A derivative of thiophene and pharmaceutical composition based on it

 

(57) Abstract:

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt. These compounds possess activity as anti-PCP agonist, and therefore can be used as psychotropic or protivoaritmicheskih agents. Also described pharmaceutical composition based on derivatives of thiophene. 2 S. and 6 C.p. f-crystals, 2 PL.

The present image is phencyclidine) action or its pharmaceutically acceptable salts, and anti-PCP the agonist, which include the specified derivative as an active ingredient.

It is known that PCP causes mental symptoms that are very similar to the various symptoms of schizophrenia, including negative symptoms (Am. J. Psychiat. , 135, 1081 (1987); Am. J. Psychiat., 148, 1301 (1991)). On the other hand, the introduction of PCP in animals causes various types of abnormal behavior. Accordingly, believe that a drug that specifically inhibits the abnormal behavior of animals, called PCP (anti-PCP activity), may be useful as an agent for the treatment of schizophrenia in humans (Shinkei Seishin Yakuri (nervous and mental pharmacology), 15(10), 651 (1993); Behav. Brain Res. , 74, 45 (1996)). In addition, because PCP has the ability to inhibit NMDA (N-methyl-D-aspartate) receptor (J. Pharm. Exp. Thera., 238, 938 (1986); Br. J. Pharmacol., 79, 565 (1982)), believe that such agents with anti-PCP activity, can also be used as agents to treat diseases caused by weakening of the functions of NMDA receptors, namely, memory impairment or cognitive abilities, delirium, or similar behavioral problems in senile dementia (J. Neurochem., 54 (2), 526 (1990); Life Science, 55 (25/26), 2147 (1994)).

Still receptor blockers is PAMINA differ to those disadvantages, they are less effective against negative symptoms, and cause extrapyramidal symptoms, etc. side effects (T. I. P. S., 13, 116 (1992)).

On the contrary, the specific anti-PCP agents can alleviate negative symptoms of schizophrenia, for which the dopamine blockers are ineffective and do not cause side effects, such as those that cause dopamine blockers.

Previously, the inventors have found that new derivatives of thiophene, having a nitrogen-containing cycloalkenes alkyl group, possess anti-PCP activity, and these results are described in WO 94/225450 or WO 95/22910.

On the other hand, JP-A-62-192379 reveals the connection represented by the following General formula:

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(see this published application for detailed definitions), which represents a thiophene derivative having a nitrogen-containing cycloalkyl group and a thiazole group, depending on the choice of substituents. Similar compounds are disclosed in JP-A-18178. In accordance with the descriptions of these published applications of these compounds have antihypoxic effect, protivoallergicheskim effect and relieves the fear effect, and can be ispolzovanie about anti-PCP activity.

In addition, in Journal of the Chemical Society, Perkin Transactions Pt. 1: Organic Chemistry, 22, 2355 (1976) disclosed a method of obtaining a compound represented by the following General formula:

(CH2Pip, CH2Pyrr, etc) (Ph, 4-MeC6H4, 4-ClC6H4-BrC6H4etc)

(see the literature on the subject detailed definitions), but in this source there is no indication of anti-PCP action of these compounds.

New thiophene derivative according to the present invention represented by the General formula (I) excludes compounds of the prior art, and their structure is clearly different from the structure of the compounds disclosed by the authors of the present invention in the above-mentioned international publications.

The authors of the present invention conducted intensive studies of compounds with specific and excellent anti-PCP efficiency, and as a result found that the thiophene derivative having a nitrogen-containing cycloalkyl lower alkyl group or nitrogen-containing unsaturated heterocycle and aryl ring or aromatic heterocycle, or its pharmaceutically acceptable salt, has excellent anti-PCP activity that led to the implementation of the present invention.

Task Nast is (I), or its pharmaceutically acceptable salt

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in which

R1represents the formula-A1-X1-R3.

R2represents, perhaps, the formula-A2-X2-R4i.e.

R2is either group-A2-X2-R4or hydrogen;

B ring represents a

1) 4-10-membered nitrogen-containing cycloalkyl ring,

or

2) a 5 - or 6-membered nitrogen-containing unsaturated heterocycle,

Ar ring is an aryl ring, which may contain a Deputy, or a 5 - or 6-membered aromatic heterocycle or an 8-10 membered bicyclic aromatic a heterocycle, which contains 1-4 one or more kinds of heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom,

A1, A2and A3the same or different from each other, each represents a bond or lower alkylenes group

X1and X2the same or different from each other, each represents a bond or a formula-O-, -S-, -NR5-,

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or

-CC

R5, R6, R7, R8, R9, R10, R11, R12and R13
R3and R4the same or different from each other, each represents a hydrogen atom, cyclic aminogroup, which may have a Deputy, and may be condensed with benzene ring, or a lower alkyl group, cycloalkyl group, aryl group or aracelio group, which respectively may have a Deputy, provided that if the Ar ring is a thiazole ring, any of A1and A2represents the lowest alkylenes group, if the Ar ring is a thiophene ring, at least one of R3and R4represents a group that is different from a hydrogen atom, and if the Ar ring is a benzene ring, one of R1and R2represents a methyl group or a halogen and the other represents a hydrogen atom, are excluded.

Another objective of the present invention is to provide pharmaceutical compositions comprising the above derivative of thiophene (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and an anti-PCP agonist.

Preferably, the just-described anti-PCP agonist was psychotropic agent or antihistaminics the optional reduction of NMDA receptors namely medicine for prevention of dementia, medication to improve problem behavior, followed by dementia, medication for the treatment of mental retardation in childhood and/or medication for the treatment of autism.

Thiophene derivative of the present invention represented by the formula (I) or its pharmaceutically acceptable salt differs in its chemical structure, the fact that it is a thiophene derivative, substituted nitrogen-containing cycloalkyl lower alkyl group or nitrogen-containing unsaturated heterocyclic group, a substituted lower alkyl group) and an aryl ring or an aromatic heterocycle, and has pharmacological activity, to improve negative symptoms of schizophrenia, which cannot be affected by the blocker of dopamine receptors.

A derivative of thiophene represented by the General formula (I) or its pharmaceutically acceptable salt is not known from the prior art and is a new connection with the new effects, which are not described in these patents, etc.

In other words, the compounds described in the above patents and literature, are excluded from the General formula compounds (I) * detailed description of the compounds of the present invention.

In determining the General formula of the present invention, the term "lower" means a branched or unbranched carbon chain containing from 1 to 6 carbon atoms, unless otherwise indicated.

Thus, examples of the "lower alkyl group" include methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, pentelow group, isopentyl group, neo-pentelow group, tert-pentelow group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropylene group, hexoloy group or isohexyl group.

Examples of "lower alkalinous group", represented by A1, A2and A3include methylene group, ethylene group, metilbutilovy group, trimethylene group, melatoninbuy group, tetramethylene group, methyltrienolone group, pentamethylene group or hexamethylene group, of which the preferred alkylene group containing from 1 to 4 carbon atoms. Among these groups are particularly preferred methylene group as "lower alkalinous group" A3.

"Cycloalkyl group, before the s in the ring, and its illustrative examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, etc., from which the preferred tsiklogeksilnogo group.

"Aryl group" is an aryl carbon ring, and his illustratione examples include benzene, biphenyl, naphthalene, anthracene, phenanthrene, etc., from them the preferred benzene.

"Kalkilya group" is a group in which an arbitrary hydrogen atom of the above "lower alkyl group" substituted phenyl group, naftilos group or similar, and its illustrative examples include a benzyl group, fenetylline group, phenylpropyl group, methylphenylethyl group, phenylbutyl group, methylpentylamino group, ethylenebutylene group, dimethyltrimethylene group, phenylmethylene group, methylphenylethyl group, phenylhexanoic group, methylphenylethyl group, naphthylmethyl group, naphthylethylene group, afterripening group, NativeWindow group, naphthylmethyl group, artilheiro company, etc.; of which the benzyl group is preferable.

1) 4-10 membered", represented by the ring B, the most preferred 4-10 membered nitrogen-containing cycloalkyl ring". Illustrative examples 4-10 - membered nitrogen-containing cycloalkyl ring" include azetidin, pyrrolidine, piperidine, hexahydroazepin, octahydrate, octahydrate, decapitalization and so on, of which the most preferred hexahydroazepin. "5 - or 6-membered nitrogen-containing unsaturated heterocycle is 5 - or 6-membered unsaturated ring, which contains 1 to 4 nitrogen atoms as heteroatoms, and its illustrative examples include pyrrole, imidazole, triazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, triazine, etc., from which the preferred imidazole.

As for the "5 - or 6-membered aromatic heterocycle or a 8 - to 10-membered bicyclic aromatic heterocycle which contains from 1 to 4 from one or more heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom" represented by Ar ring, its illustrative examples include pyrrole, imidazole, triazole, furan, oxazole, isoxazol, oxadiazole, thiophene, thiazole, isothiazol, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazin, triazine, indole, isoindole, benzimidazole, benzothiadiazole, quinoline, isoquinoline, benzodiazepin, benzopyrenes, benzopyranyl, benzotriazin, imidazopyridine, imidazopyrimidines, createrelation, etc. from which the preferred triazole, oxadiazole, thiazole, thiadiazole, imidazopyridine, imidazopyrimidines and triazolopyridine, and the most preferred triazole and oxadiazole.

Illustrative examples of the "cyclic imido, which may be condensed with a benzene ring" represented by R3and R4include succinimido, glutarimide, phthalimide etc.

Illustrative examples of the "substituent" in "cyclic imido, which may have a substituent and may be condensed with a benzene ring or a lower alkyl group, cycloalkyl group, aryl group or aranceles group which may have a substitute, presents R3and R4include halogen atom, hydroxyl group, lower alkoxygroup, carbamoyloximes, mono - or di-lower alkylcarboxylic, amino group, mono - or di-lower alkylamino, allmenalp, carbamoylating, mono - or di-lower alkylcarboxylic, carboxypropyl, lower alkoxycarbonyl group, carbs is pactically halogen atom, the nitro-group, a hydroxyl group, and the lowest alkoxygroup.

"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or iodine atom, of which a fluorine atom and a chlorine atom is preferred.

"The lowest alkoxygroup" is a branched or non-branched alkoxygroup containing from 1 to 6 carbon atoms, and its illustrative examples include a methoxy group, ethoxypropan, propoxylate, isopropoxy, butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, pentyloxy, isopentylamine, neopentylene, tert-pentyloxy and so on, of which the methoxy group is preferable.

The term "acyl" in the "alloctype" or "alluminare" means the lowest alkanoyloxy group or arilou group, and its illustrative examples include formyl group, acetyl group, propionyl group, butyryloxy group, isobutyryloxy group, valerino group, isovaleryl group, trimethylacetyl group, hexanoyl group, tert-butylacetyl group, benzoyloxy group, Dalwallinu group, untilnow group, naphthalene-carbonyl group, etc.

In some cases, the compound (I) of the present invention can provide the lot (for example, chloride-hydrogen acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids (e.g. formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, econsultancy acid, glutamic acid, etc.,).

Next, examples of salts with bases are salts of joining inorganic bases (for example, lithium, sodium, potassium, magnesium, calcium, aluminum, etc.) or organic bases (for example, methylamine, ethylamine, ethanolamine, etc., and salts of amino acids (e.g. lysine, ornithine, etc.,), and ammonium salts.

In addition, because the connection of the present invention in some cases may contain asymmetric carbon atoms, it can exist as optical isomers. And in addition, the connection may be in the form of diastereoisomeric if it contains two or more asymmetric carbon atoms. These isomers or a mixture thereof, or in a dedicated form, the sun is pouring in the form of its hydrates, various solvate (e.g., ethanol), or the polymorphic crystalline forms, and these different types of hydrate, solvate and polymorph substances are also included in the scope of the present invention.

Among the compounds of the present invention (I), preferred compounds, in which the B ring is 4-10-membered nitrogen-containing cycloalkyl ring, and more preferred compounds, in which the B ring is hexahydroazepin and/or connection, in which A3is a methylene group, more preferred compounds in which Ar ring is triazole, oxadiazole, thiazole, thiadiazole, imidazopyridine, imidazopyrimidines or createrelation, and the most preferred compounds in which Ar ring is a triazole or oxadiazole.

Especially preferred compound is 5-[5-[(hexahydro - 1H-azepin-1-yl)methyl] -2-thienyl] -3-phthalimidomethyl-1,2,4 - oxadiazole, 5-amino-3-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl]-1H-1,2,4-triazole or its pharmaceutically acceptable salt.

Thus, the compounds of the present application have been described in detail, and all of them are included in the present invention.

Ways to get

The compound (I) is for, and characteristics of the main cores or types of substituents. In such cases, it may be effective to substitute amino, and the like compounds of the present invention suitable protective groups, namely, functional groups that can be easily converted into amino, etc., Examples of such protective groups include, in addition to the above-mentioned protective groups for amino groups, as described, for example, in "Protective Groups in Organic Synthesis", 2 nd.ed. by Green and Wuts, and these groups can be arbitrarily selected and used depending on the reaction conditions. In addition to these protective groups can also be used as protective groups, other functional groups such as nitro, etc. that can easily be converted into amino, etc.

A typical way to obtain the compounds of the present invention is illustrated below.

The method of obtaining 1

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In the above reaction scheme for the ring B and A3have the above values, R14represents a lower alkyl group, a R15represents an amino group or a lower alkyl group containing a protected hydroxyl group. Examples of protective groups that can be used in this case include benzyl grupper tert-butyldimethylsilyloxy group, and acetamino group, for example tetrahydropyranyloxy group.

The compound (Ia) of the present invention is produced by the interaction of the ester compounds represented by the General formula (II), with amidoximes. This reaction can be carried out in an organic solvent, such as tetrahydrofuran, ether, dioxane or similar, in the presence of a base, such as sitedisability, letibit(trimethylsilyl)amide, sodium hydride or similar , at a temperature from low up to the boiling temperature under reflux.

If R15represents a protected hydroxyl group, removing the protection is carried out in accordance with customary methods, for example, the protective group can be easily removed, restoring or oxidizing it, or if the protective group is based benzyl, it is removed by treatment in acid conditions or gidrolizu her in acidic or basic conditions, in the case of protective groups on the basis of acyl using fluorine ions in the case of protective groups on the basis of Srila or treating in acidic conditions, in the case of protective groups on the basis of acetal.

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In the formula above, ring B and A3have the values indicated above, and X represents an atom ha is via halogenated acyl compound, the above-mentioned General formula (II'), instead of the ester compounds of General formula (II), with amidoximes. In this case, the reaction can be conducted in a solvent, such as tetrahydrofuran, dioxane, chloroform, methylene chloride, benzene, toluene or similar in the presence of an organic base, such as triethylamine, diisopropylethylamine or etc., at room temperature.

The method of obtaining 2

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In the above formulas, ring B and A3have the above values, Y represents a halogen atom, tailorshop, methoxypropyl, Succinimidyl, or the like tsepliaeva group16and R18can be the same or different from each other, and each represents a protected amino group, or a lower alkyl group, or aracelio group which may contain a hydroxyl group, a R17represents a lower alkyl group. In this case, the protective groups have the values specified above.

Compound (Ib-Ie) of the present invention is produced by the interaction of nitrile represented by the General formula (III) with sodium alkoxide, and then with cyanamide, getting derived cyanoaniline (IV), cat(III) with hydrazine and N,N-dimethylformamide, interacting (III) hydroxylaminopurine, getting derived amidoxime (V), which is then subjected to the interaction with a complex ester or anhydride of the acid, or by the interaction of (III) with hydrogen sulfide, getting derived thioamide (VI), which is then subjected to interaction with the derived ketone.

Reaction with sodium alkoxide can be performed at a temperature from room temperature up to the boiling temperature under reflux, and the reaction with cyanamide can be carried out in an organic solvent, such as tetrahydrofuran, dioxane or similar , or without solvent. The reaction with hydroxylamine can be performed at a temperature from room temperature up to the boiling point under reflux in a solvent, for example tetrahydrofuran, dioxane, methanol, ethanol or similar, in the presence of organic bases such as triethylamine, diisopropylethylamine or etc., or inorganic bases; for example, sodium hydroxide, potassium hydroxide or so on Reaction with hydrazine can be performed by boiling under reflux in a solvent such as DMF, tetrahydrofuran, dioxane or similar Reaction with a complex ether, galogenangidridy or acid anhydride mo is male or etc., in the presence of an organic base, such as triethylamine, diisopropylethylamine or etc., or inorganic bases such as sodium hydride, etc., or in a neutral conditions at a temperature from low up to the boiling temperature under reflux. The reaction with hydrogen sulfide can be carried out in a solvent such as pyridine, tetrahydrofuran, dioxane or similar, in the presence of organic bases such as triethylamine, diisopropylethylamine or similar reaction with the ketone can be carried out in a solvent, for example methanol, ethanol or etc., at temperatures from room temperature up to the boiling temperature under reflux.

