Derivatives of tricyclic triazolobenzodiazepine, methods for their preparation, pharmaceutical composition and method of treatment of allergic diseases, intermediate compounds and methods for their production

 

(57) Abstract:

Describes the new derivatives triazolobenzodiazepine in the form of prodrugs of General formula I: where R1represents hydrogen, HE, alkyl or phenylalkyl, R2, R3, R4and R5represent hydrogen, halogen, optionally protected hydroxyl, formyl, optionally substituted alkyl, alkenyl, alkoxy or etc., and Q represents a group selected from the following groups (i) to (iv), halogen or alkoxy:

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R31- R38is hydrogen, phenyl, C1-6alkyl, optionally substituted etc.; methods for their preparation, pharmaceutical composition containing them, and method of treatment of allergic diseases, intermediate compounds and methods for their preparation. New connections can be used as anti-allergic agents, with excellent bioavailability. 20 C. and 10 C.p. f-crystals, 5 PL.

The present invention relates to tricyclic derivative triazolobenzodiazepine, which possess anti-allergic activity, in the form of prodrugs, to intermediate compounds for their production, to methods for their preparation and antiallergic agents.

Known level as immunological reaction, can be divided into two types of reactions, i.e., the immediate reactions that occur immediately after stimulation, and slow reactions, which occur a few hours after the stimulation (see , for example, "Late Asthmatic Responces", P. M. O brine, J. Dolovich and F. E. Hargreave, Am. Rev. Respir. Dis., 1987; 136; 740-751). Especially important was the problem of the control of the latter reaction.

Clinical studies have shown that there are few drugs that are significantly effective in inhibiting delayed allergic reactions. Thus, in medicine there is a need to develop drugs that would be therapeutically effective for removal of both immediate and delayed reactions.

Cromoglicate sodium was known as the representative drugs for the suppression of immediate and delayed allergic reactions. This medicine is clinically administered by inhalation, as it is not effective by oral administration.

However, the introduction by inhalation has such disadvantages as the complexity of the correct administration of medication to babies, infants and children, as well as difficulties with long-term medication to patients who are very sensitive to inhalation procedures.

In recent years this area has been much research antiallergic agents and therapeutic agents for the treatment of asthma. Studied tricyclic compounds containing semiline ring include derivatives dibenzoxepin (Japanese patent application laid 10784/1988 and 78292/1993 and Journal of Chemical & Pharmaceutical Bulletin, vol. 39, No. 10, p. 2724 and R. 2729 (1991)), derivatives of dibenzoxazepine (Japanese patent application laid 184963/1991, 211071/1992, and 65257/1993 and EP 5180720), and derivatives of dibenzocycloheptadiene (WO 93/13068). Further, derivatives of tricyclic benzazepine and tricyclic derivatives benzodiazepine disclosed in EP 0686636, WO 95/18130, and WO 97/00258.

Meanwhile, methods of using prodrugs was known as one of the tools that increase the bioavailability of drugs (Keiko Toyo Seizai No Sekkei To Hyoka (Design and Assay of Oral Preparation): edited by Mitsuru Hashida, Yakugyo Jiho Co., Ltd., pp.216-231 (1995)). Chemical modification of carboxyl, hydroxyl, amino and other groups of drugs with ester, amide, acetylenic or other ties can improve the bioavailability of drugs. However, on the capacity of the contents of the invention

The authors of the present invention have synthesized derivatives of tricyclic triazolobenzodiazepine with chemically modified with a triazole ring, and found that these derivatives have superior bioavailability compared with the corresponding triazolobenzodiazepine.

In one aspect of the present invention proposed tricyclic derivatives triazolobenzodiazepine as prodrugs represented by the formula (I) and their pharmacologically acceptable salt and solvate:

< / BR>
where R1represents a hydrogen atom, hydroxyl group, WITH1-4alkyl or phenyl WITH1-4alkyl;

R2, R3, R4and R5that may be the same or different, represent any of (a) - (n):

(a) a hydrogen atom;

(b) a halogen atom;

(c) optionally substituted hydroxyl group;

(d) formyl;

(e)1-12alkyl which may be substituted by a halogen atom;

(f)2-12alkenyl, which may contain one or more carbon-carbon double bonds and may be substituted

(1) a halogen atom,

(2) cyano;

(3) -COR9where R9represents a hydrogen atom or a C1-6alkyl,

(4) -COOR10where ROrie may be the same or different, represent (i) hydrogen atom,

(ii) C1-6alkyl which may be substituted amino, optionally substituted C1-4the alkyl, phenyl, optionally substituted C1-4the alkyl which may be substituted saturated five-semiclean heterocyclic ring containing one or two nitrogen atom (the nitrogen atom may be substituted WITH1-4by alkyl), or a saturated or unsaturated five-semiclean heterocyclic ring,

(iii) phenyl which may be substituted by carboxyla, or

(iv) a saturated or unsaturated five-semiline heterocyclic ring.

(6) saturated or unsaturated five-semiclean heterocyclic ring which may be substituted WITH1-4the alkyl, or may form a bicyclic ring fused with another ring;

(g) C1-12alkoxy which may be substituted

(1) a halogen atom,

(2) a hydroxyl group,

(3) cyano,

(4)3-7cycloalkyl,

(5) phenyl,

(6)1-4alkoxy,

(7) phenoxy,

(8) amino which may be substituted WITH1-4the alkyl,

(9) -COR13where R13represents a hydrogen atom, a C1-6alkyl, phenyl, optionally substituted atom halogenide or C1-6alkyl,

(11) -CONR15R16where R15and R16that may be the same or different, represent a hydrogen atom or a C1-6alkyl which may be substituted saturated or unsaturated five-semiclean heterocyclic ring, or

(12) a saturated or unsaturated five-semiclean heterocyclic ring which may be substituted WITH1-4the alkyl or phenyl WITH1-4by alkyl;

(h) -C= N-OR16where R16represents a hydrogen atom, a C1-6alkyl, phenyl WITH1-4alkyl, or phenyl;

(i) -(CH2)mOR17where m is an integer from 1 to 4, and R17represents a hydrogen atom, a C1-6alkyl, or phenyl-C1-4-alkyl, where one or more of the hydrogen atoms of the benzene ring may be substituted WITH1-4by alkyl;

(j) -(CH2)kOR18where k is an integer from 1 to 4, and R18represents a hydrogen atom or a C1-4alkyl,

(k) -(CH2)j-COOR19where j is an integer from 0 to 4, and R19represents a hydrogen atom or a C1-6alkyl,

(l) -(CH2)p-NR20R21where p is an integer from 1 to 4, a R20and R21that may be the same or different is but replaced WITH1-4the alkyl,

(3) phenyl1-4alkyl,

(4) -COR22where R22represents a hydrogen atom or a C1-4alkyl which may be substituted by carboxyla, or

(5) -SO2R23where R23is1-4alkyl or phenyl which may be substituted by a halogen atom;

(m) -(CH2)q-CONR24R25where q is an integer from 0 to 4, and R24and R25that may be the same or different, represent a hydrogen atom, a saturated or unsaturated five-semiline heterocyclic ring, or C1-6alkyl which may be substituted saturated or unsaturated five-semiclean heterocyclic ring, or, in another embodiment, R24and R25may form a saturated or unsaturated five-semiline heterocyclic ring together with the nitrogen atom to which they are attached (and the heterocyclic ring may further contain at least one atom of oxygen, nitrogen or sulfur, may form a bicyclic ring fused with another ring, or may be replaced WITH1-4by alkyl); and

(n) -NR26R7where R26and R27that may be the same or different, represent an atom in the substituted C1-4the alkyl or C1-6alkoxy, optionally substituted by phenyl;

R31and R32that may be the same or different, represent a hydrogen atom or a C1-6alkyl which may be substituted by a halogen atom; and

Q represents a group selected from the following groups (i) to(iv), or halogen atom, or a C1-6alkoxy:

< / BR>
< / BR>
where R33is

C1-6alkyl which may be substituted C1-6alkoxy, optionally substituted C1-6-alkoxy, phenyl, optionally substituted C1-6alkoxy, amino, or nitro, or a saturated or unsaturated five-semiclean heterocyclic ring, optionally substituted C1-6alkoxy, amino or nitro,

phenyl which may be substituted WITH1-6alkoxy, amino or nitro, or

saturated or unsaturated five-semiline heterocyclic ring, optionally substituted C1-6alkoxy, amino or nitro, or

R33can form WITH1-4alkylen with R31or R32,

R34is

C1-6alkyl which may be substituted by a halogen atom, carboxyla, phenyl, optionally substituted C1-6alkoxy, amino or nitro, or is saturated is, the Mino or nitro,

phenyl which may be substituted C1-6alkoxy, amino or nitro, or

saturated or unsaturated five-semiline heterocyclic ring which may be substituted

C1-6alkoxy, amino or nitro,

R35and R36that may be the same or different, represent a hydrogen atom or a C1-6alkyl which may be substituted amino, optionally substituted C1-4the alkyl, or

R35and R36may form a saturated or unsaturated five-semiline heterocyclic ring together with the nitrogen atom to which they are attached, and

R37and R38that may be the same or different, represent1-6alkyl.

In another aspect of the present invention proposed tricyclic derivatives benzazepine as prodrugs represented by the formula (Ia) and their pharmaceutically acceptable salts and salt wadding:

< / BR>
where R41and R42that may be the same or different, represent a hydrogen atom, optionally protected hydroxyl, C1-6alkoxy which may be substituted by a halogen atom, or a C1-6alkyl which may be substituted by a halogen atom, and

R31A of the present invention can be used for the treatment of allergic diseases.

In another aspect of the present invention proposed a pharmaceutical composition comprising as active ingredient a compound represented by the formula (I) or (1A), or its pharmacologically acceptability salt or MES.

In another aspect of the present invention proposed intermediate compounds for the synthesis of compounds represented by formulas (I) or (Ia).

More specifically, the intermediate compound of the present invention is a compound represented by formula (II) or its salt or MES:

< / BR>
where R51is nitro or amino, R52represents a hydrogen atom or a protective group carboxyl, a Q, R2-R5, R31and R32have the above values.

Other intermediate compound of the present invention is a compound represented by formula (II') or its salt or MES:

< / BR>
where Q, R2-R5, R31, R32, R51and R52have the above values.

Other intermediate compound of the present invention is a compound represented by formula (VI) or its salt or MES:

< / BR>
where Q, R2- R5, R31, R32and R51R52
< / BR>
where Q, R2-R5, R31, R32and R52have the above values.

Other intermediate compound of the present invention is a compound represented by formula (VII) or its salt or MES:

< / BR>
R2-R5and R32have the above values.

Other intermediate compound of the present invention is a compound represented by formula (VIII) or its salt or MES:

< / BR>
where R61represents a protective group for triazole and R2-R5and R52have the above values.

Other intermediate compound of the present invention is a compound represented by formula (A), or its salt or MES:

< / BR>
where R41-R42and R52have the above values, provided that R41and/or R42do not represent a hydrogen atom.

Other intermediate compound of the present invention is a compound represented by the formula (XVIa) or its salt or MES:

< / BR>
where R41and R42, R51and R52have the above values.

These intermediate is a great description of the invention

Definition

In the sense used here, the term "alkyl" or "alkoxy" as a group or part of a group means an unbranched, branched or cyclic alkyl or alkoxy.

In the sense used here, the term C1-6alkyl includes the unbranched alkali, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl, branched alkali, such as isopropyl, isobutyl, tert-butyl and 3-pentyl, and cyclic alkali, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the sense used here, the term "C1-6alkoxy" includes unbranched alkoxy containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy and n-hexyloxy, branched alkoxy, such as isopropoxy, isobutoxy and tert-Butylochka, and cyclic alkoxy, such as cyclopropylamine, cyclohexyloxy.

In the sense used here, the term "C1-16alkyl" includes, in addition to the above C1-6alcelam, alkali containing from 7 to 16 carbon atoms, such as 1-etylhexyl, 5-methylhexan, heptyl, octyl, nonyl, decyl, until and pentadecyl.

In the sense used here, the term "athority atom means an oxygen atom, nitrogen or sulfur.

In the sense used here, the term "saturated or unsaturated five-semiline heterocyclic ring" means a heterocycle, containing one or more heteroatoms selected from atoms of oxygen, nitrogen and sulfur. Examples of heterocyclic rings include pyridine, imidazole, oxazole, thiazole, pyrimidine, furan, thiophene, pyrrole, pyrrolidine, piperidine, tetrapropenyl and oxazoline.

Connection

In the formula (I) each of R2, R3, R4and R5independently represents any of the groups (a)-(n).

Examples of protective groups for hydroxyl group (s) include acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, benzoyl, 4-nitrobenzoyl, 3-oxobutyryl, benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, methoxymethyl, methoxyethoxymethyl, benzoyloxymethyl, trimethylsilyl, tert-butyldimethylsilyl, triphenylsilane, 2-tetrahydropyranyl, trimethylsilylamodimethicone.

(e)1-12alkyl preferably represents C1-6alkyl, more preferably1-4alkyl.

