazol-4-yl]carbamate, fumarate.

Examples of specific compounds included in the present invention include the following compounds or their-exchangers.

(1) 4-({[5-(3-chlorophenyl)-1,3-thiazol-4-yl]carbarnoyl}ACS is)-1-methyl-1-azoniabicyclo[2.2.2]Octanate,

(2) 1-(3-phenylpropyl)-3-({[(2-phenyl-3-thienyl)carbarnoyl]oxy}methyl)-1-azoniabicyclo[2.2.2]octabrain,

(3) 1-(2-phenylethyl)-4-{[(5-phenyl-1,3-thiazol-4-yl)carbarnoyl]oxy}-1-azoniabicyclo[2.2.2]octabrain,

(4) 1-(2-phenoxyethyl)-4-{[(5-phenyl-1,3-thiazol-4-yl)carbarnoyl]oxy}-1-azoniabicyclo[2.2.2]octabrain,

(5) 4-({[5-(2,5-differenl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-methyl-1-azoniabicyclo[2.2.2]Octanate,

(6) 1-methyl-5-{[(5-phenyl-1,3-thiazol-4-yl)carbarnoyl]oxy}-1-azoniabicyclo[3.2.2]nonUnited,

(7) 4-({[5-(3-chlorophenyl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]Octanate,

(8) 4-({[5-(3-chlorophenyl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-methyl-1-azoniabicyclo[2.2.2]octabrain,

(9) 4-({[5-(3,5-dichlorophenyl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-methyl-1-azoniabicyclo[2.2.2]Octanate,

(10) 4-({[5-(2,5-differenl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-methyl-1-azoniabicyclo[2.2.2]octabrain,

(11) 4-({[5-(2,4-differenl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-methyl-1-azoniabicyclo[2.2.2]octabrain,

(12) 1-methyl-4-{[(5-phenyl-1,3-thiazol-4-yl)carbarnoyl]oxy}-1-azoniabicyclo[2.2.2]octabrain,

(13) 4-({[5-(3,5-dichlorophenyl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-methyl-1-azoniabicyclo[2.2.2]octabrain or

(14) 1-methyl-5-{[(5-phenyl-1,3-thiazol-4-yl)carbarnoyl]oxy}-1-azoniabicyclo[3.2.2]nonembroid.

The compound of formula (I) can exist in the form of geometrical isomers, depending on the types Deputy is th. In the present description, the compound of formula (I) can be described in only one form isomer, but the present invention includes other isomers, isolated forms of the isomers, or a mixture thereof.

Further, the compound of formula (I) may contain an asymmetric carbon atom and, therefore, can exist in the form of optical isomers. The present invention includes an isolated form of optical isomers of compounds of formula (I) or mixtures thereof.

Moreover, the present invention also includes pharmaceutically acceptable prodrug compounds of formula (I). Pharmaceutically acceptable prodrug refers to a compound containing a group which can be converted into the amino group, hydroxyl group, carboxyl group and the like by solvolysis or under physiological conditions. Examples of groups for the formation of prodrugs include groups described in Prog. Med., 5, 2157-2161 (1985)" or "Iyakuhin no Kaihatsu (Development of Medicines) (Hirokawa Shoten, 1990), vol. 7, Bunshi Sekkei (Molecular Design)", 163-198.

In addition, the salt of the compounds of formula (I) refers to pharmaceutically acceptable salts of the compounds of formula (I), and in some cases, it forms an acid additive salt or a salt with a base depending on the type of substituents. In particular, examples include acid additive salts with inorganic acids such as floristware the Naya acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid, phosphoric acid and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditawarkannya acid, citric acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, para-toluensulfonate acid, aspartic acid, glutamic acid and the like, and salts with various amino acids and derivatives of amino acids, such as acetylleucine and the like.

In addition, the present invention also includes various hydrates or solvate and polymorph crystalline substances the compounds of formula (I) and salts thereof. Also, the present invention includes compounds labeled with various radioactive or non-radioactive isotopes.

In the present description the following abbreviations are used.

BINAP: (R)-(+)- or (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

CHCl3: chloroform

Cs2CO3: cesium carbonate

CuCl2: chloride copper

DCE: 1,2-dichloroethane

DHM: dichloromethane

DEAD: diethylazodicarboxylate

DIBOC: di-tert-Buti is dicarbonate

DIPA: Diisopropylamine

DIPEA: N,N-diisopropylethylamine

DMA: dimethylacetamide

DMAP: N,N-dimethyl-4-aminopyridine

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

DPPA: azide diphenylphosphinic acid

DPPF: diphenylphosphinite

EtOAc: ethyl acetate

EtOH: ethanol

HCl/dioxane: a solution of hydrogen chloride/dioxane

HCl/EtOAc: the solution of hydrogen chloride/ethyl acetate

HCl/MeOH: solution of hydrogen chloride/methanol

IPE: diisopropyl ether

K2CO3: potassium carbonate

KOH: potassium hydroxide

LAH: socialogical

LiBH4: jargitakse lithium

MCPBA: metolar-derbentina acid

MEK: 2-butanone

MeCN: acetonitrile

MeOH: methanol

MgSO4: anhydrous magnesium sulfate

NBS: n-bromosuccinimide

NCS: n-chlorosuccinimide

NMP: n-organic

Na2CO3: sodium carbonate

Na2SO4: anhydrous sodium sulfate

Na2SO4-10H2O: sodium sulfate, derangere

NaH: sodium hydride

NaHCO3: sodium bicarbonate

NaOAc: sodium acetate

NaOBut: tert-piperonyl sodium

NaOEt: ethoxide sodium

NaOH: sodium hydroxide

NaOMe: sodium methoxide

P(But)3: three(tertbutyl)phosphine

PPh3: triphenylphosphine

Pd(OAc)2: palladium acetate

PdCl2(PPh3)2: dichlorobistriphenylphosphine

Pd2dba : Tris(dibenzylideneacetone) dipalladium

Pd(PPh3)4: tetrakis(triphenylphosphine)palladium (0)

rel: relative configuration

Rt: retention time

TEA: triethylamine

TFUCK: triperoxonane acid

THF: tetrahydrofuran

saturated salt solution: saturated saline solution

tBuOH: tert-butanol

tBuOK: tert-piperonyl potassium

Ways to get

The compound of formula (I) and its salt can be obtained by using various known synthesis methods, using the characteristics based on their basic skeletons or types of substituents. At the moment, depending on the types of functional groups, in some cases is effective, from the point of view of methods of production, the substitution of a functional group suitable protecting group (a group that can be easily converted into the functional group), during the stages from the original substances to intermediate compounds. Examples of such functional groups include protective groups described in "Greene's Protective Groups in Organic Synthesis (4thEdition, 2006), published P.G.M. Wuts and T.W. Greene, which can appropriately be selected and used depending on the conditions of the reactions. In these methods, the desired compound can be obtained by introducing a protective group for the implementation of the reaction and then, if necessary, removing the protective g is uppy.

In addition, the prodrug of the compounds of formula (I) can be obtained by introducing a specific group during the stages from the original materials to intermediates, in the same way as described above in relation to protective groups, or by the future implementation of the reaction using the obtained compound of formula (I). The reaction may be carried out using the method well known to specialists in this area, such as a well-known esterification, amidation, dehydration and the like.

Further, in the present application describes a typical way of obtaining the compounds of formula (I). Moreover, the methods of obtaining of the present invention is not limited to the following examples.

The method of obtaining 1

Chemical formula 6

This method of obtaining is a method of obtaining the compounds of formula (I-a) with R1=H from compound (1-a).

Stage, indicated as stage 1, represents a reaction that provides interaction between the carboxyl group of the compound (1-a) agent sideropenia, such as DPPA, sodium azide and the like, for the formation of urethane groups or urea groups by using the so-called rearrangement reaction of kurzius, which is preferably carried out in the presence of a base. As the base is usually used in isout TEA, pyridine or the like, and the reaction can be performed at room temperature, under conditions of from room temperature to heating or heating at the boiling point under reflux. In addition, obtaining also possible to carry out a method including receiving via isocyanate, which is derived from a carboxylic acid derivative, using attestations acid in the presence of concentrated sulfuric acid.

The method of obtaining 2

Chemical formula 7

where Lv represents a group to delete.

This method of production is a method of obtaining the compounds of formula (I) with compounds (2-a) as the starting material.

Stage 2 represents the reaction, providing interaction of the compound (2-a) with compound (2-b), which preferably is carried out in the presence of a base. As grounds usually use TEA, pyridine or the like, and the reaction can be performed at room temperature, under conditions of from room temperature to heating or heating at the boiling point under reflux. Here, examples of the deleted group include halogen; methansulfonate, econsultancy, benzosulfimide, pair-toluensulfonate, tripterocalyx similar.

The method of obtaining 3

Chemical formula 8

This method of production is a method of obtaining the compounds of formula (I) from compound (3-a).

Stage, indicated as step 3, represents a reaction, providing interaction of the compound (3-a) with compound (1-b), which preferably is carried out in the presence of a base (such as NaH, NaOMe, NaOEt, NaOH, KOH and the like), which contributes to a better implementation of the response. Here, examples of the deleted group Lv include halogen, methoxy, ethoxy, phenoxy, pair-nitrophenoxy and the like.

The method of obtaining 4

Chemical formula 9

This reaction is a method of obtaining the compounds of formula (I) by reacting halogenated aryl compounds (4-a) with compound airborne acid (4-b) and using the so-called reaction combinations Suzuki. The reaction may be carried out without solvent or in an inert reaction solvent such as aromatic hydrocarbons (e.g. benzene, toluene, xylene and the like), ethers (for example, THF, dioxane and the like); halogenated hydrocarbons (for example, DHM, DCE, CHCl3and the like); DMF, DMA, NMP; EtOAc, MeCN and the like, at temperatures from room temperature up to the boiling temperature under reflux. The reaction is carried out at one of the belt the presence of palladium, phosphine ligands and bases metals. As palladium can be used divalently palladium such as Pd(OAc)2and the like, or palladium with zero valency, such as Pd2dba3and similar. As the phosphine ligand can be used bidentate ligand, such as BINAP, DPPF and the like, monodentate ligand such as P(But)3and similar. As the base metal can be used K2CO3Cs2CO3, potassium phosphate, NaOButand similar. Here, examples of the deleted group Lv include halogen, tripterocalyx and the like.

The method of obtaining 5

Chemical formula 10

where A1 represents an aromatic hydrocarbon or heteroclite.

This reaction is a method of obtaining the compounds of formula (I-b) by reacting compound (4-a) with a compound of tin (5-b) and using the so-called reaction combination Steele. The reaction may be carried out without solvent or in an inert reaction solvent such as aromatic hydrocarbons (e.g. benzene, toluene, xylene and the like), ethers (for example, THF, dioxane and the like); halogenated hydrocarbons (for example, DHM, DCE, CHCl3and the like); DMF, DMA, NMP; EtOAc, MeCN and the like, at temperatures from room temperature up to the temperature to the singing under reflux. The reaction is carried out at simultaneous presence of palladium and phosphine ligands. As palladium can be used divalently palladium such as Pd(OAc)2and the like, or palladium with zero valency, such as Pd2dba3and similar. As the phosphine ligand can be used bidentate ligand, such as BINAP, DPPF and the like, monodentate ligand such as P(But)3and similar. Here, examples of the deleted group include halogen, tripterocalyx and the like.

The method of obtaining 6

Chemical formula 11

In the compound of formula (I), compounds (a, b), in which the nitrogen atom of the Aza-ring groups with internal bridge forms a Quaternary ammonium salt, or the compound (c, d), where the nitrogen atom is oxidized, can be obtained by subjecting the tertiary amine compound (1-c) compounds of the present invention the reaction of N-alkylation or N-oxylene, which is usually carried out at a final stage.

The reaction of N-alkylation can be performed using the method traditionally used for the reaction of N-alkylation, but in the specific case, it is carried out by mixing the tertiary amine compounds of the present invention with a suitable alkylating agent in a trade is nom solvent, such as DMF, CHCl3, acetone, MEK, MeCN, THF and the like at a temperature from temperature cooling with ice to room temperature or, in some cases, when heated to the boiling temperature under reflux.

Examples of the alkylating agent include alkylhalogenide, C1-6alkylarylsulfonate, C1-6alkyl-para-toluensulfonate, C1-6alkylarylsulfonate and the like.

The reaction of N-oxidation can be performed using the method traditionally used for the oxidation reaction, but in the specific case, it is carried out by mixing the tertiary amine compounds of the present invention with an appropriate amount or excess amount of oxidant in inerno a solvent such as CHCl3, DHM, DCE, and the like, alcohols such as MeOH, EtOH and the like, water or a mixed solvent of the above, the temperature of the cooling to room temperature or, in some cases, is heated at the boil under reflux. Examples of the oxidizing agent include organic percolate, such as MCPBA, and the like, periodid sodium, hydrogen peroxide and the like.

The method of obtaining 1 for intermediate compounds

Chemical formula 12

where Hal is halogen and R7represents a protective group carbon is Oh acid.

The compound (1-a) Stage 1 can be obtained as follows.

