Derivatives of 6-methoxy-1h-benzotriazol-5-carboxamide, the method of receiving and containing pharmaceutical composition

 

(57) Abstract:

Describes new derivatives of 6-methoxy-1H-benzotriazol - 5-carboxamide of the formula I, in which R1denotes ethyl or cyclopropylmethyl, R2denotes a hydrogen atom, methyl or ethyl, n is 1, 2 or 3 and the wavy line means that the configuration of the substituents on the carbon atom that is associated with the N-atom in the amide group is RS, R or S, or a pharmaceutically acceptable acid additive salts are acidic. Also describes the methods for their preparation; pharmaceutical compositions containing a compound of formula I or its pharmaceutically acceptable acid additive salt, and the new intermediate compounds. The compounds possess high antiemetic activity and activity that increase the contractility of the gastrointestinal tract. In addition, they have low depressant activity in relation to the Central nervous system (CNS) and is therefore useful for the treatment and prevention of functional disorders of the gastrointestinal tract associated with various diseases and therapeutic treatments, as a means of enhancing the contractility of the gastrointestinal tract. 6 C. and 5 C.p. f-crystals., 7 table.

Prior art

In JP-A 104572/1990 described that the compounds represented by the following formula [A] , have activity, enhancing the mobility of the gastrointestinal tract and is useful as an antiemetic or tools that increase the motility of the gastrointestinal tract:

< / BR>
[where R1denotes lower alkyl or optionally substituted aryl(lower)alkyl,

R2denotes a hydroxy, alkoxy, alkenylacyl, cycloalkane or substituted alkoxy (substituents are halogen, hydroxy or oxo),

R3denotes amino, disubstituted amino, or acylamino,

X represents a simple bond or a lower alkylene,

Y represents a simple bond or a group expressed by the formula:

-CH2-, -O-, -S-, -SO-, -SO2or-NR6-,

where R6denotes lower alkyl or optionally substituted aryl (lower) alkyl; or can form together with R1ethylene,

n is 0 or 1, and

the dotted line represents a double bond which can be present when Y represents-CH2and n is 0, provided that:

i) when Y represents-NR6or a simple bond, n is 0;

ii) when Y represents-O-, n is 1;

iii) when Y represents a simple bond or-CH2and n is 0, P1denotes optionally substituted aryl (lower) alkyl;

and

iv) when n is 0, X denotes the lowest alkylen].

However, the mentioned JP-A-104572/1990 does not contain a specific description of the compounds of this invention represented by the following formula (I) simultaneously 1H-benzotryazolyl skeleton and the nitrogen-containing 7-, 8 - or 9-membered aliphatic cycle, in particular, their optically active compounds and pharmacological activities of optically active compounds.

JP-A-83737/1977 describes that compounds represented by Priya apomorphine-induced stereotyped reactions and methamphetamine - induced stereotyped interaction and is therefore useful as CNS-depressants, in particular as antipsychotic drugs:

< / BR>
(where A IS CO denotes 4-amino-5-chloro-2-methoxybenzoyl, 5 - ethylsulfonyl-2-methoxybenzoyl or 2-methoxy-4,5 - semidomestic;

In denotes allyl or optionally substituted benzyl group, and m is 1 or 2).

In addition, JP-A-100473/1977 describes compounds represented by the following formula [C]:

< / BR>
(in which P1denotes lower alkoxy, R2denotes optionally substituted benzyl, and m is 1 or 2).

However, in the compounds represented by the above formula [B] or [C] attached to the amide component (-CONH-) cycle is a 5 - or 6-membered included in the cycle, the nitrogen atom is substituted by an allyl or benzyl group, and from this point of view, they differ from the structure of the compounds represented by the following formula (I) according to this invention. In addition, their pharmacological activity, again, different from the compounds according to the invention.

On the other hand it is known that 4-amino-5-chloro-N-[2 (diethylamino)ethyl]-2-methoxybenzamide [generic name: metoclopramide; Cf. Merck Index, Ilth ed. 6063 (1989)] has antiemetic activity and with that ActiveCare or prevention of functional disorders of the gastrointestinal tract, associated with various diseases and intake of therapeutic agents, as a means of enhancing mobility (contractility) of the gastrointestinal tract. However, metoclopramide has CNS-depressant activity resulting from its dopamine D2-receptor antagonistic activity, which is an obstacle to its clinical application. Due to the increasing complexity of life in human society and the increasing number of elderly people increases the number of patients suffering from symptoms associated with dysfunction of the gastrointestinal tract, and the necessity of treatment leads to an increase in demand for the compound or compounds with low CNS - depressant activity and yet highly antiemetic activity and activity-enhancing reduction of the gastrointestinal tract.

Description of the invention

Conducted extensive research and found that 6-methoxy-1H-benzotriazol-5-carboxamide derivatives in which the nitrogen atom in the amide moiety (-CONH-) substituted 1-substituted-azacycloheptan-3-yl group, 7-, 8 - or 9-membered ring, in particular, (R)-6-methoxy-1H-benzotriazol-5-carboxamide the amplifying reduction of the gastrointestinal tract and nevertheless possess a remarkably low CNS-depressant activity. Thus, the invention is completed scientific work.

The purpose of this invention is to obtain new 6-methoxy-1H - benzotriazol-5-carboxamide derivatives, in particular, (R)-6 - methoxy-1H-benzotriazol-5-carboxamide derivatives having the R - configuration that has both excellent antiemetic activity and activity-enhancing reduction of the gastrointestinal tract. Another purpose of this invention is to develop methods of obtaining these compounds. A further object of the invention is to obtain pharmaceutical compositions containing these compounds. In addition, the aim of the invention is also getting a new intermediate compounds useful for preparing compounds according to the invention. These and other objectives and advantages of the invention obvious to a person reading this description and following him.

According to the invention offers 6-methoxy-1H - benzotriazol-5-carboxamide derivatives represented by the following formula (I), their pharmaceutically acceptable salts are acid accession and containing pharmaceutical composition:

< / BR>
[where R1denotes ethyl or cyclopropylmethyl gr is NISTO line means, the configuration of the substituents on the carbon atom linked to the N atom in the amide moiety is racemic (RS) or optically active (R or S)].

The invention also provides compounds represented by the following formula (II) and their salts of the acid accession used as intermediates for producing compounds of formula (I) in which R2denotes a hydrogen atom;

(II)

[where R3denotes an amino protective group, and R1, n and the wavy line have the same values as adopted above for formula (I)]. In addition, the invention provides intermediate compounds of the following formulas (IV) and their salts of the acid accession used to obtain compounds of formula (I) according to this invention:

< / BR>
[where R1, n and the wavy line have the notation adopted for the formula (I)] , in particular, the compounds of the following formula (IVa) and their acid salts of accession, used as intermediates for producing compounds of formula (I) having R - configuration:

< / BR>
[where R1and n are taken to formula (I) values].

Pharmaceutically acceptable salts of the acid of preparation for compounds of formula (I) include, on the ID, hydroiodide, sulfate, phosphate and so on; and organic acid salts, harmless to human body, such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, etc. of Compounds of formula (I) and their salts of the acid accession can be obtained in the form of a hydrate or of MES, which are also included in the scope of the present invention and attached items. More specifically, can be, for example, are: 1/4 hydrate, 1/2 hydrate, monohydrate, 3/2 fumarate/4 hydrate, 3/2 fumarate/hydrat, difumarat 1/2 hydrate, etc.

Salt acid accession intermediates represented by formulas (II) and (IV) or (IVa) include, for example, pharmaceutically acceptable salts of acidic compounds, which are named above. Compounds of formulas (II) and (IV) or (IVa) and their salts of the acid accession can be obtained in the form of a hydrate or of MES, which are also included in the scope of the present invention and attached items.

Upon receipt of the compounds of formula (I) and their acid salts joining in crystalline form may contain various types of polymorphism, which is also included in the scope of the invention and the attached items.

Consider, methoxy-1H-benzotryazolyl radical can be represented by formula (I') or (I"), below:

< / BR>
[in which Az represents a group of the formula [D], to the following:

< / BR>
(in which R1, n and the wavy line have the above meanings)].

These tautomers are also included in the scope of the invention and the attached items.

The structure of the compounds according to this invention in which R2in the formula (I) represents a hydrogen atom, represented by formula (Ia), and their chemical names are also based on the named structure.

Those compounds in which R2in the formula (I) represents a methyl or ethyl group, do not have the above tautomerism.

The term "halogen", as used herein, refers to fluorine, chlorine, bromine or iodine. Specific examples of the "alkyl group" include methyl, ethyl, propyl and isopropyl. Specific examples of the "alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy. Specific examples of the "lower alkanoyl groups include acetyl and propionyl and relevant examples of "lower alkoxycarbonyl groups include methoxycarbonyl and etoxycarbonyl. "Optionally substituted benzyl group are the benzyl group, the phenyl part of which is optionally substituted one who>C3alkoxygroup, specific examples include 2-, 3 - or 4-Chlorobenzyl, 3-bromobenzyl, 4 - tormentil, 2,4 - or 3,4-dichlorobenzyl, 4-methylbenzyl, 2-,3 - or 4 - methoxybenzyl and so on, the Term "optionally substituted benzyloxycarbonyl" refers to those benzyloxycarbonyl whose phenyl radical optionally substituted by one or two of the above-mentioned halogen atoms, C1-C3-alkyl groups, C1-C3alkoxy groups, nitro groups, etc. and specific examples include benzyloxycarbonyl, 4-chlorobenzenesulfonyl, 4-bromobenzyloxycarbonyl, 2,4-dichlorobenzenesulfonyl and 4-methoxybenzeneboronic. The term "amino-protective group" means such protective groups which can be removed by hydrolysis or hydrogenolysis, and their examples include the previously defined groups: low alkanoyl, TRIFLUOROACETYL, lower alkoxycarbonyl, optionally substituted benzyl, and optionally substituted benzyloxycarbonyl, especially preferred benzyl and acetyl.