(f)2-12alkenyl preferably represents C2-6alkenyl, more preferably2-4alkenyl, most predpochtiteljno, (3) -COR9, (4) -COOR10(5) -CONR11R12or (6) saturated or unsaturated five-semiclean heterocyclic ring.

IN (5) -CONR13R12, R11and R12that may be the same or different, represent a hydrogen atom or a C1-6alkyl (preferably1-4alkyl), phenyl or a saturated or unsaturated five-semiline heterocyclic ring.

In this case, the alkyl may be further substituted amino, phenyl or a saturated or unsaturated five-semiclean heterocyclic ring.

Next, one or two hydrogen atoms of this amino can be substituted WITH1-4the alkyl.

The phenyl may be substituted WITH1-4the alkyl. In this case, WITH this1-4the alkyl may be substituted saturated five-semiclean heterocyclic ring containing one or two nitrogen atom, optionally substituted C1-4the alkyl. Preferred examples include piperidine, 4-piperidyl, 1-pyrrolidinyl, piperazinil, 4-C1-6alkylpiperidines, morpholino.

(g)1-12alkoxy is preferably C1-6alkoxy, more preferably1-4alkoxy.

This alkoxy may be substituted by (9) -COR1-4alkyl. In this case, the phenyl may be substituted by a halogen atom or WITH1-4alkoxy. Although the position of the substituent is not specifically limited, preferable 2 - and 4-position on the phenyl ring.

(h)1-12alkoxy may be substituted saturated or unsaturated five-semiclean heterocyclic ring as a substituent (12). This geterotsiklicheskikh ring is preferably a five or six-membered heterocyclic ring containing one or two nitrogen atom, for example, piperidino, 4-piperidinyl, 1-pyrrolidinyl, piperazinil, morpholino. One or more of the carbon atoms of the heterocyclic ring may be further substituted1-4the alkyl or phenyl WITH1-4the alkyl. Preferred examples of the phenyl C1-4Akilov include bensely, such as benzyl, 4-methylbenzyl, 4-Chlorobenzyl, 4-hydroxybenzyl, 4-nitrobenzyl, 4-methoxybenzyl and 4-carboxybenzoyl, phenetyl, 3-phenylpropyl and 4-phenylbutyl.

In (i) -(CH2)mOR17m represents an integer from 1 to 4, preferably an integer of 1 or 2.

In (j) -(CH2)kCOR18, k represents an integer from 0 to 4, preferably 0, 1 or 2.

In (k) -(CH2)jCOOR19, j represents Zelt an integer from 0 to 4, preferably 0, 1 or 2.

R24and R25may form a saturated or unsaturated five-semiline heterocyclic ring together with the nitrogen atom to which they are attached. This heterocyclic ring may further contain one or more atoms of oxygen, nitrogen or sulfur. Heterocyclic ring may be substituted WITH1-4the alkyl. Preferred examples of heterocyclic rings include, piperazine derivatives, piperidine, N-methylpiperazine, morpholine, succinimide, indolyl, 4-methylindole, 5-methylindole, isoindolyl, phthalimido, 4-methylphthalimide and 1,1-dioxo-2-benzothiazolyl.

In formulas (I) and (Ia) Q can represent a halogen atom, a C1-6alkoxy (preferably1-4alkoxy), or any of groups (i) to(iv).

In group (i) one or more of the hydrogen atoms of this C1-6the alkyl represented by R33may be substituted C1-6alkoxy, phenyl or a saturated or unsaturated five-semiclean heterocyclic ring (preferably a six-membered heterocycle containing one heteroatom). Further, one or more of the hydrogen atoms of this C1-6alkoxy may be substituted C1-6alkoxy. One or more of the hydrogen atoms of the phenyl and g examples of C1-6the alkyl represented by R33include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, tert-butyl, 3-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,3-diethoxy-2-propyl, 2-isopropoxyethanol, phenetyl, 3-pyridylmethyl, 4-methoxyphenethyl and 2-(2-methoxyethoxy)ethoxy.

R33may represent phenyl. The phenyl may be substituted C1-6alkoxy, amino or nitro, preferably nitro. Preferred examples of fanilow represented by R33include 4-nitrophenyl.

Further, R33may represent a saturated or unsaturated five-semiline heterocyclic ring (preferably six-membered heterocycle containing a single heteroatom). At least one hydrogen atom of the heterocyclic ring may be substituted C1-6alkoxy, amino or nitro, preferably nitro. Preferred examples of the saturated or unsaturated five-semichronic heterocyclic rings represented by R33include 4-piperazin, 4-piperidyl and 4-tetrahydrofuran.

Further, R33can form WITH1-4alkylen together with any one of R31and R32. Preferred examples1-4alkylene include methylene. If RNedstat a hydrogen atom, then-CO2R31R32is 4-(2-oxo)-1, 3-dioxolan.

In group (ii) one or more of the hydrogen atoms WITH1-16the alkyl represented by R34may be substituted by a halogen atom, carboxyla, phenyl or a saturated or unsaturated five-semiclean heterocyclic ring (preferably a six-membered heterocycle containing one heteroatom). Further, one or more of the hydrogen atoms of the phenyl and the heterocycle may be substituted C1-6alkoxy, amino or nitro.

Preferred examples1-16Akilov represented by R34include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, tert-butyl, 3-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-etylhexyl, 5-methylhexan, heptyl, octyl, nonyl, decyl, undecyl, pentadecyl, chloromethyl, 3-chloropropyl, 2-carboxyethyl, morpholinomethyl, 4-methoxybenzyl and 4-piperazinylmethyl.

R34may represent phenyl. Phenyl may be substituted C1-6alkoxy, amino or nitro, preferably amino. Preferred examples of fanilow represented by R34include 4-AMINOPHENYL.

Further, R34may represent a saturated or unsaturated five-semiclean more of the hydrogen atoms of the heterocyclic ring may be substituted C1-6alkoxy, amino or nitro, preferably amino. Preferred examples of the saturated or unsaturated five-semichronic heterocyclic rings represented by R34include 3-pyridyl and 4-pyridyl.

In group (iii) one or more of the hydrogen atoms of C1-6the alkyl represented by R35and R30may be substituted amino. Preferred examples of C1-6Akilov represented by R35and R36include 2-(N,N-dimethylamino)ethyl. Preferred examples of the saturated or unsaturated five-semichronic heterocyclic rings formed when combining R35and R36include 1 morpholino, 1-imidazolyl and 4-piperazinil.

The group of compounds represented by formula (I) includes:

a group of compounds in which R1, R2, R3, R4and R5represent a hydrogen atom or (g)1-12alkoxy (preferably C1-6alkoxy), and Q represents group (i) (preferably R33is1-4alkyl, optionally substituted C1-4alkoxy);

a group of compounds in which R1represents a hydrogen atom, R2, R3, R4and R5represent a hydrogen atom or (g)1-12alkoxy (predpochtitelno substituted C1-4alkoxy);

a group of compounds in which R1, R2and R5represent a hydrogen atom, R3and R4represent a hydrogen atom or (g)1-12alkoxy (preferably C1-6alkoxy), and Q represents group (i) (preferably R33is1-4alkyl, optionally substituted C1-4alkoxy);

a group of compounds in which R1, R2and R5represent a hydrogen atom, R3and R4represent a hydrogen atom or (f) C1-12alkenyl, and Q represents group (i)(preferably R33is1-4alkyl, optionally substituted C1-4alkoxy);

a group of compounds in which R1, R2and R5represent a hydrogen atom, R3and R4represent a hydrogen atom or (f) C1-12alkyl, and Q represents group (i) (preferably R33is1-4alkyl, optionally substituted C1-4alkoxy);

a group of compounds in which R1, R2and R5represent a hydrogen atom, R3and R4represent a hydrogen atom or (j) a group -(CH2)kCOR18, (1)-(CH2)NR20R21(m) -(CH2)qCONR22R23or (n)-NR29R30a QB>1-4alkoxy);

a group of compounds in which R1, R2, R4and R5represent a hydrogen atom, R3is (g) C1-12alkoxy (preferably C1-6alkoxy), and Q represents group (i) (preferably R33is1-4alkyl, optionally substituted C1-4alkoxy); and

a group of compounds in which R1, R2R3and R5represent a hydrogen atom, R4is (g)1-12alkoxy (preferably C1-6alkoxy), and Q represents group (i) (preferably R33is1-4alkyl, optionally substituted C1-4alkoxy).

In formulas (I) and (Ia) -CR31R32Q is preferably 2-position of the triazole ring.

One or more of the hydrogen atoms of C1-6the alkyl represented by R31and R32in formulas (I) and (Ia), and one or more of the hydrogen atoms of C1-6the alkyl and C1-6alkoxy in the alkyl part, presents R41and R42in the formula (Ia) can be substituted by a halogen atom. Examples of the substituted Akilov and alkyl parts include trifluoromethyl, 2-foretel, deformity, 2,2,2-triptorelin, trichloromethyl, 2-chloroethyl , dichloromethyl, 2,2,2-trichloroethanol, 5,5,5-triterpenes and 6,6,6-triptorelin.

Protective groups for an optionally protected hydroxyl, which may be represented by R41and R42include acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, benzoyl, 4-nitrobenzoyl, 3-oxobutyryl, benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, methoxymethyl, methoxyethoxymethyl, benzoyloxymethyl, trimethylsilyl, tributylammonium, triphenylsilane, 2-tetrahydropyranyl, trimethylsilylamodimethicone.

R41and R42represent preferably1-4alkoxy, more preferably methoxy or isopropoxy. Even more preferably, R41represented methoxy, and R42represented methoxy or isopropoxy.

A group of preferred compounds represented by formula (Ia), includes a group of compounds in which R41and R42submit C1-6alkoxy (preferably1-4alkoxy, more preferably methoxy or isopropoxy), and Q represents group (i)(preferably R33is1-4alkyl, optionally substituted C1-4alkoxy).

Among the compounds of the present invention is particularly preferred with which][1]benzazepin,

2-(1-(1,3-diethoxy-2-propoxycarbonyl)-2-methyl-propyl)-1,8-dimethoxy-4(5H),10-dioxo-2H-1,2, 3-triazolo[4,5-C][1]benzazepin,

2-(1-(1,3-diethoxy-2-propoxycarbonyl)-2-methyl-propyl)-8-isopropoxy-7-methoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin, and

8 isopropoxy-2-(1-isopropoxycarbonyl-2-methylpropyl)-7-methoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin.

In the present invention is a protective group for carboxyl represented by R52include , for example, methyl, ethyl, tert-butyl, benzyl, 4-methoxybenzyl, diphenylmethyl, 4-nitrobenzyl, tert-butyldimethylsilyl, triphenylsilane, 2-phenylsulfonyl, 2-methoxycarbonylethyl, 2-cyanoethyl and 2-trimethylsilylmethyl.

In the present invention "protective groups for triazole" represented by R61include , for example, benzyl, optionally substituted by halogen atom, hydroxyl, nitro, C1-6the alkyl or C1-6alkoxy, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, benzoyloxymethyl, methoxyethoxy.

The group preferred intermediate compounds represented by formulas (II), (II'), (VI) and (VI'), include compounds in which ecstasy a hydrogen atom, optionally protected hydroxyl, optionally substituted C1-6alkoxy, optionally substituted C1-6alkyl (preferably optionally substituted C1-6alkoxy), and Q represents group (i) (preferably R33is1-4alkyl, optionally substituted C1-4alkoxy).

The group preferred intermediate compounds represented by formulas (VII) and (VIII) include compounds in which R2and R5represent a hydrogen atom, and R3and R4each independently represents a hydrogen atom, optionally protected hydroxyl, optionally substituted C1-6alkoxy, and optionally substituted C1-6alkyl (preferably optionally substituted C1-6alkoxy).

Examples of preferred compounds represented by formulas (VI) and (VI'), include

ethyl 5-(3,4-dimethoxybenzoyl)-2-(1-isopropoxycarbonyl-hydroxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate,

ethyl 2-(1-isopropoxycarbonyl-2-methylpropyl)-5-(3-isopropoxy-4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate,

ethyl 5-(3,4-dimethoxybenzoyl)-2-(1-(1-(1,3-diethoxy-2-propoxy)carbonyloxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate and

ethyl 2-(1-(1,3-diethoxy-2-the Examples of the preferred compounds, represented by formula (VII), include

methyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate,

ethyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4 - carboxylate,

methyl 5-(3-isopropoxy-4-methoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate and

ethyl 5-(3-isopropoxy-4-methoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate.

Examples of preferred compounds represented by formula (IX) include the

methyl 4-(3,4-acid)-4-oxo-2-butenoate,

ethyl 4-(3,4-acid)-4-oxo-2-butenoate,

methyl 4-(3-isopropoxy-4-methoxybenzoyl)-4-oxo-2-butenoate and ethyl 4-(3-isopropoxy-4-methoxybenzoyl)-4-oxo-2-butenoate.

Examples of preferred compounds represented by formula (XVI) include ethyl 4-(4,5-dimethoxy-2-nitrophenyl)-4-oxo-2-butenoate and ethyl 4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-oxo-2-butenoate.