Stage 7-1 is a method of obtaining a compound (7-b) using the compound (7-a) as the starting material. Halogenated aryl can be obtained, ensuring the interaction of alkali metal salt formed with nitric acid or nitric ether, with a compound (7-a) in acidic conditions, to obtain the diazonium salt of arylaminomethylene, and adding it to the solution containing hydrogenogenic, in the presence of cuprite chrysocolla, catalyst. The reaction can be carried out in a solvent such as sulfuric acid, acetic acid, phosphoric acid, acetone, MeCN, DMSO and the like. As the halogenation agent can be used halogenated copper or halogenated iron, and as cuprite, you can use CuCl2or CuBr2. Regarding the reaction temperature, the reaction is carried out at a temperature from cooling with ice to room temperature, or from room temperature to the boiling temperature under reflux.

Stage, indicated as stage 7-2 and stage 7-2', can be performed using a method similar to the Fourth method, or the Method of obtaining 5 described above.

Stage 7-3 represents the reaction of obtaining carboxylic acid, subjecting the ester group hydrolysis or reaction of removing the protective whom you what can be applied reaction conditions, removal of the carboxyl protecting group, such as described in “Protective Groups in Organic Synthesis”, as described above. Examples of protective groups include C1-6alkyl which may be substituted;- C(=O)-C1-6alkyl which may be substituted, and, in particular, include methyl, ethyl, benzyl, allyl, and t-butyl.

The method of obtaining 2 for intermediate compounds

Chemical formula 13

where R8represents C1-6alkyl group which may be substituted with halogen, and R9represents C1-6alkyl group.

In addition, the receipt can be done in the following way in the case when the ring carbonbearing compounds (1-a), which is the original substance of Stage 1 of the Method of obtaining 1 is a thiazole.

Stage 8-1 is a method of obtaining diaminononane product (8-b) using the compound (8-a) as the starting material. Obtaining can be accomplished by reaction of the alkali metal salt formed with nitric acid or esters of nitric acid, in acid conditions to receive diazonium salts with nitrogen removal. The reaction can be carried out in a solvent such as sulfuric acid, acetic acid, phosphoric Ki the lot, acetone, MeCN, DMSO and the like.

Stage 8-2 is a method of producing compound (8-c) by reacting airborne acid or compounds of alkyl-tin with compound (8-b). The interaction can be performed in a manner analogous to the Methods of obtaining 4 and 5, described above.

Stage 8-3 represents the reaction obtain the carboxylic acid compound (1-a'), subjecting the ester group hydrolysis or reaction of removal of the protecting group, and it can be done in a manner analogous to Stage 7-3 described above.

On Stage 8-4 compound of the formula (8-e) or the formula (8-f) can be obtained from compound (8-d) and aldehyde using method TSUBOI, et al. (Bulletin of Chemical Society of Japan., 1987, Vol. 60, p. 2475), and at the Stage 8-5 thiazole compound (8-g) or a compound (8-h) can be obtained by reacting compound (8-e) or the compound (8-f) with thiourea or thioamide. The reaction is carried out in an alcohol or MeCN when heated.

Stage 8-6 is a method of obtaining diaminononane connection (8-c) 2-aminothiazoline connection (8-g), and it can be done the same way Stage 8-1 described above.

Stage 8-7 is a method of producing compound (8-i) from compound (8 g)containing 2-aminothiazolyl group, which can be applied to conditions to remove the protection of the amino group, as described specified in the above “Protective Groups in Organic Synthesis”.

Stage 8-8 is a method of obtaining N-alkyl N-tert-butoxycarbonyl product of tert-butoxycarbonyl product (8-i) using the method of KIM et al. (Synlett., 1999, pp. 1239).

Stage 8-9 is a reaction receiving carbonbearing connection (8-k), which is carried out by exposing the ester group hydrolysis or reaction of removal of the protecting group, and it can be done in a manner analogous to Stage 7-3 described above.

The method of obtaining 3 for intermediate compounds

In addition, heteroaromatic compound (4-a), used at the stage of obtaining Methods 4 and 5, in which R1represents-H, can be obtained in a manner analogous to the Method of obtaining 1.

Chemical formula 14

Moreover, some compounds of formula (I) can be obtained from the compounds of the present invention, obtained as described above, using any combination of well-known methods, which are traditionally used specialists in this area, such as alkylation, acylation, substitution reaction, oxidation, recovery, hydrolysis, removal of the protective group and the like.

The compound of formula (I) is isolated and purified in the form of a free compound, salt, hydrate, MES or its polymorphic crystalline substances the. Salt of the compounds of formula (I) can also be obtained in accordance with the usual method used for the formation of salts.

Isolation and purification carried out using conventional chemical techniques, such as extraction, fractional crystallization, various types of fractional chromatography and the like.

Various isomers can be obtained by selecting appropriate initial connection, or by separation by using the difference in physicochemical properties between the isomers. For example, an optical isomer can be obtained by the methods of the primary optical separation of racemic products (e.g., fractionated crystallization for the induction of diastereomers with optically active bases or acids, chromatography using a chiral column, etc. and the like). In addition, the isomers can also be obtained from a suitable optically active educt.

The pharmacological activity of the compounds of formula (I) were confirmed by the following tests.

The test example 1: Test of affinity for the muscarinic receptor (in vitro)

a. Preparation of the sample membrane

Took submandibular gland/heart and cerebral cortex of male SD rats (Japan SLC, Inc.) and to this was added a 10-fold volume of 25 mm Tris buffer (pH 7,4, then in the application referred to as Tris buffer)containing 3.75 malaria magnesium, followed by homogenization in ice cooling. Centrifugation was carried out at 1000 g, 4°C for 10 minutes and then made ultracentrifugation at 100000 g, 4°C for 30 minutes. The precipitate suspended in Tris buffer and stored at -80°C. then it was molded for use and testing.

b. Experiment the binding of muscarinic receptor

The sample membrane of any of the submandibular gland, heart and cerebral cortex, [3H]-N-methylscopolamine (N-methylscopolamine) and test compound were incubated in 0.3 ml of Tris buffer at 25°C for 2 hours and filtered with suction through a glass filter (Whatman GF/B) and the filter was washed 8 times with 0.3 ml of Tris buffer. The radioactivity of [3H]-N-methylscopolamine adsorbed on the filter was measured using Top Count. Further, the receptor-specific binding was determined by adding 1 μm N-methylscopolamine. The affinity of the test compounds against muscarinic receptor was defined as the dissociation constant (Ki), which was calculated from the concentration (IC50) test compound that inhibits the binding of [3H]-N-methylscopolamine as labeled ligand by 50%.

As a result, for any given link of the compounds of formula (I) results of experiments by definition antagonistic act is vnesti against the receptor binding (activity indicators, the values of Ki, nm) are presented in Table 1.

Table 1
Number exampleThe value of Ki (nm)Number exampleThe value of Ki (nm)
20,51950,2
60,451100,67
120,321300,21
260,561360,065
320,0491390,36
350,0211530,85
460,0832460,074

a. Example of test 2) Test of antagonism against muscarinic receptor (in vivo)

a. Test reducing breathing is OTA in rats

Male SD rats (250-400 g) were analizirovali by intraperitoneal introduction of pentobarbital sodium (Nembutal; 50 mg/kg) and dissected basic respiratory tract. Respiratory cater was introduced into the trachea and airway pressure were measured using a pressure sensor. After the introduction of pancuronium (0.2 mg/kg, intravenously) have a stable airway pressure before the beginning of the experiment. The experiment was carried out by introducing into the external maxillary vein/introduction into the duodenum/oral introduction/introduction to the respiratory tract of physiological solution (in the case of oral administration/introduction into the duodenum - distilled water) or injected compound and from 5-30 minutes in the case of intravenous administration, through a 0.25-6 hours in the case of oral administration into the duodenum and through 0.25 to 72 hours in case of introduction into the respiratory tract were injected intravenously carbachol dose (volume) of 30 ág/kg (1 ml/kg) and then measured the indices of airway pressure accordingly, during the 5 minute period. For the test drug was measured by the rate of inhibition carbachol-induced increase of airway pressure in the physiological solution, and the dose of test compound which inhibited the increases is of 50%, was taken as the value of the ED50.

b. The test of salivation in rats

Male SD rats (250-400 g) were analizirovali by intraperitoneal introduction of pentobarbital sodium (Nembutal; 50 mg/kg). Injected the connection (for the control group were injected with saline) and after 5 minutes was introduced carbachol at the dose of 30 mg/kg (1 ml/kg). The introduction of drugs was carried out in the same manner as in the above-described test method, by introducing into the external maxillary vein/introduction into the duodenum/oral introduction/introduction to the respiratory tract. Secreted saliva within 5 minutes directly after the introduction of carbachol was removed using cotton swabs and measured by its weight. Determined the rate of inhibition in relation to the amount of saliva in the control group, and the dose of test compound which inhibited the amount of saliva in the control group by 50%was taken as the value of ID50.

c. Test bradycardia in rats

Male SD rats (250-400 g) were anestesiologi by intraperitoneal introduction of pentobarbital sodium (50 mg/kg), round neck cut and the respiratory tract strengthened by introducing a cannula into the trachea. In conditions of artificial respiration (10 ml/kg at 90 times per minute) track your heart rate throughout vernaculus the Noah artery. Inserted a cannula in the external maxillary vein, through which was carried out by the administration of a medicinal product. Was carried out by the introduction of a cannula into the trachea and left for 10 minutes, after which the test compound was administered intravenous/injected into the duodenum/injected oral/injected into the respiratory tract (as for the control group was injected with saline in the case of intravenous/oral injection and was administered distilled water in the case of oral administration into the duodenum). After 5-30 minutes was introduced carbachol at the dose of 30 mg/kg (1 ml/kg) and determined the effect of reducing the heart rate in the control group within 5 minutes after injection. Determined the rate of inhibition in the reduction of heart rate, and the dose of test compound which inhibited the decrease in heart rate in the control group by 50%was taken as the value of ID50. For any of the compounds of the compounds of formula (I) results of action inhibition carbachol-induced reduction of the respiratory tract are presented in Tables 2 and 3. (Table 2: Definition 3 hours after oral administration, and table 3: Determination within 24 hours after introduction into the trachea 0.5 μg/kg drug, respectively).

p>
Table 2
Number example
Etc.
ID50
(ug/kg)
60,1
140,027
262,45
1100,41
1360,68
1560,091
2640,21

Based on the above test results, it was confirmed that the compound of formula (I) has an antagonistic activity against the binding of muscarinic receptor M3. Thus, it can be used for the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, asthma, chronic obstruction of the respiratory tract, pulmonary disease fibres, emphysema, rhinitis and the like; diseases of the digestive system such as irritable bowel syndrome, spastic colitis, stomach ulcers and duodenal ulcers, gastro-is Chechnya attacks or increased motility, pain from diverticulitis and smooth muscle contraction in the digestive system and the like; diseases of the urinary system, including dysuria, such as incontinence, urge to urinate, frequent urination and the like, for diseases such as neurogenic frequent urination, neurogenic bladder, nocturnal enuresis, unstable bladder, bladder spasms, chronic cystitis and the like; diseases related to lifestyle, such as obesity, diabetes and the like; motion sickness and the like.

Pharmaceutical composition that includes one or two or more types of the compounds of formula (I) or its salt as an active ingredient, can be obtained in accordance with the method, which is usually used in this field, using excipient, which is usually used in this field, i.e. pharmaceutically acceptable excipient, pharmaceutically acceptable soluble media, etc.

The introduction can be done in any form of oral administration using tablets, pills, capsules, granules, powders, liquid preparations and the like, or parenteral administration by injection, such as intraarticular, intravenous, intramuscular, using suppositories, eye drops, eye ointments, percutaneous liquid preparations, ointments, percutaneous the patches, liquid preparations for administration through mucosa, patches for insertion through the mucous membrane, inhalation, etc.

As for solid compositions for oral administration, use of tablets, powders, granules, etc. In such solid compositions one or two or more kinds of active ingredients are mixed with at least one inert excipient, such as lactose, lures, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and/or alumosilicate magnesium and the like. In accordance with a conventional method, the composition may contain inert additives such as lubricating substance, such as magnesium stearate, a leavening agent, such as sodium carboximetilkrahmal and the like, a stabilizer and solubilizer substance. If necessary, tablets or pills may have a film coating, sugar coating, gastro - or intersolubility floor.

Liquid composition for oral administration includes pharmaceutically acceptable emulsions, soluble liquid preparation, suspension, syrup, elixir and the like, and contains traditionally used inert diluent such as distilled water or EtOH. In addition to the inert diluent such liquid composition may contain auxiliary substances, such as solubilizers substances which, wetting agent and suspendisse ingredient, sweetener, flavoring, flavouring or antiseptic.

Injections for parenteral administration include aqueous or non-water soluble liquid preparations, suspensions or emulsions. The aqueous solvent includes, for example, distilled water for injection or saline. Examples of non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as EtOH, Polysorbate 80 (Pharmacopoeia of Japan) and the like. This composition may also include an agent toychest, antiseptics, wetting agent, emulsifier, dispersing agent, stabilizer or solubilizer substance. Such compositions are sterilized, for example by means of filtration through retaining bacteria filter, mixing with bactericide, or irradiation. In addition, they can also be used by obtaining a sterile solid composition and its dissolution or suspension in sterile water or a sterile solvent for injection before use.