The method of obtaining 3

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In the above reaction scheme for the ring B and A3have the above values, R19and R22may be the same or may differ from each other, and each represents a lower alkyl group or aracelio group, R20represents a hydrogen atom or a lower alkyl group, and each of R21and R23represents a lower alkyl group.

Connection (If to Ij) of the present invention receives, interacting hydrazide, presents the th acid, Carbo-lower alkoxy-2-methyltriphenylphosphonium or imitator or connection of imidate, and then carrying out the cyclization or by interaction of the compound (VII) with cyanopogon (methyl zian}.

Reaction with sulfate S-methylisothiazoline or cyanamide can be performed in a solvent, for example methanol, ethanol or etc., at temperatures from room temperature up to the boiling temperature under reflux and can be used an inorganic base, for example sodium hydroxide, potassium hydroxide or similar Reaction with a complex ester isothiocyanato acid can be carried out in a solvent, for example methanol, ethanol, THF, dioxane, ether, methylene chloride or similar, at a temperature from room temperature up to the boiling temperature under reflux. Reaction with Carbo-lower alkoxy-2-methyltriphenylphosphonium or imitator can be carried out in a solvent such as THF, dioxane, ether, methylene chloride or similar, in the presence of organic bases such as triethylamine, diisopropylethylamine or similar cyclization Reaction can be conducted in a solvent, for example methanol, ethanol or similar, or if it is not in the neutral conditions, acidic conditions using concentrated whom or under alkaline conditions, using sodium hydroxide, potassium hydroxide or etc., at temperatures from room temperature up to the boiling temperature under reflux.

The compound (If) of the present invention can be obtained using the compound of General formula (VIII) by reaction of the above halogenating compounds of General formula (II') with aminoguanidine.

The method of obtaining 4

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In the above reaction scheme for the ring B, A3and Y have the above values.

The compound (Ib) of the present invention can be obtained by activating connection carboxylic acid represented by the General formula (XII), by interaction of the compounds with cyanamide, and then through the interaction of the obtained compound (XIV) with hydroxylamine.

Activation can be done in the usual way for making a connection halide, acid anhydride or ester of succinimide. The reaction of an activated derivative of the acid (XIII) with cyanamide can be performed using an organic base, such as tetrahydrofuran, dioxane, chloroform, methylene chloride, benzene, toluene, or in the presence of an organic solvent, such as triethylamine, diisopropylethylamine in the same conditions, specified for a method of obtaining 2.

The method of obtaining 5

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In the above reaction scheme for the ring B and A3have the above values, and each of R23and R24represents a lower alkyl group.

Compound (Ik and Il) of the present invention can be obtained by interaction of the amide derivative of the acid represented by the General formula (XV) with N,N - dimethylformamidine and cyanamide, and coordinating the obtained compound (XVI) with hydroxylamine-o-sulfonic acid or a compound of hydrazine.

The reaction of N, N-dimethylformamidine can be performed at room temperature or under heating, using as solvent DMF. The reaction with hydroxylamine-o-sulfonic acid can be carried out in an organic solvent, for example methanol, ethanol or etc., in the presence of organic bases, such as pyridine, triethylamine, diisopropylethylamine or etc., at temperatures in the range from room temperature up to the boiling temperature under reflux. The reaction with the compound of hydrazine can be carried out in an organic acid, for example acetic acid or etc., as a solvent, when thenia 6

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In the above reaction scheme for the ring B and A3have the above values, a R25represents a lower alkyl group or aracelio group.

Compound (Im) of the present invention can be obtained by interacting derived acetyl represented by the General formula (XVII), with aminotriazole, by reacting the obtained compound with tert-butoxybis(dimethylamino) methane, followed by cyclization of the obtained compound (XIX).

The reaction of dehydration of aminotriazole can be performed in a solvent, for example benzene, toluene or similar in acidic conditions using acetic acid, n-toluensulfonate, triperoxonane acid or etc., at a temperature in the range from room temperature up to the boiling temperature under reflux. The cyclization reaction can be carried out in conditions similar to the conditions of the method of obtaining 3.

The method of obtaining 7

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B the above reaction scheme for the ring B, A3and Y have the above values, R26represents a lower alkyl group or aracelio group, Z represents CH or N, n=3-9.

Connection (In) of the present invention can be obtained through vzaimode removing falorni group and the formation of cyclic amine.

Reaction with 2-aminopyridine or 2-aminopyrimidine can be performed in a solvent, for example methanol, ethanol or etc., at a temperature in the range from room temperature up to the boiling temperature under reflux. Remove falorni protective group can be performed in the usual way, for example using the method, which uses hydrazine, methylamine or similar Reaction obtain the cyclic amine can be carried out using conventional reaction of amine alkylation. For example, the reaction may be carried out with alkylenediamines at a temperature in the range from room temperature up to the boiling point under reflux in a solvent such as propanol, butanol, Tetra-hydrofuran, dioxane or similar, in the presence of inorganic bases such as potassium carbonate or similar In this case to speed up the reaction, you can add potassium iodide, etc.

The way to obtain 8

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In the above reaction scheme, the ring B, A3, Ar, R1and R2have the above values.

The compound (Io) of the present invention can be obtained by metallation reaction of thiophene compounds represented by the General formula (XXIII), with subsequent interaction obtained when tetrahydrofurane, ether, toluene, or similar, in the presence of chloride bis (triphenyl-phosphine) Nickel, Diisobutyl-aluminiumhydride, n-utility and zinc chloride at a temperature in the range from -80oC to room temperature.

As compounds of General formula (I) of the present invention obtained by the methods of obtaining 1-8 contain different substituents, these compounds can also be obtained by modifying these groups. For example, a compound containing as a substituent of the amino group can be modified in its amide, urethane compound, a derivative of urea, and the like compounds in the usual way, and the compound containing ester or carboxyl group as a substituent, can be modified prior to its amide compounds and then to turn to alcohol or similar connection, restoring it in the usual way.

The compound containing a hydroxyl group can be converted later in ester, ester of carboxylic acid, urethane, and the like compounds in the usual way. Also, the hydroxyl group can be converted into the amino group by reaction Mitsunobu (Mitsunobu) phthalimide, and then removing palolo protective group in the same conditions, which UKBA in free form, either in the form of its salt, hydrate, MES or its polymorphic substances. The salt of compound (I) can also be obtained by reaction of the salt formation.

Its isolation and purification are, using conventional chemical methods such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography, etc.

Various isomers can be separated by selecting the appropriate connection or by using the differences in the physical characteristics of these isomers. So, for example, optical isomers can be divided into pure stereochemical isomers, choosing appropriate materials or separating racemic compound, for example, by the manner in which such connection is turned into its diastereoisomer salt conventional optically active base, and then carry out the separation of optical isomers.

As the compound (I) of the present invention has a specific anti-PCP activity and can improve a weakened function of NMDA receptors, it can be used as a psychotropic agent, antihistaminics agent, the agent against dementia in Alzheimer's disease, etc., as agent for improving sawing the treatment of mental retardation and autism in children.

Anti-PCP action of compound (I) of the present invention was confirmed by the following test method.

Test for anti-PCP efficiency.

Test method

PCP (3 mg/kg) administered to male Wistar rats (n = 8, weight 200-300 g) subcutaneous injection and after 30 minutes, the rats are placed in a device with a Board with holes (HBA). The test compound (10 mg/kg) administered by subcutaneous injection 15 minutes prior to the introduction of PCP. HBA is an open area the size of 40x40 cm, which is surrounded by a wall of 20 cm height and floor which has 16 holes with a diameter of 4 cm (Psychopharmacology, 52, 271 (1977)).

Quantitative assessment of the movement (movement: the number of times of movement 9 separated points) and exploratory behavior (lowering the number of times zasovyvaniya head in the hole) for rats in HBA determine within 5 minutes. In addition, male Wistar rats (n = 8), which is administered PCP (3 mg/kg) by subcutaneous injection, used as a control group.

In this pharmacological test compound of the present invention antagonisitic PCP-induced increment of the amount of movement and reduction of search behavior with statistical significance compared with the control group by Mann-Whitney U-test) (see table. etenia, represented by the General formula (I) or their salts as active ingredient, are prepared in the form of tablets, lozenges for receiving the cheek, powders, fine granules, granules, capsules, pills, solutions for oral administration (including syrups, injections, inhalations, suppositories, solutions for percutaneous injection, ointments, adhesive preparations for percutaneous introduction, the adhesive preparations for administration through mucosa (e.g., adhesive cheek drugs), solutions for use across a mucous membrane (for example, solutions for insertion through the nose), etc., using conventional pharmaceutical carriers, fillers and other auxiliary agents, and administered orally or parenteral.

Solid composition intended for oral administration in accordance with the present invention, used in the form of tablets, powders, granules, etc. and in such solid compositions one or more of the active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or aluminumagnesium. Typically, the composition may contain other functional the isthmus), baking powder (for example, calciphile cellulose or etc.), stabilizing agent (for example, lactose or similar) and solubilizers agent or facilitate solubilization agent (for example, glutamic acid, aspartic acid or etc.). If necessary, tablets or pills may be coated with a film of substances providing their dissolution in the stomach or small intestine, such as sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose or etc.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. and contain a generally used inert diluent such as purified water or ethanol. In addition to the inert diluent, this composition may also contain auxiliary agents, such as solubilizing or promote solubilization agents, moisturizing agents, suspendresume agents and so on, as well as sweetening agents, flavoring agents, fragrances and preservatives.

Preparations for parenteral administration include aqueous or nonaqueous solutions, suspensions and emulsions. Examples of diluents for use in aqueous solutions and suspensions include dis is x solutions and suspensions include propylene glycol, the polyethylene glycol, vegetable oils (e.g. olive, etc), alcohols (e.g. ethanol), Polysorbate 80 (trade mark), etc., Such compositions can contain further additives such as agents, giving isotonicity, antiseptics, wetting agents and emulsifiers, dispersing agents, stabilizers (e.g., lactose) and solubilizing or promote solubilization agents. These compositions are sterilized by filtering through retaining bacteria filter, mixed with germicidal or irradiated. In another embodiment, they can be used, first by introducing a sterile solid compositions and dissolving in sterile water or a sterile solvent for injection immediately before use.

Clinical dose of the compound of the present invention determine, given the symptoms, weight, age, gender, etc. of each patient to be treated, and the route of administration, but it usually ranges from 0.1 to 1000 mg, preferably from 1 to 200 mg per day for adults in the case of oral administration, or from 0.1 to 100 mg, preferably from 0.3 to 30 mg per day for adults in the case of parenteral administration, the daily dose may be given once a day or it can be divided into 2-4 doses per day.

Below p is eaten claims.

Example composition (tablets 20 mg

The compound of the present invention 20 mg

Lactose 75 mg

Corn starch 16 mg

Hydroxypropylcellulose - 4.5 mg

Calcixerollic was 8.8 mg

Magnesium stearate - 0.7 mg

All 125 mg

Tablets 20 mg

Using the device for coating the granules in the fluidized bed, 100 g of compound of the present invention is thoroughly mixed with 375 g of lactose and 80 g of corn starch. All of this is transformed into granules by spraying with a 10% solution of hydroxypropylcellulose. After drying the obtained granules are sieved through a sieve of 20 mesh, add 19 g calcixerollic and 3.5 g of magnesium stearate, and the resulting mixture is make pill a weight of 120 mg each in rotational teletrauma machine, using a system of matrix-punch size 7 mm x 8.4 R.

Example 1

1-[5-(3-benzyl-1,2,4-oxadiazol-5-yl)-2-thienyl] hexahydro - 1H-aspiritual

535 mg (2.0 mmol) Ethyl-5-[(hexahydro-1H-azepin-1-yl)methyl - 2-thienyl] carboxylate and 360 mg (2.4 mmol) of 2 - phenylacetonitrile dissolved in 20 ml of tetrahydrofuran, added 120 mg (3.0 mmol) of sodium hydride at room temperature, and then the mixture is boiled with about iltram concentrated under reduced pressure. To the resulting residue, water is added and the resulting mixture extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, the obtained residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol (80:1) to give 343 mg specified in the title compound in the free form. 960 mg (2,72 mmol) of the compound in the free form was dissolved in 30 ml of ethyl acetate, add 0.7 ml (2.8 mmol) of 4 N. HCl/AcOEt is added dropwise and the precipitated precipitated crystals are collected by filtration and recrystallized from acetonitrile, getting 690 mg specified in the connection header. So melting point: 189-192oC

1H-NMR ppm in DMSO-d6)

1.53 - 1.59 (2H, m), 1.65 - 1.67 (2H, m), 1.82 - 1.85 (4H, m), 3.02 - 3.08 (2H, m), 3.41 (1H, br), 4.15 (2H, s), 4.64 (2H, d, J = 5.5 Hz), 7.27 (1H, m), 7.34 (4H, br), 7.63 (1H, d, J = 3.7 Hz), 7.97 (1H, d, J = 3.7 Hz), 11.36 (1H, br)

Example 2

1-[5-(3-Phenethyl-1,2,4-oxadiazol-5-yl)-2-thienyl] hexahydro-1H-aspiritual

According to the method of example 1, 650 mg specified in the connection header is obtained from 1,34 g (5.0 mmol) of ethyl-5-[(hexahydro-1H-azepin-1-yl) -methyl-2-thienyl] carboxylate and 985 mg (6.0 mmol) of 3-phenylpropionamide.

So melting point: 180-182o<26 - 7.30 (4H, m), 7.64 (1H, d, J = 3.7 Hz), 7.98 (1H, d, J = 3.7 Hz), 11.24 (1H, br)

Example 3

1-[5-[3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl] - 2-thienyl] hexahydro-1H-estimatesare

According to the method of example 1 to obtain 560 mg specified in the connection header from 1,34 g (5.0 mmol) of ethyl-5-[(hexahydro-1H-azepin-1-yl) -methyl-2-thienyl] carboxylate and 1.07 g (6.0 mmol) of 4-phenylbutyramide.

So melting point: 174-176oC (acetonitrile)

1H-NMR ( ) ppm in DMSO-d6)

1.55 - 1.60 (2H, m), 1.64 - 1.67 (2H, m), 1.83 (4H, br), 1.98 - 2.04 (2H, m), 2.66 - 2.69 (2H, m), 2.74 - 2.77 (2H, m), 3.05 - 3.09 (2H, m), 4.66 (2H, d, J = 5.5 Hz), 7.18 - 7.31 (5H, m), 7.62 (1H, d, J = 3.7 Hz), 7.98 (1H, d, J = 3.7 Hz), 11.07 (1H, br)

Example 4

1) 5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl]-3-tetrahydropyranyloxy-1,2,4-oxadiazol

According to the method of example 1 to obtain 4.4 g specified in the connection header of 8.0 g (of 29.9 mmol) ethyl-5-[(hexahydro-1H-azepin-1-yl)-methyl-2-thienyl] carboxylate and 6.3 g (35,9 mmol) 2-(tetrahydropyranyloxy)acetamidoxime.

1H-NMR ( ppm in CDCl3)

1.55 - 1.90 (10H, m), 2.60 - 2.70 (4H, m), 3.30 - 3.73 (3H, m), 3.85 - 4.23 (4H, m), 4.70 (1H, d, J = 13.4 Hz), 4.80 - 4.96 (3H, m), 6.95 (1H, d, J = 3.7 Hz), 7.75 (1H, d, J = 3.7 Hz)

2) 5-[5-[(hexahydro-1H-azepin-1-yl)methyl} -2-thienyl] - 1,2,4-oxadi-azole-3-methanol

75 ml (75 mmol) of 1 N. HCl is added dropwise to 80 ml of ethanol solution 6,23 g (16,74 mmol) is connected is. actionnow the mixture is concentrated under reduced pressure, to the residue add 80 ml of 1 N. NaOH and the mixture extracted with ethyl acetate. Then the obtained organic layer was washed with saturated brine. The organic layer is dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol (75:1), receiving 3,76 g specified in the connection header.