Compounds of the present invention may exist as tautomers and isomers provisions formed due to the triazole ring, CIS-TRANS isomers generated by alkenyl as Deputy, and enantiomers formed by the group-COR31R32and any of these isomers and their mixtures are included in the scope of the present invention.

Compounds of this izaberete impactfully salts include salts of alkali metals or alkaline earth metals, such as salts of sodium, potassium and calcium salts galoidvodorodnykh acids, such as salts of hydrofluoric, hydrochloric, Hydrobromic and itestosterone acids, salts of inorganic acids, such as salts of nitric acid, salt perchloro acids, salts of sulfuric acid, and salts of phosphoric acid, salts of lower alkylsulfonic acids, such as salts methansulfonate acids, salts triftormetilfullerenov acids, salts econsultancy acids, salts arylsulfonic acids, such as salts of benzosulfimide acid and salts paratoluenesulfonyl acid, organic acid salts, such as salts of fumaric acid, salts of succinic acid, salts of citric acid, salts of tartaric acid, salts of oxalic acid, and salts of maleic acid, and salts of amino acids such as salts of glutamic acid and a salt of aspartic acid.

The solvate of the compounds of the present invention include hydrates and ethanol solvate.

Obtaining compounds

Compounds of the present invention can be synthesized in accordance with the following methods 1 or 2.

<Method 1>

The compound represented by formula (I) can be obtained by interacting the connection fo the where Q, R31and R32have the above values, a Hal represents a halogen atom, in a solvent which does not participate in the reaction (for example, water, ethanol, isopropyl alcohol, tetrahydrofuran, diisopropyl ether, methylene chloride, acetone, N, N-dimethylformamide, dimethyl sulfoxide), in the presence of a base at a temperature from 0 to 150oC for from 1 hour to 48 hours. Grounds that are used include organic bases such as pyridine and triethylamine, and inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide. Preferably the connection can be obtained by the reaction of N, N-dimethylformamide in the presence of sodium bicarbonate at a temperature of from 20 to 100oC for 1-24 hours. The compound represented by formula (I), obtained as a mixture of 1-substituted triazole, 2-substituted triazole and 3-substituted triazole in any proportion.

The compound represented by formula (III) can be obtained by a method described, for example, in WO 95/18130 and WO 97/00258.

The compound represented by formula (I), can be cleaned by conventional means, for example, by recrystallization, presidenial, extraction plants is Oh.

<Method 2>

The compound represented by formula (I) can be obtained by restoring the compound of formula (IIA)

< / BR>
where Q, R2-R5, R31, R32and R52have the above values, obtaining the compound represented by formula (IIb)

< / BR>
where Q, R2-R5, R31, R32and R52have the above values, and then carrying out the cyclization reaction of the compound represented by formula (IIb).

For this reaction recovery, you can use the normal way catalytic reduction (preferably in the presence of Nickel or palladium catalyst in a solvent, e.g. ethyl acetate, in which the alcohol solvent as ethanol, water or a mixture thereof), or a way to restore the system to the zinc-acetic acid, etc., Recovery can be accomplished at a temperature of from 10 to 100oC for 0.1 to 10 hours.

The cyclization reaction can be performed by subjecting the interaction of the compound represented by formula (IIb), with a strong base such as sodium hydride, potassium hydride, sodium methoxide, ethoxide or sodium tert-piperonyl potassium in a solvent which does not participate in the reaction (for example, alcohol such as methane and a mixture of two or more of these solvents at temperatures from 0 to 100oFor 1-48 hours, usually 5-24 hours.

The cyclization reaction can also be maintained in acetic acid or triperoxonane acid as the solvent, carrying out the reaction of the compound represented by formula (IIb), at a temperature of from 20 to 100oC for 1-24 hours.

After cyclization Q can be further converted into another Deputy.

In both the above reactions recovery and cyclization not observed positional isomerization substituent on the triazole. If the compound represented by formula (IIA'), use only one compound of the formula (I) receive as a single connection.

The compound represented by formula (I), can be cleaned by conventional means, for example, by recrystallization, presidenial, by solvent extraction, chromatographic column with silica gel and chromatography column with adsorbent resin (see scheme 1).

The compound represented by formula (IIA) can be synthesized according to the following scheme. In this scheme, M is lithium, magnesium chloride, magnesium bromide, magnesium iodide, zinc bromide, zinc iodide, bromide, cadmium iodide cadmium or copper, R62is sodium, C1-6R61have the above values.

The method of obtaining (1) the compounds of formula (IIA)

The compound represented by formula (IIA) can be obtained from compounds represented by the formula (V) by the following methods a, b, C or D. In accordance with methods b, C or D can be obtained compound represented by the formula (IIA) with the Deputy-CQR31R32(represented by formula (IIA')), if the Deputy is injected at the 2-position of the triazole ring.

<Method A>

The compound represented by formula (IIa) can be obtained by interaction of the compounds represented by formula (V):

< / BR>
where R2-R5and R52have the above meanings, with a compound represented by the formula (IV), in accordance with method 1. As the compound (I) obtained by the method 1, and in the same way the compound represented by formula (IIA), is a mixture of three types of isomers. For example, the compound represented by formula (V) can be obtained in accordance with the method disclosed in WO 95/18130.

<Method> (see diagram 2).

The compound represented by formula (V), is subjected to the interaction with the ketone or aldehyde represented by the formula, RLi acetonitrile) at a temperature of from -78 to 100oC, preferably -20 to 50oC for 0.1 to 24 hours, typically from 0.1 to 1 hour. In this case, in the reaction system are hemiacetal represented by the compound (V'). This reaction promotirovat, adding an acid catalyst. Preferred here acid catalysts include protonated acid, such as para-toluensulfonate acid, pyridinium salt of para-toluensulfonate acid, D-(+)-camphorsulfonic acid, triperoxonane acid, sulfuric acid, hydrochloric acid, perchloric acid and phosphoric acid and a Lewis acid such as TRIFLUORIDE complex bordetellosis ether, aluminum chloride and titanium tetrachloride.

Q in formula (IIA') can be entered, adding further variety of reagents to the compound represented by formula (V). The compound represented by formula (IIA'), where Q represents any of groups (i) to(iv), a halogen atom or C1-6alkoxy, can be obtained as follows.

(1) the Compound represented by formula (IIA'), where Q represents group (i) can be obtained by interaction of the reaction solution containing the compound represented by formula (V'), with the compound represented by the formula, R71-C(-0)-R72(where R71(where R71represents a chlorine atom, 4-nitrophenyl or 1-imidazolyl), and then through the interaction of the compounds with an alcohol represented by the formula, R33OH (where R33has the above values). Deputy Q can then be turned into another Deputy.

(2) the Compound represented by formula (IIA'), where Q represents the group (ii) can be obtained by adding allerease agent represented by R34COHal (where Hal and R34have the above values), or (R43CO)2O (where R34has the above values) to the reaction solution containing the compound represented by formula (V), optionally in the presence of a base, such as pyridine.

The compound represented by formula (IIA'), where Q represents the group (ii) can be obtained, condensing the compound represented by formula (V'), with the compound represented by the formula, R34COOH (where R34has the above values). Used preferred condensing the ins and derivatives of phosphoric acid, and dehydrating agents such as thionyl chloride and phosphorus oxychloride.

This connection can also be obtained by interaction of the compound (IIA') (where Deputy Q represents a halogen atom, which can be obtained in accordance with the method described in method (4), with sodium or potassium salt of carboxylic acid represented by the formula, R34COOH (where R34has the above values), in a solvent which does not participate in the reaction, in the presence of Tetra-n-butylammonium. Q can then be turned into another Deputy.

(3) the Compound represented by formula (IIA'), where Q represents group (iii) can be obtained by interaction of the compound obtained by the method (1) represented by formula (IIA') (where R2-R5, R31, R32and R52have the above values, and Q is-OCOR71(where R71has the above values), optionally after separation, with an amine represented by R35R36NH (where R35and R36have the above values).

(4) the Compound represented by formula (IIA'), where Q represents group (iv), a halogen atom or C1-6alkoxy, can be obtained by adding chloroformyl C1-6alkyl), or halogenation agent such as thionyl chloride or thienylboronic, to the reaction solution containing the compound (V). The reaction can be usually carried out at temperatures from -20 to 100oC for 0.1 to 48 hours.

All of the compounds represented by formula (IIA'), obtained in accordance with the method through hemiacetal represented by the compound (V'), get as triazoles, substituted in 2-position.

<Method C>

The compound represented by formula (IIA'), where Q represents group (i) can be obtained by interaction of the compounds represented by formula (V) with a compound represented by R31R32C=O (where R31and R32have the above values) (e.g., Isobutyraldehyde) in an organic solvent, such as acetone, acetonitrile or ethyl acetate, at a temperature of from -20 to 100oC, preferably from 22 to 28oC receives the connection represented by formula (V'), and then interacting compounds represented by formula (V'), in the same solution, with the compound represented HalCOOR33(where Hal and R33have the above values) (for example, isopropylcarbonate), together with carbonate of an alkali metal, the lia, when 25-60oWith, then the processing of the product, and crystallizing them processed product. Solvents that can be used for crystallization include lower alcohols such as methanol, ethanol and isopropyl alcohol. These solvents can be used together with water.

All of the compounds represented by formula (IIA'), obtained in accordance with this method will have as triazoles, substituted in 2-position. The above method is advantageous because of 1,1'-carbonyldiimidazole that roads and not stable, do not use as a reactant, not formed any by-products derived from 1,1'-carbonyldiimidazole, and compounds represented by formula (IIA'), where Q represents group (i), is obtained in high purity at a high yield.

<Method D>

The compound represented by formula (IIA'), where Q represents group (i) can be obtained by directly interacting compounds represented by formula (V) with the compound represented by formula (IV) (for example, 1-chloro-2-methylpropyl-isopropylcarbonate).

More specifically, the compound represented by formula (V) can be subjected to interaction with the compound represented formylanahalamine base, such as sodium carbonate, potassium carbonate, cesium carbonate or sodium hydroxide, and alkali metal iodide such as sodium iodide or potassium iodide at 25-60oWith over 1-70 hours.

The compound represented by formula (IIA'), can be cleaned by conventional means, for example, by solvent extraction, crystallization or chromatographic column with silica gel.

All of the compounds represented by formula (IIA') obtained in the above manner, can preferably be obtained in the form triazoles, substituted in 2-position. This, apparently, is connected with adding to the reaction system of iodide of an alkali metal. Further, this method is advantageous that the compounds represented by formula (IIA'), can simply be obtained from the compounds represented by formula (V), in a single phase. A further advantage of the method is that the formation of by-products derived from impurities contained in the ketone or aldehyde (e.g., isobutylene acid Isobutyraldehyde), presents R31R32C= O, which is subjected to interaction with the compound represented by formula (V), in methods b and C, can be avoided and it is possible to obtain high purity compounds fora), can be obtained by nitration of compounds represented by formula (VI). The nitration reaction can be conducted in the presence of nitrouse agent, such as (concentrated) nitric acid or fuming nitric acid, without a solvent or in a solvent which does not participate in the reaction (for example, acetic anhydride, sulfuric acid, methylene chloride or chloroform) at a temperature of -10 to 50oWith in 10 minutes-24 hours.

The compound represented by formula (VI) can be obtained by typing-CQR31R32in the triazole group of compounds represented by formula (VII). Deputy-COR31R32you can type in accordance with methods a, b, C or D.

The compound represented by formula (VII) can be obtained by removing the protective group from the compound represented by formula (VIII).

The removal of the protective group can be carried out by the method described by D. R. Buckle and C. J. M. Rockell, J. Chem. Soc., Per-kin Trans. I, 627 (1982); F. E. Nielsen, E. B. Pedersen, J. Heterocycl. Chem. , 22, 1963 (1985). More specifically, if R61 represents benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, 3,4,5-trimethoxybenzyl, benzoyloxymethyl or gramatically, removing the protective group can be performed by subjecting the interaction of compounds is or diluted sulfuric acid, or with an organic acid, such as triperoxonane acid, either as such or after dilution with a solvent which does not participate in the reaction (for example, methylene chloride or toluene) at a temperature of from 15 to 80oC for 1-24 hours.

The compound represented by formula (VII) can also be obtained through the interaction of the compounds represented by formula (XII) with the compound represented by the formula (XIII'), in a solvent which does not participate in the reaction (e.g. tetrahydrofuran, diethyl ether, diisopropyl ether, tert-butyl methyl ether or toluene) at a temperature of from -78 to 100oC for 15 minutes to 24 hours. The compound represented by the formula (XIII'), can easily be obtained through the interaction of the connection metal azide such as sodium azide represented by formula (X'), various alkylsilanes and various azides alkalolu with acetylenedicarbonic complex fluids.

The compound represented by formula (VII) can also be obtained through the interaction of the compounds represented by formula (IX), with a metal azide represented by formula (X'), in a solvent which does not participate in the reaction (for example, water, ethanol, is malformed or dimethylsulfoxide) at a temperature of from 0 to 120oC for 1-24 hours.