Medicines for external use include ointments, plasters, creams, jellies, preparations for application in the form of patches, sprays, lotions, eye drops, eye ointments and the like. Medicines contain traditionally used onoville ointment, the basis for lotion, aqueous or non-aqueous soluble liquid preparations, suspensions, emulsions and the like, Examples of bases for ointments or lotion include polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyoxyethylene-gidrirovannoe castor oil, glycerylmonostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, servicesecurity and the like.

Means for insertion through the mucous membrane, such as inhalation, means for insertion through the nose and such, use tools in the form of solids, liquids or semi-solid substances, and they can be obtained in accordance with the traditional methods. For example, you can add accordingly known excipient, as well as the agent for pH control, an antiseptic, a surfactant, a lubricating substance, stabilizer, thickener or similar substances. For their introduction you can use a suitable device for inhalation or insufflation. For example, the connection can be entered separately or in the form of powder formulated mixture, or in the form of a solution or suspension in combination with a pharmaceutically acceptable carrier, using traditional device or atomizer, such as a device for inhalation from a metered dose. The dry powder inhaler, etc. can the t to be designed for single or multiple injections, and you can use dry powder or containing powder capsule. Alternatively, it may be such a shape, as under pressure aerosol spray that contains a suitable propellant, such as a suitable gas, such as chlorphenesin, hydroforce, carbon dioxide and the like, or other forms.

By oral administration, the daily dose is generally from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and even more preferably from 0.1 to 10 mg/kg of body weight, administered in one dose or in 2-4 separate doses. In the case of intravenous suitable daily dose is from about 0.01 to 10 mg/kg of body weight, once a day, or two or more times a day. In addition, the drug in the form of means for insertion through the mucous membrane is administered at a dose of from about 0.001 to 100 mg/kg of body weight, once a day, or two or more times a day. In the case of administration by inhalation daily dose is from about 0.1 to 100 μg/kg of body weight, once a day, or two or more times a day. Dose respectively determined for each specific case with regard to symptoms, age, sex, and similar factors.

The compound of formula (I) can be used in combination with other therapies or preventive agents for the treatment of diseases for which the compound of formula(I), it is believed, will be effective as described above. Such combination can be administered simultaneously or separately, continuously or with the desired intervals. Drugs for joint injection can be in the form of a mixture, or may be in the form of individual drugs.

Examples

Further, in the present application is described in more detail the methods for obtaining the compounds of formula (I) with reference to Examples. In addition, the present invention is not limited to the compounds described below in the Examples. Also, each of the methods of obtaining the source compound is described with reference to the Examples of the preparation. Moreover, the methods for obtaining the compounds of formula (I) is not restricted to these specific methods of obtaining samples and, thus, the compound of formula (I) can also be obtained by a combination of such methods of obtaining or known way to obtain that is obvious to experts in this field.

Compounds are presented below in the Tables were obtained using this method get, which is obvious to experts in this field or its modifications. Structure and physico-chemical data of these compounds of the Examples and methods for their production are presented in Tables. Also, the symbols in the Tables have the following meanings.

PR.: No. of sample receipt

PR.: # Example

Synthesis: the Method get (the figure shows that the compound of the Example was obtained, using the same method as for the connection indicated by this number, as an Example).

Structure: Structural formula

data: physicochemical data. For example, NMR and MS are as follows.

NMR: Signal δ (ppm)1H-NMR using DMSO-d6as a solvent for measurement

NMR (CDCl3): Signal δ (ppm)1H-NMR, using CDCl3as a solvent for measurement

- ESI (+): the Values measured in the positive mode

- ESI (-): the Values measured in the negative mode

Example obtain 1

Under ice cooling, to a suspension of CuBr2in MeCN was added tert-butylnitrite. Further portions to the mixture was added methyl 2-amino-5,6-dihydro-4H-cyclopent[b]thiophene-3-carboxylate, followed by stirring under ice cooling for 2 hours and then at room temperature for 3 hours. To the reaction mixture was added hydrochloric acid and the aqueous layer was extracted using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN, YFLC WPrep2XY, hexane:EtOAc) to give methyl 2-bromo-5,6-dihydro-4H-cyclopent[b]thiophene-3-is carboxylate in the form of a colourless liquid.

Connection Examples get 1-1 - 1-2, presented below in the Tables, was synthesized by a method similar to that described in Example obtain 1 using the appropriate source materials.

Example of getting 2

To a solution of ethyl 2-amino-5-phenylthiazole-4-carboxylate in MeCN was added CuCl2at 0°C and to the mixture dropwise slowly added soliditet, followed by stirring for 1 hour. To the reaction mixture were added CHCl3followed by stirring at 0°C for 2 hours and then at room temperature for 2 hours. The reaction mixture was neutralized by adding 1 M aqueous NaOH solution and filtered through celite. The filtrate was extracted using EtOAc and the organic layer, in this order, washed with water and saturated saline and then dried over MgSO4. After concentration under reduced pressure the resulting residue was purified using preparative liquid chromatography, medium pressure (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to give ethyl 2-chloro-5-phenylthiazol-4-carboxylate as a yellow oil.

Example of getting 3

To a suspension of methyl 2-bromo-5,6-dihydro-4H-cyclopent[b]thiophene-3-carboxylate, phenylboronic acid and Pd(PPh3)4in dioxane was added 2 M aqueous solution of Na2CO3followed by stirring at 90°C in ECENA 15 hours. To the mixture was added water and the aqueous layer was extracted using EtOAc. The organic layer was dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to give methyl 2-phenyl-5,6-dihydro-4H-cyclopent[b]thiophene-3-carboxylate as a colourless liquid.

Connection Examples obtain 3-1 - 3-24 presented below in the Tables, was synthesized by a method similar to that described in the Example of a 3, using the appropriate source materials.

Example 4

To a solution of methyl 2-phenyl-5,6-dihydro-4H-cyclopent[b]thiophene-3-carboxylate in EtOH was added 1 M aqueous NaOH solution followed by heating at boiling under reflux for 5 hours. The reaction mixture is brought to pH 2 by adding 1 M hydrochloric acid and precipitated precipitated solid substance was collected by filtration and washed with water to obtain 2-phenyl-5,6-dihydro-4H-cyclopent[b]thiophene-3-carboxylic acid as white solid.

Connection Examples obtain 4-1 - 4-20 presented below in the Tables, was synthesized by a method similar to that described in Example 4, using an appropriate source materials.

Example of getting 5

To a solution of the Teal, 2-chloro-5-phenylthiazol-4-carboxylate in THF was added 1 M aqueous KOH solution, followed by stirring at 60°C for 30 minutes. To the reaction mixture was added 1 M hydrochloric acid solution and precipitated precipitated solid was collected through filtration to obtain 2-chloro-5-phenylthiazol-4-carboxylic acid as white solid.

Connection Examples obtain 5-1 - 5-23 presented below in the Tables, was synthesized by a method similar to that described in the Example of a 5, using the appropriate source materials.

An example of obtaining 6

To a solution of 2-phenyl-5,6-dihydro-4H-cyclopent[b]thiophene-3-carboxylic acid and TEA in toluene solution was added DPPA in toluene, followed by stirring at room temperature for 40 minutes and then stirring at 90°C for 60 minutes. In addition, to the mixture was added a solution of (3R)-hinokitiol in DMF followed by heating at boiling under reflux for 15 hours. To the reaction liquid was added water, followed by extraction using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The obtained oily substance was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain 2-phenyl-5,6-dihydro-4H-cyclopent[b]thiophene-3-amine as a pale brown oil but not required (3R)-1-azabicyclo[2.2.2]Oct-3-yl(2-phenyl-5,6-dihydro-4H-cyclopent[b]Tien-3-yl)carbamate.

Example of getting 7

To a solution of 2-bromothiophene-3-carboxylic acid and TEA in toluene was added dropwise a solution of DPPA in toluene. The reaction liquid was stirred at room temperature for 40 minutes and then stirred at 90°C for 60 minutes. To this solution was added a solution of 3-hinokitiol in DMF followed by heating at boiling under reflux for 15 hours. To the reaction liquid was added water, followed by extraction using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH) to obtain 1-azabicyclo[2.2.2]Oct-3-yl(2-bromo-3-thienyl)carbamate as a pale brown solid.

Connection Examples obtain 7-1 - 7-5 presented below in the Tables, was synthesized by a method similar to that described in Example receiving 7, using appropriate source materials.

Example obtain 8

To a solution of 2-phenylthiophene-3-carboxylic acid and TEA in toluene was added dropwise a solution of DPPA in toluene, followed by stirring at room temperature for 40 minutes and then stirring at 90°C for 60 m the chickpeas. To this solution was added tBuOH followed by heating at boiling under reflux for 15 hours. To the reaction solution was added water, followed by extraction using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to give tert-butyl (2-phenyl-3-thienyl)carbamate as a pale brown oil.

Example of getting 9

To a suspension of LAH in THF was added a solution of tert-butyl (2-phenyl-3-thienyl)carbamate in THF, followed by stirring at room temperature for 30 minutes and stirring at 70°C for 4 hours. After cooling at room temperature, to the mixture was added Na2SO4-10H2O, followed by stirring at room temperature for 30 minutes. The reaction mixture was filtered and concentrated under reduced pressure to obtain 3-methylamino-2-phenylthiophene in the form of a colorless oily substance.

Example 10

To a mixture of methyl 2-chlorisondamine, Pd(PPh3)4and [(E)-2-phenylphenyl]boric acid in dioxane was added 2 M aqueous solution of Na2CO3with the next AC is sevanam at 90°C for 5 hours. To the reaction mixture were added water and the aqueous layer was extracted using EtOAc. The organic layer was dried over MgSO4and the filtrate is then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to give methyl 2-[(E)-2-phenylphenyl]isonicotinate in the form of a pale yellow solid.

Example of getting 11

To a solution of methyl 2-[(E)-2-phenylphenyl]isonicotinate in dilute hydrochloric acid and MeOH was added platinum oxide, followed by stirring at room temperature for 8 hours in an atmosphere of hydrogen at a pressure of 3 ATM. The reaction mixture was filtered through celite and the filtrate was then concentrated under reduced pressure. To the residue was added an aqueous solution of Na2CO3and xylene and the aqueous layer was extracted using CHCl3. The organic layer was dried over MgSO4and then concentrated under reduced pressure to obtain methyl 2-(2-cyclohexylethyl)piperidine-4-carboxylate as a colorless oily substance.

Example 12

To a solution of methyl 2-[(E)-2-phenylphenyl]isonicotinate in acetic acid was added platinum oxide, followed by stirring at room temperature for 8 hours in an atmosphere of hydrogen at a pressure of 3 ATM. Reactionary see the camping was filtered through celite and the filtrate was then concentrated under reduced pressure. To the residue was added an aqueous solution of Na2CO3and were extracted using EtOAc. The organic layer was dried over MgSO4and then concentrated under reduced pressure to obtain methyl 2-(2-phenylethyl)piperidine-4-carboxylate as a colourless oil.

Example of getting 13

To a suspension of methyl 2-(2-phenylethyl)piperidine-4-carboxylate in xylene was added ethylbromoacetate and K2CO3followed by heating at boiling under reflux for 8 hours. The reaction mixture was diluted with the aid of EtOAc, the organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then filtered. The filtrate was concentrated under reduced pressure. To the residue was added hexane, and any insoluble matter was removed through filtration, followed by concentration under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to give methyl 1-(2-ethoxy-2-oxoethyl)-2-(2-phenylethyl)piperidine-4-carboxylate as a pale brown oil.

The compound of Example obtaining 13-1 presented below in the Tables, was synthesized by a method similar to that described in the Example of a 13, using the appropriate starting material.

Example of getting 14

2CO3and the aqueous layer was extracted using CHCl3. The organic layer was dried and then concentrated under reduced pressure. The obtained residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH) to give 6-(2-phenylethyl)Hinkley-3-one as pale brown oil.

The compound of Example obtaining 14-1 presented below in the Tables, was synthesized by a method similar to that described in the Example of a 14, using the appropriate starting material.

Example get 15

To a suspension of LAH in diethyl ether was added a solution of 6-(2-phenylethyl)Hinkley-3-one in THF followed by heating at boiling under reflux for 4 hours. To the reaction mixture was added Na2SO4-10H2O, followed by stirring at room temperature over night. Reactionary see the camping was filtered and the filtrate is then concentrated under reduced pressure to obtain 6-(2-phenylethyl)Hinkley-3-ol as a colourless oil.

Connection Examples obtain 15-1 and 15-2 are presented below in the Tables, was synthesized by a method similar to that described in the Example of a 15, using an appropriate source materials.

Example 16

1-azatricyclo[3.3.1.13,7]Decan-4-carbonitrile was added concentrated hydrochloric acid followed by heating at boiling under reflux for 3 hours. The reaction liquid was concentrated under reduced pressure to obtain hydrochloride of 1-azatricyclo[3.3.1.13,7]decane-4-carboxylic acid in the form of solids. This substance is used at the next stage of the reaction without purification.