So melting point: 79-81oC (isopropyl ether).

1H-NMR ( ppm in CDCl3)

1.58 - 1.78 (9H, m), 2.68 - 2.70 (4H, m), 3.88 (2H, s), 4.83 (2H, s), 6.96 (1H, d, J 3.7 Hz), 7.75 (1H, d, J = 3.7 Hz)

Example 5

1-[5-(3-Benzoyloxymethyl-1,2,4-oxadiazol-5-yl)-2 - thienyl] hexahydro-1H-aspiritual

B argon atmosphere at 0oC 20 ml tertrahydrofuran ring solution containing 820 mg (2.8 mmol) of the compound obtained in stage 2) of example 4, is added dropwise to 10 ml tetrahydropyranol suspension 118 mg (2,94 mmol) of sodium hydride and the resulting mixture is stirred for 15 minutes. Then add 0.35 ml (2,94 mmol) benzylbromide and 10 mg tetrabutylammonium, and then stirred at room temperature for 16 hours. To the reaction solution we use the Saul and dried over anhydrous magnesium sulfate.

The solvent is evaporated under reduced pressure and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol (80:1) to give 580 mg specified in the title compound in its free form. Then add 0.3 ml of 4 N. HCl/AcOEt and loose in the precipitated crystals are collected by filtration and recrystallized from a mixture of acetonitrile - ethyl acetate, getting 467 mg specified in the connection header. So melting point: 166-168oC.

1H-NMR ( ppm in DMSO-d6)

1.55 - 1.60 (2H, m), 1.65 - 1.67 (2H, m), 1.84 (4H, br), 3.04 - 3.12 (2H, m), 4.63 (2H, s), 4.67 - 4.69 (2H, m), 4.71 (2H, s), 7.33 (1H, m), 7.37 (5H, m), 7.65 (1H, d, J= 3.7 Hz), 8.03 (1H, d, J = 3.7 Hz), 11.21 (1H, br)

Example 6

[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl]-1,2,4-oxadiazol-3-yl]methylbenzoate 1.0 oxalate

450 mg (1.53 mmol) of the compound obtained in stage 2) of example 4, dissolved in 30 ml of methylene chloride, add of 0.32 ml (2.3 mmol) of triethylamine and 0.21 ml (of 1.84 mmol) of benzoyl chloride and the resulting mixture is stirred over night at room temperature. The reaction solution was washed with water, and the organic layer is dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue is treated on a chromatographic column with silica the Portion 180 mg (0,453 mmol) of this compound are dissolved in 5 ml of methanol, add 5 ml of a solution containing 40 mg (0.44 mmol) of oxalic acid and the resulting mixture was stirred at room temperature for 10 minutes. The solvent is evaporated under reduced pressure, and then to the obtained residue, add a small amount of methanol and ether to implement crystallization. Collecting the resulting crystals by filtration and drying them, get 166 mg specified in the connection header.

So melting point: 120-121oC.

1H-NMR ( ppm in DMSO-d6)

8.03 - 8.01 (2H, m), 7.97 (1H, d, J = 3.7 Hz), 7.72 (1H, m), 7.59 - 7.56 (2H, m), 7.34 (1H, d, J = 3.7 Hz), 5.56 (2H, s), 4.28 (2H, s), 2.93 (4H, brs), 1.70 (4H, brs), 1.59 (4H, brs)

Example 7

[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] ,-2 - thienyl]-1,2,4-oxadiazol-3-yl]methyl N-benzylcarbamoyl 1.0 oxalate

480 mg (1,64 mmol) of the compound obtained in stage 2) of example 4, dissolved in 10 ml of N,N-dimethylformamide, and then to this is added dropwise 5 ml of suspension in N,N-dimethylformamide 162 mg (1,64 mmol) of copper chloride (I) and 229 mg (1,72 mmol) benzenesulfonate and the resulting mixture is stirred over night at room temperature. The reaction solution is concentrated under reduced pressure and the resulting residue is dissolved in chloroform, washed with water, and then dried over anhydrous Sul is th column of silica gel, getting 690 mg specified in the title compound in the free form. Portion 520 g of this compound by the method of example 6 process 104 mg of oxalic acid, getting 398 mg specified in the connection header in the form of salt.

So melting point: 129-130oC

1H-NMR ( ppm in DMSO-d6)

8.05 (1H, t), 7.94 (1H, d), 7.32 - 7.22 (6H, m), 5.23 (2H, s), 4.26 - 4.22 (4H, m), 2.92 (4H, br), 1.70 (4H, brs), 1.59 (4H, brs)

Example 8

1-[5-(3-Aminomethyl-1,2,4-oxadiazol-5-yl)-2 - thienyl] hexahydro-1H-aspidistrafly

Under ice cooling 1.1 g (7.5 mmol) of phthalimide, of 1.97 g (7.5 mmol) of triphenylphosphine and 1.31 g (7.5 mmol) of diethylazodicarboxylate added to 50 ml of tertrahydrofuran ring of a solution containing 2.0 g (6,82 mmol) of the compound obtained in stage 2) of example 4, and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is dissolved in 50 ml of ethanol. Then added dropwise to 3.3 ml (68.2 mmol) of hydrazine hydrate is added and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is acidified by adding 1 N. HCl, and then washed with chloroform. Then the resulting aqueous layer podsadecki layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol (30: 1) to give 1.86 g specified in the title compound in the free form. 400 mg of this compound is subjected to the reaction of formation of salt using 1 N. HCl, and then precrystallization from isopropanol, receive 362 mg specified in the connection header.

So melting point: 230 - 232oC.

1H-NMR ( ppm in DMSO-d6)

1.59 - 1.66 (4H, m), 1.85 (4H, m), 3.08 (2H, br), 4.31 (2H, s), 4.67 (2H, s), 7.68 (1H, d, J=3.7 Hz), 8.05 (1H, d, J = 3.7 Hz), 8.92 (3H, br), 11.79 (1H, br)

Example 9

1-Benzyl-3-[[5-[5-[(hexahydro-1H-azepin-1 - yl)methyl]-2-thienyl]-1,2,4-oxadiazol-3-yl]methyl]urea

770 mg (2,63 mmol) of the Compound obtained in example 8, in the free form was dissolved in 20 ml of DMF and add 5 ml of DMF solution containing 369 mg (2.77 mmol) benzenesulfonate and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure and the resulting residue is dissolved in chloroform, washed with water, and then dried over anhydrous magnesium sulfate. The solvent is evaporated, and the obtained residue processing is tion in the connection header.

So melting point: 101-103oC.

1H-NMR ( ppm in CDCl3)

7.70 (1H, d, J = 3.7 Hz), 7.31 - 7.26 (5H, m), 6.95 (1H, d, J = 3.7 Hz), 5.10 (2H, m), 4.57 (2H, d, J = 5.7 Hz), 4.42 (2H, d, J = 5.7 Hz), 3.88 (2H, s), 2.71 (4H, m), 1.64 (8H, brs)

Example 10

N-[[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl] -1,2,4-oxadiazol-3-yl]methyl]benzamide 1.0 fumarate

585 mg (2.0 mmol) of the compound obtained in example 8, in the free form was dissolved in 20 ml of methylene chloride, add 0.6 ml (4.0 mmol) of triethylamine, and 0.28 ml (2.4 mmol) of benzoyl chloride and 4-DMAP (cat.) and the resulting mixture was stirred at room temperature for 19 hours. The reaction solution was washed with water and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol (80:1) to obtain 510 mg specified in the title compound in the free form. Using 140 mg (1.2 mmol) of fumaric acid, get salt from the portion of the connection 490 mg (1,24 mmol). Obtain 348 mg specified in the connection header.

So melting point: 79-81oC.

1H-NMR ( ppm in DMSO-d6)

9.22 (1H, t), 7.91 - 7.85 (3H, m), 7.58 - 7.48 (3H, m), 7.16 (1H, d), 6.92 (2H, s), 4.62 (2H, d), 3.91 (2H, s), 2.67 - 2.64 (4H, m), 1.57 (8H, brs)

Example 11

a) N-Benzyl-5-[5-[(haidro-1H-azepin-1-yl) methyl] -2-thienyl]-1,2,4-oxadiazol-3-eletromechanical

of 0.53 ml (5.2 mmol) of Benzaldehyde is added dropwise to 55 ml of 1,2-dichlorethane solution containing 1.52 g of the compound obtained in example 8, in the free form; the resulting mixture was stirred at room temperature for 2.5 hours, to this are added dropwise 1.44 g (6,76 mmol) NaBH(OAc) and 0.6 ml of acetic acid, and then the resulting mixture is stirred further at room temperature for 2 days. To the reaction solution was added concentrated aqueous ammonia, the organic layer is isolated and dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol (100:1--->80:1) to give 359 mg of the compound (b) in free form and 980 mg of the compound (a) in free form. Get their salts, using 4 N. HCl/AcOEt to obtain specified in the connection header b) (330 mg) and the compound (a) (1,036 mg).

a)1H-NMR ( ppm in DMSO-d6)

11.84 (1H, br), 10.42 (2H, br), 8.06 (1H, d), 7.70 (1H, d), 7.61 - 7.59 (2H, m), 7.45 - 7.25 (3H, m), 4.68 (2H, brs), 4.42 (2H, brs), 4.30 (2H, brs), 3.33 (2H, br), 3.08 (2H, br), 1.99 - 1.89 (4H, m), 1.67 (4H, br), 1.58 (4H, br)

Mass spectrum (fast atom bombardment, suppose m/z 383 (M++1)

b)1H-NMR ( ppm in DMSO-d6)

at 11.64 (1H, br), 8.04 (1H, d), 7.70 (1H, d), 7.55 (4H, what derevko quick lay atoms, m/z 473 (M++1)

Example 12

1) 3-Tert-butyldimethylsiloxy-5-[5-[(hexahydro - 1H-azepin-1-yl)-methyl]-2-thienyl]-1,2,4-oxadiazol

Using 12.0 g (of 44.9 mmol) of ethyl{5-[(hexahydro-1H - azepin-1-yl)methyl] -2-thienyl} -carboxylate and 12.7 g (58.3 mmol) of 3-tert-butyl-dimethylaminopropionitrile, 9,62 g specified in the connection header receive according to the method of example 1.

1H-NMR ( ppm in CDCl3)

0.04 (6H, s), 0.86 (9H, s), 1.63 - 1.70 (8H, m), 2.69 (4H, m), 2.99 (2H, t, J = 6.8 Hz), 3.87 (2H, s), 4.04 (2H, t, J = 6.8 Hz), 6.94 (1H, d, J = 3.9 Hz), 7.71 (1H, d, J = 3.9 Hz)

2) 5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1,2,4 - oxadiazol-3-ethanolgasoline

Under ice cooling of 28.4 ml (28.4 mmol) of tetrabutylammonium (1.0 M solution in THF) is added dropwise to 250 ml of tertrahydrofuran ring solution containing becomes 9.97 g of 25.2 mmol) of the compound obtained previously in stage 1), and the resulting mixture is stirred for 1 hour at the same temperature. The reaction solution is concentrated and the resulting residue is acidified by adding 1 N. HCl, and then washed with chloroform. The resulting aqueous layer podselect, adding: 4 N. NaOH, and extracted with ethyl acetate; the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then the solvent of viparita the organisations transform its salt, using 4 N. HCl/AcOEt, and then recrystallized from acetonitrile, getting 639 mg specified in the connection header.

So melting point: 229-231oC

1H-NMR ( ppm in DMSO-d6)

1.50 - 1.78 (4H, m), 1.83 (4H, br), 2.87 - 2.90 (2H, m), 3.05 - 3.09 (2H, m), 3.78 - 3.80 (2H, m), 4.66 - 4.68 (2H, m), 7.62 (1H, d, J = 3.7 Hz), 7.98 (1H, d, J = 3.7 Hz), 11.06 (1H, br)

Example 13

1-[5-[3-(2-Benzyloxyethyl)-1,2,4-oxadiazol-5-yl] -2-thienyl] -hexahydro-1H-aspiritual

According to the method of example 1 to obtain 850 mg specified in the title compound in the free form of of 1.34 g (5.0 mmol) of ethyl 5-[(hexahydro-1H-azepin-1-yl)methyl-2-thienyl] carboxylate and 1.8 g (9.28 are mmol) 3-benzyloxypropionic.

It transformed into a salt using 4 N. HCl/AcOEt, and then recrystallized from acetonitrile, getting 440 mg specified in the connection header.

So melting point: 145-147oC

1H-NMR ( ppm in DMSO-d6)

1.50 - 1.75 (4H, m), 1.84 (4H, m), 3.04 - 3.10 (4H, m), 3.82 - 3.85 (2H, m), 4.51 (2H, s), 4.66 - 4.68 (2H, m), 7.20 - 7.38 (5H, m), 7.64 (1H, d, J = 3.7 Hz), 7.98 (1H, d, J = 3.7 Hz), 11.28 (1H, br)

Example 14

1-[5-[3-(2-Ethoxyethyl)-1,2,4-oxadiazol-5-yl] -2-thienyl]hexahydro-1H-aspiritual

According to the method of example 1 507 mg specified in the connection header is obtained from 1.07 g (4.0 mmol) of ethyl 5-[(hexahydro-1H-azepin-1-yl) -methyl]-2-thienyl] carboxyl>
)

11.10 (1H, br), 7.99 (1H, d), 7.63 (1H, d), 4.67 (2H, s), 3.77 (2H, t), 3.47 - 3.43 (2H, m), 3.38 - 3.35 (4H, m), 2.99 (2H, t), 1.84 (4H, m), 1.67 - 1.64 (2H, m), 1.60 -1.55 (2H, m), 1.08 (3H, t)

Example 15

1-[5-(3-Vinyl-1,2,4-oxadiazol-5-yl)-2-thienyl] hexahydro - 1H-aspiritual

To 25 ml of tertrahydrofuran ring solution that contains 615 mg (2.0 mol) of the compound in a free form, obtained in stage 2) of example 12, added 418 mg (3.0 mmol) 4-NITROPHENOL, 786 mg (3.0 mmol) of triphenylphosphine and of 0.48 ml (3.0 mmol) of diethylazodicarboxylate and the resulting mixture is stirred over night at room temperature. The reaction solution was concentrated, and the obtained residue is treated through column chromatography with silica gel, getting 260 mg specified in the title compound in the free form. It transformed into a salt using 4 N. HCl/AcOEt, getting 191 mg specified in the connection header.

So melting point: 173-174oC

1H-NMR ( ppm in DMSO-d6)

11.07 (1H, br), 8.03 (1H, d, J = 3.7 Hz), 7.64 (1H, d, J = 3.7 Hz), 6.85 (1H, m), 6.40 (1H, m), 5.94 (1H, m), 4.68 (2H, s), 3.39 - 3.34 (4H, br), 1.84 (4H, br), 1.67 - 1.64 (2H, m), 1.61 - 1.57 (2H, m)

Example 16

2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl] -1,2,4-oxadiazol-3-yl]ethylbenzoic 1.0 oxalate

According to the method of example 6 to obtain 580 mg specified in the title compound in the free form 450 mzinene turn into salt, using 112,5 mg (1.25 mmol) of oxalic acid, getting 384 mg specified in the connection header.

So melting point: 121-123oC

1H-NMR ( ppm in DMSO-d6)

7.96 - 7.90 (3H, m), 7.60 (1H, m), 7.52 (2H, t, J = 7.9 Hz), 7.32 (1H, br), 4.65 (2H, t, J= 6.1 Hz), 4.25 (2H, br), 3.26 (2H, t, J=6.1 Hz), 2.92 (4H, brs), 1.69 (4H, brs), 1.59 (4H, brs)

Example 17

2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl-1,2,4-oxadiazol-3-yl]ethyl 4-methoxybenzoate oxalate

According to the method of example 6 get 444 mg specified in the connection header of 307 mg (1.0 mmol) of the compound obtained in stage 2) of example 12, in the free form and 205 mg (1.2 mmol) of 4 - methoxybenzylamine.

So melting point: 131-132oC.

1H-NMR ( ppm in DMSO-d6)

7.91 (1H, d), 7.88 - 7.86 (2H, m), 7.31 (1H, d), 7.04 - 7.02 (2H, m), 4.60 (2H, t), 4.25 (2H, br), 3.82 (3H, s), 3.24 (2H, t), 2.92 (4H, br), 1.69 (4H, br), 1.59 (4H, br)

Example 18

2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1,2,4 - oxadiazol-3-yl]ethyl 4-perbenzoate oxalate

According to the method of example 6 receive 438 mg specified in the connection header of 307 mg (1.0 mmol) of the compound obtained in stage 2) of example 12, in the free form and 0.14 ml (1.2 mmol) of 4 - tormentilla

So melting point: 96-97oC.