Obtaining the compounds represented by formula (VIII)

The compound represented by formula (VIII), it is possible to learn, interacting compounds represented by formula (IX), with an organic azide represented by formula (X), such as parameterized. The reaction may be carried out at the interaction of the compounds represented by formula (IX) with a compound represented by formula (X').

The compound represented by formula (IX) can be obtained by interaction of the compounds represented by formula (XI), with chlorine, bromine or iodine in a solvent which does not participate in the reaction (for example, water, ethanol, isopropyl alcohol, tetrahydrofuran, diisopropyl ether, methylene chloride, acetic acid, N,N-dimethylformamide or dimethylsulfoxide) at a temperature of from -10 to 30oC for 10 minutes to 24 hours, then subjecting the obtained halide compound to interact with an organic base, such as triethylamine, diisopropylethylamine, triisopropanolamine, pyridine, picoline, lutidine, kallidin or quinoline, or Neorganicheskie base, such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate or bicarbon, isopropyl alcohol, tetrahydrofuran, diisopropyl ether, methylene chloride, acetone, toluene, N,N-dimethylformamide or dimethylsulfoxide) at a temperature of from 0 to 50oC for 1-24 hours.

The compound represented by formula (XI) can be obtained by a method described, for example, in Eur. J. Med. Chem., 23, 45 (1988), or in U.S. patent N4562068.

The compound represented by formula (VIII) can be obtained by transforming alabanza represented by the formula (XIV), in the ORGANOMETALLIC compound represented by the formula (XII) (for example, M represents lithium, magnesium chloride, magnesium bromide, magnesium iodide, zinc bromide, zinc iodide, bromide, cadmium iodide, cadmium, copper or similar), and then interacting compounds represented by formula (XII) with the compound represented by the formula (XIII) in a solvent which does not participate in the reaction (e.g. tetrahydrofuran, diethyl ether, diisopropyl ether, tert-butyl methyl ether or toluene) at a temperature of from -78 to 100oC for 15 min-24 hours. The compound represented by the formula (XIII) can be easily obtained by subjecting the interaction of azide (X), obtained, for example, by the way, opened in J. Heterocyclic Chem., 21, 1669 (1984), with acetylenedicarbonic complex deity, removing the protective group from the compound represented by the formula (XV). The removal of the protective group can be performed in the manner described in connection with the removal of the protective group from the compound represented by formula (VIII), to obtain compounds represented by formula (VII).

The compound represented by formula (V) can also be obtained through the interaction of the compounds represented by formula (XVI) with the compound represented by formula (X'). The reaction can be conducted in the manner described above in connection with the reaction of the compound represented by formula (IX) with a compound represented by formula (X').

The compound represented by formula (V) can be obtained by nitration of compounds represented by formula (VII). The nitration can be carried out by the method described above in connection with the nitration of compounds represented by formula (VI) to obtain a compound represented by the formula (IIA).

The compound represented by the formula (XV) can be obtained by interaction of the compounds represented by formula (XVI) with the compound represented by formula (X). The reaction can be conducted in the manner described above in connection with the reaction of the compound represented by formula (IX), with coeliadinae, represented by the formula (XVII), in the manner described above in connection with obtaining a compound represented by the formula (IX) from the compound represented by formula (XI).

The compound represented by formula (XVII) can be obtained by a method described, for example, in Eur. J. Med. Chem. 23, 45 (1988) or in U.S. patent 4562068.

The compound represented by the formula (XV) can be obtained by nitration of compounds represented by formula (VIII). The nitration can be carried out by the method described above in connection with the nitration of compounds represented by formula (VI), to obtain compounds represented by formula (IIA).

In addition, the compound represented by the formula (XV) can be obtained, for example, by the way, opened in WO 95/18130

The pharmaceutical composition

Oral administration of compounds represented by formula (I) according to the present invention, the experimental animals showed that in this case, the compound represented by formula (III), determined in plasma at higher concentrations compared with the introduction of the compounds represented by formula (III). WO 95/18130 and WO 97/00258 disclose the use of compounds represented by formula (III), as a therapeutic agent the various mucous membranes, including the digestive tract, is converted in vivo to the compound represented by formula (III), which exhibits anti-allergic activity.

Compounds of the present invention can be used as therapeutic agents for the treatment of allergic diseases such as bronchial asthma, eczema, urticaria, allergic gastroenteritis, allergic rhinitis and allergic conjunctivitis. The term "therapy" or "treatment" include "preventing" or "prevention".

For oral administration the compound of the present invention can be prepared using conventional pharmaceutically acceptable excipients (e.g. lactose, crystalline cellulose, starch and calcium phosphate), binders (e.g. starch, matricarioides and hydroxypropylcellulose), leavening agents (for example, calcixerollic, calcium carbonate, etc.,) and lubricating agents (magnesium stearate, talc and so on) in the form of tablets, capsules, granules, dry syrups and various liquid preparations that are commonly used in medicine to treat by conventional means. In addition, these different drugs can be also drugs with a slow release, which releases the ingredient in t is I antiallergic action, compounds represented by formula (III), compounds of the present invention can be used to treat non-oral routes of administration. Dose forms for these purposes include, but are not limited to) tablets for reception under language, suppositories, inhalations, nasal drops, eye drops in my eyes, and drugs absorbed through the skin, for example patches or ointments/creams.

Although the content of the compounds of the present invention in the pharmaceutical composition depends on the drug, it usually takes from about 1 to 70 weight. %, preferably from about 5 to 50 wt.%, based on the weight of the entire composition.

The dose for treatment of allergic diseases can appropriately be determined individually, taking into account the purpose of use, age and sex of the patient, severity of symptoms, etc.

However, in the case of oral preparations, tablets under the tongue or suppositories, the compound of the present invention or its salt or the MES can be entered at a dose in the range of from 0.05 to 5 g/day, preferably 0.1 to 1.0 g/day in one dose or divided into several times. As for the other dose forms, the dose can be appropriately increase or decrease, depending blowing examples which should not limit the invention.

Example obtain 1

7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo[4,5-C] [1]-benzazepin

(a) 1H. utility (26,8 ml, with 40.2 mmol) are added to a solution of Diisopropylamine (6,0 ml, 42.8 mmol) in tetrahydrofuran (75 ml) in an argon atmosphere at -78oC. This mixture is stirred for 1 hour. It adds ethylpropyl (3.4 ml, of 33.5 mmol) and a solution of 4,5-dimethoxy-2-nitrobenzaldehyde (5.0 g, with 23.7 mmol) in tetrahydrofuran (50 ml) in that order, and the resulting mixture stirred at -78oWith another 1.5 hours. To this reaction mixture is added a solution of acetic acid (7.0 ml, 122 mmol) in tetrahydrofuran (20 ml), and then add water. The mixture is extracted with ethyl acetate. The organic layer is washed with diluted hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated saline in this order. The organic layer is dried over magnesium sulfate. The solvent is evaporated under reduced pressure, obtaining the ethyl 4-hydroxy-4-(4,5-dimethoxy-2-nitrophenyl)-2-butenoate in the form of oil (8,59 g). The obtained ethyl 4-hydroxy-4-(4,5-dimethoxy-2-nitrophenyl)-2-butenoate dissolved in toluene (80 ml).

To the solution was added 4-methoxybenzoate the PRS is cooled to room temperature, and then purified through column chromatography with silica gel (hexane:ethyl acetate=2:1).

The precipitate formed in the eluate is collected by filtration, obtaining a mixture of 1: 5 (2,60 g, 23%) ethyl 4-(hydroxy-(4,5-dimethoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate (a-1: a less polar product (LP) and ethyl 5-(hydroxy-(4,5-dimethoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (a-2: the more polar product (MP)). On the other hand, the filtrate is concentrated under reduced pressure, obtaining a mixture of 2.5:1 (4.68 g, 42%) of compound (a-1: (LP)) and compound (a-2 (Mr)).

a 2.5:1 mixture of a-1 (LP) and a-2 (MP):

1H NMR (l3): 1,38 (15/7H, t) 1,39 (6/7H, t) 3,56 (6/7H, s), and 3.72 (6/7H, s), 3,78 (15/7H, s), 3,91 (6/7H, s), 3,97 (15/7H, s), 3,99 (15/7H, s) to 4.41 (4/7H, kV) of 4.44 (10/7H, kV), equal to 4.97 (5/7H, m), 5,07 (2/7H, m), 5,48 (2/7H, m), 5,78 (5/7H, m), 5,71 (2/7H, m), of 5.84 (5/7H, m), 6,32 (2/7, C), 6,83 (10/7H, m), 6,67 (4/7H, m), 6,99 (4/7H, m), 7,07 (2/7H, m), 7,21 (10/7H, m), of 7.48 (2/7H, s), 7,51 (5/7H, s), 7,71 (5/7H, s).

The mass spectrum with elektronniy blow: m/z 472 (M+).

(b) manganese Dioxide (14 g) are added to a solution mixture of 2.5:1 (4,63 g of 9.80 mmol) of compound a-1 and the compound a-2 obtained in stage (a), in methylene chloride (100 ml). The resulting mixture was stirred at room temperature overnight. To this add dioxide mintroute through celite, then washed with ethyl acetate. The solvent is evaporated under reduced pressure. The residue is purified on a chromatographic column with silica gel (hexane:ethyl acetate=2:1) to give ethyl 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate as a brown crystalline powder (b-1:LP) (2,75 g, 60%) and ethyl 1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate as a brown crystalline powder (b-2: MP) (1.12 g, 24%).

b-1 (LP):

1H NMR (Dl3): to 1.38 (3H, t), of 3.78 (3H, s), 3,98 (3H, s), was 4.02 (3H, s), 4,43 (2H, HF), 5,72 (2H, s), 6,85 (2H, d), of 6.99 (1H, s), from 7.24 (2H, d), of 7.69 (1H, s).

The mass spectrum with electron impact: m/z 471 (M++1).

b-2 (MP):

1H NMR (Dl3): to 1.19 (3H, t), with 3.79 (3H, s), 3,91 (3H, s), of 4.00 (3H, s), 4,10 (2H, HF), 5,79 (2H, s), to 6.80 (1H, s), to 6.88 (2H, d), 7,42 (2H, d), 7,52 (1H, s).

The mass spectrum with electron impact: m/z 470 (M+).

(C) 1H. an aqueous solution of sodium hydroxide (13 ml) was added to a solution of ethyl 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (b-1) (3.04 from g, 6,46 mmol) obtained in stage (b), in tetrahydrofuran (40 ml). This mixture was stirred at room temperature for 3.5 hours. The reaction solution was diluted with ether, and added to it the salt solution. The solvent is evaporated under reduced pressure, obtaining 1-(4-methoxy-benzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylic acid as a pale yellow oil (C-1': LP) (2.55 g, 89%). The obtained 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylic acid (C-1':LP) (1.07 g, 2,42 mmol) was dissolved in a mixed solvent consisting of ethanol (50 ml) and ethyl acetate (50 ml). Add 10% palladium-on-charcoal grill. The mixture is stirred in hydrogen atmosphere at room temperature for 4 hours. To the reaction solution was added methylene chloride to dissolve the precipitated precipitate crystals, and then filtered through celite. The resulting filtrate is concentrated under reduced pressure, obtaining 4-(2-amino-4,5-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1H-1.2,3-triazole-5-carboxylic acid (c-1: LP) (1.06 g, 100%).

C-1' (LP):

1H NMR (Dl3): of 3.78 (3H, s) to 3.99 (3H, s) 4,06 (3H, s), of 6.02 (2H, s), at 6.84 (2H, d), 6,94 (1H, s), 7,40 (2H, d), 7,76 (1H, s), 13,80 (1H, Shir. C).

Mass spectrum of secondary ions: m/z 443 (M'+1).

C-1 (LP):

1H NMR (CDCl3): of 3.78 (3H, s), 3,88 (3H, s), of 3.94 (3H, s), the 6.06 (2H, s), 6,11 (1H, s) 6,86(2H, d), was 7.45 (2H, d), 8,58 (1H, s).

Mass spectrum of secondary ions: m/z 413 (M++1).

Similarly, ethyl 1-(4-methoxybenzyl)-5-(4,5-d is aStore tetrahydrofuran (100 ml) 1H. aqueous solution of sodium hydroxide (13 ml) at room temperature for 3.5 hours. So get 1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylic acid (C-2':Mr) (2,32 g, 79%) as a crystalline yellow powder.

C-2' (Mr)

1H NMR (CDCl3): of 3.80 (3H, s), of 3.94 (3H, s), of 4.00 (3H, s) 5,79 (2H, s), 6.89 in (1H, s) 6,91 (2H, d), 7,47 (2H, d), 7,54 (1H, s).

Mass spectrum of secondary ions: m/z 443 (M++1).