As preferred examples of compounds of this invention represented by formula (I) may be the following compounds and their pharmaceutically acceptable acid salt of accession:

N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1-methyl - 1H-benzotriazol-5-carboxamid,

(R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1-methyl-1H - benzotriazol-5-carboxamid,

(R)-1-ethyl-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6 - methoxy-1H-benzotriazol-5-carboxamid,

N-(1-ethyl-1H-heptahydrate-3-yl)-6-methoxy-1H-benzotriazol - 5-carboxamid,

N-(1-ethyl-1H-heptahydrate-3-yl)-6-methoxy-1-methyl-1H - benzotriazol-5-carboxamid,

N-(1-ethyl-1H-octahydrate-3-yl)-6-methoxy-1H-benzo-triazole - 5-carboxamide,

(R)-N-(1-cyclopropylmethyl-1H-hexahydroazepin-3-yl)-6-methoxy - 1H-benzotriazol-5-carboxamide and

(R)-N-(1-cyclopropylmethyl-1H-hexahydroazepin-3-yl)-6-methoxy - 1-methyl-1H-benzotriazol-5-carboxamide.

In particular, the compounds of formula (I) in which R1denotes ethyl and R2denotes hydrogen or methyl, are preferred.

Preferred in respect of the configuration are those compounds of formula (I), in which the configuration of the substituents on the carbon atom linked to the N atom of the amide moiety is racemic (RS) or optically active (R), in particular, the latter is more preferable.

As for azacycloheptane cycle, pripodnyatoe n = 1 - preferred.

Of the above compounds, particularly preferred of these compounds and their pharmaceutically acceptable acid salt of accession:

(R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1H-benzotriazol - 5-carboxamide (hereinafter designated as compound 7) and

(R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1-methyl-1H - benzotriazol-5-carboxamide (hereinafter designated as compound 2).

In addition to the above mentioned compounds, the following compounds and their pharmaceutically acceptable salts are acid accession can be given as specific examples of other preferred compounds included in this invention:

(R)-N-(1-ethyl-1H-heptahydrate-3-yl)-6-methoxy-1H-benzotriazol - 5-carboxamid,

(R)-N-(1-ethyl-1H-octahydrate-3-yl)-6-methoxy-1H - benzotriazol-5-carboxamid,

(R)-N-(1-ethyl-1H-heptahydrate-3-yl)-6-methoxy-1-methyl-1H - benzotriazol-5-carboxamide and

(R)-N-(1-ethyl-1H-octahydrate-3-yl)-6-methoxy-1-methyl-1H - benzotriazol-5-carboxamide.

Compounds according to this invention can be obtained, for example, in the following ways:

Method (a)

The compounds of formula (I) can be obtained mutually is methyl, ethyl or aminosidine group)

or their reactive derivatives with compounds represented by formula (IV) below:

< / BR>
[in which R1, n and the wavy line have the meanings described for formula (I)].

In this case, when R2ain the formula (III) denotes an amino protective group, the reaction product must then be subjected to hydrolysis or hydrogenolysis to turn R2ain the hydrogen atom with the aim of obtaining the compounds of formula (I). The interaction of compounds of the formula (III) with compounds of the formula (IV) can be performed by well-known amidation reaction.

Examples of reactive derivatives of compounds of formula (III) include complex lower alkalemia ethers (including, methyl ester), active esters, acid anhydrides and galodamadruga acids (including acid chloride acid) [when used as a compound of the formula (III) in which R2adenotes a hydrogen atom, anhydrides of acids and galodamadruga acids are excluded] . Specific examples of the active esters include n-nitrophenyloctyl ether, pentachlorphenol ether, ester N-hydroxysuccinimide, an ester of N-hydroxyphthalimide, ester 1-hydroxybenzothiazole, 8A acid uses a symmetric acid anhydride or mixed acid anhydride, specific examples of the latter include anhydrides, mixed with alkylchlorosilanes, such as ethylchloride or isobutylparaben; anhydrides, mixed with aralkylamines, such as benzylchloride; anhydrides, mixed with arilkhlormyetanov, such as phenylcarbamate, and anhydrides, mixed with alkhanovym acids such as isovalerianic acid and Pavlova acid.

As the amino-protective groups, which can serve R2amay be used such protective groups which can be removed by hydrolysis or hydrogenolysis, and their examples include: lower alkanoyl, TRIFLUOROACETYL, lower alkoxycarbonyl, optionally substituted benzyl, and optionally substituted benzyloxycarbonyl, especially preferred acetyl.

When used by themselves, the compounds of formula (III), the reaction can be carried out in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-hydrochloride, N,N'-carbonyldiimidazole, N,N'-carbondisulphide, 1-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl and papapostolou anhydride. When the condensing means using N,N'-dizick is to be added N-hydroxysuccinimide, 1 - hydroxybenzotriazole, 3-hydroxy-1,2,3-benzotriazin-4-(3H)-he, N - hydroxy-5-norbornene-2,3-dicarboximide or the like.

The interaction of these compounds of the formula (III) or their reactive derivatives with compounds of the formula (IV) are carried out either in a solvent or in no solvent. Used solvents should be appropriately selected in accordance with the form of the parent compound and so forth, they include: aromatic hydrocarbons, such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride and chloroform; alcohols such as ethanol and isopropyl alcohol; ethyl acetate, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, ethylene glycol and water. These solvents can be used both separately and in the form of a solvent mixture of several kinds. If desired, this reaction is carried out in the presence of a base, specific examples of the base include alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; carbonates of alkali metals such as sodium carbonate and potassium carbonate; bicarbonate of an alkali metal such as sodium bicarbonate hilmarton. Excessive amounts of the compounds of formula (IV) may also act as a base. The reaction temperature varies depending on the type of the parent compounds and so on, but is usually in the range from about -30oC to 200oC, preferably from approximately -10oC to 150oC.

When the compounds of formula (III) in which R2ameans aminosidine group, for example, the lowest alkanoyl, TRIFLUOROACETYL, lower alkoxycarbonyl or optionally substituted benzyloxycarbonyl interact with the compounds of the formula (IV), forming the compounds of formula (I) in which R2adenotes a suitable protective group, the products can be hydrolyzed to convert into compounds of formula (I) in which R2denotes hydrogen.

The hydrolysis reaction can be carried out essentially by known methods, for example, the interaction of the product with water in a suitable solvent under acidic or basic environment. As solvents can be used, for example, alcohols such as methanol, ethanol, isopropyl alcohol or the like, dioxane, water or a liquid mixture. Specific examples of the acid used to create the acidic environment include neo is ant, acetic, propionic and oxalic acid; and silica gel. When used as a compound of the formula (III) in which R2adenotes acetyl group, using silica gel easy it acetyl group, turning R2in the hydrogen atom. Specific examples of bases to create an alkaline environment include alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; and carbonates of alkali metal such as sodium carbonate or potassium. The reaction temperature is usually in the range from about 20oC to 100oC.

When the compound of the formula (III) in which R2ameans, along with the aforementioned examples of the amino-protective group, optionally substituted benzyl or benzyloxycarbonyl group, is reacted with a compound of formula (IV) with the formation of the compounds of formula (I) in which R2adenotes a suitable protective group, the hydrogenolysis product may make such R2in hydrogen. The hydrogenolysis can be carried out in generally known manner, for example, the interaction of the product with hydrogen in a suitable solvent in the presence of a catalyst such as palladium-on-carbon, Raney Nickel, etc. as used solvents is e mixture. The reaction temperature is usually used in the range from about 0oC to 80oC. the Reaction is carried out at normal or increased pressure.

The compounds of formula (III) in which R2adenotes hydrogen or an amino-protective group (lower alkanoyloxy group, trifluoracetyl group, lower alkoxycarbonyl group or optionally substituted benzyloxycarbonyl group) and their reactive derivatives can be obtained by the method described, for example, in JP-A-80858/1976 (U.S. patent 4.039.672) or similar methods.

The compounds of formula (III) in which R2adenotes methyl, ethyl or amino-protective group (optionally substituted benzyl group), can be obtained by the method using 4-chloro-2-methoxy-5-nitrobenzoic acid as starting substances, including the transformation of this compound in an appropriate, adequate amide structure suitable amine, such as Propylamine according to the following stage 1 in figure 4, the introduction of a methyl, ethyl or optionally substituted benzyl group, R2position and restoring the received product on the following stages 2 and 3 in scheme 4, the floor of the BU (b), described below, and then, the hydrolysis product is essentially known manner.

Specific examples of methods for obtaining compounds of formula (IV) below.

Those compounds of formula (IV) in which n=1 can be obtained, for example, the method illustrated by the following scheme 1.

< / BR>
[In the above scheme I, Tr denotes triphenylmethyl group, X represents a reactive ester residue of an alcohol, R1has the previously defined meaning and the wavy line indicates a racemic or optically active configuration as previously defined].

Stage 1:

The reaction between the compound of formula (A) and chlorotriphenylmethane usually carried out in a suitable solvent in the presence of a base. Used solvent and base are the same as those cited for the above method (a). The reaction temperature is usually in the range from about -10oC to 150oC, preferably from 0oC to 100oC. as R and S isomers of the formula (A), which is the starting compounds, can be used for industrial optically active compounds or industrial racemic compound can be optically separated, for example, by the way, esis, 1978, 614-616. This method optical resolution or synthesis of optically active compounds in itself well known.

Stage 2:

The compounds of formula (C) can be obtained by reduction of compounds of formula (B) using a metal hydride, such as diisobutylaluminum, socialogical, sodium bis(2-methoxyethoxy)alumalite or the like. Specific examples of solvents include, for example, ethers such as diethyl ether, tetrahydrofuran, and so on; aromatic hydrocarbons such as benzene, toluene and so forth; and halogenated hydrocarbons such as methylene chloride, chloroform, etc., the Reaction temperature varies depending on the type of metal hydride, although it usually remains in the range of about -10oC to 100oC, preferably, from about 0oC to 50oC.

Stage 3:

The reaction of the compound of formula (C) with R1- introducing agent represented by the formula, R1-X, usually carried out in a suitable solvent in the presence of a base. As a reactive ester residue of the alcohol, denoted by X, can be named, for example, halogen atoms such as chlorine, bromine is benzolsulfonate. Specific examples of the solvent include aromatic hydrocarbons such as benzene, toluene; ketones, such as acetone, methyl ethyl ketone; ethers such as tetrahydrofuran, dioxane; alcohols, such as ethanol, isopropyl alcohol, acetonitrile, chloroform, ethyl acetate, dimethylformamide, dimethylsulfoxide, and the liquid mixture. Specific examples of the base are the same as listed above for the method (a). When X in R1- introducing agent (R1X) denotes chlorine or bromine, for a calm reaction add the alkali metal iodide such as sodium iodide or potassium iodide. The reaction temperature varies depending on the type of R1- introducing agent, although it usually is in the range from about 0oC to 200oC, preferably from approximately 80oC to 150oC.