Example of getting 17

To a solution of hydrochloride of 1-azatricyclo[3.3.1.13,7]decane-4-carboxylic acid in EtOH was added concentrated sulfuric acid followed by heating at boiling under reflux for 18 hours. The reaction liquid was concentrated under reduced pressure and then diluted with the aid of EtOAc. The EtOAc layer in this order was washed in an aqueous solution of NaHCO3and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure to obtain a yellow oily substance. This substance was purified using column chromatography on silica gel (CHCl3:MeOH) to give the floor is l 1-azatricyclo[3.3.1.1 3,7]decane-4-carboxylate as a yellow solid.

Example of getting 18

To a suspension of LAH in THF was added dropwise a solution of ethyl 1-azatricyclo[3.3.1.13,7]decane-4-carboxylate in THF at a temperature of from 0 to 5°C, followed by stirring at the same temperature for 1 hour. To the reaction mixture while cooling with ice in the order added water, 15% aqueous NaOH solution and then water. Any insoluble matter was removed through filtration through celite followed by washing with the aid of EtOAc. The filtrate was dried over MgSO4and then concentrated under reduced pressure to obtain 1-azatricyclo[3.3.1.13,7]Decan-4-ylmethanol in the form of a colorless oily substance.

Connection Examples get 18-1 - 18-11 presented below in the Tables, was synthesized by a method similar to that described in the Example of a 18, using an appropriate source materials.

Example of getting 19

To a solution of methyl 2-phenylthiophene-3-carboxylate and NCS in CHCl3added perchloro acid, followed by stirring at 50°C during the night. To the reaction mixture were added water and the aqueous layer was extracted using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. Receive the config residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to give methyl 5-chloro-2-phenylthiophene-3-carboxylate in the form of a white solid.

Example of getting 20

To 60% oil solution of NaH in MeOH was added ethyl 2-chloro-5-phenylthiazol-4-carboxylate, followed by stirring at 70°C for 1 hour. To the reaction mixture was added water, followed by extraction using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH) to give methyl 2-methoxy-5-phenylthiazol-4-carboxylate as white solid.

Example of getting 21

To a solution of ethyl 2-methyl-5-phenyl-1,3-thiazole-4-carboxylate in carbon tetrachloride was added NBS followed by heating at boiling under reflux. The reaction liquid was filtered and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc = 8:1 to 6:1) to obtain ethyl 2-(methyl bromide)-5-phenyl-1,3-thiazole-4-carboxylate (21a) and ethyl 2-(dibromomethyl)-5-phenyl-1,3-thiazole-4-carboxylate (21b) in the form of a yellow solid, respectively.

The compound of Example obtaining 21-1, presents the who in Tables, synthesized in a manner analogous to the one described in Example receiving 21, using the appropriate starting material.

Example of getting 22

A suspension of ethyl 2-(methyl bromide)-5-phenyl-1,3-thiazole-4-carboxylate obtained in Example receiving 21, and NaOAc in MeCN was heated at the boil under reflux. To the reaction mixture was added water, followed by extraction using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc = 4:1) to obtain ethyl 2-(acetoxymethyl)-5-phenyl-1,3-thiazole-4-carboxylate as a pale yellow solid.

An example of retrieving 23

To a solution of ethyl 2-(acetoxymethyl)-5-phenyl-1,3-thiazole-4-carboxylate obtained in Example getting 22 in EtOH was added 1 M aqueous NaOH solution, followed by stirring at room temperature. The reaction liquid was neutralized by adding 1 M hydrochloric acid and was extracted using CHCl3. The organic layer was washed with saturated saline solution, dried and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc = 1:1) to obtain ethyl 2-(guide oxymethyl)-5-phenyl-1,3-thiazole-4-carboxylate as a pale yellow solid.

Example of getting 24

To a solution of ethyl 2-(hydroxymethyl)-5-phenyl-1,3-thiazole-4-carboxylate obtained in Example receiving 23, DHM at 0°C was added TRIFLUORIDE bis(2-methoxyethyl)aminocore (Deoxo-Fluorine(R)), followed by stirring for 30 minutes. The reaction was stopped by adding to the reaction mixture aqueous solution of NaHCO3with the subsequent extraction by adding EtOAc. The organic layer was washed with saturated saline, dried over Na2SO4and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc) to give ethyl 2-(permitil)-5-phenyl-1,3-thiazole-4-carboxylate as a pale yellow oily substance.

Connection Examples get 24-1 and 24-2 are presented below in the Tables, was synthesized by a method similar to that described in Example get 24 using aldehyde compounds of Examples obtain 25 and 25-1, as described below as the starting materials.

Example get 25

To a solution of aqueous solution of dibromo product (21b)obtained in Example getting 21 in EtOH was added an aqueous silver nitrate solution followed by heating at boiling under reflux for 15 minutes. To the reaction liquid was added a 1 M solution of hydrochloric acid, precipitated precipitated solid is emesto was removed via filtration and the filtrate was then extracted using CHCl 3. The organic layer was washed with saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc) to give ethyl 2-formyl-5-phenyl-1,3-thiazole-4-carboxylate as a pale yellow solid.

The compound of Example obtaining 25-1 presented below in the Tables, was synthesized by a method similar to that described in Example receive 25 using the appropriate starting material.

Example of getting 26

A solution of ethyl 3-chloro-2-oxo-3-phenylpropanoate and cryptorchidectomy in MeCN was heated at the boil under reflux. To the reaction mixture were added an aqueous solution of Na2CO3with the subsequent extraction using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain ethyl 5-phenyl-2-(trifluoromethyl)-1,3-thiazole-4-carboxylate as white solid.

Example of getting 27

To a suspension of methyl (2-bromo-4-were)carbamate and Hinkley-3-ol and MS4A in toluene was added a 60% oil solution of NaH, followed by heating at copaceni the under reflux for 36 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3: MeOH) to obtain 1-azabicyclo[2.2.2]Oct-3-yl-2-bromo-4-were)carbamate in the form of a white solid.

Example of getting 28

To a suspension of ethyl 5-bromothiazole-4-carboxylate, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and Pd(PPh3)4in dioxane was added 2 M aqueous solution of Na2CO3followed by heating at boiling under reflux for 4 hours. To the reaction mixture were added water and the aqueous layer was extracted using EtOAc. The organic layer was dried over MgSO4and then concentrated under reduced pressure. The residue was purified using chromatography on silica gel (hexane:EtOAc) to obtain ethyl 5-(1-methyl-1H-pyrazole-4-yl)-1,3-thiazole-4-carboxylate in the form of a brown solid substance.

An example of obtaining 29

Sodium portions were added to EtOH at 60°C under stirring. EtOH was removed by evaporation and to the mixture was added diethyl ether, and then to the mixture was added dropwise ethyl 2,2-dichloro-3-oxobutanoate at 0°C. To the reaction mixture was added dropwise 2,6-differentally, followed by stirring at 0°C for 30 minutes and then nahrawan the m by boiling under reflux for 4 hours. To the reaction mixture was added a mixture of ice-water, followed by neutralization with 2 M HCl solution and extracted using EtOAc. The organic layer was washed with saturated saline solution, dried and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc = 85:15 to 6:4) to give ethyl 2-chloro-3-(2,6-differenl)oxiran-2-carboxylate as a yellow oil.

Example 30

To a solution of ethyl 2-chloro-3-(2,6-differenl)oxiran-2-carboxylate in EtOH was added thiourea followed by heating at boiling under reflux for 4 hours. To the reaction mixture was added a mixture of ice-water, followed by addition of K2CO3for alkalizing mixture. Precipitated precipitated solid substance was collected by filtration and washed with water to obtain ethyl 2-amino-5-(2,6-differenl)-1,3-thiazole-4-carboxylate as a yellow solid.

An example of retrieving 31

To a solution of ethyl 2-amino-5-(2,6-differenl)-1,3-thiazole-4-carboxylate in THF slowly was added dropwise tert-butylnitrite when heated by boiling under reflux. After completion of adding dropwise the solution continued to stir at the same temperature for 4 hours. The reaction mixture was cooled to room temperature with subsequent the brilliant addition of water and extraction with the aid of EtOAc. The organic layer was washed with saturated saline solution, dried and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc = 9:1-7:3) to obtain ethyl 5-(2,6-differenl)-1,3-thiazole-4-carboxylate as a yellow oily substance.

Example of getting 32

To a mixed solution of ethyl 2-amino-5-phenyl-1,3-thiazole-4-carboxylate, acetic acid and sulfuric acid was slowly added an aqueous solution of NaNO2(5 ml) at 0°C, followed by stirring at the same temperature for 1 hour. This solution was added to aqueous solution (40 ml)containing CuCN, NaCN and NaHCO3(30 g), for 30 minutes, followed by stirring at the same temperature for 1 hour. To the mixture was added EtOAc and any insoluble matter was filtered through celite. The filtrate was extracted using EtOAc, the organic layer was dried and the solvent was removed by evaporation under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc = 5:1 to 3:1 to 2:1) to obtain ethyl 2-cyano-5-phenyl-1,3-thiazole-4-carboxylate as a yellow solid.

An example of obtaining 33

To a solution of ethyl 2-cyano-5-phenyl-1,3-thiazole-4-carboxylate in THF was added 1 M aqueous KOH solution, followed by stirring at room temperature for 2 hours. To the reaction mixture was added 1 M hydrochloric acid solution and precipitated precipitated solid was collected through filtration to obtain 2-carbarnoyl-5-phenyl-1,3-thiazole-4-carboxylic acid as a pale yellow solid.

An example of retrieving 34

To a solution of ethyl 5-bromo-1,3-thiazole-4-carboxylate in toluene was added 2-(tributylstannyl)-1,3-thiazole and PdCl2(PPh3)2followed by heating at boiling under reflux for 6 hours. To the mixture was added water and the aqueous layer was extracted using EtOAc. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to give ethyl 2,5'-bis-1,3-thiazole-4'-carboxylate as a yellow solid.

The compound of Example obtaining 34-1 presented below in the Tables, was synthesized by a method similar to that described in Example obtain 34, using the appropriate starting material.

Example of getting 35

To a solution of ethyl 2-amino-5-phenylthiazole-4-carboxylate in THF was added DIBOC, DMAP and TEA, followed by stirring at room temperature. To the reaction mixture was added 1 M hydrochloric acid solution, followed by extraction with SIP the soup EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to give ethyl 2-[(tert-butoxycarbonyl)amino]-5-phenyl-1,3-thiazole-4-carboxylate as a yellowish-white amorphous substance.

Example of getting 36

To a solution of ethyl 2-[(tert-butoxycarbonyl)amino]-5-phenyl-1,3-thiazole-4-carboxylate in THF was added EtOH, PPh3and DEAD, followed by stirring at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to give ethyl 2-[(tert-butoxycarbonyl)(ethyl)amino]-5-phenyl-1,3-thiazole-4-carboxylate as a yellow oil.

Connection Examples get 36-1 and 36-2 are presented below in the Tables, was synthesized by a method similar to that described in Example receive 36, using an appropriate source materials.

An example of retrieving 37

To 60% oily suspension of NaH in THF under ice cooling was added diethylphosphonoacetate. The reaction mixture was stirred for 30 minutes under ice cooling and then when cooled l the house was added to a mixture of the hydrochloride Hinkley-3-one and THF, followed by stirring at room temperature for 3 hours and then stirring at 60°C for 3 hours. The reaction mixture was cooled to room temperature, followed by addition of water and extraction with the aid of EtOAc. The organic layer was extracted with 1 M hydrochloric acid. The aqueous layer was podslushivaet 6 M aqueous NaOH solution and was extracted using CHCl3. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure to obtain a mixture of ethyl (2E)-1-azabicyclo[2.2.2]Oct-3-evidencethat and ethyl (2Z)-1-azabicyclo[2.2.2]Oct-3-evidencethat in the form of a colorless oil.

An example of retrieving 38

To Hinkley-4-ylacetonitrile (500 mg), which was synthesized by the method described in published Japanese translation of PCT application No. 2001-521033, was added concentrated hydrochloric acid (3 ml) followed by heating at boiling under reflux. The reaction mixture was concentrated under reduced pressure, added with toluene followed by concentration under reduced pressure. To the residue was added EtOH (10 ml) and concentrated sulfuric acid (1 ml) followed by stirring at 100°C. the Reaction mixture was concentrated under reduced pressure, neutralized by adding 1 M aqueous NaOH solution and was extracted using CHCl3. The organic layer was dried over MgSO 4and then concentrated under reduced pressure to obtain ethyl Hinkley-4-ilaclama (500 mg) as a yellow oily substance.

An example of retrieving 39

To 4-methylbenzenesulfonate 1-benzyl-5-hydroxy-1-azoniabicyclo[3.2.1]octane (800 mg), which was synthesized by the method described in published Japanese translation of PCT application No. 63-290878, was added a mixture of EtOH (8 ml), 10% Pd/carbon at 50% hydration (200 mg) and ammonium formate (500 mg) followed by heating at boiling under reflux. The reaction mixture was podslushivaet the addition of 1 M aqueous NaOH solution and was extracted with mixed solvent (CHCl3:MeOH = 9:1). The organic layer was dried over MgSO4and then concentrated under reduced pressure to obtain 1-azabicyclo[3.2.1]octane-5-ol (180 mg) as a colorless oily substance.

The compound of Example obtaining 39-1 presented below in the Tables were obtained by the method similar to that described in Example receiving 39 using the substance of Example, receiving 44, described later, as the starting material.