(d) Tributylamine (of 0.64 ml, 2,69 mmol), 2-fluoro-1-methylpyridine paratoluenesulfonyl (793 mg, 2,80 mmol) and 3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-2-he (563 mg, a 3.06 mmol) are added in that order to a solution of 4-(2-amino-4,5-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1H-1,2, 3-triazole-5-carboxylic acid (s-1)(1,05 g, 2.55 mmol) in methylene chloride (30 ml) in an argon atmosphere under ice cooling. The resulting mixture was stirred under ice cooling for 1 hour and then stirred at room temperature for 2 hours.

To the reaction mixture, water is added, the resulting mixture is extracted with chloroform. The organic layer is washed with diluted hydrochloric acid, water, saturated aqueous sodium bicarbonate and saturated saline solution. The organic layer is dried over without the a Finance, washed with diethyl ether and water, dried, receiving 7,8-dimethoxy-3-(4-methoxybenzyl)-4(5H), 10-deoxy-3H-1,2,3, tetrazolo[4,5-C] [1] benzazepin in the form of crystalline powder yellow (d-1:LP)(477 mg, 48%).

d-1 (LP):

1H NMR (DMSO-d6): and 3.72 (3H, s), 3,84 (6N, C) 6,09 (2H, s), make 6.90 (2H, d), 7,16 (1H, s), 7,30 (2H, d), to 7.67 (1H, s), 11,33 (1H, s).

The mass spectrum with electron impact: m/z 394 (M+).

(e) Anisole (0.5 ml) and triperoxonane acid (5.0 ml) are added to 7,8-dimethoxy-3-(4-methoxybenzyl)-4(5H), 10-dioxo-3H-1,2,3,-triazolo[4,5-C] [1] benzazepine (d-1)(471 mg, 1,19 mmol). This mixture was stirred at 60oC for 3 hours. Then the solvent is evaporated under reduced pressure. The precipitate is collected by filtration, washed with diethyl ether and water, and then dried, obtaining mentioned in the title compound 7,8-dimethoxy-4(5H), 10-dioxo-1H-1,2,3-triazolo-[4,5-C][1]benzazepin (e) in the form of a yellow powder (319 mg, 98%). 7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo-[4,5-C] [1]benzazepin (e) (238 mg, 0,867 mmol) is dissolved in 1N. aqueous solution of sodium hydroxide. This solution is purified on Diaion HP-20 (water:acetone= 9: 1), obtaining specified in the header content: sodium salt of 7,8-dimethoxy-4(5H), 10-dioxo-1H-1,2,3-triazolo-[4,5-C][1]benzazepine (e') in the form of light as the(1H, C).

Mass spectrum of secondary ions: m/z 275 (M++1).

e':

The mass spectrum with a field desorption: m/z 274 (M+-Na+1).

Example of getting 2

Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate

Anisol (1 mg) are added to a solution of a mixture of approximately 1:1 (4.4 g) of ethyl 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (example obtain 1, b-1) and ethyl 1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtain 1, b-2) in triperoxonane acid (10 ml), the mixture was stirred at 60oC for 10 hours. After the mixture is allowed to cool, the solvent is evaporated under reduced pressure, followed by azeotropic distillation with toluene. The resulting crystals are collected by filtration, washed with diethyl ether, and then dried, obtaining the ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (3.12 g, 95%).

1H NMR (CDCl3): of 1.42 (3H, t), of 4.00 (3H, t), of 4.00 (3H, s), a 4.03 (3H, s), 4,47 (2H, HF), 7,02 (1H, s), to 7.67 (1H, s).

Example of getting 3

Ethyl 4-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate and ethyl 5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1-(4-methoxybenzoyl)-1H-1,2,3-thiazolidinone (75 ml) in an argon atmosphere at -78oC, the mixture is stirred for one hour. Then add ethylpropyl (2,9 ml of 28.2 mmol) and a solution of 5-isopropoxy-4-methoxy-2-nitrobenzaldehyde (4.5 g, an 18.8 mmol) in tetrahydrofuran in sequence, the mixture was stirred at -78oC for an additional 1.5 hours. To the reaction solution was added a solution of acetic acid (5,9 ml, 102 mmol) in tetrahydrofuran (20 ml). Then add water, extracted with ethyl acetate. The organic layer is washed with diluted hydrochloric acid, water, saturated aqueous sodium bicarbonate and saturated saline solution. The organic layer is dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, obtaining the ethyl 4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-hydroxy-2-butynoate (7,27 g). The obtained ethyl 4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-hydroxy-2-butynoate dissolved in toluene (60 ml). To the solution was added 4-methoxybenzoate (9.2 grams, of 56.4 mmol). The resulting mixture was heated at 100oWith under stirring overnight. The reaction solution is cooled to room temperature. The solvent is evaporated under reduced pressure. The residue is purified on a chromatographic column with silica gel (hexane:ethyl acetate= 1: 2), polyol-5-carboxylate (a-1: a less polar product (LP) and ethyl 5-(1-hydroxy-(5-isopropoxy-4-methoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (a-2: (more polar product (MP)).

1:1 mixture of a-1 (LP) and 2 (Mr):

1H NMR (Dl3): 1,34-1.55V (N, m) and 3.59 (1H, d), of 3.77 (3H, s), 3,(2 (3H, s) to 4.41 (2H, q), 4,69 was 4.76 (1H, m), of 5.81 (1H, s), of 5.83 (1H, s), PC 6.82 (2H, d), 6, 93 (1H, d), 7,20 (2H, d), the 7.43 (1H, s), to 7.67 (1H, C).

The mass spectrum with electron impact: m/z 501 (M++1).

(b) Active dioxide, magnesium (24 g) are added to a solution mixture 1:1 (7.01 g, 14,02 mmol) of the compound (a-1) and compound (a-2), previously obtained in stage (a), in methylene chloride (160 ml), the mixture was stirred at room temperature overnight. The reaction solution is filtered through celite, washed with methylene chloride. The solvent is evaporated under reduced pressure, obtaining a mixture of 1:1 (6,98 g, 100%) ethyl 4-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate (b-1: LP) and ethyl 5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (b-2: Mr) in the form of foam.

A mixture of 1:1 b-1 (LP), b-2 (MP):

1H NMR (CDCl3): 1,17 (3/2H, t), 1,37 was 1.43 (9/2H, m), of 3.78 (3H, s), 3,97 (3/2H, s), 3,99 (3/2H, s) 4,08 (1H, HF), 4,42 (1H, HF), 4,55 - 4,60 (1/2H, m), of 4.67-4.72 in (1/2H, m), 5,70 (1H, s), 5,78 (1H, s), 6,79 (1/2H, s, 6,84-to 6.88 (2H, m), 6,97 (1/2H, s), 7,24 (1H, d), 7,42 (1H, d), 7,52 (1/2,H, C), to 7.67 (1/2N, C).

The mass spectrum with electron impact: m/z 498 (M+).

The intermediate connection 1: Methyl 4-(3,4-dimetho the Il 4-(3,4-acid)-4-oxo-2-butenoate (201 mg, 0.8 mmol) in methylene chloride (5 ml) under cooling with ice for 20 minutes. The resulting mixture was stirred under ice cooling for 1 hour. Then the temperature of the reaction mixture was raised to room temperature. The reaction solution is treated in the usual way, getting a methyl 2,3-dibromo-4-(3,4-acid)-4-oxobutanoate (332 mg, 100%) as a mixture of diastereoisomers (ratio in a mixture of 61: 39) as a colourless foam. A mixture of diastereoisomers used in the next reaction without separation.

Main component:1H NMR (Dl3): 3,74 (3H, s) to 3.92 (3H, s), of 3.95 (3H, s), a 4.83 (1H, d), 5,44 (1H, d), 6,91 (1H, d), 7,49 (1H, d), to 7.64 (1H, DD).

The mass spectrum with electron impact: m/z 411 (M++1).

Secondary component:1H NMR (Dl3): 3,88 (3H, s), of 3.94 (3H, s), of 3.96 (3H, s), 4,96 (1H, d), 5,62 (1H, d), 6,92 (1H, d), EUR 7.57 (1H, d), to 7.64 (1H, DD).

The mass spectrum with electron impact: m/z 411 (M++1).

A solution of triethylamine (27 mg) in methylene chloride (0.5 ml) are added to a solution of methyl 2,3-dibromo-4-(3,4-acid)-4-oxobutanoate (49 mg, 0.1 mmol), obtained earlier in methylene chloride (0.5 ml). This mixture was stirred at room temperature for 15 minutes, and then refluxed with stirring for 2 hours. This San: ethyl acetate), getting listed in the title compound as yellow crystals (21 mg, 71%).

1H NMR (Dl3): the 3.89 (3H, s), of 3.95 (3H, s) to 3.99 (3H, s) 6,94 (1H, d),7,56 (1H, d), of 7.82 (1H, DD).

The mass spectrum with electron impact: m/z 248 (M+).

Intermediate compound 2. Ethyl 4-(3,4-acid)-4-oxo-2-butenoate

Described above with respect to the Intermediate 1 the procedure is repeated, getting ethyl 2,3-dibromo-4-(3,4-acid)-4-oxobutanoate (7,3 g, 95%) as a mixture of diastereoisomers in the form of a colourless foam (mixture in ratio=63:37) from a solution of ethyl 4-(3,4-acid)-4-oxo-2-butenoate (4.8 g, 18 mmol) in methylene chloride (500 ml) and a solution of bromine (1.1 ml) in methylene chloride (100 ml). A mixture of diastereoisomers used in the next reaction without separation.

Main component:1H NMR (Dl3): of 1.24 (3H, t), of 3.94 (3H, s), of 3.97 (3H, s), 4,20 (2H, HF), 4,84 (1H, d), 5,46 (1H, d), 6,93 (1H, d), 7,51 (1H, d), 7,66 (1H, DD).

The mass spectrum with electron impact: m/z 424 (M+).

Secondary component:1H NMR (Dl3): to 1.38 (3H, t), of 3.96 (3H, s), 3,98 (3H, s), 4,36 (2H, q), equal to 4.97 (1H, d), the 5.65 (1H, d), 6,94 (1H, d), to 7.59 (1H, d), to 7.67 (1H, DD).

The mass spectrum with electron impact: m/z 424 (M++1).

A solution of ethyl 2,3-dibromo-4-(3,4-dimethoxyphenyl is inflorida (5 ml) is subjected to interaction, and treated in the manner described above in connection with intermediate connection 1. The crude product is purified on a chromatographic column with silica gel (hexane:ethyl acetate), obtaining mentioned in the title compound (2.4 g, 82%) as yellow crystals.

1H NMR (CDCl3): of 1.37 (3H, t), of 3.94 (3H, s), 3,98 (3H, s), 4,35 (2H, HF), to 6.95 (1H, d), EUR 7.57 (1H, d), 7,83 (1H, DD).

The mass spectrum with electron impact: m/z 262 (M+).

Intermediate compound 3. Ethyl 4-(4,5-dimethoxy-2-nitrophenyl)-4-oxo-2-butenoate

Repeat the procedure described above in connection with intermediate connection 1, to obtain ethyl 2,3-dibromo-4-(4,5-dimethoxy-2-nitrophenyl) -4-oxobutanoate (337 mg, 100%) as a mixture of diastereoisomers in the form of a light brown oil (the ratio in the mixture=2:1), from a solution of ethyl 4-(4,5-dimethoxy-2-nitrophenyl)-4-oxo-2-butenoate (199 mg, 0.6 mmole) in methylene-chloride (10 ml), and a solution of bromine (0.04 ml) in methylene chloride (5 ml). A mixture of diastereoisomers used in the next reaction without separation.

Main component:1H NMR (Dl3): of 1.32 (3H, t), 4,01 (6N, (C), or 4.31 (2H, q), of 5.03 (1H, d), 5,52 (1H, d), of 6.99 (1H, s), 7,63 (1H, s).

Secondary component:1H NMR (Dl3): of 1.34 (3H, t), 4,01 (6N, (C), or 4.31 (2H, q), 4,91 (1H, d), a 5.25 (1H, d), 7,02 (1H, s), obtained above, in methylene chloride (1 ml). The crude product is purified on a chromatographic column with silica gel (hexane:ethyl acetate), obtaining mentioned in the title compound (17 mg, 29%) as a yellow crystalline powder.

This connection can also be obtained by oxidation of ethyl 4-hydroxy-4-(4,5-dimethoxy-2-nitrophenyl)-2-butenoate described in example obtain 1, in methylene chloride with active manganese dioxide under normal reaction conditions (for example, at room temperature for 10 hours).

1H NMR (Dl3): of 1.36 (3H, t) to 4.01 (3H, s), was 4.02 (3H, s), 4,27 (2H, HF), 7,06 (1H, s), 7,55 (1H, s).

Intermediate compound 4.

Methyl 5-(3,4-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate and methyl 4-(3,4-dimethoxybenzoyl)-3-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate.

A solution of 4-methoxybenzylamine (37 mg, 0.2 mmol) in toluene (1 ml) was added to a solution of methyl 4-(3,4-acid)-4-oxo-2-butenoate (47 mg, 0.2 mol) (intermediate compound 1) in toluene (1 ml). The resulting mixture was stirred at 100oC for 18 hours. The reaction solution is concentrated under reduced pressure. The residue is purified on a chromatographic column with silica gel (hexane: ethyl acetate), obtaining specified in the header of soybeans is 1%).