Stage 4:

The reaction at this stage is usually carried out in a suitable solvent in the presence of an inorganic acid such as diluted hydrochloric acid, diluted sulfuric acid or the like. Specific examples of the solvent include alcohols such as methanol, ethanol; ethers, such as diethyl ether, is the temperature varies depending on the species used source of the connection, although she is normally in the range from about 0oC to 100oC.

The compounds of formula (IV') can also be obtained when changing places order the stage 2 reaction recovery, and stage 3 - response introduction R1in the above scheme 1. This means that the introduction of R1in the compound of formula (B) (stage 2') and subsequent recovery (stage 3') can lead to the corresponding compound of formula (D). In the reaction stage 2' is preferable to use a strong base such as sodium hydride, instead of the inception, as described for the method (a). In addition, in a redox reaction 3' it is desirable to use, for example, bis (2-methoxyethoxy)-alumoweld sodium.

The compounds of formula (IV) in which n is 2 or 3, get, for example, by the method illustrated in the following scheme 2:

< / BR>
(in which Y denotes a halogen atom, n' is 2 or 3 and R1and X have the previously adopted value).

Stage 1 in the above scheme 2 can be performed in a manner analogous to stage 2', modified by way of the approach adopted in illustrating the scheme 1, using as starting substances, for example, industrial output 2-azacycloheptane J. Am. Chem. Soc. 80, 6233-6237 (1958). Stages 3 and 4 can be performed, for example, following the method described in Helv.Chim.Acta, 41, 181-188 (1958).

The compounds of formula (IV) can also be obtained by the method illustrated in the following scheme 3:

< / BR>
(in which R1, Tr and n have adopted higher values).

Stage 1 above scheme 3 is carried out in a suitable solvent, the resulting compound of formula (E) to the anionic form under the influence of a strong base, and then subjecting the interaction of it with dry ice.

The transformation of the carboxyl group in the amino group in stage 2 can be performed by the interaction of the compounds of formula (F) with etelcharge.com and sodium azide in a suitable solvent, followed by heating the obtained acylated and the influence of acid on the isocyanate product. Triphenylmethane at stage 3, the interaction on stage 4 and removing triphenylmethyl group at the stage 5 can be performed in a manner analogous to, respectively, stages 1, 2 and 4 of scheme 1.

The parent compound of formula (E) can be obtained by way of the stage 1 scheme 2, using as starting compound-caprolactam, 2-azacycloheptane or 2-azacycloheptane.

On STRs is(IV'). Whereas, the final products (IV) or (IV"') obtained by the method of scheme 2 or scheme 3, are racemic. Racemic compounds of the formula (IV) can be divided into two optical isomers are known essentially ways. For example, the compound of formula (IV) is treated with an optically active acid to the formation of salts or amides of diastereomers who share fractionated by recrystallization or column chromatography, and then transformed into free base.

Compounds of the above formula (IV) are new.

Compounds represented by the following formula (IVa) and having the R - configuration:

< / BR>
(in which R1and n have the above meanings, are used as new intermediate compounds of formula (I) having R - configuration, compounds represented by the following formula (IVb):

< / BR>
(in which R1has the above values) are particularly preferred.

Method (b)

The compounds of formula (I) can be obtained by diazotization of the compounds of the formula (V) below:

< / BR>
(in which R1, R2, n and the wavy line have the above significance) for education benzodiaz is the formation of compounds of formula (I) by diazotization of the compounds of the formula (V), is the diazotization, usually used for aromatic amines. As diastereomer agents can be used, for example, alkalemia esters of nitrous acid such as sodium nitrite, tert - butyl nitrite and isoamylase. Closing the loop using nitrous acid is usually performed by adding first an excessive amount of inorganic acid (e.g. hydrochloric acid) or organic acids (e.g. acetic acid) to aqueous solution of compounds of formula (V) or its acid salt of joining, and then adding an aqueous solution of sodium nitrite. The reaction temperature withstand typically in the range from about -20 to 60oC, preferably from about 0oC to 25oC. the Response of the closed loop using Olkiluoto ester of nitrous acid is usually carried out in a suitable solvent by reacting the compounds of formula (V) or its acid salt of accession (for example, hydrochloride, acetate) with alkilany ester of nitrous acid. Examples of suitable solvent include methanol, acetic acid, acetic acid, dioxane, 1,2-dimethoxyethane, tetrahydrofuran, acetone and methylene chloride. The reaction temperature Oba oC to 80oC.

Starting compound represented by the formula (V) can be obtained, for example, by the method, which is illustrated by the following scheme 4.

< / BR>
(in which Z denotes a halogen atom and R2, Az and the wavy line have the above values).

Stage 1:

The interaction of compounds of formula (J) or their reactive derivatives with compounds of the formula (IV) perform in a manner analogous to the method (a). The source connection

formula (J) can be obtained, for example, by the method described in Helv. Chim.Acta. 40, 369-372 (1957).

Stage 2:

The interaction of compounds of formula (K) with the compounds represented by the formula; H2N-R2perform without the use of a solvent or in an appropriate solvent.

Examples of the solvent include alcohols such as methanol and ethanol; dimethyl formamide, dimethyl sulfoxide and water. The reaction temperature is usually used in the range from about 0oC to 150oC.

Stage 3:

The recovery of the compounds of formula (L) carry out the conventional way. For example, the compound of formula (L) can be processed in a suitable solvent vosstanavlivaya, tin, zinc, iron) or metal salts (for example, tin chloride) with acids (e.g. hydrochloric acid, acetic acid), while the ferric chloride or tin can itself be used as the reducing agent. Recovery can also be accomplished by hydrogenation of compounds of formula (L) in a suitable solvent in the presence of a catalyst. Specific examples of the catalyst include palladium - on-carbon, Raney Nickel and platinum oxide. The solvent should be selected according to the nature of the used reducing agent or the type of recovery method. As solvents commonly used alcohols such as methanol or ethanol; ethyl acetate, acetone, acetic acid, dioxane, water or a liquid mixture. The reaction temperature also varies depending on the reducing means or methods of recovery used in each case, although she is normally in the range from about 10oC to 100oC, and catalytic reduction is the preferred interval is approximately 10oC to 50oC.

Thus obtained compounds of formula (V) can be used as the source from which R2denotes a hydrogen atom, can also be obtained by the hydrogenolysis of compounds represented by formula (IIa) below:

< / BR>
[in which R3aindicates the amino-protective group (for example, optionally substituted benzyl or optionally substituted benzyloxycarbonyl), and R1, n and the wavy line have the above significance].

The hydrogenolysis may be performed in conventional manner, for example, by the interaction of the compounds or with hydrogen in a suitable solvent and in the presence of a catalyst such as palladium-on-carbon, Raney Nickel or the like, or hydrogen donor (e.g., ammonium formate, cyclo-hexene) in the presence of a catalyst such as palladium-on-carbon. As a solvent, for example, use alcohols, such as ethanol or methanol, water, acetic acid, dioxane or tetrahydrofuran. The reaction temperature is usually used at intervals of approximately 0oC to 80oC. the Reaction is carried out at normal or increased pressure.

The compounds of formula (IIa) in which R3adenotes optionally substituted benzyl group, can be obtained by the method (b) using as starting compounds the strong group. Starting compound (V) can be obtained by the process illustrated by scheme 4. In this case, the reduction reaction stage 3 is preferably carried out using a combination of metal or metal salt with an acid, or iron, or tin chloride.

The compounds of formula (IIa) in which R3adenotes optionally substituted benzyloxycarbonyl group can be obtained by the method (a), using as starting compounds are those compounds of formula (III) in which R2adenotes optionally substituted benzyloxycarbonyl group, which in turn can be obtained, for example, by the method described in JP-A-80858/1976 (U.S. patent 4.039.672) or by methods similar to this.

Method (d)

The compounds of formula (I) in which R2denotes a hydrogen atom, can also be obtained by hydrolysis of compounds of formula (IIb) below:

< / BR>
[in which R3bindicates the amino-protective group (for example, lower alkanoyl, TRIFLUOROACETYL, lower alkoxycarbonyl or optionally substituted benzyloxycarbonyl), and R1, n and the wavy line have the above significance].

The hydrolysis reaction can be carried out essentially investisiani environment. The solvent can be, for example, used alcohols such as methanol, ethanol, isopropyl alcohol and the like; dioxane, water or mixtures thereof. Specific examples of the acid used to create an acid environment, include mineral acids such as hydrochloric, Hydrobromic and sulfuric acid; organic acids such as formic, acetic, propionic and oxalic acid; and silica gel. When the compound of the formula (IIb) contains acetyl group as R3bthe use of silica gel allows you to easily split acetyl group and make the connection in the connection formula (I) in which R2denotes a hydrogen atom. Specific examples of the base used to create an alkaline environment, include alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; and carbonates of alkali metal such as sodium carbonate, potassium carbonate and so on, the reaction Temperature is usually maintained within the range from about 20oC to 100oC.

The compounds of formula (IIb), which are intermediate products, according to this invention can be obtained in the way described earlier (a) using as starting compounds are those compounds folino substituted benzyloxycarbonyl, which in turn can be obtained, for example, a method described in JP-A-80858/1976 (U.S. patent 4.039.672), or an equivalent ways.

The methods (a), (b), (c) and (d) the configuration of the parent compounds of formula (IV), (V), (IIa) and (IIb) are saved in the formation of compounds of formula (I). Therefore, it is preferable to obtain the compounds of formula (I) having a given configuration, use the original connection with the appropriate configuration. Furthermore, it is possible to apply racemic original connection to obtain the racemic compounds of formula (I), which can then be optically separated by conventional methods.

Compounds obtained by the above methods can be isolated and purified by using common methods, such as chromatography, recrystallization, pereosazhdeniya etc.

The compounds of formula (I) and compounds of the formulas (IIa) and (IIb) are obtained in free base form or acid salt accession, that depends on the type of starting compounds, the reaction conditions and processing. Salt acid accession can be converted into the free base by treatment such basis as the carbonate of an alkali metal or a hydroxide of an alkali metal. That is hypoxia acids according to conventional methods.