1H-NMR ( ppm in DMSO-d6)

8.01 - 7.98 (2H, m), 7.91 (1H, d), 7.38 - 7.33 (3H, m), 4.64 (2H, t), 4.28 (2H, br), 3.26 (2H, t)] ethyl 4-nitrobenzoate

According to the method of example 6 receive 439 mg specified in the connection header of 307 mg (1.0 mmol) of the compound obtained in stage 2) of example 12, free-form and 4-nitrobenzylamine.

So melting point: 67-69oC

1H-NMR ( ppm in CDCl3) 8.40 - 8.10 (4H, m), 7.72 (1H, d, J = 3.7 Hz), 6.96 (1H, d, J = 3.7 Hz), 4.79 (2H, t, J = 6.4 Hz), 3.80 (2H, s), 3.27 (2H, t, J = 6.4 Hz), 2.70 (4H, br), 1.64 (8H, br)

Example 20

2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl] -1,2,4-oxadiazol-3-yl]ethylcyclohexylamine

According to the method of example 6 receive 409 mg specified in the connection header of 307 mg (1.0 mmol) of the compound obtained in stage 2) of example 12, in the free form and 0.16 ml (1.2 mmol) of cyclohexanecarbonitrile

So melting point: 41-42oC

1H-NMR ( ppm in CDCl3)

7.72 (1H, d), 6.95 (1H, d), 4.48 (2H, t), 3.88 (2H, s), 3.10 (2H, t), 2.69 (2H, t), 2.70 - 2.68 (4H, m), 2.29 (1H, m), 1.90 - 1.86 (2H, m), 1.75 - 1.61 (10H, m), 1.47 - 1.37 (2H, m), 1.31 - 1.16 (4H, m)

Example 21

2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl] -1,2,4-oxadiazol-3-yl]acetate 1.0 fumarate

According to the method of example 6 to obtain 330 mg specified in the connection header of 615 mg (2.0 mmol) of the compound obtained in stage 2) of example 12, in the free form and 0.38 ml (4.0 mmol) of acetic anhydride.

So melting point: 105-106oC

1H-NMR ( ppm in DMSO-d
Example 22

1-[5-[(3-Methyl-1,2,4-oxadiazol-5-yl)-2-thienyl]hexahydro-1H - azepin

According to the method of example 1 to obtain 280 mg specified in the connection header of 570 mg (of 7.70 mmol) acetamidoxime and 1.03 g (of 3.85 mmol) ethyl-5-[(hexahydro-1H-azepin-1-yl)methyl-2-thienyl] carboxylate.

So melting point: 45-46oC

1H-NMR ( ppm in CDCl3)

7.71 (1H, d), 6.95 (1H, d), 3.88 (2H, s), 2.70 - 2.64 (4H, m), 2.43 (3H, s), 1.64 (8H, brs)

Example 23

2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl] -1,2,4-oxadiazol-3-yl]ethyl N-benzylcarbamoyl 1.0 fumarate

According to the method of example 7 to obtain 570 mg specified in the title compound in the free form of 610 mg (1,98 mmol) of the compound in a free form, obtained in stage 2) of example 12, and 278 mg (2,08 mmol) benzenesulfonate. Portion 560 mg of this compound turned into salt, using 141 mg fumaric acid, getting 366 mg specified in the connection header.

So melting point: 138-139oC

1H-NMR ( ppm in DMSO-d6)

7.84 (1H, d, J = 3.7 Hz), 7.72 (1H, t), 7.30 - 7.16 (5H, m), 6.62 (2H, s), 4.36 (2H, t, J = 6.1 Hz), 4.15 (2H, d, J = 6.1 Hz), 3.93 (2H, s), 3.07 (2H, t, J = 6.1 Hz), 2.68 - 2.66 (4H, m), 1.61 - 1.58 (8H, m)

Example 24

2-[5-[5-[(Hexahydro-1H-azepin-1-yl) methyl] -2 - thienyl]-1,2,4-oxadiazol-3-yl]ethyl N-ethylcarbamate 1.0 oxalate

According to the method of example 7 to obtain 198 mg of the criminal code of the RA 12, and 82 mg (1.15 mmol) utilizationof.

So melting point: 112-113oC

1H-NMR ( ppm in DMSO-d6)

7.92 (1H, d), 7.33 (1H, d), 7.12 (1H, br), 4.31 (2H, t), 4.27 (2H, br), 3.05 (2H, t), 3.00 - 2.93 (6H, m), 1.70 (4H, br), 1.59 (4H, br), 0.98 (3H, t)

Example 25

2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1,2,4 - oxadiazol-3-yl]ethyl N-(2-chloroethyl)carbamate 1.0 oxalate

According to the method of example 7 receive 437 mg specified in the connection header of 462 mg (1.5 mmol) of the compound in a free form, obtained in stage 2) of example 12, and 0.15 ml of 1.65 mmol) 2-chlorotriazine.

So melting point: 71-72oC

1H-NMR ( ppm in DMSO-d6)

7.92 (1H, d), 7.45 (1H, t), 7.34 (1H, d), 4.35 (2H, t), 4.29 (2H, br), 3.56 (2H, t), 3.29 - 3.24 (2H, m), 3.07 (2H, t), 2.94 (4H, br), 1.71 (4H, br), 1.59 (4H, br)

Example 26

2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl] -1,2,4-oxadiazol-3-yl]ethyl N-BUTYLCARBAMATE 1.0 oxalate

According to the method of example 7 receive 573 mg specified in the connection header of 462 mg (1.5 mmol) of the compound in a free form, obtained in stage 2) of example 12, and to 0.19 ml (1,65 mmol) n - utilizationof.

So melting point: 109-110oC

1H-NMR ( ppm in DMSO-d6)

7.93 (1H, d), 7.37 (1H, d), 7.13 (1H, t), 4.34 - 4.30 (4H, m), 3.06 (2H, t), 2.99 (4H, m), 2.94 - 2.91 (2H, m), 1.72 (4H, br), 1.59 (4H, br), 1.36 - 1.30 (2H, m), 1.26 - 1.20 (2H, m), 0.86 (3H, t)

Example 27

2-[5-[5-[(Hexahydro get 7 378 mg specified in the connection header of 462 mg (1.5 mmol) of the compound in a free form, obtained in stage 2) of example 12, and to 0.19 ml (1,65 mmol) of tert-utilizationof

So melting point: 140-141oC

1H-NMR ( ppm in DMSO-d6)

7.92 (1H, d), 7.34 (1H, d), 6.90 (1H, br), 4.29 - 4.27 (4H, m), 3.04 (2H, t), 2.95 (4H, br), 1.71 (4H, br), 1.59 (4H, br), 1.18 (9H, s)

Example 28

2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl] -1,2,4-oxadiazol-3-yl]ethyl N-cyclohexylcarbamate 1.0 oxalate

According to the method of example 7 receive 363 mg specified in the connection header of 462 mg (1.5 mmol) of the compound in a free form, obtained in stage 2) of example 12, and 0.25 ml (1,95 mmol) cyclohexylsulfamate.

So melting 78-79oC

1H-NMR ( ppm in DMSO-d6)

7.92 (1H, d), 7.35 (1H, d), 7.08 (1H, d), 4.31 (2H, t), 3.38 (1H, m), 3.21 (1H, br), 3.05 (2H, t), 2.96 (4H, br), 1.71 (6H, br), 1.59 (6H, br), 1.22 - 1.06 (6H, m)

Example 29

2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl] -1,2,4-oxadiazol-3-yl]ethyl N-phenylcarbamate

According to the method of example 7 receive 515 mg specified in the connection header of 462 mg (1.5 mmol) of the compound in a free form, obtained in stage 2) of example 12, and 232 mg (1,95 mmol) phenylisocyanate

So melting point: 68-70oC

1H-NMR ( ppm in DMSO-d6)

7.73 (1H, d), 7.37 - 7.27 (3H, m), 7.05 (1H, m), 6.96 (1H, d), 6.66 (1H, br), 4.60 (2H, t), 3.88 (2H, br), 3.16 (2H, t), 2.70 - 2.68 (4H, m), 1.65 (8H, m)

Example 30

2-[5-[5-[(Hexahydro-1H-azepin-1-Sanogo in the connection header of 462 mg (1.5 mmol) of the compound in a free form, obtained in stage 2) of example 12, and 320 mg (1,95 mmol) 4 - nitrophenylacetate

So melting point: 73-74oC

1H-NMR ( ppm in DMSO-d6)

8.29 - 8.26 (2H, m), 8.22 - 8.19 (2H, m), 7.54 (1H, m), 6.96 (1H, d), 4.79 (2H, t), 3.88 (2H, br), 3.28 (2H, t), 2.70 - 2.68 (4H, m), 1.66 - 1.63 (8H, m)

Example 31

2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl] -1,2,4-oxadiazol-3-yl]ethyl N-(4-methoxyphenyl) carbamate 1.0 oxalate

According to the method of example 7 receive 652 mg specified in the connection header of 462 mg (1.5 mmol) of the compound in a free form, obtained in stage 2) of example 12, and 291 mg (1,95 mmol) 4-methoxyphenylalanine.

So melting point: 83-84oC

1H-NMR ( ppm in DMSO-d6)

9.45 (1H, br), 7.93 (1H, d), 7.36 - 7.33 (3H, m), 6.86 - 6.82 (2H, m), 4.45 (2H, t), 4.27 (2H, br), 3.69 (3H, s), 3.15 (2H, t), 2.93 (4H, br), 1.70 (4H, br), 1.59 (4H, br)

Example 32

2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl] -1,2,4-oxadiazol-3-yl]ethyl N-(4-forfinal)carbamate 1.0 oxalate

According to the method of example 7 receive 465 mg specified in the connection header of 462 mg (1.5 mmol) of the compound in a free form, obtained in stage 2) of example 12, and 267 mg (1,95 mmol) 4-perteneciente.

So melting point: 93-94oC

1H-NMR ( ppm in DMSO-d6)

9.70 (1H, br), 7.93 (1H, d), 7.46 - 7.42 (2H, m), 7.34 (1H, d), 7.10 (2H, t), 4.47 (2H, t), 4.30 (2H, br), 3.16 (2H, t), 2.96 - 2.94 (4H, m), 1.70 (enyl) carbamate 1.0 oxalate

According to the method of example 7 to obtain 440 mg specified in the connection header of 462 mg (1.5 mmol) of the compound in a free form, obtained in stage 2) of example 12, and 271 mg (1,65 mmol) 2-nitrophenylacetate

So melting point: 88-89oC

1H-NMR ( ppm in DMSO-d6)

9.87 (1H, br), 7.96 - 7.93 (2H, m), 7.69 - 7.61 (2H, m), 7.35 - 7.30 (2H, m), 4.47 (2H, t), 4.31 (2H, br), 2.96 (2H, br), 1.71 (4H, br), 1.59 (1H, br)

Example 34

N-[2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1,2,4-oxadiazol-3-yl]ethyl]phthalimidopropyl

To 100 ml of anhydrous tetrahydrofurane solution of 5.0 g (16,27 mmol) of the compound in a free form, obtained in stage 2) of example 12, add 3,59 g (24.4 mmol) of phthalimide, of 3.84 ml (24.4 mmol) of diethylazodicarboxylate and to 6.39 g (24.4 mmol) of triphenylphosphine, followed by stirring at room temperature for 10 hours. The reaction solution is concentrated under reduced pressure, and the obtained residue is treated through column chromatography with silica gel, elwira a mixture of ethyl acetate-n-hexane (1:1), receiving of 8.9 g of a mixture containing the connection specified in the header, in the free form. The obtained solid is crushed, acidified by adding 1 N. HCl, and then add ethyl acetate and stirred for 1 hour. Fallen so in sieges is live from acetonitrile, getting 724 mg specified in the connection header.

So melting point: 181-182oC.

1H-NMR ( ppm in DMSO-d6)

11.13 (1H, br), 7.94 (1H, d), 7.90 - 7.83 (4H, m), 7.63 (1H, d), 6.66 (2H, d), 3.97 (2H, t), 3.36 (4H, m), 3.13 (2H, t), 1.84 (4H, m), 1.67 - 1.55 (4H, m)

Example 35

1) -Cyano-2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxamidine

3,68 g (68,08 mmol) of sodium Methoxide are added to 210 mg of the methanol solution containing 7.5 g (34,04 mmol) 2 - cyano-[5-[(hexahydro-1H-azepin-1-yl)methyl] thiophene and the resulting mixture is stirred for 24 hours at room temperature in argon atmosphere. To the reaction solution was added to 3.9 ml (68,08 mmol) of acetic acid and 2.15 g (51,06 mmol) of cyanamide and again the mixture was stirred at room temperature for 24 hours. The reaction solution is concentrated and to the residue is added a mixture of chloroform-methanol (20:1), then washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol (50:1--->10:1), receiving 2,62 g specified in the connection header.

1H-NMR ( ppm in DMSO-d6)

9.02 (1H, br), 8.49 (1H, br), 7.84 (1H, d), 7.01 (1H, d), 3.80 (2H, s), 2.59 (4H, br), 1.56 (8H, brs)

2) 1-[5-(3-Amino-restauraut in 55 ml of tetrahydrofuran and added dropwise 11 ml of methanol, of 1.41 g (19,98 mmol) hydroxyl - americanled and to 4.23 ml (29,97 mmol) of triethylamine and then the resulting mixture was refluxed for 21 hours. The reaction solution is concentrated under reduced pressure, to the obtained residue, add a mixture of chloroform-methanol (10: 1), then washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol (75: 1) to give 2.58 g specified in the connection header.

So melting point: 135-136oC

1H-NMR ( ppm in DMSO-d6)

7.68 (1H, d), 7.09 (1H, d), 6.35 (2H, s), 3.87 (2H, s), 2.65 - 2.63 (4H, brs), 1.58 (8H, brs)

Example 36

1-[5-(4-Amino-4H-1,2,4-tetrazol-3-yl)-2 - thienyl]hexahydro-1H-azepin

2.0 g (remaining 9.08 mmol) 2-Cyano-[5-[(hexahydro-1H-azepin-1-yl) methyl]-thiophene add to 13.5 ml of hydrazine hydrate is added, followed by boiling under reflux for 5 hours. After spontaneous cooling to room temperature the reaction solution is poured into a mixture of ice-water, and dropped in the precipitated crystals are collected by filtration, washed with water and dried over night at 70oC under reduced pressure, obtaining of 1.97 g specified in the header of soedinen CLASS="ptx2">

So melting point: 104-105oC

1H-NMR ( ppm in DMSO-d6)

8.44 (1H, s), 7.72 (1H, d), 7.00 (1H, d), 6.34 (2H, s), 3.83 (2H, s), 2.64 - 2.62 (4H, m), 1.57 (8H, brs)

Example 37

1) 4-Benzylamino-3-[5-[(hexahydro-1H-azepin-1 - yl)methyl] -2-thienyl]-1,2,4-triazole

0,31 ml (3.0 mmol) of Benzaldehyde are added to 10 ml of a methanol solution containing 831 mg (3.0 mmol) of the compound of example 36 and the resulting mixture was stirred at room temperature for 4 hours. While cooling with ice add 827 mg (3.9 mmol) NaBH(OAc)3and 0.35 ml of acetic acid and the resulting mixture was again stirred at room temperature for 9 days. The reaction solution was washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol (25:1) to give 600 mg specified in the title compound.