The less polar compound:

1H NMR (Dl3): 3,71 (3H, s), and 3.72 (3H, s), a 3.87 (3H, s), 3,88 (3H, s), of 5.75 (2H,s ), to 6.80 (2H, d), PC 6.82 (1H, d), 7,26 (2H, d), 7,58 (1H, DD), a 7.62 (1H, d).

The mass spectrum with electron impact: m/z 411 (M+).

The more polar compound:

1H NMR (CDCl3): of 3.60 (3H, s) to 3.64 (3H, s), 3,81 (3H, s), 3,85 (3H, s), 5,43 (2H, s ), to 6.57 (1H, d), 6,60 (1H, d), 6,77 (1H, d), of 6.99 (2H, d), 7,25 (1H, d)

The mass spectrum with electron impact: m/z 411 (M++1).

The intermediate compound 5. Ethyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate

In the same way as the intermediate compound 4, a solution of 4-methoxybenzylamine (1.8 g) in toluene (10 ml) was added to a solution of ethyl 4-(3,4-acid)-4-oxo-2-butenoate (intermediate 2) (2.4 g, 9.2 mmol) in toluene (80 ml). The resulting mixture was stirred at 100oC for 18 hours. The reaction solution is concentrated under reduced pressure, obtaining a mixture of ethyl 5-(3,4-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate and ethyl 4-(3,4-dimethoxybenzoyl)-3-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate in the form of oil. This oil is used in the next reaction without further purification.

Main component:1H NMR (Dl3): a 1.08 (3H, t), 3,68 (3H, s), 3,88 (3H, s) to 3.92 (3H, s), 4,18 (2P (Dl3): to 1.14 (3H, t), of 3.80 (3H, s), of 3.94 (3H, s), of 3.95 (3H, s), are 4.24 (2H, q), of 5.82 (2H,s), 6,85-of 6.90 (3H, m), 7,33 (2H, d), 7,63 (1H, DD), to 7.68 (1H, d).

The mixture obtained above crude product, triperoxonane acid (7.9 ml) and anisole (1.2 g) is heated with stirring at 90oC for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue is added ethyl acetate. The mixture is extracted with saturated aqueous sodium bicarbonate. The aqueous layer was neutralized with hydrochloric acid and again extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting mentioned in the title compound in the form of a solid light-yellow color (2.9 g, 91% in two stages).

1H NMR (Dl3): of 1.23 (3H, s), of 3.95 (3H, s), of 3.96 (3H, s), or 4.31 (2H, q), 5,59 (2H, s), 6.87 in (1H, d), 7,41 (1H, DD), a 7.62 (1H, d).

The intermediate compound 6. Ethyl 5 (or 4)-(3,4-dimethoxy-benzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4(or 5)-carboxylate

(a) a Solution of utility in hexane (1,58 M of 0.24 ml, 0,39 mmol) is added at -78oTo a solution of 4-bromoveratrole (50 μl, 0.35 mmol) in tetrahydrofuran (1.5 ml) in an argon atmosphere. After 15 minutes, this solution was added at -78oWith the solution dityuanisaunt for 40 minutes. To the reaction solution was added saturated aqueous solution of ameriglide. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried. The solvent is evaporated. The residue is purified on a chromatographic column with silica gel (hexane: ethyl acetate), obtaining specified in the title compound in the form of a single compound (60 mg, 40%). The value of Rf(thin layer chromatography on silica gel) and spectrum data1H NMR same as for the main component a mixture of two isomers position obtained by converting the intermediate compound 5 in triazole compound.

1H NMR (CDCl3): a 1.08 (3H, t), 3,68 (3H, s), 3,88 (3H, s) to 3.92 (3H, s), 4,18(2H, HF), the 5.51 (2H, s), only 6.64 (2H, d), to 6.67 (1H, d), 6,86 (2H, d), 7,07 (1H, DD), 7,31 (1H, d).

The mass spectrum with electron impact: m/z 425 (M+).

(b) a Solution of 4-bromoveratrole (183 mg, 0.84 mmol) in tetrahydrofuran (1 ml) are added to a mixture of magnesium (33 mg, 1.36 mg atom) in tetrahydrofurane (1 ml) at room temperature in argon atmosphere. After 20 minutes the reaction solution is refluxed for 30 minutes. To this add a small amount of iodine, and then stirred for another 20 minutes. The reaction solution is added to the ladanyi ice. The temperature of the reaction solution increases, the reaction solution was stirred at room temperature for 3 days. To stop the reaction to the reaction solution was added saturated aqueous solution of ameriglide. The reaction mixture is treated as in stage (a), purified through column chromatography with silica gel (hexane:etranzact), getting mentioned in the title compound (68 mg, 19%).

Intermediate compound 7.

Ethyl 5-(4,5-dimethoxy-2-nitro-benzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate and ethyl 4-(4,5-dimethoxy-2-nitro-benzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate.

In the manner described above in connection with intermediate connection 4, 4-methoxybenzoate (19 ml) was added to a solution of ethyl 4-(4,5-dimethoxy-2-nitrophenyl)-4-oxo-2-butenoate (17 mg, by 0.055 mmol), obtained as described above in connection with intermediate connection 3, in toluene (1 ml). The resulting mixture was stirred at 60oC for 20 hours. The reaction solution concentrate. The residue is purified on a chromatographic column with silica gel (hexane:ethyl acetate) to give a yellow crystalline powder (a mixture of the less polar product: the more polar product=2:3)(19 mg, 73%). The value of Rf(b-1 (more polar product) and b-2 (less polar product) received in the sample receiving 1.

Intermediate compound 8. Ethyl 5-(3,4-dimethoxybenzoyl)-2-(1-isopropoxycarbonyl-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate

Monohydrate paratoluenesulfonyl acid (482 mg, 2.5 mmol) and Isobutyraldehyde (3.4 ml, 37 mmol) are added to a solution of ethyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate (7.7 g, 25 mmol), obtained in the manner described above in connection with intermediate connection 5, in methylene chloride (115 ml) in an argon atmosphere at -20oC. the Mixture is stirred at -20oWith in an hour. To it add carbonyldiimidazole (6.2 g, 38 mmol), then stirred at -20oC for one hour. To this add isopropyl alcohol (20 ml). The resulting mixture was cooled to -30oC. Add triperoxonane acid (5.8 ml, 75 mmol). This mixture was stirred at room temperature for 18 hours. The reaction solution is treated in the usual way, purified through column chromatography with silica gel (hexane: ethyl acetate), obtaining mentioned in the title compound as a colourless liquid (10,9 g, 93,4%).

1H NMR (Dl3): of 0.87 (3H, d) and 1.15 (3H, d), of 1.27 (3H, t), of 1.28 (3H, d), of 1.33 (3H, d), was 2.76 (1H, m), of 3.94 (3H, s), of 3.96 (3H, s), 4,34 (2H, HF), the 4.90 (1H, Sept), is 6.54 (1H, d),and-2-nitrobenzoyl)-2-(1-isopropoxycarbonyl-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate

70% nitric acid (1 ml) is added to ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(1-isopropoxycarbonyl-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate (86 mg, 0,19 mmol) as an intermediate compound 8, while cooling with ice. The resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was poured on ice, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline solution in that order and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting mentioned in the title compound in the form of a single compound (49 mg, 52%). The value off(thin layer chromatography on silica gel) and spectrum data1H NMR same as for the connection specified in the header of example 20(a).

1H NMR (Dl3): to 0.72 (3H, d), of 1.05 (3H, d), 1,25 (3H, d), of 1.28 (3H, d), the 1.44 (3H, t), of 2.56 (1H, m) 4,00 (3H, s) 4,08 (3H, s), of 4.49 (2H, q), is 4.85 (1H, m), 6.35mm (1H, d), 7,06 (1H, s), a 7.62 (1H, s).

Example 1

1-(1-Isopropoxycarbonyloxymethyl)-7,8-dimethoxy-4(5H), 10-dioxo-1H-1,2,3-triazolo[4,5-C] [1] benzazepin (substituted in 1-position), 2-(1-isopropoxycarbonyloxymethyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C] [1] benzazepin (substituted in 2-put 3-position)

1-iodometrically (2,82 g) and sodium bicarbonate (919 mg) are added to a solution of 7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo[4,5-C][1] benzazepine (example obtain 1) (1,00 g) in N,N-dimethylformamide (20 ml) in an argon atmosphere. The resulting mixture was stirred at 60oC for 18 hours. The solvent is evaporated under reduced pressure. To the residue is added water and ethyl acetate. The organic layers was separated, washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting mixture was again purified on a chromatographic column with silica gel (hexane:ethyl acetate). The result is a compound substituted at the 3-position (275 mg), compound substituted in 2-position (55 mg), and compound, substituted in the 1-position (66 mg), in order of elution, each in the form of a yellow powder.

1-(1-isopropoxycarbonyloxymethyl)-7,8-dimethoxy-(5H), 10-dioxo-1H-1,2,3-triazolo[4,5-C][1]benzazepin (substituted in 1-position

1H NMR (Dl3): of 1.24 (3H, d), of 1.29 (3H, d), and 2.14 (1H, d), 3,98 (3H, s) 4,08 (3H, s), 4.80 to the 4.90 (2H, m), 7,10 (1H, s), 7,74 (1H, s), 7,80 (1H, HF), 11,07 (1H, s).

2-(1-isopropoxycarbonyloxymethyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[,06 (3H, C) 4,85-of 4.95 (2H, m), 6,85 (1H, s), 7,13 (1H, HF), 7,87 (1H, s), becomes 9.97 (1H, s).

3-(1-isopropoxycarbonyloxymethyl)-7,8-dimethoxy-4(5H), 10-dioxo-3H-1,2,3-triazolo[4,5-C][1]benzazepin (substituted in 3-position).

1H NMR (Dl3): to 1.21 (3H, d), of 1.29 (3H, d), 2,12 (1H, d), of 4.00 (3H, s) to 4.01 (3H, s), 4.75 V-4,85 (2H, m), to 6.57 (1H, s), of 7.90 (1H, s), to $ 7.91 (1H, HF), 8,86 (1H, s).

Example 2

7,8-Dimethoxy-4(5H), 10-dioxo-1-(pivaloyloxymethyl)-1H-1,2,3-triazolo[4,5-C] [1] -benzazepin (substituted in 1-position), 7,8-dimethoxy-4(5H), 10-dioxo-2-(pivaloyloxymethyl)-2H-1,2,3-triazolo[4,5-C] [1] benzazepin (substituted in 2-position) and 7,8-dimethoxy-4(5H),10-dioxo-3-(pivaloyloxymethyl)-3H-1,2,3-triazolo[4,5-C] [1]benzazepin (substituted in 3-position)

Specified in the title compound (345 mg, 89%) was obtained as a mixture of three compounds of ethyl 7,8-dimethoxy-4 (5H), 10-dioxo-1H-1,2,3-triazole[4,5-C] [1]benzazepine (example obtain 1)(296 mg) by the method of example 1, except that instead of 1-iodometrically use pivaloyloxymethyl and sodium iodide. The resulting product was then purified through column chromatography with silica gel (hexane:ethyl acetate), separating three isomers as a yellow powder.

7,8-dimethoxy-4(5H), 10-dioxo-1-(pivaloyloxymethyl)-1H-1,2,3-triazolo[4,5-C][1]benzazepin (samase the

7,8-dimethoxy-4 (5H), 10-dioxo-2- (pivaloyloxymethyl) -2H-1,2,3-triazolo[4,5-C][1]benzazepin (substituted in 2-position)

1H NMR (Dl3): 1,16 (N, C) of 3.84 (3H, s), 3,85 (3H, s), is 6.54 (2H, s), 7,17 (1H, s), to 7.64 (1H, s), 11,17 (1H, s).

7,8-dimethoxy-4(5H), 10-dioxo-3-(pivaloyloxymethyl)-3H-1,2,3-triazolo[4,5-C][1]benzazepin (substituted in 3-position)

1H NMR (CDCl3): 1,12 (N, C) a 3.83 (3H, s), 3,86 (3H, s) 6,70 (2H, s), 7,20 (1H, s), to 7.59 (1H, s), of 11.29 (1H, s).

Example 3

2-(Ethoxycarbonylmethyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(3A) Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (70 mg) and the monohydrate paratoluenesulfonyl acid (17 mg) is suspended in methylene chloride (6 mg) in an argon atmosphere, to this add paraformaldehyde (6 mg). The resulting mixture was stirred at room temperature for 30 minutes. To this add pyridine (0.05 ml) and ethylchloride (0.04 ml), the mixture was stirred at room temperature for one hour. Then to this add pyridine (0,02 ml) and ethylchloride (0.04 ml), the mixture is stirred for 10 minutes. The solvent is evaporated under reduced pressure. To this add ethyl acetate (15 ml) and saturated aqueous solution of bikar is rbonate sodium (10 ml) and saturated saline (10 ml) in that order, dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, obtaining the ethyl 2-(ethoxycarbonylmethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate in the form of foam light yellow (48 mg, 53%).