Below are the results of tests of typical compounds according to this invention and monohydrate hydrochloride metoclopramide (metoclopramide) (Compound A), industrial tools to enhance contractility of the gastrointestinal tract and discusses the characteristic pharmacological actions of the compounds according to the invention.

Here is the list of compounds according to this invention, used in pharmacological tests, indicating their patterns and numbers of connections.

The compound of example 1 (compound 1)

N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1-methyl-1H - benzotriazol-5-carboxamide.

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The compound of example 2 (compound 2)

(R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1-methyl-1H - benzotriazol-5-carboxamid

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The compound of example 4 (compound 4)

1-ethyl-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy 1H - benzotriazol-5-carboxamid

< / BR>
The compound of example 5 (compound 5)

(R)-1-ethyl-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1H - benzotriazol-5-carboxamid

< / BR>
The compound of example 6 (compound 6) N-(1-ethyl-1H - hexahydroazepin-3-yl)-6-methoxy-1H-benzotriazol-5-carboxamid

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The compound of example 7 (compound 7a) the Teal-1H-hexahydroazepin-3-yl)-6-methoxy-1H-benzotriazol - 5-carboxamid/2 fumarate

The compound of example 9 (compound 9)

N-(1-ethyl-1H-heptahydrate-3-yl)-6-methoxy-1H-benzotriazol - 5-carboxamid

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The compound of example 10 (compound 10)

N-(1-ethyl-1H-octahydrate-3-yl)-6-methoxy-1H-benzotriazol - 5-carboxamid

< / BR>
The compound of example 11 (compound 11)

N-(1-cyclopropylmethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1H - benzotriazol-5-carboxamid

< / BR>
The compound of example 12 (compound 12)

(R)-N-(1-cyclopropylmethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1H - benzotriazol-5-carboxamid

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The compound of example 13 (compound 13)

(R)-N-(1-cyclopropylmethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1 - methyl-1H-benzotriazol-5-carboxamid

< / BR>
The compound of example 14 (compound 14)

N-(1-ethyl-1H-heptahydrate-3-yl)-6-methoxy-1-methyl-1H - benzotriazol-5-carboxamid

< / BR>
The compound of example 15 (compound 15)

N-(1-ethyl-1H-octahydrate-3-yl)-6-methoxy-1-methyl-1H - benzotriazol-5-carboxamid

< / BR>
The compound of example 3 (compound 3)

(S)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1-methyl-1H - benzotriazol-5-carboxamid

< / BR>
The compound of example 8b (compound 8b)

(S)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1H-benzotriazol - 5-carboxamid/2 fumarate

< / BR>
Experiment 1

Inhibitory effect on apomorphine-induced vomiting

A group of 3-4 dogs (Beagle, 8-15 kg) is used to study inhibitory effects of the tested compounds on apomorphine-induced vomiting, according to the method of Chen and Ensor [cf.J.Pharmacol. Exp. Ther., 98 245-250 (1950)].

Compound dissolved or suspended in 0.5% solution of tragakant, administered orally two hours before subcutaneous injection of apomorphine hydrochloride (0.3 mg/kg). Then within one hour counts the number of bouts of vomiting. The number of episodes of vomiting in the treated compound group compared with the number of attacks in the corresponding control (not received dose) group and calculate the percent inhibition. The results are shown in table 1.

From table 1 it is evident that almost all compound according to this invention show equal to or greater than metoclopramide hydrochloride monohydrate (compound A) activity in the inhibition of apomorphine-induced vomiting.

Experiment 2: Activity-enhancing contractility of the gastrointestinal tract

Testing is carried out according to the method Scarpignato et before the beginning of the experiment and give oral 1.5 ml test Breakfast (phenol red 0,05% 1.5% aqueous solution of methylcellulose). Fifteen minutes after injection Breakfast delete the stomach and measure the amount of phenol red remaining in the stomach. Compound dissolved or suspended in 0.5% solution of tragakant, give orally 60 minutes before the test Breakfast. The degree of contractility of the gastrointestinal tract are calculated according to the number of phenol red remaining in the stomach, and the activity of the tested compounds expressed through increased degree of contractility in comparison with the control. The number of animals used is 4 for the tested compounds according to this invention and 5 for compound A used for comparison. The results are shown in table 2.

As follows from table 2, each test compound according to this invention shows equal to or greater than the monohydrate of metoclopramide hydrochloride (compound A) activity in enhancing contractility of the gastrointestinal tract.

Experiment 3: Effects on contractility of the gastrointestinal tract, detained by cholecystokinin or morphine

The test is carried out according to the method Scarpignato et al.[cf. Arch.Int.Pharmacod yn., 246, 286-294(1980)].

Male Wistar rats, vasami the Breakfast, morning (phenol red 0,05% 1.5% aqueous solution of methylcellulose). Fifteen minutes after injection Breakfast delete the stomach and measure the amount of phenol red remaining in the stomach.

Compound, 10, 30 or 100 mg/kg each, are dissolved or suspended in 0.5% solution of tragakant, give orally 60 minutes before the test Breakfast. Contractility of the gastrointestinal tract slow subcutaneous injection of cholecystokinin 3 mg/kg or morphine 3 mg/kg 5 minutes before the injection of phenol red. The number of animals used was 5-10. The results are shown in table 3.

The tested compound 2 (compound of example 2) according to this invention at doses of 300-100 mg/kg significantly improves the contractility of the gastrointestinal tract, detained by cholecystokinin.

The test compound 7b (the compound of example 7b) according to this invention at doses of 10, 30 or 100 mg/kg significantly improves the contractility of the gastrointestinal tract, delayed by cholecystokinin or morphine, and shows excellent activity, enhancing contractility of the gastrointestinal tract (gastroprokinetic activity) compared with gastric emptying, delayed cholecystokinin and 0 or 100 mg/kg does not show improved activity relative to the delayed emptying of the bowel caused by cholecystokinin or morphine.

Experiment 4

Effects on contractility of the gastrointestinal tract in which in the minds of dogs.

Four healthy hound dog group, both sexes, weighing 10-12 kg, exposed to anesthesia by intravenous injection of pentobarbital sodium (Nembutal, 30 mg/kg body weight), and the abdominal cavity is opened under aseptic conditions. According to the method of measurement of contraction of circular muscles extraluminally power sensors sewn into serosomyotomy layer of the gastric cavity, 3 cm proximal to the ring pylorus, the duodenum, the jejunum, the middle intestine and the end of the ileum, according to the method of Ito et al. [cf. Gastrointerol. Japan. 12, 275-283 (1977)].

For intragastric (i.g.) administering drugs slastikov tube (Fr, 6.5) injected into the cavity suffering from gastritis of the body and the tube is fixed on the adjacent serosa. Lead wire these sensors and the receiver for the study of the stomach is removed from the abdominal cavity and then carried out through the skin incision is made between the shoulder blades. After surgery, n is up in isolated experimental cells and give food to 10 A. m. (before noon), water give unlimited.

Compound 3 and 10 mg/kg) suspended in 0.5% solution of tragakant and i enter.g. through inside slastikov up.

Compounds 2 and 7b according to this invention at doses of 3 and 10 mg/kg cause a reduction similar to the internal digestive movements in feeding those who exist in the minds of dogs. Thus, it is found that the compound exhibit significant activity that increase the contractility of the gastrointestinal tract (gastroprokinetic activity). In contrast, compound A does not cause reduction of digestive move.

Experiment 5 Effect of inhibition of explorative activity.

Use a group of 5 male mice (Std-ddy strain 20-25 g). Two hours after oral administration of the tested compounds in the form of 0.5% tragacanth solution or suspension, mice are placed individually in the box for testing (23 x 35 x 30 cm) on the counter activity Animex'a (Farad Co.). After that immediately begin activity and continue for three minutes. The average estimated value for the processed connection group compared with similar value to sootvetst on the way.

The results are shown in table 4.

As follows from table 4, each test compound according to this invention shows a much smaller effect of inhibition explorative abilities than metoclopramide hydrochloride monohydrate (compound A). This result leads to the conclusion that the compounds according to this invention have a significantly lower suppression of the Central nervous system in comparison with the influence of the connection A.

Experiment 6: Acute toxicity.

Use a group of 5 mice-males (Std-ddy strain 25-30 g). The test compound is administered orally to a subject animal in the form of 0.5% of tragacantha solution or suspension and 7 days after administration of the tested compounds observed loss of animals and determine the 50% lethal dose (LD50).

The results are shown in table. 5.

As can be seen from the above test results, the compounds of formula (I) according to this invention and their pharmaceutically acceptable salts are acid accession possess significant inhibitory activity against vomiting and activity enhancing contractility of the gastrointestinal tract (gastroprokinetic accessto agents, enhance contractility of the gastrointestinal tract (gastroprokinetic funds) for the treatment and prevention of various gastrointestinal functional disorders associated with various diseases and drug treatments: for example, diseases such as: anorexia, nausea, vomiting, feeling of fullness of stomach discomfort in the upper part of the gastrointestinal tract, stomach pain, heartburn and belching, which are observed in acute and chronic gastritis, asolutely reflux, stomach ulcers and duodenal ulcers, Castroneves, bathygastry, paralytic ileus after surgery, geriatric bowel obstruction, dumping syndrome, scleroderma, diabetes, impaired esophageal and biliary ducts, puerilia periodic vomiting, upper respiratory tract infection: for example, mucous colitis, constipation, diarrhea in infants: for example, nausea and vomiting accompanying the reception of anti-cancer drugs or drugs of levodopa, or after x-ray irradiation.

Of the compounds according to this invention, compounds 2, 7a and 7b show particularly high activity increased reduction in the gastrointestinal tract.

The pharmaceutical what I depending on the kinds of compounds, the routes of administration, severity of illness, patient age, and the like, but is usually used in the range from 0.01 to 10 mg/kg/day, preferably from 0.1 to 3 mg/kg/day.