Example of getting 40

In a bath with ice to DIPA (4,1 ml) was added dropwise a 1 M solution of n-utility in hexane (10.1 ml). The reaction mixture was diluted using diethyl ether (10 ml) followed by stirring for 20 minutes. Next, the reaction mixture was stirred at -78°C and to MESI was added dropwise a solution of ethyl 1-benzylpiperidine-3-carboxylate (6.0 g) in diethyl ether (20 ml) followed by stirring at -50°C for 15 minutes. Next, after adding at 70°C 1,3-dibromopropane (2,8 ml) the mixture was slowly returned to room temperature. Then the mixture was heated at the boil under reflux for 30 minutes. The reaction mixture was cooled, diluted with water and was extracted with diethyl ether. The organic layer was dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to give ethyl 1-benzyl-(3-bromopropyl)piperidine-3-carboxylate (1.08 g) as a colorless oily substance.

An example of retrieving 41

A mixture of ethyl 1-benzyl-(3-bromopropyl)piperidine-3-carboxylate (1.08 g), toluene (10 ml) and CHCl3(2 ml) was heated at the boil under reflux for 2 hours. This mixture was cooled to room temperature and then concentrated under reduced pressure. To the residue was added EtOAc and the solid was collected through filtration to obtain 1-benzyl-5-(etoxycarbonyl)-1-azoniabicyclo[3.3.1]monobromide (942 mg) as colorless solids.

An example of retrieving 42

A mixture of 1-benzyl-5-(etoxycarbonyl)-1-azoniabicyclo[3.3.1]monobromide (932 mg), 10% Pd/carbon with 50% hydrating (25 mg) and EtOH (15 ml) was stirred at room temperature in a hydrogen atmosphere at a pressure of 3 ATM. Re clonney the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain a colorless solid. This solid matter was added CHCl3and a saturated aqueous solution of NaHCO3and the organic layer was separated. Next, the aqueous layer was extracted using CHCl3. The organic layer was collected, dried over MgSO4and then concentrated under reduced pressure to obtain ethyl 1-azabicyclo[3.3.1]nonan-5-carboxylate (376 mg).

The compound of Example obtaining 42-1 presented below in the Tables were obtained by the method similar to that described in Example obtain 42, using the substance of Example, receiving 56, described later, as the starting material.

Example of getting 42-2

To a solution of 1-benzyl-1-azoniabicyclo[2.2.1]heptane-4-carboxylate (3.25 g) in MeOH was added 10% Pd on carbon, 50% hydrating (650 mg), followed by stirring at room temperature for 5 hours in an atmosphere of hydrogen at a pressure of 3 ATM. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was dissolved in MeOH and added sulfuric acid (3 ml) followed by heating at boiling under reflux for 1 hour. The reaction mixture was neutralized with an aqueous solution of K2CO3and were extracted using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. Remainder the eyes of the Ali using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3: MeOH: 28% aqueous ammonia) to obtain methyl 1-azabicyclo[2.2.1]heptane-4-carboxylate (890 mg) as a colorless oily substance.

An example of retrieving 43

To a solution of DIPA (3.1 ml) in THF (30 ml) was added dropwise 2,6 M solution (8.6 ml) n-utility in hexane at -70°C. After stirring at 0°C for 40 minutes to the mixture dropwise at -70°C was added EtOAc (2.3 ml), followed by stirring for 5 minutes. To the mixture was added dropwise a solution of 1-benzylation-4-she (3.6 g) in THF (10 ml) followed by stirring for 40 minutes. To the reaction mixture were added saturated aqueous solution of NH4Cl followed by the addition of water and extraction with the aid of EtOAc. The organic layer was washed with saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH: aqueous ammonia) to obtain ethyl (1-benzyl-4-hydroxyether-4-yl)acetate (5.0 g) as a yellow oily substance.

The compound of Example obtaining 43-1 presented below in the Tables, was synthesized by a method similar to that described in Example receiving 43 using the appropriate starting material.

An example of retrieving 44

To a solution of 1-benzyl-4-(2-hydroxyethyl)sepan-4-ol (2.0 g) in DHM (20 ml) was added pyridine (4 ml) and para-toluensulfonate (1.68 g) at 0°C, followed by stirring at 0°C for 3 hours and then at room temperature overnight. The reaction mixture was concentrated under reduced pressure, podslushivaet by adding a saturated aqueous solution of NaHCO3and then was extracted using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure to obtain a pale red solid. To the mixture was added EtOAc and the solid substance was sprayed and collected by filtration to obtain 4-methylbenzenesulfonate 1-benzyl-5-hydroxy-1-azoniabicyclo[3.2.2]nonane (1.85 g) as a pale red powder.

An example of retrieving 45

To a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)-3-hydroxypyrrolidine-1-carboxylate (6,35 g) in THF (100 ml) was added LiBH4(1.01 g) and then heated at the boil under reflux for 4 hours. The reaction mixture was cooled to room temperature, then added water and was extracted using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure to obtain tert-butyl 3-hydroxy-3-(2-hydroxyethyl)pyrrolidin-1-carboxylate (4,72 g) as a colorless oily substance.

An example of retrieving 46

At cryogenic cooling (-10°C to 0°C)to a solution of tert-butyl 3-is hydroxy-3-(2-hydroxyethyl)pyrrolidin-1-carboxylate (4,72 g) in pyridine (10 ml) was added para-toluensulfonate (1.68 g), followed by stirring at room temperature over night. The reaction mixture was concentrated under reduced pressure and to the mixture was added 1 M hydrochloric acid solution, followed by extraction using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to give tert-butyl 3-hydroxy-3-(2-{[(4-were)sulfonyl]oxy}ethyl)pyrrolidin-1-carboxylate (3.25 g) as a colorless oily substance.

An example of retrieving 47

To a solution of tert-butyl 3-hydroxy-3-(2-{[(4-were)sulfonyl]oxy}ethyl)pyrrolidin-1-carboxylate (3,24 g) in EtOH was added 4 M HCl/dioxane, followed by stirring at room temperature over night. The reaction mixture was concentrated under reduced pressure, followed by addition of an aqueous solution of Na2CO3and extraction using EtOAc. The aqueous layer was washed with the aid of EtOAc and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (CHCl3:MeOH:aqueous ammonia = 7:3:0,3) to obtain 1-azabicyclo[2.2.1]heptane-4-ol (950 mg) as a colorless solid.

Example obtain 48

To DIPA (3.6 ml) according to plan added 2,64 M solution of n-utility in hexane (8,93 ml) at -78°C, followed by stirring for 30 minutes. To the reaction mixture were added ethyl 1-benzyl-pyrrolidin-3-carboxylate (5.0 g), followed by stirring for 30 minutes. To the reaction mixture was added dropwise a solution of 1,2-dibromethane (6,05 g) in THF, followed by warming to room temperature and stirring for 2 hours. To the reaction mixture were added an aqueous solution of K2CO3with the subsequent extraction using EtOAc. The aqueous layer was concentrated under reduced pressure and to the residue was added EtOH, followed by stirring at room temperature for 30 minutes. Any insoluble matter was removed through filtration and the filtrate was concentrated under reduced pressure. To the residue was added EtOH, followed by stirring at room temperature for 10 minutes. Any insoluble matter was removed through filtration and the filtrate was concentrated under reduced pressure to obtain 1-benzyl-1-azoniabicyclo[2.2.1]heptane-4-carboxylate (3.25 g) as a colourless solid.

An example of retrieving 49

To a solution of ethyl 2-methyl-1,3-thiazole-4-carboxylate (14,53 g) in MeCN (150 ml) was added NBS (cushion 22.66 g) and then heated at the boil under reflux for 3 hours. To the reaction mixture was added NBS (of 7.55 g) and then heated at the boil under reflux for 2 hours. Under ice cooling to actionnow mixture was added saturated aqueous solution of NaHCO 3followed by stirring for 5 minutes and then extracted using EtOAc. The organic layer was dried over MgSO4and then concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane:EtOAc = 100:0 to 60:40) to obtain ethyl 5-bromo-2-methyl-1,3-thiazole-4-carboxylate (charged 8.52 g) as a yellow solid.

Example of getting 50

A mixture of the hydrochloride of 1-azabicyclo[2.2.1]heptane-3-one (Journal of Medicinal Chemistry, 1990, 33, pp. 2690-2697) (350 mg), platinum oxide (35 mg) and EtOH (5 ml) was stirred at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain hydrochloride of 1-azabicyclo[2.2.1]heptane-3-ol as a pale brown solid.

Connection Examples obtain 50-1 and 50-2 are presented below in the Tables, was synthesized by a method similar to that described in Example receive 50 using the appropriate source materials.

An example of retrieving 51

A mixture of 1-azabicyclo[3.3.1]nonan-4-carbonitrile (US 5834499, Reference Example 44) (1.7 g) and concentrated hydrochloric acid (10 ml) was heated at the boil under reflux for 4 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To about what TATKO was added EtOH (10 ml) and concentrated sulfuric acid (2 drops) followed by heating at boiling under reflux for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure and to the residue was added CHCl3and 10% aqueous solution of K2CO3and the layers were separated. The aqueous layer was extracted using CHCl3and the organic layer was then combined, washed with saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia) to obtain ethyl 1-azabicyclo[3.3.1]nonan-4-carboxylate (2.2 g) as a pale brown oily substance.

The compound of Example obtaining 51-1 presented below in the Tables, was synthesized by a method similar to that described in Example obtaining 51, using the appropriate starting material.

An example of retrieving 52

To a mixture of the hydrochloride (2.3 g) 1-azabicyclo[3.2.1]Octan-4-it (Journal of Medicinal Chemistry, 1993, 36, pp. 683-689), dimethoxyethane (23 ml) and tBuOH (4.6 ml) was added tBuOK (1.60 g), followed by stirring at room temperature for 1 hour. To the reaction mixture was added para-toluensulfonate (a 3.06 g), followed by stirring in a bath with ice. To the reaction mixture was added tBuOK (3,19 g) two separate portions, followed by stirring for 30 minutes is then stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction using CHCl3. The organic layer, in this order, washed with water and saturated saline solution and then was extracted with 1 M hydrochloric acid. The aqueous layer was washed with the aid of EtOAc and concentrated under reduced pressure to obtain a pale brown solid (1.9 g). This substance was added concentrated hydrochloric acid (10 ml), was heated at the boil under reflux for 4 hours, cooled to room temperature and then concentrated under reduced pressure. To the residue was added EtOH (20 ml) and concentrated sulfuric acid (2 drops) followed by heating at boiling under reflux for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure and the residue mixture was neutralized by adding 1 M aqueous NaOH solution and was extracted using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia) to obtain ethyl 1-azabicyclo[3.2.1]about the tan-4-carboxylate (850 mg) as a colorless oily substance.

The compound of Example obtaining 52-1 presented below in the Tables, was synthesized by a method similar to that described in Example receiving 52, using 1-benzylation-4-one.

Example of getting 53

To a mixture of the hydrochloride (21,63 g) 1-azabicyclo[3.2.1]octane-6-she (Journal of Medicinal Chemistry, 1993, 36, pp. 683-689), dimethoxyethane (210 ml) and tBuOH (43 ml) under ice cooling was added tBuOK (15 g), followed by stirring at room temperature for 40 minutes. Next, while cooling with ice to the mixture was added para-toluensulfonate (28,74 g), to which two separate portions was added tBuOK (30 g), followed by stirring for 30 minutes and stirring at room temperature for 4 hours. To the reaction mixture was added water, followed by extraction using CHCl3. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia) to obtain the product with low polarity (6,17 g) and highly polar product (4.9 g), 1-azabicyclo[3.2.1]octane-6-carbonitrile in the form of a yellow oily substance and diluted brown solid, respectively.

When the EP obtain 54

A mixture of the product with high polarity (1.44 g) 1-azabicyclo[3.2.1]octane-6-carbonitrile received in the Sample receiving 53, and concentrated hydrochloric acid (15 ml) was heated at the boil under reflux for 4 hours, cooled to room temperature and then concentrated under reduced pressure. Further to the residue was added MeOH followed by concentration under reduced pressure. To the residue was added MeOH (25 ml) and sulfuric acid (0,67 ml) followed by heating at boiling under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and utverjdali to dryness and to the residue was added CHCl3and 1 M aqueous solution of K2CO3. The aqueous layer was extracted using CHCl3, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia) to obtain methyl 1-azabicyclo[3.2.1]octane-6-carboxylate (657 mg) as a colorless oily substance.

The compound of Example obtaining 54-1 presented below in the Tables, was synthesized by a method similar to that described in Example obtaining 54, using the appropriate starting material.

Example of getting 55

To DIPA (3,22 ml) at -8°C was added dropwise 2,64 M solution of n-utility in hexane (7,97 ml) followed by stirring for 30 minutes. To the reaction mixture were added ethyl 1-benzylation-4-carboxylate (5.0 g), followed by stirring for 30 minutes. Next, to this mixture was added dropwise a solution of 1-bromo-2-chlorethane (3,02 g) in THF, followed by warming to room temperature and stirring for 2 hours. To the reaction mixture were added an aqueous solution of K2CO3with the subsequent extraction using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia). The desired fractions were collected and concentrated under reduced pressure. After concentration under reduced pressure to a residue, part of which was utverjdali, added EtOAc, followed by purification using column chromatography on silica gel (EtOAc) to give ethyl 1-benzyl-4-(2-chloroethyl)azepin-4-carboxylate (4.11 g) in the form of a colorless oily substance.