1H NMR (CDCl3): of 1.31 (3H, t), of 1.44 (3H, t) to 4.01 (3H, s), a 4.03 (3H, s), 4,25 (2H, q), of 4.49 (2H, HF), 6,21 (2H, s), 7,02 (1H, s), 7,66 (1H, s).

The mass spectrum with electron impact: m/z 452 (M+).

(3b) Ethyl 2-(ethoxycarbonylmethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (45 mg) obtained in stage (3), dissolved in ethyl acetate (1 ml). To the solution was added palladium hydroxide (15 mg). The resulting mixture is stirred in hydrogen atmosphere at room temperature for 15 hours. The reaction solution is filtered through celite. The resulting filtrate is concentrated under reduced pressure, obtaining the ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(ethoxycarbonylmethyl)-2H-1,2,3-triazole-4-carboxylate in the form of a yellow oil (40 mg, 95%).

1H NMR (CDCl3): of 1.27 (3H, t) of 1.33 (3H, t), 3,66 (3H, s), 3,90 (3H, s), 4,27 (2H, HF), 4,34 (2H, q), x 6.15 (1H, s) 6,38 (2H, s), of 6.49 (2H, Shir. C) 6,76 (1H,s).

The mass spectrum with electron impact: m/z 422 (M+).

(3C) ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(atoxic the l). This solution was stirred at 100oC for 2 hours. After the solution is allowed to cool, the solvent is evaporated under reduced pressure. To the residue water is added. The precipitate is collected by filtration, washed with saturated aqueous sodium bicarbonate and water, dried, obtaining mentioned in the title compound as a yellow crystalline powder (20 mg, 56%).

1H NMR (DMSO-d6): of 1.23 (3H, t), of 3.84 (3H, s), 3,86 (3H, s), 4,22 (2H, HF), 6,56 (2H, s), 7,18 (1H, s), the 7.65 (1H, s), and 11.2 (1H, Shir.C).

The mass spectrum with electron impact: m/z 376 (M+).

Example 4

2-(Msobuttoniconandcaption)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(4A) According to the method of example 3 (3A), provided that isobutyl-chloroformate used instead of ethylchloride will receive 2-(msobuttoniconandcaption)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (172 mg, 90%) as a pale yellow oil from ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (140 mg).

1H NMR (Dl3): 0,92-0,96 (6N, m) of 1.44 (3H, t), 1.93 and-2,04 (1H, m), 3,90-3,98 (2H, m) 4,00 (3H, s), a 4.03 (3H, s), 4,50 (2H, HF), 6,21 (2H, s), 7,01 (1H, s), the 7.65 (1H, s).

The mass spectrum with electron impact: m/z 480 (M+).
1H NMR (CDCl3): 0,93-0,96 (6N, m) of 1.27 (3H, t), 1,95-2,02 (1H, m), the 3.65 (3H, s), 3,90 (3H, s) to 3.99 (2H, d), 4,34 (2H, q), x 6.15 (1H, s) 6,38 (2H, s), of 6.49 (2H, Shir.C) 6,76 (1H, s).

The mass spectrum with electron impact: m/z 450 (M+).

(4C) According to the method of example 3 (3C) specified in the title compound (45 mg, 31%) was obtained as yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(msobuttoniconandcaption)-2H-1,2,3-triazole-4-carboxylate (143 mg) obtained in stage (4b).

1H NMR (DMSO-d6): , to 0.87 (3H, d), of 0.89 (3H, d), of 1.27 (3H, t), 1,88-of 1.95 (1H, m), 3,83 (3H, s), 3,85 (3H, s), 3,98 (2H, DD), to 6.57 (2H, s), 7,18 (1H, s), the 7.65 (1H, s), 11, 16 (1H, Shir.C).

The mass spectrum with electron impact: m/z 404 (M+).

Example 5

2-(Hexyloxybenzoyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(5A) According to the method of example 3 (3A), provided that hexyl-chloroformate (0.2 ml) is used instead of ethylchloride will receive 2-(hexyloxybenzoyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (168 mg, 83%) as a pale yellow oil from 5-(4,5-dimethoxy,90 (3H, m), 1,20-1,32 (6N, m) of 1.44 (3H, t), 1,58-to 1.67 (2H, m) 4,00 (3H, s), a 4.03 (3H, s), 4,18 (2H, t), 4,50 (2H, q), of 6.20 (2H, s),7,01 (1H, s), the 7.65 (1H, s).

The mass spectrum with electron impact: m/z 508 (M+).

(5B) According to the method of example 3 (3b) to obtain ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(hexyloxybenzoyl)-2H-1,2,3-triazole-4-carboxylate (149 mg, 96%) as a yellow oil from ethyl 2-(hexyloxybenzoyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate, (165 mg) obtained in stage (5A)

1H NMR (CDCl3): to 0.88 (3H, t), of 1.27 (3H, t), 1,31-1,43 (6N, m), 1,62 was 1.69 (2H, m), 3,66 (3H, s), 3,90 (3H, s), 4,20 (2H, t), 4,34 (2H, q), x 6.15 (1H, s), 6,37 (2H, s), 6,50 (2H, Shir.C) 6,77 (1H, s).

The mass spectrum with electron impact: m/z 478 (M+).

(5C) According to the method of example 3 (3C) specified in the title compound (88 mg, 68%) was obtained as yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(hexyloxybenzoyl)-2H-1,2,3-triazole-4-carboxylate (145 mg) obtained in stage (5b).

1H NMR (Dl3): or 0.83 (3H, t), 1,24 of 1.28 (6N, m), 1,58-of 1.62 (2H, m), of 3.84 (3H, s), 3,86 (3H, s) to 4.17 (2H, t), 6,56 (2H, s), 7,18 (1H, s), the 7.65 (1H, s), 11, 16 (1H, Shir.C).

The mass spectrum with electron impact: m/z 432 (M+).

Example 6

2-(n-Butoxycarbonylmethyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-tri instead of ethylchloride, obtain ethyl 2-(n-butyloxycarbonyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (166 mg, 88%) as a yellow oil from ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (140 mg).

1H NMR (Dl3): of 0.94 (3H, t), 1,35-of 1.41 (2H, m) of 1.44 (3H, t), 1,61 by 1.68 (2H, m) 4,00 (3H, s), a 4.03 (3H, s), 4,19 (2H, t), 4,50 (2H, q), of 6.20 (2H, s), 7,02 (1H, s), 7,66 (1H, s).

The mass spectrum with electron impact: m/z 480 (M+).

(6b) According to the method of example 3 (3b) to obtain ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(n-butoxycarbonylmethyl)-2H-1,2,3-triazole-4-carboxylate (150 mg, 100%) as a yellow oil from ethyl 2-(n-butoxycarbonylmethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate, (160 mg) obtained in stage (6A).

1H NMR (Dl3): or 0.83 (3H, t), of 1.27 (3H, t), 1,36-of 1.42 (2H, m), 1,63 was 1.69 (2H, m), 3,66 (3H, s), 3,91 (3H, s), 4,20 (2H, t), 4,34 (2H, q), x 6.15 (1H, s) 6,38 (2H, s), 6,50 (2H, Shir.C) 6,76 (1H, s).

The mass spectrum with electron impact: m/z 450 (M+).

(6C) According to the method of example 3 (3C) specified in the title compound (78 mg, 64%) was obtained as yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(n-butoxycarbonylmethyl)-2H-1,2,3-triazole-4-carboxylate (150 mg) obtained in stage (6b).

1

The mass spectrum with electron impact: m/z 404 (M+).

Example 7

2-(Isopropoxycarbonyloxymethyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(7a) According to the method of example 3 (3A), provided that 1M toluene solution (6 ml) isopropylcarbamate used instead of ethylchloride receive a mixture of 2:1 (906 mg), ethyl 2-(isopropoxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate and ethyl 2-(isopropoxycarbonyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate as a pale yellow foam from ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (700 mg).

1H NMR (Dl3): 1,29 (6N, e), 1,43 of 1.50 (3H, m), 4,01-4,04 (6N, m), 4,47-4,55 (2/3H, m), 5,28 to 5.35 (1/3H, m) to 6.19 (4/3H, s), 7,01 (2/3H, s),? 7.04 baby mortality (1/3H, s), 7,65 (2/3, (C), to 7.67 (1/3H, s).

(7b) a Mixture of 2:1 (870 mg), ethyl 2-(isopropoxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate and ethyl 2-(isopropoxycarbonyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate, obtained in stage (7a), treated according to the method of example 3 (3A). The reaction product is purified on a chromatographic column with silica gel (hexane: ethyl acetate) to give a mixture of 4:1 (612 mg), ethyl 5-(2-amino-4,5-dimetix isopropoxycarbonyl)-2H-1,2,3-triazole-4-carboxylate (150 mg, 100%) as a pale yellow foam.

1H NMR (Dl3): between 1.25-1.30 (3H, m), 1,31 (6N, e), 3,66 (3H, s), 3,90 (3H, s), 4,32-4,39 (2H, m), 4,90-4,96 (4/5H, m), and 5.30-5,46 (1/5H, m), 6,14 (1H, s), 6,36 (8/5H, s) of 6.49 (2H, Shir.C) 6,77 (1H, s).

(7C) According to the method of example 3 (3C) specified in the title compound (450 mg, 75%) are obtained in the form of powder light yellow color from a mixture of 4:1 (610 mg), ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(isopropoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylate and ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(isopropoxycarbonyl)-2H-1,2,3-triazole-4-carboxylate, obtained in stage (7b).

1H NMR (DMSO-d6): 1,25 (6N, e), of 3.84 (3H, s), 3,85 (3H, s), a 4.83-4,88 (1H, m), 6,66 (2H, s), 7,18 (1H, s), the 7.65 (1H, s), 11,16 (1H, s).

Example 8

2-(Benzoyloxymethyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo [4,5-C][1]benzazepin

(8A) According to the method of example 3 (3A), provided that the benzoyl chloride (0,28 ml) is used instead of ethylchloride get the crude product ethyl 2-(benzoyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (230 mg) as a pale yellow oil from ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (210 mg).

(8b) According to the method of example 3 (3b) get the crude product ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(benzoyloxy is ethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate, (230 mg) obtained in stage (8A).

(8C) According to the method of example 3 (3C) specified in the title compound (40 mg, yield after three stages 56%) are obtained in the form of a yellow powder of the crude product ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(benzoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate, obtained in stage (8b).

1H NMR (DMSO-d6): is 3.82 (3H, s), of 3.84 (3H, s), to 6.80 (2H, s), 7,14 (1H, s), 7,56 (1H, s), a 7.62 (1H, s), 7,72 (1H, t), 8,01 (2H, d), 11,14 (1H, Shir. C).

Example 9

2-(Eurolocker)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(9a) According to the method of example 3 (3A), provided that lauroyl-chloride (0,37 ml) is used instead of ethylchloride, obtain ethyl 2-(eurolocker)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (190 mg, 85%) as a pale yellow oil from ethyl 5-(4,5-Dimetcote-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (140 mg).

1H NMR (Dl3): to 0.88 (3H, t), 1,20-1,30 (N, m) of 1.44 (3H, t), 1,55-1,65 (2H, m) to 2.35 (2H, t) to 4.01 (3H, s), a 4.03 (3H, s), 4,50 (2H, HF), to 6.19 (2H, s), 7,03(1H, s), the 7.65 (1H, s).

The mass spectrum with electron impact: m/z 562 (M+).

(9b) According to the method of example 3 (3b) get the crude product ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(eurolocker)-2H-1,2,3-triazole-4-carboxyla elata, (172 mg) obtained in stage (9a).

1H NMR1H NMR[CDCl3]: 0,86 (3H, t), 1,24-1,29 (N, m) of 1.27 (3H, t), 1,55-1,65 (2H, m), of 2.38 (2H, t), 3,66 (3H, s), 3,90 (3H, s), 4,34 (2H, q), x 6.15 (1H, s), 6,36 (2H, s), 6,50 (2H, Shir.C) to 6.75 (1H, s).

The mass spectrum with electron impact: m/z 532 (M+).

(9c) According to the method of example 3 (3C) specified in the title compound (95 mg, 70%) was obtained as yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(eurolocker)-2H-1,2,3-triazole-4-carboxylate (150 mg) obtained in stage (b).

1H NMR (DMSO-d6): or 0.83 (3H, t), 1,15-1,20 (N, m) and 1.51 (2H, m), is 2.41 (2H, t), of 3.84 (3H, s), 3,85 (3H, s), is 6.54 (2H, s), 7,18 (1H, s), the 7.65 (1H, s), 11,17 (1H, Shir.C).

The mass spectrum with electron impact: m/z 486 (M+).

Example 10

7,8-Dimethoxy-4(5H), 10-dioxo-2-(palmitoylation)-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(10A) According to the method of example 3 (3A), provided that palmitoylated (0,49 ml) is used instead of ethylchloride, obtain ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(palmitoylation)-2H-1,2,3-triazole-4-carboxylate (194 mg, 79%) as a pale yellow oil from ethyl 5-(4,5-Dimetcote-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (140 mg).