When using compounds of formula (I) or their pharmaceutically acceptable acid salts of the accession to the above-described medical use, they are usually administered to the patient in the form of pharmaceutical formulations of the compositions by mixing with carriers customarily used for medical compositions and do not react with the compounds according to this invention. More specifically, for example, can be named devices such as lactose, Inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch, sucrose, magnesium alumosilicate, synthetic aluminium silicate, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropylmethyl, calcium carboxymethyl cellulose, ion exchange resin, methylcellulose, gelatine, juice of acacia, pullulan, hydroxypropylcellulose, little is substituted hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, low-viscosity anhydrous silicic to the anew fatty acid ester, sodium lauryl sulfate, glycerin, glycerides of saturated fatty acids, anhydrous lanolin, glycoregulation, Polysorbate, macrogol, vegetable oil, paraffin, water, propylene glycol, ethanol, sodium chloride, sodium hydroxide, hydrochloric acid, citric acid, benzyl alcohol, glutamic acid, glycine, methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, and the like.

The pharmaceutical compositions can be taken in any preparative form, such as tablets, capsules, granules, powders, syrups, suspensions, injections, poultices, suppositories and the like, obtained by using common methods. Liquid preparations can be taken in such forms which before use are dissolved or suspended in water or other suitable medium. Tablets and granules may be coated membranes by methods, which themselves are well known.

The compounds of this invention represented by formula (I) in which R2denotes hydrogen, exhibit good solubility in water and therefore is particularly suitable for liquid preparations.

These preparations may contain at least 0.01% of the compounds of formula (I) according to this invention or its pharmaceutically priemlemii other therapeutically acceptable components.

The best variant embodiment of the invention

Further, the invention is disclosed more specifically by standard examples and experimental examples, it is clear that they do not limit the scope of the invention. Identification of the compounds was conducted on the basis of data such as elemental analysis, mass spectrum, UV spectrum, IR spectrum, NMR spectrum, etc.

The following standard and experimental examples, sometimes for simplicity, write the following symbols are used:

[Solvent for recrystallization]

A: ethanol

E: diethyl ether

[Deputy]

Me: methyl

Et: ethyl

: cyclopropyl

Ph: phenyl

NMR

J: constant communication

s: singlet

d: doublet

DD: double doublet

t: triplet

kV: Quartet

m: multiplet

user. from: broadened singlet

[Other designations]

her: enantiomeric excess of

Example 1 [reaction according to the method (b)]

Obtaining N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1-methyl - 1H-benzotriazol-5-carboxamide (compound 1):

To 40 ml of an aqueous solution containing about 3.0 g of 5-amino-N -(1-ethyl-1H-hexahydroazepin-3-yl)-2-methoxy-4-methylaminomethyl obtained in prevident 10 ml of an aqueous solution, containing 0.8 g of sodium nitrite, and then stirred for one hour at the same temperature. The reaction mixture is alkalinized water sodium hydroxide and extracted with chloroform. The extract is washed with water, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure, obtaining an oily residue. The oil is subjected to column chromatography on silica gel, and then elute and cleaned with a mixture of chloroform-methanol (9:1). The obtained solid product is recrystallized from toluene - n-hexane, giving 2.3 g specified in the title compound, so pl. 103-104oC.

Example 2 [reaction according to method (b)]

Obtaining (R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1-methyl - 1H-benzotriazol-5-carboxamide (compound 2):

An aqueous solution of acetic acid containing (R)-5 - amino-N-(1-ethyl-1H-hexahydroazepin-3-yl)-2-methoxy-4 - methylaminomethyl obtained following standard example 5, cooled to 5oC and added dropwise to 50 ml of an aqueous solution containing 6.6 g of sodium nitrite. The mixture is stirred for one hour at this temperature and then for two hours at room temperature. The reaction mixture was alkalinized with an aqueous solution of sodium hydroxide and extracted with ethyl acetate. Extralocal oily residue. The oil is subjected to column chromatography on silica gel and then elute and cleaned with a mixture of chloroform-methanol (9:1). The resulting solid product is recrystallized from toluene-n-hexane, obtaining 26.7 g specified in the title compound, so pl. 118-120oC.

[]2D7- 70,6o(C=1.0, ethanol).

Example 3 [reaction according to the method (b)]

Obtain (S)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1 - methyl-1H-benzotriazol-5-carboxamide (compound 3):

The reaction and the treatment is carried out in a manner analogous to example 2, using an aqueous solution of (S)-5-amino-N-(1-ethyl-1H-hexahydroazepin - 3-yl)-2-methoxy-4-methylaminomethyl obtained following standard example 6. The resulting product is recrystallized from a mixture of toluene-n-hexane, obtaining mentioned in the title compound, so pl. 119-120oC.

Example 4 [reaction according to method (b)]

Obtain 1-ethyl-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1H - benzotriazol-5-carboxamide (compound 4):

The reaction and the treatment is carried out according to the method of example 1 using an aqueous solution of 5-amino-N-(1-ethyl-1H-hexahydro-azepin-3-yl) -4-ethylamino-2-methoxybenzamide obtained following standard example 7. The resulting product precrystallization method (b)]

Obtaining (R)-1-ethyl-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy - 1H-benzotriazol-5-carboxamide (compound 5);

The reaction and the processing performed according to the method of example 1 using an aqueous solution of (R)-5-amino-N-(1-ethyl-1H-hexahydroazepin-3-yl) -4-ethylamino-2-methoxybenzamide obtained by standard example 8. The product is obtained in the form of oil: mass spectrum (m/z): 346 (MN+).

Example 6 [reaction according to method (a)]

Obtaining N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1H - benzotriazol-5-carboxamide (compound 6):

To 10 ml dimethylformamide solution containing 0.85 grams of 6-methoxy-1H-benzotriazol-5-carboxylic acid, added to 0.78 g of N,N'-carbonyldiimidazole and stirred for 6 hours at room temperature. To the reaction mixture are added 0.75 g of 3-amino-1-ethyl-1H - hexahydroazepin and then stirred for 14 hours at room temperature. After termination of the reaction, the solvent was evaporated under reduced pressure and the residue is subjected to column chromatography on silica gel, using an elution and purification using chloroform-methanol (10:1). The resulting product is recrystallized from ethanol-diethyl ether, obtaining 1.3 g specified in the title compound, so pl. 156-158oC.

1

Example 7 [reaction according to method (a)] and [(reaction according to method (d)]

Obtaining (R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6 - methoxy-1H-benzotriazol-5-carboxamide (compound 7a):

a) [reaction according to the method (a)]

To 150 ml dimethylformamide solution containing 10 g of 6-methoxy-1H-benzotriazol-5-carboxylic acid, added 9.0 g of N,N'-carbonyldiimidazole and stirred for 6 hours at room temperature. To the reaction mixture are added 8.8 g (R)-3-amino-1-ethyl-1H-hexahydroazepin and stirred for 14 hours at room temperature. After termination of the reaction, the solvent was evaporated under reduced pressure and the residue is subjected to column chromatography on silica gel, elwira and cleaning chloroform-methanol (10:1). The resulting product is recrystallized from a mixture of diethyl ether-n-hexane, obtaining 12 g specified in the title compound (compound 7a), so pl. 127-128oC.

(a') Mentioned in the title compound one more time recrystallized from ethyl acetate-n-hexane, obtaining mentioned in the title compound, so pl. 142-144oC.

[]2D5- 71,9o(C=1.0, methanol).

This connection with liquid chromatography high resolution (IHVR) corresponds to BP the conditions GHUR

GHUR-column: SUMICHIRAL OA-4900; 4.6 mm x 250 mm, manufactured by Sumitomo Chemical Analysis Center

Mobile phase: n-hexane-methylene chloride-ethanol-triperoxonane acid(400:100:100:0.6)

The flow rate: 1.0 ml/min

temperature: 25oC

detection: 230 nm.

From the initial substance, having the R-configuration mentioned in the title compound with an optical purity of 99% or higher receive a method GHUR, racemization does not occur. In addition, as shown below in example 8, compound S-configuration with an optical purity of 99% EE or higher is obtained from the source connection S-configuration, without racemization. These facts clearly show that the configuration specified in the title compound, obtained in this example, the R.

(b) Obtained above in stage (a) the product is treated with fumaric acid to convert it to the corresponding fumarate, which is recrystallized from isopropyl alcohol-methanol, receiving 3/2 fumarate specified connection (compound 7b), so pl. 131-133oC.

(b') the Product obtained above in stage (a), treated with fumaric acid to convert it to the corresponding fumarate, which is recrystallized from isopropyl alcohol, getting 3/2 fumarate pointed to by the t fumaric acid and converted into the corresponding fumarate, which is recrystallized from ethanol-isopropyl alcohol, getting 3/2 fumarate/4 hydrate specified in the title compound, so pl. 166-168oC.

(C) Reaction using compounds of formula (III) in which R2denotes acetyl group (aminosidine group)

[reaction according to method (a)]:

To 31,5 g of 1-acetyl-6-methoxy-1H-benzotriazol-5-carboxylic acid type of 20.3 g of triethylamine and 400 ml of ethyl acetate and to the mixture is added dropwise at -7oC - -10oC 17,5 g ethylchloride. After a subsequent 2-hour stirring at -5oC - -7oC, to the mixture is added dropwise 80 ml of an ethyl acetate solution containing of 22.8 g (R)-3-amino-1-ethyl-1H-hexahydroazepin and the mixture is stirred for one hour at this temperature and then for 16 hours at room temperature. The reaction mixture is washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue is dissolved in 1000 ml of a mixture of chloroform-methanol (8: 1) and then added to a solution of 180 g of silica gel and subsequently stirred for 16 h at room temperature.

The silica gel was removed by filtration and the residue washed with 1000 ml of a mixture of chloroform-metadate four (24) g obtained above crude product is treated with a 2.5-3-fold volume (22,5 g) fumaric acid and the resulting fumarate is recrystallized from methanol - isopropyl alcohol, receiving 25 g 3/2 fumarata specified in the title compound, so pl. 131-133oC.

(d) [reaction according to the method (d)]

To 1.85 g (R)-1-acetyl-N-(1-ethyl-1H-hexahydroazepin-3-yl)- 6-methoxy-1H-benzotriazol-5-carboxamide obtained by following the example 17, add 55 ml of a mixture of chloroform - methanol (8:1). Then add to 18.5 g of silica gel and the mixture is stirred for 16 hours at room temperature. The silica gel was removed by filtration and the residue is washed with a mixture of chloroform-methanol (9:1) containing 1% aqueous ammonia. The solvent is evaporated under reduced pressure, getting 1.78 g of crude target product.