An example of receiving 56

A solution of ethyl 1-benzyl-4-(2-chloroethyl)azepin-4-carboxylate (4.1 g) in MeCN (200 ml) was stirred at 40°C for 10 hours. The reaction mixture was concentrated under reduced pressure to obtain 1-benzyl-5-(etoxycarbonyl)-1-azoniabicyclo[32.2]nonanchored (4.1 g) as a colorless oily substance.

An example of retrieving 57

Connection Examples retrieve 57 - 57-3 presented below in the Tables, was synthesized by a method similar to that described in Example 6, using the appropriate starting material.

In order to save space on the paper, the symbol SB (below) in the Tables of Examples obtain the above means the following.

Example 1

To a solution of 1-azabicyclo[2.2.2]Oct-4-yl(2-phenyl-3-thienyl)carbamate (120 mg) in DHM (10 ml) in portions under ice cooling was added MCPBA (90 mg). After stirring for 30 minutes the reaction liquid was concentrated under reduced pressure and the residue was purified using column chromatography on silica gel (CHCl3:MeOH = 20:1 to 10:1, were subjected to the processing for separating fluids using 28% aqueous ammonia) to give 1-oxide-1-azabicyclo[2.2.2]Oct-4-yl(2-phenyl-3-thienyl)carbamate (105 mg) as a colorless amorphous substance.

Example 2

To a solution of 2-phenyl-5,6-dihydro-4H-cyclopent[b]thiophene-3-amine (110 mg) in pyridine (2 ml) was added (3R)-Hinkley-3-ol and (3R)-1-azabicyclo[2.2.2]Oct-3-illicibethan (231 mg), synthesized from triphosgene, followed by stirring at room temperature for 30 minutes and then stirring at 80°C for 15 hours. To the reaction mixture was added water, followed by extraction using the and EtOAc. The organic layer, in this order, washed with water and saturated saline, then was dried over MgSO4and concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH) to obtain colorless oily substance (135 mg). This substance was dissolved in EtOH and to the mixture was added fumaric acid (38 mg). The precipitated crystalline substance was collected by filtration to obtain (3R)-1-azabicyclo[2.2.2]Oct-3-yl (2-phenyl-5,6-dihydro-4H-cyclopent[b]Tien-3-yl)carbamylphosphate (103 mg) as a white solid.

Example 3

To a solution of triphosgene (362 mg) in DHM (3 ml) at 0°C was added pyridine (162 mg) and then to the mixture was added dropwise a solution of CIS-2-phenylcyclohexylamine (300 mg) in DHM (3 ml) followed by stirring at room temperature for 40 minutes. To 60% oily suspension of NaH (110 mg) in THF (1.5 ml) at 0°C was added 1-azabicyclo[2.2.2]Oct-3-ylmethanol (363 mg), followed by stirring at room temperature for 20 minutes and to the mixture dropwise at 0°C was added the above solution DHM, followed by stirring at 80°C for 1 hour. To the reaction mixture were added saturated aqueous solution of NaHCO3with the subsequent extraction using EtOAc. The organic layer is specified then the (DKE), washed with water and saturated saline solution, dried over MgSO4and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (CHCl3:MeOH:28% aqueous ammonia = 80:10:1) to obtain colorless oily substance (100 mg). The obtained oily substance was dissolved in a mixed solvent (EtOAc:EtOH = 1:1) and to the mixture was added fumaric acid (32 mg). The mixture was concentrated under reduced pressure, and then to the mixture was added a mixed solvent (EtOAc:IPE) and precipitated precipitated solid was collected through filtration to obtain 1-azabicyclo[2.2.2]Oct-3-ylmethyl rel-[(1R,2R)-2-phenylcyclohexyl]carbamylphosphate (103 mg) as a colorless solid.

Example 4

To a solution of 1-azabicyclo[2.2.2]Oct-3-ylmethyl (2-phenyl-3-thienyl)carbamate (100 mg) in EtOAc (2 ml) at room temperature was added logmean (36 μl), followed by stirring overnight. The reaction mixture was filtered, and then concentrated under reduced pressure and dried by freezing to produce 1-methyl-3-({[(2-phenyl-3-thienyl)carbarnoyl]oxy}methyl)-1-azoniabicyclo[2.2.2]Actinidia (88 mg) as a yellow amorphous substance.

Example 5

In a solution mixture of 1-azabicyclo[2.2.2]Oct-3-yl(2-bromo-3-thienyl)carbamate (295 mg), Pd(PPh3)4(103 mg), 4-ftorpolimernoj acid (187 mg) and 1,4-dioxane(3 ml) was added 2 M aqueous solution of Na 2CO3(0,89 ml) followed by stirring for 5 hours under heating at 90°C. the Reaction mixture was diluted with water and was extracted using EtOAc. The organic layer was washed with water and brought to pH 1 with 1 M hydrochloric acid. Next, the aqueous layer washed with the aid of EtOAc and brought to pH 10 with an aqueous solution of NaOH and the aqueous layer was extracted using CHCl3. The organic layer was dried over MgSO4and concentrated under reduced pressure. The residue was purified using a core column chromatography on silica gel (manufactured by Fuji Silysia Chemical Ltd., YAMAZEN YFLC WPrep2XY, CHCl3). The collected fraction was concentrated under reduced pressure and the resulting oil was dissolved in EtOAc, followed by addition of 4 M HCl/EtOAc, concentrated under reduced pressure and drying by curing. To the obtained residue were added EtOH and EtOAc for crystallization to obtain 1-azabicyclo[2.2.2]Oct-3-yl [2-(4-forfinal)-3-thienyl]carbamate, hydrochloride (135 mg) as a white solid.

Example 6

To a solution of 5-phenyl-1,3-thiazole-4-carboxylic acid (250 mg) in toluene (6 ml) at room temperature was added dropwise TEA (221 ml) and DPPA (315 μl), followed by stirring at the same temperature for 40 minutes. Then after stirring at 90°C for 40 minutes, to the mixture was added a solution of 1-asabis the CLO[2.2.2]Oct-4-ylmethanol (241 mg) in a mixture of DMF (2 ml)/toluene (2 ml) followed by heating at boiling under reflux for 2 hours. To the reaction liquid was added a saturated aqueous solution of NaHCO3with the subsequent extraction using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium pressure (YAMAZEN YFLC WPrep2XY, eluent; CHCl3:MeOH:28% aqueous ammonia = 80:10:1) to obtain yellow oily substance. To this solution in EtOH (2 ml) at room temperature was added a mixture of 4 M HCl/EtOAc (1 ml) followed by stirring, and the solvent was concentrated under reduced pressure. The resulting residue was re led from a mixture of EtOH/ether to obtain 1-azabicyclo[2.2.2]Oct-4-ylmethyl(5-phenyl-1,3-thiazol-4-yl)carbamate, hydrochloride (145 mg) as a yellow solid.

Example 7

To a solution of 1-azabicyclo[2.2.2]Oct-4-ylmethyl (2-carbarnoyl-5-phenyl-1,3-thiazol-4-yl)carbamate (100 mg) in DMF (5 ml) at 0°C was added phosphorus oxychloride (48 μl), followed by stirring for 1 hour. To the reaction mixture were added EtOAc and subsequent dilution, the addition of an aqueous solution of NaHCO3and extraction using EtOAc. The organic layer, in this order, washed with water and saturated saline, then was dried and conc who was narrowly under reduced pressure. The residue was purified using column chromatography on silica gel (CHCl3:MeOH:28% aqueous ammonia = 9:1:0,1) and the resulting brown oily substance was dissolved in EtOAc, followed by addition of 4 M HCl/EtOAc and mixing. The mixture was concentrated under reduced pressure, to the mixture was added EtOAc and precipitated precipitated solid was collected through filtration to obtain 1-azabicyclo[2.2.2]Oct-4-ylmethyl (2-cyano-5-phenyl-1,3-thiazol-4-yl)carbamate, hydrochloride (33 mg) as a pale brown solid.

Example 8

1-azabicyclo[2.2.2]Oct-3-ylmethyl [5-(4-forfinal)-1,3-thiazol-4-yl]carbamate (120 mg) was subjected to HPLC (CHIRALPAK AD-H, and 0.46 cm ×25 cm)to separately collect enantiomer 8a (retention time: about 12.8 minutes, 51 mg) and enantiomer 8b (retention time: about 16.9 minutes, 54 mg) as a white solid, respectively.

Conditions: mobile phase; hexane:EtOH:diethylamine = 50:50:0.1, flow rate; 0.5 ml/min, column temperature; 40°C, the wavelength detection; 254 nm.

Each of the enantiomers was dissolved in EtOH and to the mixture was added fumaric acid to obtain fumarata, respectively.

Example 9

In a mixed solvent (MeOH:EtOAc = 5 ml:5 ml) to 1-azabicyclo[2.2.2]Oct-4-ylmethyl tert-butyl(5-phenyl-1,3-thiazole-2,4-diyl)bicarbonate was added 4 M HCl/EtOAc (7 ml), followed by stirring at room temperature the tour during the night. The reaction mixture was concentrated under reduced pressure, to the residue was added EtOAc and the solid was collected through filtration to obtain 1-azabicyclo[2.2.2]Oct-4-ylmethyl (2-amino-5-phenyl-1,3-thiazol-4-yl)carbonatedihydroxide in the form of a white solid.

Example 10

To a solution of 5-phenyl-1,3-thiazole-4-carboxylic acid (300 mg) in toluene (6 ml) at room temperature was added dropwise TEA (672 μl) and DPPA (409 μl), followed by stirring at the same temperature for 20 minutes. Then after stirring at 90°C for 5 minutes, to the mixture was added a mixture of 3-aminophenylacetylene (407 mg) and DMF (2 ml) followed by heating at boiling under reflux for 1 hour. To the reaction liquid was added water, followed by extraction using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium pressure (YAMAZEN YFLC WPrep2XY, eluent; CHCl3:MeOH:28% aqueous ammonia = 80:10:1) to give oily substance. This substance was dissolved in EtOH followed by the addition at room temperature of 10% HCl/MeOH and concentrated under reduced pressure. To the obtained residue were added EtOH and EtOAc and the OST is ulali survived, precipitated precipitated solid substance was collected by filtration and washed through with EtOAc obtaining hydrochloride 1-(1-azabicyclo[2.2.2]Oct-3-yl)-3-(5-phenyl-1,3-thiazol-4-yl)urea (15 mg) as a white solid.

Example 11

To a solution of 5-phenyl-1,3-thiazole-4-carboxylic acid (400 mg) in toluene (5 ml) at room temperature was added TEA (380 μl). To the reaction liquid was added dropwise a solution of DPPA (546 μl) in toluene (5 ml) followed by stirring at the same temperature for 20 minutes. After stirring at 90°C for 5 minutes, to the mixture was added a mixture of 1-azabicyclo[3.2.1]Oct-5-ylmethanol (357 mg) and DMF (2 ml) followed by heating at boiling under reflux for 1 hour. To the reaction liquid was added water, followed by extraction using EtOAc. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium pressure (YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:28% aqueous ammonia = 80:10:1) to give oily substance. This substance was dissolved in EtOAc followed by the addition at room temperature of 4 M HCl/dioxane. Precipitated precipitated solid substance was collected by filtration and washed using EtAc obtaining 1-azabicyclo[3.2.1]Oct-5-ylmethyl (5-phenyl-1,3-thiazol-4-yl)carbamate, hydrochloride (174 mg) as a white solid.

Example 12

To a solution of 5-phenyl-1,3-thiazole-4-carboxylic acid (385 mg) in toluene (5 ml) at room temperature was added TEA (314 μl). Further dropwise added DPPA (486 μl), followed by stirring at the same temperature for 30 minutes. After stirring at 90°C for 5 minutes, to the mixture was added a mixture of 1-azabicyclo[3.3.1]non-5-ylmethanol (291 mg), DMF (1 ml) and toluene (4 ml) followed by stirring at 90°C for 30 minutes. The reaction mixture was cooled to room temperature and then to the mixture was added CHCl3and water to separate an organic layer. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia). The collected fraction was concentrated under reduced pressure, followed by addition of 4 M HCl/EtOAc and concentrated under reduced pressure. For separation of the aqueous layer to the residue was added EtOAc and water. The aqueous layer was neutralized using NaHCO3and were extracted using CHCl3. The organic layer, in this order, washed with water and saturated salt solution, dried on the MgSO 4and then concentrated under reduced pressure to obtain resin (129 mg). This substance was dissolved in EtOH followed by the addition of a solution of fumaric acid (40 mg) in EtOH and concentrated under reduced pressure to obtain 1-azabicyclo[3.3.1]non-5-ylmethyl(5-phenyl-1,3-thiazol-4-yl)carbamylphosphate (161 mg) as a colorless amorphous fluorescent substances.