1H-NMR ( ppm in CDCl3)

8.63 (2H, d), 7.95 (2H, d), 7.84 (1H, d), 7.61 - 7.53 (3H, m), 6.95 (1H, d), 3.89 (2H, s), 2.71 - 2.69 (4H, m), 1.68 - 1.62 (8H, m)

2) 1-[5- (4-Benzylamino-4H-1,2,4-triazole-3-yl)-2-thienyl] hexahydro-1H-azepin

Under ice cooling to 58 mg (1.5 mmol) sodium borohydride we use is nnow the mixture is stirred at room temperature for 24 hours. The reaction solution is concentrated and add chloroform and aqueous ammonia to the resulting residue. Then the obtained organic layer is isolated and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol-aqueous ammonia (100:10:1) to give 353 mg specified in the connection header

So melting point: 79-81oC

1H-NMR ( ppm in DMSO-d6)

8.61 (1H, s), 7.67 (1H, d), 7.37 - 7.27 (5H, m), 7.19 (1H, t), 6.99 (1H, d), 4.22 (2H, d), 3.84 (2H, s), 2.65 - 2.62 (4H, m), 1.59 (8H, brs)

Example 38

1) Amidinohydrolase 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid

6,07 g (21,7 mmol) Sulfate S-methylisothiazoline and 43.5 ml (43,5 mmol) 1 N. NaOH is added to 11,0 g (43,4 mmol) 2- (hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide, to the reaction mixture add methanol to obtain a homogeneous solution (130 ml), and then the resulting solution was stirred at room temperature for 10 days. After removing insoluble substances by filtration, the solvent is evaporated and the resulting residue is directly injected into the chromatographic column filled with silica gel, elwira mixture of chlorate-d6)

10.37 (1H, br), 7.13 (1H, d), 6.76 (1H, d), 6.73 (4H, br), 3.71 (2H, s), 2.59 - 2.57 (4H, m), 1.56 (8H, brs)

2) 1-[5-(5-Amino-1H-1,2,4-triazole-3-yl)-2 - thienyl]hexahydro-1H-azepin

80 ml of an ethanol solution containing 7,32 g (24,8 mmol) of the compound obtained previously in stage 1), refluxed for 8 days. The reaction solution is concentrated and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol-aqueous ammonia(100:10:1--->40:10:1), receiving 5,98 g specified in the connection header. A portion of 1.5 g of this compound is recrystallized from 25 ml of acetonitrile, getting 1.26 g of crystals.

So melting point: 160-161oC

1H-NMR ( ppm in DMSO-d6)

11.95 (1H, brs), 7.20 (1H, brs), 6.86 (1H, brs), 6.04 (2H, brs), 3.76 (2H, s), 2.61 - 2.59 (4H, m), 1.56 (8H, brs)

Example 39

5-Amino-H-benzyl-3-[5-[(hexahydro-1H-azepin-1 - yl)methyl] -2-thienyl] -1H-1,2,4-triazole-1-carboxamide

5 ml of N,N-Dimethylformamide solution containing 331 mg (2.49 mmol) benzenesulfonate, added to 75 ml of N,N-dimethylformamide solution containing 690 mg (2.49 mmol) of the compound of example 38, and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution is concentrated and the resulting residue is dissolved in x is the remainder processed through column chromatography with silica gel, elwira a mixture of chloroform-methanol (75:1) to give 1.07 g is specified in the header connection It is crystallized by adding an appropriate amount of diethyl ether, and then recrystallized from a mixture of ethyl acetate-n-hexane, getting 564 mg interest of the connection.

So melting point: 130-131oC

1H-NMR ( ppm in DMSO-d6)

7.45 (1H, d, J = 3.7 Hz), 7.40 - 7.31 (5H, m), 7.24 (1H, t), 6.84 (1H, d, J = 3.7 Hz), 6.27 (2H, brs), 4.57 (2H, d, J = 6.1 Hz), 3.83 (2H, s), 2.68 - 2.66 (4H, m), 1.65 - 1.60 (8H, m)

Example 40

1) Ethyl-N1-[5-[(hexahydro-1H-azepin-1 - yl)methyl]-2-dienoyl]-N2-examinational

of 7.4 ml (52,5 mmol) of Triethylamine are added to 150 ml of anhydrous dichloromethane solution containing carboethoxy-3-methylthiosemicarbazone (30,86 mmol) and 6,33 g (25,0 mmol) 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5 - carboxylic acid hydrazide and the resulting mixture is refluxed for 36 hours. The reaction solution was washed with water and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is treated through column chromatography with silica gel, gaining 5.7 g specified in the connection header.

1H-NMR ( ppm in CDCl3)

11.45 (1H, br), 8.10 (1H, d), 6.94 (1H, d), 6.12 (2H, br), 4.38 (2H, m), 3.87 (2H,BR>
352 mg (1.0 mmol) of the compound obtained previously in stage 1), dissolved in 5 ml of acetic acid and the resulting solution was refluxed for 3 hours. The reaction solution is concentrated under reduced pressure, add aqueous ammonia and chloroform to the obtained residue, and the obtained organic layer is isolated and dried over anhydrous magnesium sulfate. Then the solvent is evaporated and the resulting residue is treated through column chromatography with silica gel, getting 248 mg specified as the header connection

1H-NMR ( ppm in CDCl3)

7.51 (1H, d), 6.85 (1H, d), 4.45 - 4.29 (2H, m), 3.96 (2H, brs), 2.81 (4H, br), 1.61 (8H, br), 1.33 (3H, t) MS (FAB, Pos, m/z 335 (M++1)

Mass spectrum (fast atom bombardment, suppose m/z 335 (M++1)

Example 41

5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1H-1,2,4-triazole-3-methanol

Under ice cooling 20 ml of anhydrous tertrahydrofuran ring solution containing 502 mg (1.5 mmol) of the compound of example 40, is added dropwise to 5 ml of anhydrous tetrahydropyranol suspension of 85.4 mg (2.25 mmol) of sociallyengaged and the resulting mixture was stirred at the same temperature for 4 hours. To the reaction mixture add decahydrate sodium sulfate obtained insoluble Eskay column, elwira a mixture of chloroform-methanol (10:1) to give 312 mg specified in the connection header.

So melting point: 159-161oC.

1H-NMR ( ppm in DMSO-d6)

13.89 (1H, br), 7.37 (1H, d), 6.93 (1H, d), 5.62 (1H, br), 4.57 (2H, d), 3.81 (2H, s), 2.63 - 2.60 (4H, m), 1.57 (8H, brs)

Example 42

1-[5-[(5-Methyl-1H-1,2,4-triazole-3-yl] -2 - thienyl] hexahydro-1H-aspidistrafly

To 5 ml of an Ethanol solution containing 1.01 g (4.0 mmol) of 2- (hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide, added to 2.8 ml (20 mmol) of triethylamine and 2.48 g (20 mmol) of ethylacetoacetate and the resulting mixture was stirred at room temperature for 21 hours. Then add 1.2 g of ameriglide and the resulting mixture was stirred at 80oC for 4 hours. The reaction solution is concentrated and added 28% aqueous ammonia and chloroform to the residue, and then the obtained organic layer is isolated and dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol (80:1), receiving 814 mg specified in the title compound in its free form. Turning this compound in its salt using 4 N. HCl/ethyl acetate, receive 593 mg of the criminal code is 11.06 (1H, br), 7.59 (1H, d), 7.45 (1H, d), 4.56 - 4.55 (2H, d), 3.38 - 3.33 (2H, m), 3.10 - 3.02 (2H, m), 2.39 (3H, s), 1.85 - 1.83 (4H, m), 1.68 - 1.63 (2H, m), 1.60 -1.54 (2H, m)

Example 43

1-[5-(5-Amino-1,3,4-oxadiazol-2-yl)-2 - thienyl]hexahydro-1H-azepin

2.5 g (23,57 mmol) Cyanogenmod added to 250 ml of an ethanol solution containing 5,43 g (21,43 mmol) 2- (hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide and the resulting mixture was stirred at room temperature for 2 hours and then at 50oC for 7 hours. The reaction solution is concentrated under reduced pressure, add saturated aqueous sodium bicarbonate solution and chloroform to the residue. Then allocate the resulting organic layer washed his saturated brine, dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is recrystallized from ethyl acetate, getting 2,43 g specified in the connection header.

So melting point: 232-234oC.

1H-NMR ( ppm in DMSO-d6)

7.33 (1H, d), 7.23 (2H, s), 7.00 (1H, d), 3.83 (2H, s), 2.63 - 2.61 (4H, m), 1.57 (8H, brs)

Example 44

1-Benzyl-3-[5-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1,3,4-oxadiazol-2-yl] urea

of 0.14 ml (1.1 mmol) Benzenesulfonate added to 20 ml of a pyridine solution containing 278 mg auktsionnyi the solution is concentrated under reduced pressure, and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol (50:1) to give 406 mg specified in the connection header

So melting point: 184-185oC

1H-NMR ( ppm in DMSO-d6)

10.96 (1H, br), 7.97 (1H, t), 7.48 (1H, d, J = 3.7 Hz), 7.37 - 7.24 (5H, m), 7.07 (1H, d, J = 3.7 Hz), 4.41 (2H, d, J = 5.7 Hz), 3.86 (2H, s), 2.64 (4H, brs), 1.58 (8H, brs)

Example 45

1) 4-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2-thienyl]-1 - benzyldimethylamine

5 ml of an ethanol solution containing 928 mg (from 6.22 mmol) benzylisothiocyanate, is added dropwise to 15 ml of an ethanol solution containing 1.5 g (of 5.92 mmol) 2-(hexahydro-1H - azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide and the resulting mixture was stirred at room temperature for 2 hours and then refluxed for 1 hour. The reaction solution is cooled with a mixture of ice-water and loose in the precipitated crystals are collected by filtration, washed thoroughly with cold ethanol, and then dried under reduced pressure, getting 2,19 g specified in the connection header.

1H-NMR ( ppm in DMSO-d6)

8.06 (1H, t), 7.94 (1H, d), 7.32 - 7.22 (6H, m), 5.23 (2H, s), 4.26 - 4.22 (4H, m), 2.92 (4H, brs), 1.70 (4H, brs), 1.59 (4H, brs)

2) 1-[5-(5-Amino-1,3,4-thiadiazole-2-yl)-2-thienyl]hexahydro - 1H-ASAP the Hai 1), and the resulting mixture is stirred as it is for 1 hour and then at room temperature for 3 hours. The reaction solution was poured on ice, alkalinized 5 N. aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The resulting organic layer is dried over anhydrous magnesium sulfate, the solvent is evaporated, and then the obtained residue is recrystallized from a mixture of ethyl-acecad-n - hexane, getting 482 mg specified in the connection header.

So melting point: 156-157oC

1H-NMR ( ppm in CDCl3)

7.17 (1H, d, J = 3.9 Hz), 6.83 (1H, d, J = 3.9 Hz), 5.44 (2H, brs), 3.83 (2H, s), 2.69 - 2.66 (4H, m), 1.65 - 1.62 (8H, m)

Example 46

1-Benzyl-3-[5-[5-[(hexahydro-1H-azepin-1 - yl)methyl]-2-thienyl]-1,3,4-thiadiazole-2-yl]urea

5 ml of N,N-Dimethylformamide solution containing 132 mg (1,16 mmol) benzenesulfonate, is added dropwise to 25 ml of N,N - dimethylformamide solution containing 342 mg (1,16 mmol) of the compound obtained in stage 2) of example 45, and the resulting mixture was stirred at room temperature for 22 hours. The reaction solution is concentrated under reduced pressure, to the residue is added chloroform and water and the organic layer is isolated and dried over anhydrous magnesium sulfate. The solvent is roform-methanol(40:1~25:1), getting 399 mg specified in the connection header

So melting point: 232-233oC

1H-NMR ( ppm in DMSO-d6)

11.13 (1H, br), 7.41 (1H, d, J = 3.7 Hz), 7.36 - 7.25 (5H, m), 7.16 (1H, brs), 6.98 (1H, d, J = 3.7 Hz), 4.37 (2H, d, J = 6.1 Hz), 3.82 (2H, s), 2.64 - 2.62 (4H, m), 1.58 (8H, br)

Example 47

N-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl]-1,3,4-thiadiazole-2-yl]benzamide

According to the method of example 10 get 396 mg specified in the header connections using 350 mg (1,19 mmol) of the compound obtained in stage 2) of example 45, 0.33 ml (2,38 mmol) of triethylamine, 0.18 mg (1.55 mmol) of benzylchloride and a catalytically effective amount of 4-N,N - dimethylaminopyridine.

So melting point: 219-221oC

1H-NMR ( ppm in DMSO-d6)

13.04 (1H, br), 8.14 (2H, d), 7.66 (1H, d), 7.59 - 7.56 (3H, m), 7.04 (1H, d), 3.88 (2H, s), 2.68 - 2.66 (4H, m), 1.60 (8H, m)

Example 48

1-[5-(5-Benzylamino-1,3,4-thiadiazole-2-yl)-2-thienyl]hexahydro-1H-azepin

of 0.37 ml (to 3.67 mmol) of benzaldehyde is added dropwise to 100 ml of 1,2-dichlorethane solution containing 1.08 g (to 3.67 mmol) of the compound obtained in stage 2) of example 45, and the resulting mixture was stirred at room temperature for 90 minutes, add 1,02 g (7,34 mmol) NaBH(AOc)3and 0.42 ml (7,34 mmol) of acetic acid and the resulting mixture was again stirred at room temperature tecola in this order, and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue is purified on a chromatographic column with silica gel, getting 270 mg specified in the connection header.

So melting point: 165-166oC

1H-NMR ( ppm in DMSO-d6)

8.40 (1H, t), 7.38 - 7.26 (5H, m), 7.22 (1H, d, J = 3.7 Hz), 6.93 (1H, d, J = 3.7 Hz), 4.52 (2H, d, J = 5.5 Hz), 3.79 (2H, s), 2.62 - 2.60 (4H, m), 1.57 (8H, br)

Example 49

1-[5-(5-Ethylamino-1,3,4-thiadiazole-2-yl)-2-thienyl]hexahydro - 1H-azepin

By way of example 45 to obtain 820 mg specified in the connection header of 760 mg (3.0 mmol) of 2-(hexahydro-1H - azepin-1-yl)methyl)-thiophene-5-carboxylic acid hydrazide and 288 mg (3.3 mmol) ethylisothiocyanate.

So melting point: 112-114oC

1H-NMR ( ppm in DMSO-d6)

7.88 (1H, t), 7.22 (1H, d), 6.93 (1H, d), 3.80 (2H, s), 3.34 - 3.29 (2H, s), 2.63 - 2.61 (4H, m), 1.57 (8H, br), 1.20 (3H, t)

Example 50

1-Ethyl-3-[5-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1,3,4-thiadiazole-2-yl]urea

By way of example 46 get 220 mg specified in the connection header of 200 mg (of 0.68 mmol) of the compound obtained in stage 2) of example 45, and 51 mg (0,72 mmol) utilizationof.

So melting point: 203-204oC

1H-NMR ( ppm in DMSO-d6)

10.99 (1H, brs), 7.41 (1H, d, J = 3.7 Hz), 6.98 (1H, d, J = 3.7 Hz), 6.6 is)methyl] -2 - thienyl]-1,3,4-thiadiazole-2-yl]ndimethylacetamide

By way of example 47 get 380 mg specified in the connection header of 350 mg (1,19 mmol) of the compound obtained in stage 2) of example 45, and 0.15 ml of acetic anhydride.

So melting point: 248-249oC

1H-NMR ( ppm in DMSO-d6)

12.61 (1H, br), 7.52 (1H, d, J = 3.7 Hz), 7.0 (1H, d, J = 3.7 Hz), 3.83 (2H, s), 3.64 - 3.62 (4H, m), 2.21 (3H, s), 1.58 (8H, brs)

Example 52

1) 5-[(Hexahydro-1H-azepin-1-yl)methyl] -thiophene - 5-N-methoxy-N-methylcarbamic

8.0 g (29,0 mmol) 2-(Hexahydro-1H-azepin-1-yl) methylthiophene-5-carboxylic acid hydrochloride are suspended in 300 ml of tetrahydrofuran, add 10.1 ml (72,5 mmol) of triethylamine, 4.12 g (30,46 mmol) of hydroxybenzotriazole and a 8.34 g (of 43.5 mmol) and WSCD.HCl and the resulting mixture was stirred at room temperature for 1 hour. Then add 3.51 g (36,0 mmol) N, O-dimethylhydroxylamine-hydrochloride and at 8.36 ml (60,0 mmol) of triethylamine and then stirred overnight. To the reaction solution was added ethyl acetate and water and the organic layer is isolated and dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol (80: 1) to give 7.51 g specified in the connection header.

1H-NMR ( ppm, the hydro-1H-azepin-1-yl)methyl]thiophene

B stream of argon at 0oC to 39.0 ml (40,4 mmol) metallyte (1,04 M solution in diethyl ether) is added dropwise to 70 ml of anhydrous solution of tetrahydrofuran containing 9,51 g (33,68 mmol) of the compound obtained previously in stage 1), and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 3 hours. To the reaction solution was added water and ethyl acetate and the resulting organic layer is isolated and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol (80: 1), receiving 7,10 g specified in the connection header.