Example 8 [reaction according to method (a)]

Obtain (S)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy - 1H-benzotriazol-5-carboxamide (compound 8):

a) Replacing (R)-3-amino-1-ethyl-1H-hexahydroazepin example 7 (S)-3-amino-1-ethyl-1H-hexahydroazepin, which is subjected to interaction and treated according to the method of example 7, get mentioned in the title compound.

(b) the above product is treated with fumaric acid and converted into the corresponding fumarate. Recrystallization from isopropyl alcohol gives 3/2 fumarate specified in the title compound, so pl. 156-158oC.

Specified in sahlawi is istota 99% or higher.

(b') Obtained above in stage (a) the product is treated with fumaric acid to the above stage (b) and the resulting fumarate is recrystallized from ethanol-isopropyl alcohol. Get difumarate/2 hydrate specified in the title compound, so pl. 148-151oC.

Examples 9-12 - reaction method (a)

Repeating example 6 except that 3-amino-1-ethyl-1H - hexahydroazepin replace the corresponding 3-amino-1-substituted-1-hexahydroazepin.

In this way we obtain compounds shown in table 6.

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Example 13 [reaction according to method (b)]

Obtaining (R)-N-(1-cyclopropylmethyl-1H-hexanitroethane-3-yl)- 6-methoxy-1-methyl-1H-benzotriazol-5-carboxamide (compound 13):

Using the original connection, an aqueous solution of (R)-5-amino-N-(1-cyclopropylmethyl-1H-hexahydroazepin - 3-yl)-2-methoxy-4-methylaminomethyl receive, using the reaction and a processing method similar to the example below in example 18 and the standard examples 1 and 4. This solution is treated and processed in a manner analogous to example 1, and the obtained product is recrystallized from toluene, giving specified in the title compound, so pl. 127-128oC.

P is-5-carboxamide (compound 14).

Repeat example 6, except that 6-methoxy-1H - benzotriazol-5-carboxylic acid and 3-amino-1-ethyl-1H - hexahydroazepin used in example 6, replacing 6-methoxy-1-methyl-1H-benzotriazol-5-carboxylic acid and 3-amino - 1-ethyl-1H-heptahydrate, respectively. The resulting product is recrystallized from ethanol-diethyl ether mixture, getting mentioned in the title compound, so pl. 116-118oC.

Example 15 [reaction according to method (a)]

Obtaining N-(1-ethyl-1H-octahydrate-3-yl)-6-methoxy-1-methyl - 1H-benzotriazol-5-carboxamide (compound 15):

Repeat example 6, except that 6-methoxy-1H-benzotriazol-5-carboxylic acid and 3-amino-1-ethyl-1H-hexahydroazepin used in example 6, replacing 6-methoxy-1-methyl-1H-benzotriazol-5-carboxylic acid and 3-amino-1-ethyl-1H-octahydrate, respectively. The resulting product is recrystallized from ethyl acetate, getting mentioned in the title compound, so pl. 155-156oC.

In the following examples 16-24 described methods of synthesis of intermediates used to produce compounds according to this invention.

Example 16 [reaction according to method (b)]

Obtain 1-benzyl-N-(1-ethyl-1H-hexahydroazepin group]:

To 6 ml of an aqueous solution of hydrochloric acid containing about 1.5 g of 5-amino-4-benzylamino-N-(1-ethyl-1H-hexahydroazepin-3-yl)- 2-methoxybenzamide obtained by standard example 9 add 30 ml of 5N hydrochloric acid and 70 ml of water. Then to the solution was added while cooling 1 ml of an aqueous solution containing 0.29 grams of sodium nitrite, and then stirred for 30 minutes under the same conditions, and one hour at room temperature. The reaction mixture is alkalinized 48% aqueous solution of sodium hydroxide and extracted with chloroform. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure, obtaining an oily residue. The residue is subjected to column chromatography on silica gel, elwira and cleaning with a mixture of chloroform-methanol (20:1). The obtained solid product is recrystallized from diethyl ether, giving 1.1 g specified in the title compound, so pl. 136-137oC.

Example 17 [reaction according to method (a)]

Obtain 1-acetyl-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy - 1H-benzotriazol-5-carboxamide [compound of formula (IIb) in which R3bdenotes acetyl group]:

To 31,5 g of 1-acetyl-6-methoxy-1H-benzotriazol-5-carbonitrile at -7oC - -10oC, followed by stirring for two hours at -5oC - -7oC. To the mixture is added dropwise eighty (80 ml) of an ethyl acetate solution containing of 22.8 g (R)-3-amino-1-ethyl - 1H-hexahydroazepin and stirred for one hour, and then for 16 hours at room temperature. The reaction mixture is washed successively with water and then saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining 36 g specified in the title compound in the form of a solid product, so pl. 134-135oC (recrystallized from ethyl acetate)

1H-NMR spectrum (CDCl3, M. D.): 1.04 (3H, t, J=7.0 Hz), of 1.5-2.1 (6H, m), 2,45-2,95 (6H, m) of 3.00 (3H, s), 4.09 to (3H, s), 4,35 (1H, user.s), 7.76 (1H, s), 8.60 (1H, d, J=9.0 Hz), of 8.95 (1H, s).

Example 18 (reaction scheme 1)

Obtaining (R)-3-amino-1-ethyl-1H-hexahydroazepin;

(1) stage 1:

To a stirred suspension of 173 g (R) - amino-caprolactam-hydrochloride, 266 g of triethylamine and 1,700 ml of chloroform added by portions under ice cooling 293 g chlorotriphenylmethane. the resulting mixture was stirred for one hour under the same conditions and then two hours at room temperature. The reaction mixture is washed with water and Susumu residue added while heating and stirring, 600 ml of a mixture n-hexane - the ethyl acetate (2:1). The resulting crystalline precipitate is collected by filtration, washed with 1,000 ml of a mixture n-hexane - ethyl acetate (10:1) and dried, giving 290 g (R)--triphenylethylene--caprolactam, so pl. 189oC.

(2) stage 2':

To a mixture of 300 g of product obtained above, 193 g of ethane iodide and 1,500 ml of tetrahydrofuran is gradually added under stirring and at room temperature 42 g of 60% sodium hydride, and then stirred for 1.5 hours under the same conditions. The vessel is then cooled in the ice water to the mixture and slowly add water to dissolve the insoluble compounds. The reaction mixture was concentrated under reduced pressure and to the residue add 1,000 ml of ethyl acetate. The solution is washed with water, the organic layer is dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. To the resulting oily residue add 350 ml of a mixture of hexane-ethyl acetate (50:1) and the resulting crystalline precipitate is collected by filtration and dried, obtaining 287 g (R)-1-ethyl-3-triphenylethylene-1H-hexahydroazepin-2-it, so pl. 127oC.

(3) stage 3':

To 615 g of a 70% toluene solution of sodium bis(2-methoxy - ethoxy)aluminum hydride added 1400 ml of toluene and added to the mixture of 280 g of product obtained above when moving dobavlaut under ice cooling 1,000 ml of a 15% aqueous solution of sodium hydroxide and separating the organic layer, then the aqueous layer was extracted with 1,500 ml of toluene. The combined organic layer washed with water and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. Thus obtained oily residue is crystallized from ethanol. The resulting crystals are collected by filtration and dried, obtaining 247 g (R)-1-ethyl-3-triphenylethylene-1H-hexahydroazepin, so pl. 83 - 84oC.

(4) stage 4;

To a mixture of 177 g of the above product and 50 ml of tetrahydrofuran, add 700 ml of 10% hydrochloric acid, then stirred for 2 hours at room temperature. The reaction mixture was washed with diethyl ether. Then to the aqueous layer add excessive amounts of potassium carbonate, and then extracted with chloroform. The liquid extract is dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. So, get 65 g specified in the title compound in the form of butter.

1H-NMR spectrum (CDCl3, M. D.): 1.04 (3H, t, J=7.5 Hz), 1,3-1,9 (8H, m), 2,42 (1H, DD, J=13.5 Hz and 6.9 Hz), 2,5-2,6 (4H, m), 2.70 (1H, DD, J=13,5, J= 3.5 Hz), 2,98 (1H, m).

Example 19 (reaction scheme 1)

Obtaining (R)-3-amino-1-cyclopropylmethyl-1H-hexahydroazepin:

(1) stage 2;

To a mixture of 370 ml of toluene and 37 g of (R)--tra of diisobutylaluminium, with the next 16-hour stirring. After termination of the reaction, to the mixture is added dropwise water to decompose the excess diisobutylaluminium. The precipitated salt is removed by filtration and the filtrate was washed with aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. Thus obtain 34 g of (R)-3-triphenylethylene-1H-hexahydroazepin in the form of butter.

(2) stage 3:

To a mixture of 10 g of the obtained product and 100 ml of methyl ethyl ketone added to 10.5 g of potassium carbonate and 5.1 g of cyclopropanemethylamine and the mixture is heated 5 hours at boiling temperature under reflux. After termination of the reaction, insoluble materials are removed by filtration and the filtrate concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, elwira and cleaning chloroform-methanol (10: 1), giving 10 g of (R)-1-cyclopropylmethyl-3 - triphenylethylene-1H-hexahydroazepin in the form of butter.

(3) stage 4:

To a mixture of 9.0 g of the product obtained above and 10 ml of tetrahydrofuran was added 100 ml of 10% hydrochloric acid and subsequently stirred for 5 hours at room temperature. The reaction mixture is washed with diethyl ether the magnesium and the solvent evaporated under reduced pressure, obtaining 4.0 g specified in the title compound in the form of butter.

Example 20 (reaction scheme 1)

Obtain 3-amino-1-ethyl-1H-hexahydroazepin:

(1) stage 1:

To a stirred suspension of 125 g-amino-caprolactam, 118 g of triethylamine and 600 ml of chloroform added under ice cooling 288 g chlorotriphenylmethane. The mixture is additionally stirred for one hour under the same conditions and then stirred for 2 hours at room temperature. Thus obtained precipitate is collected by filtration, thoroughly washed with acetone and dried, receiving 330 g-triphenylethylene--caprolactam, so pl. 240-241oC.