Example 13

To a mixture of 1-azabicyclo[2.2.2]Oct-4-ylmethyl(2-{[2-(benzyloxy)ethyl]amino}-5-phenyl-1,3-thiazol-4-yl)carbonatedihydroxide (350 mg) and TFOC (3.5 ml) under nitrogen atmosphere was added thioanisole (362 μl), followed by stirring at room temperature over night. The reaction mixture was concentrated under reduced pressure, podslushivaet the addition of 1 M aqueous NaOH solution and was extracted with mixed solvent (CHCl3:MeOH = 8:1). The organic layer was dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia). The collected fraction was concentrated under reduced pressure, then the residue was added EtOAc and precipitated precipitated solid substance was sprayed, collected by means of filtration and washed through with EtOAc obtaining 1-azabicyclo[2.2.2]Oct-4-ylmethyl {2-[(2-hydroxyethyl)amino] - phenyl-1,3-thiazol-4-yl}carbamate (110 mg) as a colorless solid.

Example 14

To a solution of 5-phenyl-1,3-thiazole-4-carboxylic acid (385 mg) in toluene (8 ml) at room temperature was added TEA (285 μl). To the reaction mixture dropwise added DPPA (404 μl), followed by stirring at the same temperature for 40 minutes. Furthermore, after stirring at 90°C for 5 minutes, to the mixture was added a mixture of 1-azabicyclo[3.2.2]nonan-5-ol (313 mg) and DMF (3 ml) followed by stirring at 110°C for 1 hour. The reaction mixture was cooled to room temperature, and then adding to acidification of 1 M hydrochloric acid and extracted using EtOAc. The aqueous layer was podslushivaet the addition of 1 M aqueous NaOH solution and was extracted using CHCl3. The organic layer, in this order, washed with water and saturated saline solution, dried over MgSO4and then concentrated under reduced pressure. The residue was purified using preparative liquid chromatography, medium-pressure silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia) to obtain a yellow amorphous fluorescent substances. This substance was added EtOAc and the resulting solid was collected via filtration and washed through with EtOAc obtaining 1-azabicyclo[3.2.2]non-5-yl(5-phenyl-1,3-thiazol-4-yl)carbamate (238 mg) as colorless powder.

Example 15

Received a solution of 1-azabicyclo[3.2.1]Oct-6-ylmethyl(5-phenyl-1,3-thiazol-4-yl)carbamate in EtOH (1 ml) and subjected to preparative HPLC (CHIRALCEL OD, and 0.46 cm ×25 cm)to separately collect enantiomer 15a (retention time: about 6.2 minutes) and enantiomer 15b (retention time: about 7.9 minutes). Each of the enantiomers was subjected to recrystallization from a mixed solvent (hexane:EtOH) to give a colorless solid.

Conditions: mobile phase; hexane:EtOH:diethylamine = 50:50:0.1, flow rate; 0.9 ml/min, column temperature; 40°C, the wavelength detection; 254 nm.

The compounds set forth in Tables 18-41, obtained using the above method of production, of way, which is obvious to a person skilled in this field, or modification of this method. The Table presents the number of Examples (synth.), indicates that the compounds can be obtained in the way that the structure of the compounds of Examples. Physico-chemical data presented below in Tables 42-57.

Industrial applicability

The compound of formula (I) or its salt has an antagonistic effect on the binding of the muscarinic receptor M3and therefore can be used as a prophylactic and/or therapeutic agent for the treatment of inflammatory diseases such as chronic obstructive pulmonary disease (HOUSEHOLDS who), asthma and the like.

1. The compound of formula (I) or its salt
[Chemical formula 15]

R1represents-H or C1-6alkyl;
R2is an Aza-ring with an internal bridge selected from the group comprising formulas (a), (b), (C) and (d):
[Chemical formula 16]

where the ring carbon atom in Aza-ring with an internal bridge may be substituted by one or more groups R22;
m, n and p have the meanings respectively 1 or 2;
r is 0 or 1;
R21represents a C1-6alkyl, -C1-6alkyl-O-phenyl or-C1-6alkyl-phenyl;
R22represents a C1-6alkyl-cycloalkyl or-C1-6alkyl-phenyl;
R3is thienyl, phenyl, pyridyl, pyrazinyl, thiazolyl or pyrazolyl,
each of which may be substituted by one or more R31;
R31represents a halogen, -OH, -CN, -CF3C1-6alkyl or-O-C1-6alkyl;
ring And represents a group consisting of thiophene, thiazole, isothiazole, thiadiazole, oxazole, I-oxazole, cyclohexane, norbornane, benzothiophene and 5,6-dihydro-4H-cyclopentadiene, each of which may be substituted by a group selected isgroup, consisting of one or more RA1;
where RA1represents a halogen, -CN, -NH2With1-6alkyl, -O-C1-6alkyl, -CONH2, -NH-C1-6alkyl, -NH-C1-6alkyl-O-C1-6alkyl-phenyl, -NH-C1-6alkyl-phenyl or-NH-C1-6alkyl-HE,
where C1-6the alkyl may be substituted by one or more halogen atoms;
V represents-NH - or-O-;
W represents -(CH2)q-;
q is 0, 1 or 2;
X-is protivoiadie; and
represents a simple bond;
provided that when ring a is a cyclohexane, R3represents phenyl which may be substituted by one or more R31.

2. The compound or its salt according to claim 1, in which ring a represents a group selected from the group comprising thiophene, thiazole and cyclohexane, each of which may be substituted by a group selected from the group consisting of one or more RA1.

3. The compound or its salt according to claim 2, in which R1represents-N.

4. The compound or its salt according to claim 3, in which
R3represents phenyl which may be substituted by one or more R31,
where R31represents a halogen, -OH, -CN, -CF3, -C1-6alkyl or-O-C1-6alkyl.

5. Connect the s or its salt according to claim 4, in which R2is an Aza-ring with an internal bridge selected from the group consisting of formulas (a), (b), (C) and (d), where in case (a) or (C), m, n, p have the value(2, 1, 1), (1, 1, 2) or (2, 1, 2) for each sequence.

6. The compound or its salt according to claim 5, in which R2is an Aza-ring with an internal bridge selected from the group consisting of formulas (a) and (b), and
R21represents a C1-6alkyl, -C1-6alkyl-O-phenyl or-C1-6alkyl-phenyl.

7. The compound or its salt according to claim 6, in which ring a is a thiazole, which can be substituted by a group selected from the group consisting of one or more RA1.

8. The compound or its free base according to claim 7 which is a
(1) 1-azabicyclo[2.2.2]Oct-4-ylmethyl(5-phenyl-1,3-thiazol-4-yl)carbamate, hydrochloride,
(2) 1-azabicyclo[3.2.2]non-5-yl(5-phenyl-1,3-thiazol-4-yl)carbamate, hydrochloride,
(3) (3R)-l-azabicyclo[2.2.2]Oct-3-yl[(1R,2S)-2-phenylcyclohexyl]carbamate, hydrochloride,
(4) 1-azatricyclo[3.3.1.1-3,7-]Dec-4-yl(5-phenyl-1,3-thiazol-4-yl)carbamate, hydrochloride,
(5) 1-azabicyclo[2.2.2]Oct-3-ylmethyl(2-phenyl-3-thienyl)carbamate, hydrochloride,
(6) 1-azabicyclo[2.2.2]Oct-4-yl[5-(4-forfinal)-1,3-thiazol-4-yl]carbamate, hydrochloride,
(7) 1-azabicyclo[3.2.1]Oct-6-ylmethyl(5-phenyl-1,3-thiazol-4-yl)carbamate, hydrochloride or
(8) 1-azabicyclo[2.2.2]Oct-3-ylmethyl[5-(4-f is arvanil)-1,3-thiazol-4-yl]carbamate, fumarate.

9. Connection or aminoalkenes according to claim 2, which is a
(1) 4-({[5-(3-chlorophenyl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-methyl-1-azoniabicyclo[2.2.2]Octanate,
(2) 1-(3-phenylpropyl)-3-({[(2-phenyl-3-thienyl)carbarnoyl]oxy}methyl)-1-azoniabicyclo[2.2.2]octabrain,
(3) 1-(2-phenylethyl)-4-{[(5-phenyl-1,3-thiazol-4-yl)carbarnoyl]oxy}-1-azoniabicyclo[2.2.2]octabrain,
(4) 1-(2-phenoxyethyl)-4-{[(5-phenyl-1,3-thiazol-4-yl)carbarnoyl]oxy}-1-azoniabicyclo[2.2.2]octabrain,
(5) 4-({[5-(2,5-differenl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-methyl-1-azoniabicyclo[2.2.2]Octanate,
(6) 1-methyl-5-{[(5-phenyl-1,3-thiazol-4-yl)carbarnoyl]oxy}-1-azoniabicyclo[3.2.2]nonUnited,
(7) 4-({[5-(3-chlorophenyl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]Octanate,
(8) 4-({[5-(3-chlorophenyl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-methyl-1-azoniabicyclo[2.2.2]octabrain,
(9) 4-({[5-(3,5-dichlorophenyl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-methyl-1-azoniabicyclo[2.2.2]Octanate,
(10) 4-({[5-(2,5-differenl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-methyl-1-azoniabicyclo[2.2.2]octabrain,
(11) 4-({[5-(2,4-differenl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-methyl-1-azoniabicyclo[2.2.2]octabrain,
(12) 1-methyl-4-{[(5-phenyl-1,3-thiazol-4-yl)carbarnoyl]oxy}-1-azoniabicyclo[2.2.2]octabrain,
(13) 4-({[5-(3,5-dichlorophenyl)-1,3-thiazol-4-yl]carbarnoyl}oxy)-1-methyl-1-azoniabicyclo[2.2.2]octabrain or
(14) 1-methyl-5-{[(5-phenyl-1,3-thiazol-4-yl)carbamoyl is]oxy}-1-azoniabicyclo[3.2.2]nonembroid.

10. Pharmaceutical composition having an antagonistic effect on muscarinic receptor M3containing an effective amount of the compound or its salt according to claim 1, and a pharmaceutically acceptable carrier or excipient.

11. Pharmaceutical composition for preventing or treating inflammatory diseases, comprising the compound or its salt according to claim 1.

12. The use of compound or its salt according to claim 1 to obtain a pharmaceutical composition for the prevention or treatment of inflammatory diseases.

13. The use of compound or its salt according to claim 1 for the prevention or treatment of inflammatory diseases.

14. A method of preventing or treating inflammatory diseases comprising administration to a patient an effective amount of the compound or its salt according to claim 1.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new N-cyclic sulphonamido-compounds and their pharmaceutically acceptable salts of formula : of formula 1a of formula 1b of formula 1c where the ring A means phenyl, thienyl which can be substituted by halogen, or pyridinyl; a value of the ring B is presented in the patent claim, and also a pharmaceutical composition containing them, and a method of treating Alzheimer's disease.

EFFECT: compounds are gamma-secretase inhibitors and can be used for treating Alzheimer's disease.

16 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new piperidine derivative, with the following general formula (I) where R1 - R4 each stands for any of the univalent groups, indicated below: R1 stands for a hydrogen atom, halogen atom, inferior alkyl, which can be substituted with a halogen atom or OH; -O-inferior alkyl, which can be substituted with a halogen atom; -O-aryl, aryl, -C(=O)-inferior alkyl, COOH, -C(=O)-O-inferior alkyl, -C(=O)-NH2, -C(=O)NH-inferior alkyl, -C(=O)N-(inferior alkyl)2, OH, -O-C(=O)-inferior alkyl, NH2, -NH-inferior alkyl, -N-(inferior alkyl)2, NH-C(=O)- inferior alkyl, CN or NO2; R2 and R3 each stands for a hydrogen atom; and R4 stands for any of the univalent groups (a), (b) and (c), shown below in formula 2 where in the above indicated groups (a), (b) and (c), A stands for a pyrrolidine, piperidine, morpholine, piperizine or oxazepane ring; B stands for a pyrrolidine or piperidine ring; R5 and R8-R11 can be identical or different from each other and each stands for a hydrogen atom, -C(=O)-O-inferior alkyl, cycloalkyl or tetrahydropyrane; R6 stands for a hydrogen atom, -C(=O)-O-inferior alkyl, OH, -inferior alkylene-OH or -C(=O)-pyridine; and R7 stands for a hydrogen atom. The invention also pertains to pharmaceutical salts of the piperidine derivative, as well as medicinal compositions.

EFFECT: obtaining new biologically active compounds and a medicinal composition, based on these compounds, which is a sodium channel inhibitor.

10 cl, 91 ex, 22 tbl

FIELD: medicine, chemical-pharmaceutical industry, chemical technology.

SUBSTANCE: invention relates to using biologically active derivatives of ajmaline possessing anti-arrhythmic effect. Method for synthesis of N4-propylajmalinium salts with carboxylic acids is carried out by neutralization of N4-propylajmalinium hydroxide with equivalent amount of carboxylic acid in homogenous phase. The end substance is isolated by distillation of solvent with the yield of salts 97-99%. Method provides preparing acetate, l-lactate, hydrooxalate, hydromalonate, hydrosuccinate, hydroglutarate, l-hydrotartrate, hydrocitrate, salicylate and p-aminobenzoate. Stable solution of N4-propylajmalinium hydromalonate in water for injection of a medicinal agent comprises sodium metabisulfite as antioxidant, 5-30 mg/ml of N4-propylajmalinium hydromalonate, ascorbic acid as antioxidant taken in the effective amounts. Preferably, stable solution of N4-propylajmalinium hydromalonate comprises 10 mg of N4-propylajmalinium hydromalonate/ml of solution, 0.20 wt.-% of sodium metabisulfite and 0.05 wt.-% of ascorbic acid as measured for solution of N4-propylajmalinium hydromalonate. Invention provides the development stable aqueous compositions of N4-propylajmalinium salts for injection of medicinal agent by selection of antioxidants.