1H-NMR ( ppm in CDCl3)

7.55 (1H, d), 6.91 (1H, d), 3.83 (2H, d), 2.67 - 2.55 (4H, m), 2.52 (3H, s), 1.62 (8H, br)

3) (E)-N-[1-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl]-ethylidene] -4H-1,2,4-triazole-4-amine

of 1.93 g (22, 95mm mmol) 4-Amino-1,2,4-triazole and a catalytically effective amount of p-toluensulfonate acid is added to 50 ml of toluene solution containing 1.19 g (5.0 mmol) of the compound obtained previously in stage 2), and the mixture was refluxed for 1 week in the apparatus with the trap Dina-Rtgcasino order and dried over anhydrous magnesium sulfate, then the solvent is evaporated under reduced pressure, obtaining 1.28 g specified in the connection header.

1H-NMR ( ppm in CDCl3)

8.21 (2H, s), 7.48 (1H, d, J = 4.0 Hz), 7.94 (1H, d, J = 4.0 Hz), 3.85 (2H, s), 2.69 - 2.65 (4H, m), 2.35 (3H, s), 1.64 (8H, br)

4) (E,E)-N-(3-dimethylamino-1-[5-[(hexahydro-1H-azepin-1 - yl)methyl]-2-thienyl]-2-propylidene-4H-1,2,4-triazole-4-amine

2.76 ml (13,38 mmol) Tert-butoxybis(dimethylamine) methane (reagent of Brodarica (Bradereck) is added dropwise to 50 ml of tertrahydrofuran ring solution containing 1.23 g (of 4.05 mmol) of the compound obtained previously in stage 3), and the resulting mixture was stirred at room temperature for 48 hours in an argon atmosphere. The reaction solution is concentrated under reduced pressure, getting to 1.38 g specified in the connection header.

1H-NMR ( ppm in CDCl3)

8.23 (2H, s), 7.3 - 6.90 (3H, m), 4.74 (1H, d), 3.86 (2H, s), 2.89 (6H, s), 2.70 - 2.64 (4H, m), 1.63 (8H, br)

5) 6-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1,2,4-triazolo[4,3-b]pyridazin

717 mg (2.0 mmol) of the compound obtained previously in stage 4), dissolved in 20 ml of acetic acid and the resulting mixture is refluxed for 4 hours. The reaction solution is concentrated under reduced pressure, to the residue is added saturated aqueous solution of Bichat over anhydrous magnesium sulfate, the solvent is evaporated and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of acetone-toluene (2: 1) to give 690 mg specified in the connection header. After recrystallization of this compound from a mixture of ethyl acetate-isopropyl ether to obtain 174 mg of the target compound.

So melting point: 101-102oC.

1H-NMR ( ppm in CDCl3)

9.06 (1H, s), 8.09 (1H, d), 7.54 (1H, d), 7.49 (1H, d), 6.96 (1H, d), 3.88 (2H, s), 2.73 - 2.70 (4H, m), 1.68 -1.59 (8H, m)

Example 53

1) N, N-Dimethyl-N-[5-[(hexahydro-1H-azepin-1-yl)methyl]-2 - thienyl]-formamidine

and 3.72 g (15,65 mmol) 5-[(Hexahydro-1H-azepin-1-yl)methyl] thiophene-2-carboxamide are dissolved in 30 ml of N,N-dimethylformamide, add 3.4 ml (25.6 mmol) of N,N-dimethylformamidine and the resulting mixture was stirred at 80oC for 4 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is dissolved in chloroform, washed with water, and then dried over anhydrous magnesium sulfate. Viparita solvent, get 3,82 g specified in the connection header.

1H-NMR ( ppm in CDCl3)

8.58 (1H, s), 7.73 (1H, d), 6.88 (1H, d), 3.85 (2H, s), 3.19 (6H, s), 2.71 - 2.62 (4H, m), 1.62 (8H, brs)

2) 1-[5-(1,2,4-Oxidiazol-5-yl)-2-thienyl]hexahydro-1H - azepin 1.0 oxalate
< the, containing 1,91 g (of 7.25 mmol) of the compound obtained previously in stage 1), and the resulting mixture is stirred over night at room temperature. The reaction solution is concentrated under reduced pressure, to the residue add 10% aqueous solution of K2CO3, cooling water, and the resulting mixture extracted with chloroform. Then the obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol(100:1~80:1), receiving 42 mg specified in the title compound in the free form. Portion 40 mg of this compound in the free form was dissolved in 5 ml of methanol and add 2 ml of chloroform, methanol solution containing 13 mg of oxalic acid, and the resulting mixture was concentrated under reduced pressure. Then the obtained residue is recrystallized from methanol and diethyl ether, receiving 33 mg specified in the connection header.

So melting point: 131-132oC.

1H-NMR ( ppm in DMSO-d6)

9.48 (1H, br), 7.37 (1H, d), 7.19 (1H, d), 4.51 (2H, s), 3.14 (1H, br), 3.10 (1H, br), 1.80 (2H, m), 1.60 (4H, m)

Example 54

1-[5-(1H-1,2,4-Triazole-3-ausnog acid 440 mg (1.5 mmol) of the compound, previously obtained in stage 1) of example 53, and the resulting mixture was stirred at room temperature for 120 hours, and the idea at 80oC for 4 hours. The reaction solution is concentrated under reduced pressure, added 28% aqueous ammonia and chloroform, and then the obtained organic layer is isolated and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the obtained residue (333 mg) is recrystallized from ethyl acetate, receiving 99 mg specified in the title compound.

So melting point: 129-130oC

1H-NMR ( ppm in DMSO-d6)

9.11 (1H, s), 7.42 (1H, d), 6.95 (1H, d), 3.80 (2H, s), 2.63 - 2.61 (4H, m), 1.57 (8H, brs)

Example 55

1) 5-[(Hexahydro-1H-azepin-1-yl)methyl]-2-thiophenemethyl

19 g Hydroxylaminopurine add to 500 ml of an ethanol solution containing 70 g of 2-cyano-[5-(hexahydro-1H-azepin-1-yl) -methyl]thiophene, and the resulting mixture was stirred at 80oC for 5 hours. The reaction solution is concentrated and added 500 ml of a saturated aqueous solution of sodium bicarbonate and the mixture extracted three times with 300 ml of chloroform. The organic layers are combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated pretannage in the connection header.

1H-NMR ( ppm in CDCl3)

1.61 (8H, s), 2.50 - 2.80 (4H, m), 3.82 (2H, s), 4.56 (2H, br), 6.82 (1H, d), 7.10 (1H, d), 7.27 (1H, br)

2) Ethyl-3-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl]- 1,2,4-oxadiazol-5-carboxymethylated

Under ice cooling 0.5 ml of triethylamine and 0.4 ml of ethylchlorohydrin added to 20 ml chloroformate solution containing 831 mg of the compound obtained in stage 1) of example 55, and the resulting mixture was stirred at 40oC for 3 hours. To the reaction solution was added 50 ml of a saturated aqueous solution of sodium bicarbonate for the separation layer and the organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue is purified on a chromatographic column with silica gel, add 4 n hydrochloric acid-ethyl acetate, and then dropped when the crystals are collected by filtration, getting 370 mg specified in the connection header.

So melting point: 178-179oC.

1H-NMR ( ppm in DMSO-d6)

1.37 (3H, t), 1.50 - 1.90 (8H, m), 3.05 - 3.20 (2H, m), 3.35 - 3.50 (2H, m), 4.46 (2H, q), 4.67 (2H, d), 7.53 (1H, d), 7.91 (1H, d), 10.05 (1H, br)

Example 56

1) 1-[5-(5-Tert-butyldimethylsilyloxy-1,2,4-oxadiazol - 3-yl)-2-thienyl]hexahydro-1H-azepin

220 mg of sodium Hydride is added to OU the mixture is stirred at room temperature for 1 hour, add 1.8 g of ethyl-2-tert-butyldimethylsilyloxy, and then the resulting mixture was stirred at 60oC for 3 hours. To the reaction solution was added 200 ml of saturated brine and the resulting mixture was extracted three times with 100 ml of ethyl acetate. The organic layers are combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue is purified on a chromatographic column with silica gel, obtaining 1.1 g specified in the connection header.

1H-NMR ( ppm in CDCl3)

0.03 (6H, s), 0.78 (9H, s), 1.04 - 1.60 (8H, m), 2.40 -2.60 (4H, m), 3.70 (2H, s), 4.78 (2H, s), 6.75 (1H, d), 7.46 (1H, d)

2) 1-[5-(5-Hydroxymethyl-1,2,4-oxadiazol-3-yl)-2-thienyl] hexahydro-1H-aspiritual

to 4.0 ml of 1.0 n Solution tetramethylenedisulfotetramine added to 10 ml of tertrahydrofuran ring of a solution containing 1.1 g of 1-[5-[5-tert-butyldimethylsilyloxy-1,2,4-oxadiazol-3-yl) -2-thienyl] hexahydro-1H-azepine, and the resulting mixture is stirred for 2 hours at room temperature. The reaction solution is concentrated under reduced pressure, the obtained residue is purified on a chromatographic column with silica gel. Then add 4 n hydrochloric kislovka connection.

So melting point: 171-172oC

1H-NMR ( ppm in DMSO-d6)

1.50 - 1.75 (4H, m), 1.75 - 1.90 (4H, s), 3.00 - 3.20 (2H, m), 3.30 - 3.45 (2H, m), 4.63 (2H, d), 4.79 (2H, s), 6.11 (1H, br), 7.55 (1H, d), 7.79 (1H, d), 10.74 (1H, br)

Example 57

1) 1-[5-(5-Tert-butoxycarbonylamino-1,2,4 - oxadiazol-3-yl)-2-thienyl]hexahydro-1H-azepin

Using 1.7 g of 5-(hexahydro-1H-azepin-1-yl)methyl-2 - typename-oxime and 2.0 g of N-tert-butoxycarbonylamino complex ethyl ester, obtain 1.1 g specified in the header, connection method stage 1) of example 56.

1H-NMR ( ppm in CDCl3)

1.47 (9H, s), 1.63 (8H, br), 2.50 - 2.80 (4H, m), 3.86 (2H, d), 4.58 (2H, d), 5.20 (1H, br), 6.91 (1H, d), 7.61 (1H, d)

2) 1-[5-(5-Aminomethyl-1,2,4-oxadiazol-3-yl)-2-thienyl]hexahydro-1H-aspidistrafly 1/2 hydrate

1.1 g of 1-[5-(5-Tert-butoxycarbonylamino-1,2,4 - oxadiazol-3-yl)-2-thienyl]hexahydro-1H-azepine dissolved in 30 ml of 4 n/ a hydrochloric acid-1,4 dioxane and the resulting solution was stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure and the resulting residue is recrystallized from ethyl acetate, getting 966 mg specified in the connection header.

So melting point: 203-204oC.

1H-NMR ( ppm in DMSO-d6)

1.50 - 1.75 (4H, br), 1.85 (4H, s), 3.00 - 3.20 (2H, pin-1-yl)methyl] -2-thienyl]-1,2,4-oxazol-5-yl]acetate hydrochloride

3.6 g of Diethylmalonate added to 100 ml of toluene solution containing 2.0 g of 5-[(hexahydro-1H-azepin-1-yl)methyl]-thiophene-2 - amidoxime and the resulting mixture is stirred over night at 100oC. the Reaction solution was concentrated under reduced pressure, the obtained residue is purified on a chromatographic column with silica gel. Then add 4 N. hydrochloric acid-ethyl acetate and the precipitate is recrystallized from a mixture of ethanol-diethyl ether, obtaining 1.6 g specified in the title compound (Yield 53%)

So melting point: 122-123oC.

1H-NMR ( ppm in CDCl3)

1.22 (3H, t), 1.50 - 1.70 (4H, m), 1.75 - 1.90 (4H, m), 3.00 - 3.15 (2H, m), 3.30 - 3.45 (2H, m), 4.17 (2H, q), 4.37 (2H, s), 4.65 (2H, d), 7.53 (1H, d), 7.81 (1H, d), 10.34 (1H, br)

Example 59

1-[5-(5-Hydroxyethyl-1,2,4-oxadiazol-3-yl)-2-thienyl] hexahydro-1H-aspiritual

Under ice cooling to 650 mg of sodium borohydride is added to 40 ml of solution in THF, containing 1.5 g 2-[3-[5-[(hexahydro-1H-azepin-1 - yl)methyl]-2-thienyl] -1,2,4-oxazol-5-yl) acetate in the form of a free base, to the resulting mixture add 27 ml of methanol gradually, over about 1 hour while stirring and stirring is continued for another 1 hour. Under ice cooling to the reaction solution was added 1 N. hydrochloric acid, until the mixture is shaken out three times with chloroform, 50 ml The organic layers are combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue is purified through column chromatography with silica gel, add 4 N. hydrochloric acid-ethyl acetate, and precipitated when the crystals are collected by filtration and recrystallized from a mixture of ethanol-ethyl acetate, getting 725 mg specified in the connection header.

So melting point: 186-187oC

1H-NMR ( ppm in DMSO-d6)

1.50 - 1.70 (4H, m), 1.75 - 1.90 (4H, m), 3.00 - 3.20 (4H, m), 3.30 - 3.40 (2H, m), 3.85 (2H, t), 4.65 (2H, d), 7.51 (1H, d), 7.78 (1H, d), 10.27 (1H, br)

Example 60

1) 1-[5-(5-Tert-butoxycarbonylamino-1,2,4 - oxadiazol-3-yl)-2-thienyl]hexahydro-1H-aspidistrafly

Using 2.9 g of 5-[(hexahydro-1H-azepin-1-yl)methyl]-2-thiophene - amidoxime and 2.0 g of N-tert-butoxycarbonyl- -alanine methyl ester, 1.2 g specified in the connection header receive by way of example 56.

1H-NMR ( ppm in CDCl6)

1.44 (9H, s), 1.63 (8H, s), 2.55 - 2.80 (4H, m), 3.11 (2H, t), 3.60 (2H, t), 3.86 (2H, s), 5.15 (1H, br), 6.91 (1H, d), 7.61 (1H, d)

2) 1-[5-(5-Aminoethyl-1,2,4-oxadiazol-3-yl)-2-thienyl] hexahydro-1H-azepin

Using 1.1 g of 1-[5-(5-tert-butoxycarbonylamino-1,2, 4-oxadiazol-3-yl)-2-thienyl]hexahydro-1H-azepin, polochak">

So melting point: 210-211oC

1H-NMR ( ppm in DMSO-d6)

1.50 - 1.75 (4H, m), 1.84 (4H, s), 2.40 - 2.60 (2H, t), 3.10 - 3.20 (2H, t), 3.40 - 3.50 (4H, m), 4.63 (2H, d), 7.56 (1H, d), 7.80 (1H, d), 8.15 (3H, br), 11.00 (1H, br)

Example 61

1) 5-[(Hexahydro-1H-azepin-1-yl)methyl]-2 - thiophencarboxylic

3 ml of Triethylamine are added to 50 ml of a pyridine solution containing 4.6 g of 1-(5-cyano-2-thienyl)hexahydro-1H-azepine and stirring at room temperature, gaseous hydrogen sulfide is bubbled into the mixture in small portions gradually over 2 hours. The reaction solution is concentrated under reduced pressure, to the resulting residue are added 50 ml of saturated aqueous sodium bicarbonate solution and the resulting mixture is extracted with three times 50 ml of chloroform. The organic layers are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure and the obtained residue is purified on a chromatographic column with silica gel, obtaining 4.3 g specified in the connection header.

1H-NMR ( ppm in DMSO-d6)

1.56 (8H, s), 2.45 - 2.75 (4H, m), 3.74 (2H, s), 6.94 (1H, d), 7.54 (1H, d), 9.30 (1H, br), 9.47 (1H, br)

2) 1-[5-(4-Methylthiazole-2-yl)-2-thienyl]hexahydro-1H - aspidistrafly

730 mg of Chloroacetone added to 30 ml of ethanol recut over night at 80oC. the Reaction solution is cooled on ice, the pH adjusted to 1 by adding hydrochloric acid, and then concentrated under reduced pressure. The obtained residue is recrystallized from acetonitrile, receiving 1.6 g specified in the connection header.