(2) stage 2':

To a solution of 100 g of product obtained above and 65 g of ethane-iodide in 500 ml of dimethylformamide added gradually under stirring at room temperature for 12 g of 60% sodium hydride, followed by stirring for 4 hours under the same conditions. Then all poured into ice water and extracted with diethyl ether. The extract is washed with water and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting crystals are collected by filtration and dried, obtaining 88 g of 1-ethyl-3-triphenylethylene-1H - hexahydroazepin-2-it, so pl. 120-121oC.

(3) stage wala. Next, under stirring and cooling with ice add 83 g of product obtained above, and then stirred for one hour under the same conditions and for 2 hours at room temperature. To the reaction mixture while cooling with ice water and 48% aqueous solution of sodium hydroxide, the organic layer separated. The organic layer is washed with water and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. Thus obtained oily residue is crystallized from ethanol. The crystals are collected by filtration and dried, receiving 65 g of 1-ethyl-3 - triphenylethylene-1H-hexahydroazepin, so pl. 85-86oC.

(4) stage 4:

To a mixture of 134 g of product obtained above and 30 ml of tetrahydrofuran is added 500 ml of 10% hydrochloric acid, followed by stirring for 2 hours at room temperature. The reaction mixture was washed with diethyl ether. Then add an excess of potassium carbonate to the aqueous layer and extracted with chloroform. The extract is dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure, which gives 48 g specified in the title compound in the form of butter.

1H-NMR spectrum (CDCl3, M. D.): the 1.04 (3H, so J=7.5 Hz), 1,3-1,9 (8H, m), 2,42 (1H, DD, J=13.5 Hz and 6.9 Hz), 2,5-2,6 (4H, m)hydrazidine:

Repeat example 20, except that the amino-caprolactam used in stage 1, here replaced by (S) - amino-caprolactam. Specified in the title compound obtained as oil.

Example 22 (reaction scheme 1)

Obtain 3-amino-1-cyclopropylmethyl-1H-hexahydroazepin:

Repeat example 18, except that (R) - triphenylethylene--caprolactam used in stage 1, in this case, replace triphenylethylene - caprolactam. Specified in the title compound obtained as oil.

Example 23 (reaction scheme 2)

Obtain 3-amino-1-ethyl-1H-heptahydrate:

(1) stage 1:

To a solution of 27 g of 2-azacycloheptane and 50 g of ethane iodide in 250 ml of tetrahydrofuran is gradually added under stirring and ice cooling 10 g of 60% sodium hydride. The reaction mixture is stirred 4 hours at room temperature and poured into ice water, followed by extraction with diethyl ether. The extract is dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The residue is subjected to column chromatography on silica gel, elwira and cleaning chloroform-methanol (100:1) to give 36 g of 1-ethyl-1H - heptahydrate-2-it is in the form of butter.

1
To a solution of 25 g of product obtained above in 250 ml of chloroform added in portions with stirring and ice cooling 34 g pentachloride phosphorus, with subsequent additional 30 minutes of mixing under the same conditions. To the obtained mixture under stirring and ice cooling 0.4 g of iodine and then slowly added dropwise and under the same conditions 25 g of bromine, followed by heating to the boiling temperature under reflux for 2 hours. The solvent is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed successively with water and aqueous sodium thiosulfate solution and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure.

The residue is subjected to column chromatography on silica gel, elwira and cleaning with a mixture of n-hexane-ethyl acetate (4:1). Thus obtained crystals are recrystallized from n-hexane to give 10 g of a mixture of 3-bromo-1-ethyl-1H-heptahydrate-2-it 3-chloro-1-ethyl-1H-heptahydrate-2-it.

(3) stage 3:

A mixture of 10 g of the above mixture, 12 g of sodium azide, 2.0 g of sodium iodide and 100 ml of dimethylformamide is stirred overnight at 80oC, poured into ice water and extracted with diethylaminophenyl the residue is subjected to column chromatography on silica gel, elwira and purifying n-hexane-ethyl acetate (4: 1), giving 4.8 g of 3-azide-1-ethyl - 1H-heptahydrate-2-it is in the form of butter.

1H-NMR spectrum (CDCl3, M. D.): of 1.18 (3H, t, J=7 Hz), 1.5 and 1.8 (6H, m) and 2.2 (2H, m), is 3.08 (1H, m), or 3.28 (1H, m), 3,53 (1H, m), 3,76 (1H, m), 4,0 (1H, DD, J=10.5 Hz, J=5.6 Hz).

(4) stage 4:

To of 36.4 g of a 70% toluene solution of bis (2 - methoxyethoxy)-aluminum hydride, sodium was added 100 ml of toluene and the resulting solution was gradually added under stirring and ice cooling addition of 4.8 g of product obtained above, followed by stirring at room temperature for 2 hours. To the reaction mixture successively added under stirring and cooling with ice water and 48% aqueous solution of sodium hydroxide and the mixture extracted with diethyl ether. The extract is dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure, obtaining 3.8 g specified in the title compound in the form of butter.

Example 24 (reaction scheme 3)

Obtain 3-amino-1-ethyl-1H-octahydrate:

(1) To a solution of 17 g of 2-azacycloheptane and 29 g of ethane iodide in 200 ml of 1,2-dimethoxyethane gradually added under stirring at room temperature, 6.0 g of 60% sodium hydride, followed by stirring under these conditions, the Oh and dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, obtaining 20 g of 1-ethyl-1H-octahydrate-2-it is in the form of butter.

(2) stage 1:

To 200 ml of tertrahydrofuran ring of a solution containing 20 g of product obtained above, is added dropwise and with cooling with ice 78 ml of 2M-diisopropylamide lithium in tetrahydrofuran, followed by stirring for one hour. The reaction mixture was poured onto dry ice and the resulting mixture was diluted with water and washed with ethyl acetate. The aqueous layer was podkalyvayut of concentrated hydrochloric acid, extracted with chloroform, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, getting 14 grams of 3-carboxy-1-ethyl - 1H-octahydrate-2-it, so pl. 109-110oC (recrystallization from diethyl ether-n-hexane).

(3) stage (2):

To 100 ml of acetone solution containing 12 g of product obtained above, add 12 ml of water and 7.0 ml of triethylamine. To the mixture is added dropwise and under ice cooling 30 ml of acetone solution containing 8.0 g of ethylchloride, with a subsequent 30-minute stirring. Then, 30 ml of an aqueous solution containing of 6.1 g of sodium azide, add extravert diethyl ether. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, the obtained residue is added 200 ml of toluene. The solution is stirred while heating to 70oC to stop the expansion and the temperature was then raised to 100oC, with subsequent 2-hour stirring. After termination of the reaction, the solvent was evaporated under reduced pressure. To the obtained residue is added under stirring and ice cooling to 120 ml of 20% hydrochloric acid followed by heating to the boiling temperature under reflux for 1.5 hours. The reaction mixture is washed with ethyl acetate and the aqueous layer was alkalinized with excess potassium carbonate and extracted with chloroform. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, obtaining 8.5 g of 3-amino-1-ethyl-1H-octahydrate-2-it is in the form of butter.

(4) stage 3:

To a solution of 8.5 g of the product obtained above in chloroform added to 7.0 ml of triethylamine and then added by portions under ice cooling 14 g chlortrianisene, with subsequent 3-hour stirring at to the anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The residue is subjected to column chromatography, in which elute and remove the ethyl acetate-n-hexane (1:10) to give 14 g of 3-triphenylethylene-1-ethyl-1H-octahydrate-2-it is in the form of a solid substance, so pl. 160-162oC (recrystallization from n-hexane-ethyl acetate).

(5) stage 4:

To 30 g of a 70% toluene solution of bis (2 - methoxyethoxy)aluminum hydride, sodium was added 100 ml of toluene, to which were then added gradually with stirring and ice cooling 14 g videolooking product. The mixture is stirred over night at room temperature. After cooling, the reaction mixture there was added dropwise 2n aqueous solution of sodium hydroxide and then add a 48% solution of sodium hydroxide. The solution is extracted with ethyl acetate. The extract is washed successively with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The residue is subjected to column chromatography on silica gel, elwira and purifying ethyl acetate-n-hexane (1:10), giving 13 g of 3-triphenylethylene-1-ethyl-1H-octahydrate.

(6) stage 5:

To a mixture of 13 g of the product obtained above and 3 ml thetemperature. The reaction mixture was washed with diethyl ether. The aqueous layer was alkalinized excessive amounts of potassium carbonate and extracted with chloroform. The extract is dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure, obtaining 5.0 g specified in the title compound in the form of butter.

The standard example 1 (reaction stage 1 scheme 4)

Getting 4-chloro-N-(1-ethyl-1H-hexahydroazepin-3-yl)-2-methoxy-5-nitrobenzamide

To a suspension of 14.7 g of 4-chloro-2-methoxy-5-nitrobenzoic acid, 300 ml of chloroform and 1 ml of dimethylformamide add to 22.7 g of thionyl chloride and the mixture is heated for one hour to the boiling temperature under reflux. After termination of the reaction the solvent is evaporated under reduced pressure and the residue is dissolved in 200 ml of methylene chloride, added to the mixture under ice cooling and 12.9 g of triethylamine and 9.0 g of 3-amino - 1-ethyl-1H-hexahydroazepin, followed by stirring at room temperature for 15 minutes, the Reaction mixture was washed successively with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue is subjected to column chromatography, elwira and O2">

The standard example 2 (reaction stage 1 scheme 4)

Obtaining (R)-4-chloro-N-(1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide:

Repeat the standard example 1, except using (R)-3-amino-1-ethyl-1H-hexahydroazepin. Specified in the title compound obtained as a solid substance.

The standard example 3 (reaction stage 1 scheme 4)

Obtain (S)-4-chloro-N-(1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide:

Repeat the standard example 1, except using (S)-3-amino-1-ethyl-1H-hexahydroazepin. Specified in the title compound obtained as solid product.

The standard example 4 (reaction stages 2 and 3 of scheme 4)

Obtaining 5-amino-N-(1-ethyl-1H-hexahydroazepin-3-yl)-2 - methoxy-4-methylaminomethyl:

(1) stage 2:

To 100 ml of ethanol containing 4.9 g of 4-chloro-N -(1-ethyl-1H-hexahydroazepin-3-yl)-2-methoxy-5-nitrobenzamide add 50 ml of 30% ethanolic solution of methylamine, followed by heating to the boiling temperature under reflux for 1.5 hours. The solvent is evaporated under reduced pressure and the resulting residue water is added. The crystals are collected by filtration, washed with water and dried that d is g product obtained above is dissolved in 200 ml of 20% aqueous methanol. To the solution was added 10%-palladium-on - carbon and the mixture hydronaut at atmospheric pressure and room temperature. Once absorbed theoretical amount of hydrogen, palladium-on-carbon is removed by filtration and the methanol from the filtrate evaporated under reduced pressure. Thus obtained aqueous solution specified in the title compound.