EFFECT: improved preparing method.

7 cl, 5 tbl, 5 ex

FIELD: organic chemistry, chemical technology, virology.

SUBSTANCE: invention relates to a new method for synthesis of a novel compound - 3,6-diazahomoadamantane of the formula: . Compounds of 3,6-diazahomoadamantane class possess an antiviral effect comparable with antiviral effect of aminoadamantane, elicit strychnine-like activity and show bactericidal, fungicide and algicidal properties and can be used as an antiviral preparation. Method for synthesis of 3,6-diazahomoadamantane involves interaction of 1-phenylthio-3,6-diazahomoadamantane-9-one with 65-66% hydrazine hydrate at boiling to form 1-phenylthio-3,6-diazahomoadamantane-9-one hydrazone that is subjected for reduction in Kizhner-Wolf reaction by alloying with alkali and then 1-phenylthio-3,6-diazahomoadamantane is desulfurized with Raney nickel in isopropyl alcohol at boiling.

EFFECT: improved method of synthesis.

2 cl, 1 ex

The invention relates to methods for producing compounds of formula (XVIIb):

where

R1represents optionally protected or modified iminomethylene group, optionally protected or modified hydroxymethylene group; and

R4is-H; or

R1and R4together form a group of the formula (IV), (V), (VI) or (VII):

R5represents-H or-IT;

R7represents-och3and R8is HE, or R7and R8together form a group-O-CH2-O-;

R14aand R14bthey are both-H or one is-H and the other represents-OH, -och3or-och2CH3or R14aand R14btogether form ketogroup; and R15

and derivatives of 21-cyanocobalamine formula (XVIb):

The invention also relates to new compounds:

These compounds possess both antibacterial and antitumor activity

The invention relates to pharmaceutical industry and relates to new compounds of the hydrochloride of N-(-hydroxyethyl)tsitizina formula (I) exhibiting high antiarrhythmic activity and low toxicity

FIELD: chemistry.

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

EFFECT: efficient method of obtaining the compounds.

12 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (R)- quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate or salt thereof, involving: 1) converting a compound which is 4-amino-3-methoxypiperidine-1-carboxylate to a salt; 2) converting the ethyl 4-amino-3-methoxypiperidine-1-carboxylate salt into ethyl 4-(diphenylamine)-3-methoxypiperidine-1-carboxylate 3) treating ethyl 4-(diphenylamino)-3-methoxypiperidine-1-carboxylate with hydroxide or hydride of an alkali metal to obtain 3-methoxy-N,N-diphenylpiperidine-4-amine 4) obtainijng a chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine by bringing 3-methoxy-N,N-diphenylpiperidine-4-amine into contact with a chiral splitting agent and extracting the obtained chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine; optional recrystalisation of product 4; converting product 4 or 5 to a base to obtain product 4 or 5 in form of a free base; 7) bringing product 6 into contact with ethyl 6-bromohexanoate to obtain ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 8) esterification of ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate using (R)-quinuclidin-3-ol with a Lewis acid to obtain (R)- quinuclidin-3-yl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 9) removing protection from the 4-amine group of product 8 to obtain (R- quinuclidin-3-yl 6- [(3S,4R)-4-amino-3-methoxypiperidin-1-yl)hexanoate; 10) acylation of product 9 4-amino-5-chloro-2-methoxybenzoic acid to obtain (R)- quinuclidin-3-yl 6-((38,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate; 11) optional conversion of product 10 into a salt.

EFFECT: method increases output of the end product and reduces content of impurities.

7 cl, 3 ex, 6 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I where X1-X4 each independently represent CR1, B represents -C(O)-O- or -C(O)-NH-CH2-, Y represents S or NH, R1 represents H, C1-C4alkoxy, unsubstituted or substituted by once or several times with F, or Het, and Het stands for heterocyclic group, fully saturated, partly saturated or fully unsaturated, containing in cycle 5-10 atoms, of which at least one atom represents N, O or S, unsubstituted or substituted once or several times with C1-C8alkyl, or to its pharmaceutically acceptable salt.

EFFECT: obtaining pharmaceutical composition for selective activation/stimulation of nicotine receptors α7 on the basis of said compound, as well as to their application for treatment of patient, suffering from psychotic disease, neurodegenerative disease, including cholinergic system dysfunction and/or condition of memory failure and/or failure of cognitive abilities.

52 cl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I , in which A denotes hydrogen, B denotes methyl or B is in a trans-position relative oxygen; X denotes CH2; Y denotes a group of formula , , ,

, or ;

, in which the left-hand bond is to an oxygen atom, and the right-hand bond is to the group R; R denotes 5-indolyl; in form of a free base or an acid addition salt. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-7, to a method of preventing and treating psychiatric and neurodegenerative disorders in a person, as well as a method of treating and preventing diseases or pathological condition in which α7 nAChR activation plays a role.

EFFECT: obtaining novel biologically active compounds having α7 nAChR agonist activity.

16 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I

in form of a salt, where R1 and R2 each independently denotes phenyl, where one or both R1 and R2 are substituted in one, two or three positions by the following groups: halogen, C1-C8alkyl or C1-C8alkoxy, and R3 is hydroxy, or R1 and R2 each denotes an unsubstituted phenyl, and R is hydrogen, C1-C8alkyl, C1-C8alkoxy or C1-C8alkylthio, or R1 is C3-C8cycloalkyl and R2 is phenyl or a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes oxygen and sulphur, and R3 is hydroxy, or -CR1R2R3 denotes 9-hydroxy- 9H-fluoren-9-yl or 9-hydroxy-9H-xanthen-9-yl, and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, optionally substituted with phenyl, or R1 and R2 each denotes an unsubstituted phenyl, and R3 is hydroxy and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is 5-methyl-3-isoxazolyl or R1 and R2 each denote unsubstituted phenyl, and R3 is hydroxy and R4 is 1-ethyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen, R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, provided that the formula I compound is not (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrazin-2-ylcarbamoylmethy)-1-azoniumbicyclo[2.2.2]octane, (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide or (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-8, as well as to methods for synthesis of formula I compounds.

EFFECT: obtaining new biologically active compounds which have M3 muscarinic receptor mediated activity.

14 cl, 254 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat diseases mediated by the nicotinic acetylcholine receptor, such as derangement of memory. In general formulae , and A is an indazolyl, benzothiazolyl or isobenzothiazolyl group which corresponds to structural formulae a) to c) respectively or X is O; R1 is H, F, Cl, Br, I, cycloalkyl containing 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; ; R2 is H; R3 is H; R4 is H, F, Cl, Br, I, cycloalkyl which contains 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; R5 is H; Ar is an aryl group containing 6 carbon atoms which is unsubstituted or substituted once or several times with halogen; and Het is a 5- or 6-member heteroaromatic group containing a heteroatom in the ring which is selected from N, O and S, or a 6-member saturated heterocyclic group which contains a heteroatom in the ring which is selected from N and O; and their pharmaceutically acceptable salts, where, if the said compound has formula I, the indazolyl group of group A is bonded through its 3rd, 4th or 7th position, the benzothiazole group of group A is bonded through the 4th or 7th position, the isobenzothiazole group of group A is bonded through the 3rd, 4th or 7th position.

EFFECT: obtaining compounds with properties of nicotinic acetylcholine receptor (nAChR) ligands, and pharmaceutical compositions based on the said compounds.

53 cl, 95 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where B represents a hydrogen atom or a group selected from -R1, -OR1, hydroxy, - O(CO)R1, cyano and non-aromatic heterocycle which is a saturated or unsaturated C3-C10carbocyclic ring in which one or more carbon atoms, preferably 1 or 2 carbon atoms, are substituted with oxygen atoms as heteroatoms, where R1 is selected from a group containing hydrogen atoms, C1-C8alkyl, C2-C8alkenyl and C3-C8cycloalkyl, where the alkyl group is unsubstituted or substituted with one or more substitutes selected from halogen atoms and C1-C4alkyl, and where the alkenyl group is unsubstituted or substituted with one or more substitutes selected from C1-C4alkyl, n equals an integer from 0 to 4, A is selected from a group containing -CH2-, -CH=CR3-, -CR3=CH-, -CR3R4-, -O-, -CO-, -O-(CH2)2-O-, where R3 and R4 each independently represents a hydrogen atom or C1-C8alkyl, m equals an integer from 0 to 8, p equals 2, and the bicyclic azonium ring contains a substitute on position 3, including all possible configurations of asymmetrical centres, D is selected from a group containing: or where R5 is selected from a group containing phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, R6 is selected from a group containing 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, C3-C8cycloalkyl, C1-C8alkyl, C2-C8alkenyl and phenylethyl, R7 represents a hydrogen atom or a group selected from hydroxyl, hydroxymethyl and methyl, Q represents a single bond or a group selected from -CH2-, -CH2CH2-, -O-, -O-CH2-, equals an integer from 0 to 3, X represents a pharmaceutically acceptable anion of mono- or polybasic acid, under the condition that the B-(CH2)n-A-(CH2)m- group does not represent a straight C1-4alkyl and that the following compounds are excluded: 1-allyloxycarbonylmethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-azoniumbicyclo[2.2.2]octane and 1-carboxymethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-azoniumbicyclo [2.2.2]octane. The invention also relates to a method of producing formula (I) compounds, to a pharmaceutical composition, to use of compounds in any of paragraphs 1-14, as well as a combined product.

EFFECT: obtaining novel biologically active compounds with antagonistic activity towards muscarine receptors M3.

21 cl, 64 ex

FIELD: medicine.

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

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

27 cl, 16 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of common formula (I) , in which: A, if available, means (C1-C6)-alkyl; R1 means group NR6R7, (C4-C7)-azacycloalkyl, (C5-C9)-azabicycloalkyl, besides, these groups, unnecessarily, are substituted with one or more substituents, selected from (C1-C5)-alkyl or halogen; A-R1 is such that nitrogen of radical R1 and nitrogen in position 1 of pyrazole are necessarily separated at least by two atoms of carbon; R3 means radical H, OH, NH2, ORc, NHC(O)Ra or NHSO2Ra; R4 means phenyl or heteroaryl, unnecessarily, substituted with one or more substituents, selected from halogen, CN, NH2, OH, ORc, C(O)NH2, phenyl, polyfluoroalkyl, linear or ramified (C1-C6)-alkyl, besides these substituents, unnecessarily, are substituted with halogen, and moreover, heteroaryl radicals are 3-10-member, containing one or more heteroatoms, selected from sulphur or nitrogen; R5 means radical H, linear or ramified (C1-C6)-alkyl; Ra means linear or ramified (C1-C6)-alkyl; Rc means linear or ramified (C1-C6)-alkyl, (poly)fluoroalkyl or phenyl; R6 and R7, independently from each other, means hydrogen, (C1-C6)-alkyl; R6 and R7 may create 5-, 6- or 7-member saturated or non-saturated cycle, which includes one heteroatom, such as N, and which, unnecessarily, substituted with one or more atoms of halogen; to its racemates, enantiomers, diastereoisomers and their mixtures, to their tautomers and their pharmaceutically acceptable salts, excluding 3-(3-pyridinyl)-1H-pyrazole-1- butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine. Invention is also related to methods for production of compounds of formula (I) and to pharmaceutical composition intended for treatment of diseases that appear as a result of disfunction of nicotine receptors α7 or favorably responding to their modulation, on the basis of these compounds.

EFFECT: production of new compounds and pharmaceutically acceptable composition on their basis, which may find application in medicine for treatment, prophylaxis, diagnostics and observance over development of psychiatric or neurological disorders or diseases of central nervous system, when cognitive functions deteriorate or quality of sensor information processing drops.

16 cl, 106 ex

Adhesive product // 2441649

FIELD: medicine.

SUBSTANCE: invention describes adhesive product consisting of stretchable base and adhesive layer that is put in thin layer on at least one side of the base, where the stretchable base contains connective layer of fabric subject to goffering process, the adhesive layer contains 10% by weight or more of methyl salicylate from total mass of the layer, moisture permeability of all adhesive product is 1-350 g/m2*24 hours measured at the temperature 40°C and relative humidity 90%, and methyl salicylate has AUC0-24 in plasma in the range from 3.0 to 60.0 ng*h/ml in the values of average ± standard deviation, salicylic acid as the metabolite of methyl salicylate has AUC0-24 in plasma in the range from 5,000 to 13,000 ng*h/ml in the values of average ± standard deviation, when the adhesive product is put on the human skin for 8 hours so that the contacting amount of adhesive layer is 50-300 g/m2 and the area of contact is 280 cm2.

EFFECT: product is capable of stable absorption through the skin.

7 cl, 3 tbl, 3 dwg, 6 ex

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