So melting point: 187-190oC

1H-NMR ( ppm in DMSO-d6)

1.50 - 2.00 (8H, m), 2.38 (3H, s), 3.00 - 3.20 (2H, m), 3.35 - 3.45 (2H, m), 4.54 (2H, s), 7.32 (1H, s), 7.46 (1H, d), 7.58 (1H, d), 7.70 (1H, br), 11.36 (1H, br)

Example 62 1)

2-[5-phthalimidomethyl-2-thienyl]imidazo[1,2-a] pyridine

5-Bromoacetyl-2-(phthalimidomethyl)thiophene (0,80 g) and 2 - aminopyridine (0,23 g) is dissolved in anhydrous ethanol (50 ml) and refluxed for 6 hours. The resulting crystals are collected by filtration and purified through column chromatography with silica gel (chloroform:methanol = 100:1), receiving 0,38 g specified in the connection header.

1H-NMR ( ppm in DMSO-d6)

8.48 (1H, d), 8.24 (1H, s), 7.90 (4H, s), 6.79 - 7.56 (5H, m), 4.95 (2H, s)

2) 2-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] imidazo [1,2-a]-piridinkarboksamid

2-[5-Phthalimidomethyl-2-thienyl]imidazo[1,2-a]pyridine (0,38 g) and hydrazinehydrate (0,058 g) dissolved in a mixed solvent of methanol (10 ml) and chloroform (5 ml) and heated overnight at boiling under reflux. the alance silica gel (chloroform: methanol = 4:1), getting 0.14 g of intermediate aminomethylation. This intermediate compound (0.14 g) and 1,6-dibromohexane (0.16 g), potassium carbonate (0,19 g) and potassium iodide (0.05 g) is added to n-butanol (10 ml) and the resulting mixture is refluxed for 6 hours. The reaction solution is filtered, the resulting filtrate is concentrated and purified through column chromatography with silica gel (chloroform:methanol = 10:1), and then the purified product is converted into its salt using 4 N. hydrochloric acid - ethyl acetate in ether solution, getting 0,061 g specified in the connection header. T

So melting point: 214-217oC

Mass spectrum (bombing will believe, atoms m/z) (312 (M++1)

Example 63

1) 2-[5-Phthalimidomethyl-2-thienyl]imidazo[1,2-a]pyrimidine

Using 2-aminopyrimidine specified in the header connection get in the way of stage 1) of example 62.

1H-NMR ( ppm in DMSO-d6)

8.91 (1H, dd), 8.50 (1H, dd), 8.22 (1H, s), 7.90 (4H, d), 7.44 (1H, d), 7.00 - 7.13 (2H, m), 4.97 (2H, s)

2) 2-[5-[(Hexahydro-1H-azepin-1-yl)methyl]-2-thienyl]imidazo [1,2-a]-pyrimidinium

Specified in the title compound is obtained by way of stage 2) of example 62 using 2-[5-phthalimidomethyl-2-thienyl] imidazo[1,2-a] pyrimidine as starting material, and receiving salt, IP>8.92 (1H, dd), 8.51 (1H, dd), 8.21 (1H, s), 7.43 (1H, d), 7.05 (1H, dd), 6.99 (1H, d), 6.59 (2H, s), 3.88 (2H, s), 2.50 (4H, brd), 1.59 - 1.66 (8H, br)

Example 64

Ethyl-4-[5-[(Hexahydro-1H-azepin-1-yl)methyl]-2 - thienyl]benzoate

While cooling with ice and 3.8 ml (1 ad) diisobutylaluminium-toluene solution is added to 100 ml of anhydrous tertrahydrofuran ring solution of 2.5 g of bis(triphenylphosphine)Nickel (II) chloride and the resulting mixture is stirred for 10 minutes and then add 4.3 g of ethyl-4-iodobenzoate. Then the solution obtained from 3.0 g of 1-(2-thienyl)hexahydro-1-azepine, 60 ml of anhydrous tetrahydrofuran (THF, 9.6 ml (1,6 N.) solution of n-utility-hexane and 5.4 ml (1 ad ) ethereal solution of zinc chloride injected into the previously obtained mixture via cannula at -78oC in argon atmosphere, and then during the night stirred at room temperature. The reaction solution is filtered through celite, and the obtained filtrate is concentrated under reduced pressure, the obtained residue was added 100 ml of saturated aqueous sodium bicarbonate solution and the resulting mixture is extracted three times with 100 ml of chloroform. The organic layers are combined, washed with saturated salt brine and concentrated under reduced pressure.

The obtained residue is purified on a chromatographic column with filtrowanie, getting 290 mg (4%) specified in the connection header.

So melting point: 194-197oC

1H-NMR ( ppm in DMSO-d6)

1.34 (3H, t), 1.55 - 1.90 (8H, m), 3.10 - 3.20 (2H, m), 3.30 - 3.50 (2H, m), 4.33 (2H, q), 4.62 (2H, d), 7.92 (1H, d), 7.70 (1H, d), 7.82 (2H, d), 8.01 (2H, d), 9.85 (1H, br)

Example 65

3-Amino-5-[5-[(pyrrolidin-1-yl)methyl]-2-thienyl]-1H-1,2,4 - triazole

By way of example 38 obtain 580 mg specified in the connection header of 1.8 g (7,99 mmol) 2-(1-pyrrolidinyl)methylthiophene-5-carboxylic acid hydrazide.

So melting point: 180-181oC

1H-NMR ( ppm in DMSO-d6)

11.96 (1H, brs), 7.21 (1H, brs), 6.87 (1H, brs), 6.05 (2H, brs), 3.70 (2H, s), 2.51 - 2.48 (4H, m), 1.73 - 1.66 (4H, m)

Example 66

1-[5-(5-(Amino-1H-1,2,4-triazole-3-yl)-3 - thienyl]hexahydro-1H-azepin

By way of example 38 get 2,03 g is specified in the header connections of 3.32 g (of 13.1 mmol) of 4-(hexahydro-1H-azepin-1-yl) methyl-thiophene-2-carboxylic acid hydrazide.

So melting point: 167-168oC

1H-NMR ( ppm in DMSO-d6)

12.02 (1H, br), 7.33 (1H, s), 7.18 (1H, s), 6.03 (2H, br), 3.56 (2H, s), 2.56 - 2.51 (4H, m), 1.55 (8H, s)

Example 67

1-[2-[5-(5-Amino-1H-1,2,4-triazole-3-yl)-2 - thienyl]ethyl]hexahydro-1H-azepin

By way of example 38 get 2,39 g specified in the connection header from 3,70 g (13.84 mmol) 5-[2-(hexahydro-1H-azepin-1-yl) -ethyl]thiophene-2-carbon is 1H, s), 6.79 (1H, s), 6.00 (2H, br), 2.90 - 2.86 (2H, m), 2.70 - 2.62 (6H, m), 1.59 - 1.56 (8H, m)

Example 68

3-Amino-5-[5-(1H-imidazol-1-ylmethyl)-2-thienyl] -1H-1,2,4-triazole

By way of example 38 obtain 177 mg specified in the connection header from 360 mg (1,36 mmol) of 2-(1H-imidazol-1-yl)methylthiophene - 5-carboxylic acid hydrazide.

So melting point: 178-180oC.

1H-NMR ( ppm in DMSO-d6)

12.03 (1H, brs), 7.75 (1H, brs), 7.24 (1H, d), 7.22 (1H, brs), 7.03 (1H, d), 6.91 (1H, brs), 6.09 (2H, brs), 5.38 (2H, brs)

Example 69

2-Amino-5-[5-(1H-imidazol-1-ylmethyl)-2-thienyl] -1,3,4-oxadiazol-hydrobromide

By way of example 43 receive 866 mg specified in the connection header of 1,11 g (5.0 mmol) of 2-(1H - imidazol-1-yl)methylthiophene-5-carboxylic acid hydrazide.

So melting point: 261-262oC

1H-NMR ( ppm in DMSO-d6)

9.28 (lH, s), 7.86 (1H, s), 7.71 (1H, s), 7.43 (1H, s), 7.37 - 7.34 (3H, m), 5.77 (2H, brs)

Example 70

N-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl] -1,3,4-oxadiazol-2-yl] benzenedithiol

1.8 ml (15.0 mmol) of benzoyl chloride is added to 15 ml of pyridine solution containing 278 mg (1.0 mmol) of the compound of example 43 and the resulting mixture was stirred at 80oC for 10 days. The reaction solution is concentrated under reduced pressure, the obtained residue is added chloroform, imaut on a chromatographic column with silica gel. Then, the resulting crystals are recrystallized from a mixture of ethanol-diisopropyl ether, getting 241 mg specified in the title compound.

So melting point: 182-184oC

1H-NMR ( ppm in DMSO-d6)

12.23 (1H, br), 10.96 (1H, br), 8.04 (2H, d), 7.75 (1H, d), 7.68 (1H, t), 7.61 - 7.54 (3H, m), 4.65 (2H, s), 3.45 - 3.43 (2H, br), 3.10 (2H, br), 1.85 (4H, brs), 1.65 (4H, br)

Example 71

1-[5-(5-Benzylamino-1,3,4-oxadiazol-2-yl)-2-thienyl] hexahydro-1H-azepin

of 0.13 ml (1.05 mmol) Benzenesulfonate added to 25 ml of the combined acetonitrile solution containing 253 mg (1.0 mmol) 2- (hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide and the resulting mixture was stirred at room temperature for 40 hours, add 718 mg (2.2 mmol) of 1,2 - dibromo-1,1,2,2-tetrachlorethane, 1,22 ml of triethylamine and of 1.16 g of triphenylphosphine, and then the resulting mixture was stirred at room temperature for 9 hours. The reaction solution is concentrated and add chloroform to the residue, and then washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is purified through column chromatography with silica gel, getting 122 mg specified in the title compound in the free form. Of 117 mg of this compound are salt, using 27 mg y theoC.

1H-NMR ( ppm in DMSO-d6)

8.42 (1H, t), 7.45 (1H, d), 7.38 - 7.26 (7H, m), 4.43 (2H, d), 4.32 (2H, br), 3.00 (4H, brs), 1.72 (4H, brs), 1.59 (4H, brs)

Example 72

1-[5-(5-Hydroxy-1,3,4-oxadiazol-2-yl)-2-thienyl]hexahydro - 1H-azepin

760 mg (3.0 mmol) of 2-(Hexahydro-1H-azepin-1 - yl)methylthiophene-5-carboxylic acid hydrazide are dissolved in 30 ml of tetrahydrofuran and add 3 ml of N, N-dimethylformamide, 583 mg (3.6 mmol) of 1,1'-carbonyldiimidazole and 0.84 ml (6.0 mmol) of triethylamine and the resulting mixture is refluxed for 3 hours. The reaction solution is concentrated and to the residue is added chloroform, then washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is purified through column chromatography with silica gel, getting 793 mg specified in the connection header.

So melting point: 117-119oC

1H-NMR ( ppm in CDCl3)

8.84 (1H, br), 7.44 (1H, d), 6.91 (1H, d), 3.89 (2H, brs), 2.74 - 2.71 (4H, m), 1.74 - 1.58 (8H, m)

Example 73

1-[5-[5-(2-Pyridyl)-1,3,4-oxadiazol-2-yl] -2 - thienyl] hexahydro-1H-sepenobscot

8 ml of Pyridine and 1.28 g of the hydrochloride of the acid chloride pikolinos acid is added to 50 ml of dichloromethane solution containing 1,010 mg (4.0 mmol) of 2-(hexahydro-1H-azepin-1-yl)metaltype auktsionnyi the solution washed with water, and then dried over anhydrous magnesium sulfate. The solvent is evaporated, and then the obtained residue is subjected to azeotropic distillation 4 times with 50 ml of toluene, to deliver 1.5 g of crystals. A portion of the crystals in 268 mg (0.75 mmol) dissolved in 30 ml of dichloromethane, added to 0.23 ml of triethylamine and 140 mg (0.83 mmol) of 2-chloro-1,3 - dimethylimidazolidine under ice cooling and the resulting mixture was stirred at room temperature for 4 days. The reaction solution is washed with water, dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is purified through column chromatography with silica gel, receiving 87 mg specified in the title compound in the free form. Portion 75 mg of this compound turned into salt, using 19 mg of oxalic acid. Get 76 mg specified in the connection header.

So melting point: 217-218oC

1H-NMR ( ppm in DMSO-d6)

8.80 (1H, d), 8.25 (1H, d), 8.08 (1H, m), 7.86 (1H, d), 7.66 (1H, m), 7.33 (1H, brs), 4.29 (2H, brs), 1.72 (4H, brs), 1.61 (4H, brs)

Example 74

1-[5-(5-Methyl-1,3,4-oxadiazol-2-yl)-2-thienyl] hexahydro-1H-sepenobscot

Using 507 mg (2.0 mmol) 2-(hexahydro-1H-azepin - 1-yl)-methylthiophene-5-carboxylic acid hydrazide and 0.23 ml (2.4 mmol) of acetic anhydride, by the way note the m in DMSO-d6)

7.68 (1H, d), 7.28 (1H, d), 4.28 (2H, s), 2.56 (3H, s), 1.71 (4H, brs), 1.59 (6H, brs)

Example 75

1-[5-(5-Phenyl-1,3,4-oxadiazol-2-yl)-2-thienyl]hexahydro-1H - azepin

687 mg (4.0 mmol) of Methylbenzimidazole added to 7 ml of pyridine solution containing 507 mg (2.0 mmol) 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide and the resulting mixture is refluxed for 4 hours. The reaction solution is concentrated and to the residue is added chloroform, then washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is purified through column chromatography with silica gel, receiving 110 mg specified in the connection header.

So melting point: 95-97oC

1H-NMR ( ppm in CDCl3)

8.13 - 8.10 (2H, m), 7.68 (1H, d), 7.56 - 7.50 (4H, m), 3.89 (2H, s), 2.72 - 2.70 (4H, m), 1.73 - 1.60 (8H, m)

Example 76

N-Benzyl-5-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1H-1,2,4-triazole-3-carboxamide

1.0 g (3.0 mmol) of the compound obtained in example 40, dissolved in 3.3 ml (30.0 mmol) of benzylamine, and the resulting solution was stirred at 80oC for 4 hours. To the obtained residue is added chloroform, washed with water and dried over anhydrous magnesium sulfate. The solvent you diisopropyl ether and recrystallized from a mixture of ethyl acetate-n-hexane, getting 997 mg specified in the title compound.

So melting point: 137-139oC.

1H-NMR ( ppm in DMSO-d6)

9.20 (1H, br), 7.53 (1H, d), 7.34 (5H, br), 7.25 (1H, t), 6.99 (1H, d), 4.48 (2H, d), 3.82 (2H, s), 2.61 (4H, brs), 1.54 (8H, brs)

Example 77

N-Benzyl-5-[5-[(hexahydro-1H-azepin-1 - yl)methyl]- 2-thienyl]-1H-1,2,4-triazole-3-ylmethylamino, 3/2 fumarate

10 ml of Anhydrous tertrahydrofuran ring solution containing 594 mg (1.5 mmol) of the compound obtained in example 76, is added dropwise to 5 ml of anhydrous tetrahydropyranol suspension containing 230 mg (6.0 mmol) of sociallyengaged and the resulting mixture is refluxed for 11 hours. Then add 460 mg (12,0 mmol) sociallyengaged, and the mixture was again refluxed for 3 days. To the reaction mixture add decahydrate sodium sulfate, and the resulting insoluble substance is filtered off. The solvent is evaporated, and then the obtained residue is purified on a chromatographic column with silica gel, receiving 104 mg specified in the title compound in the free form. A portion of this compound in 74 mg turned into salt, using 33 mg of fumaric acid and precrystallization it from methanol. The result is 63 mg specified in reception is 7.26 (1H, m), 6.97 (1H, brs), 6.60 (3H, s), 3.86 - 3.84 (4H, m), 3.80 (2H, brs), 2.68 - 2.66 (4H, m), 1.58 (8H, brs)

Example 78

[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2-thienyl]-1H-1,2,4-triazole-3-yl]methylbenzoate

According to the method of example 6 to obtain 351 mg specified in the connection header of 292 mg (1.0 mmol) of the compound of example 41.