The standard example 5 (reaction in stages 2 and 3 of scheme 4)

Obtaining (R)-5-amino-N-(1-ethyl-1H-hexahydroazepin-3-yl)-2 - methoxy-4-methylaminomethyl:

(2) stage 2

To 600 ml of an ethanol solution containing of 56.8 g (R) -4-chloro-N-(1-ethyl-1H-hexahydroazepin-3-yl)-2-methoxy - 5-nitrobenzamide, add 300 ml of 40% aqueous solution of methylamine, followed by heating to the boiling temperature under reflux for 2 hours. The solvent is evaporated under reduced pressure and the resulting crystalline precipitate is collected by filtration. The precipitate is washed with water and dried, obtaining 32 g (R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-2-methoxy-4-methylamino - 5-nitrobenzamide.

(2) stage 3:

33.2 g of product obtained above add 200 ml of methanol, 400 ml of water, 80 ml of acetic acid and 2.0 g of 10% palladium-on-carbon and the mixture hydronaut at atmospheric Yes what is the carbon is removed by filtration and the methanol from the filtrate evaporated under reduced pressure. Thus obtained aqueous solution of acetic acid containing specified in the title compound.

Standard examples 6-8 (reaction in stages 2 and 3 of scheme 4)

Getting 4-substituted amino-5-amino-N-(1-ethyl-1H - hexahydroazepin-3-yl)-2-methoxybenzamide or its optical isomers:

Using 4-chloro-N-(1-ethyl-1H-hexahydroazepin-3-yl)- 2-methoxy-5-nitrobenzamide having the same configuration as the final products and the corresponding amines, interaction, and processing is performed according to the standard way of example 5, receiving aqueous solutions of the compounds listed in table 7.

< / BR>
The standard example 9 (reaction in stages 2 and 3 of scheme 4)

Obtaining 5-amino-4-benzylamino-N-(1-ethyl-1H - hexahydroazepin - 3-yl)-2-methoxybenzamide:

(1) stage 2:

To 50 ml of an ethanol solution containing 2.0 g of 4-chloro-N -(1-ethyl-1H-hexahydroazepin-3-yl)-2-methoxy-5-nitrobenzamide add 6.0 g of benzylamine and heated to the boiling temperature under reflux for 22 hours. The solvent is evaporated under reduced pressure. To the residue water is added and then extracted with chloroform. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate; the solvent based mixture of chloroform-methanol (12:1), that gives 2.4 g of 4-benzylamino-N -(1-ethyl-1H-hexahydroazepin-3-yl)-2-methoxy-5-nitrobenzamide in the form of a solid substance.

(2) stage 3:

1.6 g of the product obtained above add 6 ml conc. hydrochloric acid and 3 ml of ethanol. Then additionally add a solution of 2.6 g chloride rowdygirl in 3 ml of ethanol, followed by stirring for 1 hour at 80oC. After termination of the reaction, the ethanol is evaporated under reduced pressure, obtaining an aqueous solution of hydrochloric acid containing specified in the title compound.

The standard example 10

Getting 6-methoxy-1-methyl-1H-benzotriazol-5-carboxylic acid [compound of formula (III), R2ain which a denotes a methyl group]:

1) Repeat the standard example 1, except that 3-amino-1-ethyl-1H-hexahydroazepin substituted Propylamine. Thus, receive a 4-chloro-2-methoxy - 5-nitro-N-propylbenzamide in the form of a solid product.

(2) 4-chloro-N-(1-ethyl-1H-hexahydroazepin-3-yl)-2-methoxy-5 - nitrobenzamide used in the standard example 4 (1), replace the above product, and the interaction and the treatment is carried out in a manner analogous to the standard sample 4. So, get 5-amino-2-methoxy-4-methylamin-4-methylaminomethyl, used in example 1 was replaced with the above product. The interaction and the treatment is carried out by the method of example 1, which gives 6-methoxy-1-methyl-N-(1-propyl)-1H - benzotriazol-5-carboxamide in the form of a solid connection.

(4) a Mixture of 6.9 g of the product obtained above and 100 ml of conc. hydrochloric acid is heated to boiling point under reflux for 5.5 hours. The reaction mixture is cooled and concentrated under reduced pressure. The resulting crystalline precipitate is collected by filtration, washed with water and dried, obtaining 3.2 g specified in the title compound.

Example composition 1

Obtain tablets (1,000 tablets):

(R)-N-(1-ethyl-1H - hexahydroazepin-3-yl)-6-methoxy-1-methyl-1H-benzotriazol-5-carboxamide (compound 2) - 5 grams

Lactose - 80 g

Corn starch 30 grams

Microcrystalline cellulose - 25g

Hydroxypropylcellulose 3 g

Low-viscosity silicic anhydride - 0.7 g

Magnesium stearate - 1.3 grams

The above components are mixed and granularit in the usual way, pelletizing get 1,000 tablets (145 mg/tablet).

Example composition 2

Getting capsules (1,000 capsules):

(R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1H-benzothia - 3.5 grams

Low-viscosity silicic anhydride and 1.8 g

Magnesium stearate is 2.7 grams

The above compounds are mixed, granularit conventional manner and filled into 1000 capsules.

Example of part 3

Obtaining powder:

(R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1H - benzotriazol-5-carboxamid/2 fumarate (compound 7b) - 10 g

Lactose - 960 g

Hydroxypropylcellulose - 25g

Low-viscosity silicic anhydride and 5 g

The above components are mixed and are in the powdered drug by a common way.

Example of part 4

The preparation for injection (1,000 capsules):

(R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1H - benzotriazol-5-carboxamid/2 fumarate (compound 7b) - 10 g

Sorbitol - 100 g

Water for injection - g.s. - Total 2.000 ml

(R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1H - benzotriazol-5-carboxamid/2 fumarate and sorbitol are dissolved in parts of water for injection. The remaining portion of water for injection is added to the total number. The resulting solution was filtered through a membrane filter (0.22 μm). The filtrate is filled into 2 ml ampoules and sterilized at 121oC for 20 minutes.

Industrial applicability

As noted previously, soedineniya have both excellent antiemetic activity and activity enhance contractility of the gastrointestinal tract, showing less suppressor activity against CNS and, therefore, useful as a means of enhancing the contractility of the gastrointestinal tract for the treatment or prevention of various functional disorders of the gastrointestinal tract associated with various diseases and their therapy. Intermediate compounds according to this invention are useful as synthetic intermediates for compounds of formula (I) in which R2denotes a hydrogen atom. In addition, the intermediate compounds of this invention represented by formula (IVa), useful as intermediates for compounds of formula (I) having R-configuration.

1. Derivatives of 6-methoxy-1H-benzotriazol-5-carboxamide of General formula I

< / BR>
in which R1denotes ethyl or cyclopropylmethyl;

R2denotes a hydrogen atom, methyl or ethyl;

n is 1,2 or 3;

the wavy line indicates that the configuration of the substituents on the carbon atom linked to the nitrogen atom in the amide group is RS, R or S,

or its pharmaceutically acceptable acid salt additive.

2.ing group.

3. Connection under item 1 or 2, having the R-configuration.

4. Connection under item 1 or 2, with RS-configuration.

5. (R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1H-benzotriazol-5-carboxamide or its pharmaceutically acceptable additive acid salt.

6. Pharmaceutical composition having antiemetic activity and activity that increase the contractility of the gastrointestinal tract, characterized in that it comprises as active ingredient an effective amount of a derivative of 6-methoxy-1H-benzotriazol-5-carboxamide of General formula I

< / BR>
in which R1denotes ethyl or cyclopropylmethyl;

R2denotes a hydrogen atom, methyl or ethyl;

n denotes 1, 2 or 3;

the wavy line means that the configuration of the substituents on the carbon atom that is associated with the N-atom in the amide group is RS, R or S,

or its pharmaceutically acceptable additive acid salt, and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to p. 6, characterized in that it comprises as active ingredient (R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1H-benzotriazol-5-carboxamide or its pharmaceutically acceptable is the quality of the active ingredient (R)-N-(1-ethyl-1H-hexahydroazepin-3-yl)-6-methoxy-1-methyl-1H-benzotriazol-5-carboxamide or its pharmaceutically acceptable acid additive salt.

9. The way to obtain 6-methoxy-1H-benzotriazol-5-carboxamide derivative represented by the formula I

< / BR>
in which R1denotes ethyl or cyclopropylmethyl;

R2denotes a hydrogen atom, methyl or ethyl;

n is 1, 2 or 3;

the wavy line means that the configuration of the substituents on the carbon atom linked to the nitrogen atom in the amide radical, is RS, R or S,

or its pharmaceutically acceptable acid salt additive, including the interaction of the compounds represented by formula III

< / BR>
in which R2Adenotes hydrogen, methyl, ethyl or aminosidine group

or its reactive derivative with the compound represented by formula IV

< / BR>
in which R1denotes ethyl or cyclopropylmethyl;

n denotes 1, 2 or 3;

the wavy line means that the configuration of the substituents on the carbon atom that is associated with the N-atom of the amide group, is RS, R or S,

and when one of the reagents is used as a compound of the formula III in which R2Ameans aminosidine group, make the R2Ain the corresponding product in the hydrogen atom by hydrolysis or hydrogenolysis of the above mentioned product Il CLASS="ptx2">

10. The derivative of 6-methoxy-1H-benzotriazol-5-carboxamide of the formula II

< / BR>
in which R1denotes ethyl or cyclopropylmethyl;

R3means aminosidine group;

n denotes 1, 2 or 3;

the wavy line means that the configuration of the substituents on the carbon atom that is associated with the N-atom in the amide radical, is RS, R or S,

or its acid additive salt.

11. Derived (R)-3-amino-1H-hexahydroazepin formula IVb

< / BR>
in which R1denotes ethyl or cyclopropylmethyl,

or its acid additive salt.

 

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