The mass spectrum of the bombing put the atoms (m/z 397 (M++1)

1H-NMR ( ppm in CDCl3)

8.04 (2H, d), 7.56 (1H, t), 7.50 (1H, d), 7.41 (3H, t), 6.87 (1H, d), 5.49 (2H, s), 3.87 (2H, s), 2.74 - 2.66 (4H, m), 1.70 - 1.54 (8H, m)

Example 79

1-[5-[5-(2-Pyridyl)-1H-1-2,4-triazole-3-yl] -2-thienyl] hexahydro-1H-azepin

81 mg (1.5 mmol) of sodium Methoxide added 13.5 ml of a methanol solution containing 1.56 g (15.0 mmol) of 2-cyanopyridine, and stirred at room temperature for 3.5 hours. The reaction mixture is cooled on ice, added with ice cooling of 0.085 ml (1.5 mmol) of acetic acid, and 1.52 g (6.0 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide, and then the resulting mixture was stirred at room temperature for 24 hours. Fallen thus precipitated crystals are collected by filtration, receiving of 1.97 g of crystals. Portion in 894 mg (2.5 mmol) of these crystals are dissolved in 13 ml of acetic acid and refluxed for 6,5 chat over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is treated through column chromatography with silica gel, getting 715 mg specified in the connection header.

So melting point: 160-162oC.

1H-NMR ( ppm in DMSO-d6)

14.74 (1H, br), 8.72 (1H, d), 8.12 (1H, d), 8.01 (1H, dt), 7.54 (1H, m), 7.50 (1H, d), 6.98 (1H, d), 3.83 (2H, s), 2.68 - 2.60 (4H, m), 1.58 (8H, brs)

Example 80

1-[5-(2-Methyl-2H-1,2,4-triazole-3-yl)-2-thienyl] hexahydro-1H-azepine hydrochloride

0.3 ml (5,59 mmol) Methylhydrazine added dropwise 6.5 ml of a solution in acetic acid 820 mg (2.8 mmol) of the compound obtained in stage 1) of example 53, and the resulting mixture was refluxed for 5 days. Then add 0.6 ml (11, 18 mmol) methylhydrazine and the mixture was again refluxed for 2 days. The solvent is evaporated, add 28% aqueous ammonia and chloroform, and then the obtained organic layer is isolated and washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue purified on a chromatographic column with silica gel. Get it salt using 4 N. HCl-ethyl acetate, and then recrystallized from acetonitrile, getting 204 mg specified in the connection header.

So 4.07 (3H, s), 3.40 - 3.34 (2H, m), 3.13 -3.05 (2H, m), 1.83 (4H, brs), 1.66 - 1.58 (4H, m)

Example 81

1-[5-[3-(2-Pyridyl)-1,2,4-oxadiazol-5-yl)-2-thienyl] hexahydro-1H-sepenobscot

Using 1.07 g (4.0 mmol) of ethyl 5-[(hexahydro-1H-azepin - 1-yl)-methyl-2-thienyl]carboxylate and 823 mg (6.0 mmol) of 2-pyridylmethylene, obtain 149 mg specified in the title compound in the free form by the method of example 1. Portion 72 mg of this compound turned into salt, using 18 mg of oxalic acid. Get 57 mg specified in the connection header.

So melting point: 164-166oC

1H-NMR ( ppm in DMSO-d6)

8.79 (1H, d), 8.14 (1H, d), 8.08 - 8.03 (2H, m), 7.64 (1H, m), 7.40 (1H, d), 4.34 (2H, s), 2.98 (4H, br), 1.73 (4H, brs), 1.61 (4H, brs)

Example 82

1) 0-[5-(Hexahydro-1H-azepin-1-yl)methyl-2 - thenoyl]-3-phthalimidopropyl

9,59 g (93,0 mm) 3-Aminopropionitrile dissolved in 288 ml of 1,3-dimethyl-2-imidazolidinone add of 14.46 g (97,65 mmol) of anhydride and phthalic acid and the resulting mixture was stirred at room temperature for 1 hour and then at 140oC for 2 hours. The reaction solution is cooled to room temperature and add the 15.6 ml (111,6 mmol) of triethylamine and 16.4 g (55,8 mmol) of the hydrochloride of 5-(hexahydro-1H - azepin-1-yl)methyl-2-thiophenecarbonitrile. The resulting mixture peremeshivayte crystals are collected by filtration and washed with distilled water, getting 19,96 g 0-[5-(hexahydro-1H-azepin-1-yl)methyl-2 - thenoyl]-3-phthalimido-propionamidoxime (79% yield based on hydrochloride (hexahydro-1H-azepin-1-yl)-methyl-2 - thiophenecarbonitrile).

1H-NMR ( ppm in DMSO-d6)

7.85 (4H, s), 7.00 (1H, d), 6.57 (1H, d), 3.82 (2H, s), 2.51 (4H, br), 1.56 (8H, brs)

2) N-[2-[5-[5-[(Hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl]-1,2,4-oxadiazol-3-yl]ethyl]phthalimidopropyl

To to 2.57 g 0-[5-(Hexahydro-1H-azepin-1-yl)methyl-2-thenoyl] -3 - phthalimidopropyl add 100 ml of xylene and the resulting mixture is refluxed for 8 hours. The reaction solution is cooled to room temperature, filtered and cooled with ice add 2 ml of 4 N. hydrochloric acid-ethyl acetate. Then dropped in the precipitated crystals are collected by filtration, obtaining 2.2 g (yield 82%) specified in the connection header.

Example 83

1-[5-(5-Amino-1H-1,2,4-triazole-3-yl)-2 - thienyl)hexahydro-1H-azepin

500 ml of 1,3-Dimethyl-2-imidazolidinone and 18.0 g (163,2 mmol) aminophenylalanine add to 24,0 g (81,6 mmol) 5- (hexahydro-1H-azepin-1-yl)methyl-2-thiophenecarbonitrile and the resulting mixture was stirred at room temperature for 1 hour. Then add 16.3 g (60% in oil, 408 mmol) and the resulting mixture AC is water and 500 ml of n-hexane to separate the layers. To the obtained lower layer add 1000 ml of saturated brine, and then this mixture is extracted seven times with 500 ml of ethyl acetate. An ethyl acetate layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure and add 1000 ml of acetonitrile. While cooling with ice, add 150 ml of 4 N. hydrochloric acid-ethyl acetate and precipitated in the precipitated crystals are collected by filtration. The obtained crystals are added to 200 ml of 1 n sodium hydroxide, extracted three times with 200 ml of ethyl acetate, dried over anhydrous sodium sulfate, and then concentrated to 1/10 volume under reduced pressure. Fallen thus precipitated crystals are collected by filtration, getting 10.4 g (yield 51%) specified in the connection header.

In the example in the end of the description table.2 shows the chemical structures of the compounds obtained in examples 1-83.

In addition to presenting other illustrative compound, the following compounds can be synthesized analogously to the above-described method of obtaining, by the methods disclosed in the examples, or modifications of them, or by other methods or their modifications, known to specialists.

5-benzylamino-3-[5-[(hexahydro-1H-azepin-1-yl) methyl] -2-thienyl] -1H-1,2,4-triazole

5-amine is)methyl] -2-thienyl]-1H-1,2,4-thiadiazole

5-benzoylamino-3-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl]-1H-1,2,4-thiadiazole

5-benzylamino-3-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl] -1H-1,2,4-thiadiazole

5-aminomethyl-3-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1H-1,2,4-triazole

5-phthalimidomethyl-3-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl]-1H-1,2,4-triazole

3 benzylamino-5-[5-[(hexahydro-1H-azepin-1-yl) methyl] -2-thienyl] -1,2,4-oxadiazol

3 benzylamino-5-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1,2,4-oxadiazol

2 benzoylamino-5-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl] -1,3,4-oxadiazol

2 benzylamino-5-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1,3,4-oxadiazol

4 benzylamino-3-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl]-1H-1,2,4-triazole

4 benzoylamino-3-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2 - thienyl]-1H-1,2,4-triazole

5-benzylamino-3-[5-[(hexahydro-1H-azepin-1-yl) methyl] -2-thienyl]-1H-1,2,4-triazole

5-benzoylamino-3-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl]-1H-1,2,4-triazole

1-benzyl-3-[[3-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1H-1,2,4-triazole-5-yl]methyl]urea

5-benzoylamino-3-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1H-1,2,4-triazole

5-benzoyloxymethyl-3-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl]-1H-1,2,4-triazo[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl]-1H-1,2,4-triazole

[3-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -1H-1,2,4 - triazole-5-yl]methyl-N-benzylcarbamoyl

5-amino-3-[5-[(pyrrolidin-1-yl)methyl]-2-thienyl]-1H-1,2, 4-triazole

5-amino-3-[4-[(hexahydro-1H-azepin-1-yl)methyl] - 2-thienyl] -1H-1,2,4-triazole

1-[5-(2-tridil)-2-thienyl]hexahydro-1H-azepin

1-[5-(2-furyl)-2-thienyl]hexahydro-1H-azepin

1-[5-(2-pyrimidyl)-2-thienyl]hexahydro-1H-azepin

1-[5-(4-amino-2-pyridyl)-2-thienyl]hexahydro-1H-azepin

1-[5-(4-AMINOPHENYL)-2-thienyl]hexahydro-1H-azepin

5-amino-3-[5-(hexahydro-1H-azepin-1-yl)methyl-2-thienyl] - 1,2,4-oxadiazol

2-amino-4-[5-(hexahydroazepin)methyl-2-thienyl]imidazol

1. A derivative of thiophene of the General formula I or its pharmaceutically acceptable salt:

< / BR>
in which R1represents the formula A1-X1-R3,

R2is a possible formula AND2-X2- R4,

the ring represents 1) 4-10-membered nitrogen-containing cycloalkyl ring or 2) a 5 - or 6-membered nitrogen-containing unsaturated heterocycle,

the ring of the AG represents an aryl ring or a 5-membered aromatic heterocycle which contains 2 or 3 of one or more kinds of heteroatoms selected from the group consisting of a nitrogen atom, the heteroatoms, selected from the group consisting of nitrogen atom,

AND1AND2and a3the same or different from each other, each represents a bond or lower alkylenes group

X1and X2the same or different from each other, and each represents a bond or a formula-O-, -S-, -NR5-,

< / BR>
< / BR>
< / BR>
R5, R6, R7, R8, R9, R10, R12and R13the same or different from each other, each represents a hydrogen atom or a lower alkyl group;

R3and R4the same or different from each other and each represents a hydrogen atom, cyclic aminogroup, which may be substituted and may be condensed with benzene ring, or a lower alkyl group, cycloalkyl group, aryl group or aracelio group, which may, respectively, be substituted, provided that if the AG ring is a thiazole ring, one of A1and A2represents the lower alkylenes group, if the AG ring is thiophene ring, at least one of R3and R4represents a group other than a hydrogen atom; and, if the AG ring represents a benzene ring, the case when one of R1me.

2. A derivative of thiophene or its pharmaceutically acceptable salt p. 1, where In the ring is 4 to 10-membered nitrogen-containing cycloalkyl ring.

3. A derivative of thiophene or its pharmaceutically acceptable salt under item 1 or 2, where the ring is hexahydroazepin ring.

4. A derivative of thiophene or its pharmaceutically acceptable salt according to any one of paragraphs.1 to 3, where a3represents a methylene group.

5. A derivative of thiophene or its pharmaceutically acceptable salt according to any one of paragraphs. 1 - 5, where the ring of the AG represents a thiazole, oxadiazole, triazole, thiadiazole, imidazopyridine, imidazopyrimidines or triazolopyridine.

6. A derivative of thiophene under item 1, which is 5-[5-[(hexahydro-1H-azepin-1-yl)methyl] -2-thienyl] -3-phthalimido-ethyl-1,2,4-oxadiazole, 5-amino-3-[5-[(hexahydro-1H-azepin-1-yl)-methyl] -2-thienyl]-1H-1,2,4-triazole or its pharmaceutically acceptable salt.

7. Pharmaceutical composition having anti-PCP activity, characterized in that it contains a derivative of thiophene or its pharmaceutically acceptable salt according to any one of paragraphs.1 to 6 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition under item 8, which is

 

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The invention relates to a new derived tetrazole having effect in reducing blood sugar and lipid in the blood, and it contains the tool for use in the treatment of diabetes and hyperlipemia

The invention relates to new chemical compound is 2-(N-morpholin)-4-methylpyridine, which can be used as inhibitors of acid corrosion of steel by acid treatment of wells or refineries

The invention relates to derivatives of 5-phenyl-3-(piperidine-4-yl)-1,3,4-oxadiazol-2(MN)-it General formula I, in which R1is a group (C1-C4)alkyl or the group (C3-C7)cycloalkenyl; X1is a hydrogen atom or halogen or the group (C1-C4)alkoxy or or1and X1together, the group of the formula-och2O-, -O(CH2)2-; -O(CH2)2O - or-O(CH2)3O-; X2is a hydrogen atom or amino group; X3is a hydrogen atom or halogen; R2is a hydrogen atom or a possibly substituted group (C1-C6)alkyl, or a phenyl group(C1-C4)alkyl which may be substituted on the phenyl ring, or a phenyl group(C2-C3)alkenyl, or group of phenoxy(C2-C4)alkyl or cyclo(C3-C7)alkylaryl, or group of 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl, or gruppa General formula -(CH2)nFROM a-Z, in which n = 1 to 6, a Z - group piperidine-1-yl or 4-(dimethylamino)piperidine-1-yl

The invention relates to new isoxazol derivative of General formula I, where R1denotes optionally substituted C6-C14airgroup or 5-6-membered heterocyclic group containing one heteroatom selected from nitrogen, oxygen, sulfur; R2denotes a hydrogen atom, halogen atom, optionally substituted C1-C6alkyl group, a C2-C6alkenylphenol group2-C6alkylamino group3-C10cycloalkyl group3-C10cycloalkenyl group, cyano, carboxitherapy,1-C7alkanoglu,2-C7alkoxycarbonyl group or optionally substituted carbamoyl; R3denotes optionally substituted by an amino group or a saturated 5-6-membered heterocyclic group containing a nitrogen atom; X represents an oxygen atom or a sulfur atom; n denotes an integer from 2 to 6, and their pharmaceutically acceptable salts

The invention relates to new chemical compounds, in particular derivatives (1,2,3-triazolyl)-1,2,5-oxadiazole General formula I, where R = NH2or< / BR>
and, if R1= N, R2lowest hydroxyalkyl, or, if R1- lower alkyl, lower hydroxyalkyl, aryl, R2= N, the lower hydroxyalkyl or a radical of General formula-C(O)R3where R3= HE, NH2, lower alkyl or lower alkoxyl, potentiating NO-dependent activation of the soluble form of guanylate cyclase (RGC)

The invention relates to compounds of formula I:

< / BR>
where X denotes O, S, NH or NA;

Y represents substituted with R2aziridinyl, azetidinone, pyrolidine, piperidinyl, hexahydroazepin or pieperazinove the rest;

R1indicatesor< / BR>
R2represents CrH2r-COOR3;

R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

B denotes H, a, cycloalkyl with 3-7 C atoms, Ar-CkH2kor aydinbey the rest;

Ar denotes unsubstituted or mono - or twice substituted with A, Cl, Br, I, NO2, CN, OA, OH, NH2, NHA and/or NA2phenyl or benzyl residue;

"k" denotes 1, 2, 3 or 4;

"m" and "r" each, independently of one another, denote 0, 1, 2, 3 or 4; and

"n" represents 2, 3 or 4,

and their physiologically acceptable salts

The invention relates to new 4-substituted piperidine derivative that is related to ones antagonists neirokinina 2 (NK), which can be used, for example, in the treatment of diseases such as asthma, and method of production thereof

The invention relates to benzothiadiazine General formula I, in which X represents hydrogen or halogen, Y represents-CN or-NR1R2where l denotes an integer of 1 or 2, m represents an integer of 0, 1 or 2, n denotes an integer equal to 2, 3 or 4, except for the case when Y - SP, n may be equal to 1, R1denotes hydrogen, (C1-C6)alkyl or alkoxycarbonyl, R2denotes hydrogen, (C1-C10)alkylsulphonyl, (C3-C12)cycloalkylcarbonyl, hydroxy(C1-C6)alkylsulphonyl, phenylcarbinol, possibly substituted with halogen, cryptomaterial, thienylboronic or benzotriazolyl, or R1and R2together with the nitrogen atom to which they are bound, form a loop formula II, where a denotes C=0 or CH2In stands WITH a= 0, SNON, CH2or CH2CH2and Z represents hydrogen, and their pharmaceutically acceptable additive salts of acids, provided that when X=N, n can be 4, and R1and R2cannot be both hydrogen
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