1H NMR (CDCl3): to 0.88 (3H, t), 1,20-1,30 (24N, m) of 1.44 (3H, t), of 1.55 to 1.6 arene: m/z 618 (M+).

(10b) According to the method of example 3 (3b) to obtain ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(palmitoylation)-2H-1,2,3-triazole-4-carboxylate (158 mg, 88%) as a yellow oil from ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(palmitoylation)-2H-1,2,3-triazole-4-carboxylate, (190 mg) obtained in stage (10A).

1H NMR (Dl3): to 0.88 (3H, t), 1,24-1,29 (24N, m) of 1.27 (3H, t), 1,60-1,65 (2H, m), of 2.38 (2H, t), 3,66 (3H, s), 3,91 (3H, s), 4,34 (2H, q), x 6.15 (1H, s), 6,36 (2H, s), 6,50 (2H, Shir.C) 6,76 (1H, s).

The mass spectrum with electron impact: m/z 588 (M+).

(10C) According to the method of example 3 (3C) specified in the title compound (117 mg 82%) was obtained as yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(palmitoylation)-2H-1,2,3-triazole-4-carboxylate (155 mg) obtained in stage (b).

1H NMR (DMSO-d6): 0,84 (3H, t). 1,14-1,21 (24N, m),1,51 (2H, m), is 2.41 (2H, t), of 3.84 (3H, s), 3,85 (3H, s), is 6.54 (2H, s), 7,18 (1H, s), the 7.65 (1H, s), 11,18 (1H, Shir.C).

The mass spectrum with electron impact: m/z 542 (M+).

Example 11

2-(4-)(Chlorotyrosine)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(11a) According to the method of example 3 (3A), provided that 4-chlorobutyrate (0,36 ml) is used instead of ethylchloride, obtain ethyl 2-(4-chlorobutyronitrile-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (280 mg).

1H NMR (CDCl3): of 1.45 (3H, t), 2,05 with 2.14 (2H, m), 2,55-of 2.64 (2H, m), 3,55-of 3.60 (2H, m), was 4.02 (3H, s), a 4.03 (3H,s), 4,50 (2H, HF), from 6.22 (2H, s), 7,03 (1H, s), the 7.65 (1H, s).

The mass spectrum with electron impact: m/z 484 (M+).

(11b) According to the method of example 3 (3b) to obtain ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-chlorobutyronitrile)-2H-1,2,3-triazole-4-carboxylate (270 mg, 91%) as a yellow oil from ethyl 2-(4-chlorobutyronitrile)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate, (315 mg).

1H NMR(CDCl3): 1,24-of 1.29 (3H, m), 2,12 (2H, m) 2,60 (2H, t), to 3.58-3,61 (2H, m), the 3.65 (3H, s), 3,91 (3H, s), 4,34 (2H, q), x 6.15 (1H, s) 6,38 (2H, s), 6,51 (2H, Shir.C) 6,74 (1H, s).

The mass spectrum with electron impact: m/z 454 (M+). (11C) By the method of example 3 (3C) specified in the title compound (180 mg, 74%) was obtained as yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-chlorobutyronitrile)-2H-1,2,3-triazole-4-carboxylate (270 mg).

1H NMR (DMSO-d6): 1,96-2,03 (2H, m), of 2.38 (2H, t), 3,66 (2H, t), 3,83 (3H, s), 3,85 (3H, s), is 6.54 (2H, s), to 7.15 (1H, s), 7,63 (1H, s), 11,14 (1H, Shir.C).

The mass spectrum with electron impact: m/z 408 (M+).

Example 12

2-(4-Aminobenzoylamino)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(12A) By the method of example 3 (3A), provided, Thu whom yl)-2-(4-nitrobenzyloxy)-2H-1,2,3-triazole-4-carboxylate (118 mg, 56%) as a pale yellow foam from ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (140 mg).

1H NMR (CDCl3): of 1.45 (3H, t), of 4.00 (3H, s), a 4.03 (3H, s), 4,51 (2H, HF), 6,48 (2H, s), 7,06 (1H, s), a 7.62 (1H, s), to 8.20 (2H, d), 8,30 (2H, d).

The mass spectrum with electron impact: m/z 529 (M+).

(12b) According to the method of example 3 (3b) to obtain ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-aminobenzoylamino)-2H-1,2,3-triazole-4-carboxylate (100 mg, 98%) as a yellowish brown oil from ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(4-nitrobenzyloxy)-2H-1,2,3-triazole-4-carboxylate, (115 mg) obtained in stage (12b).

1H NMR CDCl3: of 1.29 (3H, t), of 3.54 (3H, s) to 3.89 (3H, s) to 4.15 (2H, Shir. C) to 4.33 (2H, q), 6,14 (1H, s) 6,40 (2H, s), 6,56 (2H,s), 6,56 is 6.67 (2H, m), 6,76 (1H, s), 7,83-to $ 7.91 (2H, m).

The mass spectrum with electron impact: m/z 469 (M+).

(12C) According to the method of example 3 (3C) specified in the title compound (54 mg, 59%) was obtained as yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-aminobenzoylamino) -2H-1,2,3-triazole-4-carboxylate (102 mg) obtained in stage (12b).

1H NMR (DMSO-d6): a 3.83 (3H, s), 3,85 (3H, s), 6,21 (2H, s), 6,56 (2H, s), of 6.68 (2H, s), 7,16 (1H, s), to 7.64 (1H, s), to 7.67 (2H, d), 11,14 (1H, Shir. C).

The mass spectrum with elemetal) -2H-1,2,3-triazole,5-C][1]benzazepin

(13A) By the method of example 3 (3A), provided that thionyl chloride (0.06 ml) is used instead of ethylchloride, obtain ethyl 2-chloromethyl-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (146 mg, 92%) as a pale yellow foam from ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (140 mg).

1H NMR (Dl3): of 1.45 (3H, t), of 4.00 (3H, s), a 4.03 (3H, s), 5,98 (2H, s),? 7.04 baby mortality (1H, s), 7,66 (1H, s).

The mass spectrum with electron impact: m/z 398 (M+).

(13b) According to the method of example 3 (3b) to obtain ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-chloromethyl-2H-1,2,3-triazole-4-carboxylate (120 mg, 93%) as a pale yellow oil from ethyl 2-chloromethyl-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate, (140 mg) obtained in stage (13A).

1H NMR (Dl3): of 1.28 (3H, t), 3,66 (3H, s), 3,91 (3H, s), 4,34 (2H, q), x 6.15 (1H, s), 6.42 per (2H, s), 6.73 x (2N, Shir.C) of 6.73 (1H, s).

The mass spectrum with electron impact: m/z 368 (M+).

(13C) According to the method of example 3 (3s), 2-chloromethyl-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-C] [1] benzazepin (66 mg, 66%) receive in the form of a light yellow colour powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-chloromethyl - 2H-1,2,3-triazole-4-carboxylate (114 mg) obtained in stage (13b).

1H YAM is hit: m/z 322 (M+).

(13d) 2-Chloromethyl-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-C] [1] benzazepin (47 mg) obtained in stage (13C), dissolved in N,N-dimethylformamide (5 ml). To the solution was added Tetra-n-butylammonium (10.5 mg), nicotinic acid (20 mg) and potassium carbonate (34 mg). The resulting mixture was stirred at 70oC for 1.5 hours. After the reaction mixture is allowed to cool, the reaction solution is treated in the usual way, separate and purify, getting mentioned in the title compound (41 mg, 67%) as light yellow colour powder.

1H NMR (DMSO-d6): of 3.84 (3H, s), 3,85 (3H, s), 6,83 (2H, s), 7,16 (1H, s), 7,60 (1H, s), to 7.64 (1H, s), 8,35 (1H, DDD), 8,86 (1H, DD), 9,12 (1H, d), 11,16 (1H, Shir. C). Mass spectrum by fast atom bombardment: m/z 410 (M++1).

Example 14

7,8-Dimethoxy-4(5H), 10-dioxo-2-(4-pyridylcarboxylic)-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(14a) By the method of example 13 (13d), provided that isonicotinoyl acid (24 mg) used in place of nicotinic acid, get mentioned in the title compound (30 mg, 46%) as a pale yellow powder of 2-chloromethyl-7,8-dimethoxy-4 (5H), 10-dioxo-2H-1,2,3-triazolo [4,5-C][1]benzazepine (52 mg) obtained in stage (13C).

1H NMR (d6): a 3.83 (3H, what derevko fast atom: m/z 410 (M++1).

Example 15

2-(1-Isobutyryloxy)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo [4,5-C][1]benzazepin

(15A) According to the method of example 3 (3A), provided that acetaldehyde (0,13 ml) and thionyl chloride (0.7 ml) used in place of paraformaldehyde and ethylchloride actually obtain ethyl 2-(1-chloroethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (736 mg, 74%) as a pale yellow foam from ethyl 5-(4,5-Dimetcote-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (840 mg).

1H NMR (Dl3): of 1.45 (3H, t), and 2.14 (3H, d),4,01 (3H, s), a 4.03 (3H, s), 4,50 (2H, HF), 6.42 per (1H, HF), 7,06 (1H, s), to 7.64 (1H, s).

Liquid chromatography-mass spectrometry: m/z 413 (M++1).

(15b) According to the method of example 3 (3b) to obtain ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-chloroethyl)-2H-1,2,3-triazole-4-carboxylate (545 mg, 80%) as a pale yellow foam from ethyl 2-(1-chloroethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate, (735 mg) obtained in stage (15A).

1H NMR (Dl3): of 1.28 (3H, t), 2,28 (3H, d), the 3.65 (3H, s), 3,91 (3H, s), 4,35 (2H, q), x 6.15 (1H, s), 6,51 (2H, Shir.C) and 6.6 (1H, HF), to 6.75 (1H, s).

Liquid chromatography-mass spectrometry: m/z 383 (M++1).

(15C) According to the method of example 3 (3s), 2-(1-chloroethyl)-7,8-dimethoxy-4(5H), but-4,5-dimethoxybenzoyl)-2-(1-chloroethyl) -2H-1,2,3-triazole-4-carboxylate (540 mg), obtained at the stage of (15b).

1H NMR (DMSO-d6): 2,20 (3H, d), of 3.84 (3H, s), 3,86 (3H, s), 7,18 (1H, s), 7,21 (1H, HF), the 7.65 (1H, s), 11,19 (1H, Shir.C).

Mass spectrum by fast atom bombardment: m/z 337 (M++1).

(15d) According to the method of example 13 (13d), provided that instead of ethylchloride use somaclonal acid (0,023 ml), get mentioned in the title compound (32 mg, 41%) as a light yellow powder from ethyl 2-(1-chloroethyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepine (67 mg) obtained in stage (15C).

1H NMR (DMSO-d6): of 1.05 (3H, d), of 1.10 (3H, d), a 1.88 (3H, d), 2,60-to 2.67 (1H, m), of 3.84 (3H, s), 3,85 (3H, s), 7,18 (1H, s), 7.23 percent (1H, HF), the 7.65 (1H, s), 11,16 (1H, Shir.C). Liquid chromatography-mass spectrometry: m/z 389 (M++1).

Example 16

7,8-Dimethoxy-2-(4-methoxyphenylacetonitrile)-4(5H), 10-dioxo-N-1,2,3-triazolo[4,5-C][1]benzazepin

(16A) According to the method of example 3 (3A), provided that methylenechloride solution of the acid chloride obtained from parameterdefinitions acid (400 mg) and thionyl chloride (0,88 ml) is used instead of ethylchloride, obtain ethyl 5-(4,5-dimethoxy-2-nitrobenzyl)-2-(4-methoxyphenylacetyl)-2H-1,2,3-triazole-4-carboxylate (210 mg, 66%) as a pale yellow oil from ethyl 5-(4,5-dimethoxy-2-nitro (2H, C), with 3.79 (3H, s), of 4.00 (3H, s), a 4.03 (3H, s), 4,50 (2H, q), of 6.20 (2H, s), at 6.84 (2H, d), 7.03 is N, C) 7,14 (2H, d), to 7.64 (1H, s).

Liquid chromatography-mass spectrometry: m/z 528 (M+).

(16b) According to the method of example 3 (3b) to obtain ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-methoxyphenylacetyl)-2H-1,2,3-triazole-4-carboxylate (180 mg, 95%) as a yellow oil from ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(4-methoxyphenylacetyl)-2H-1,2,3-triazole-4-carboxylate, (200 mg) obtained in stage (16A).

1H NMR (CDCl3): of 1.28 (3H, t), of 3.60 (3H, s) to 3.64 (2H, s), with 3.79 (3H, s), 3,91 (3H, s), 4,35 (2H, q), x 6.15 (1H, s), 6,37 (2H, s), 6,50 (2H, Shir. C) of 6.73 (1H, s), at 6.84 (2H, d), 7,17 (2H, d).

Liquid chromatography-mass spectrometry: m/z 499 (M++1).

(16C) According to the method of example 3 (3C) specified in the title compound (118 mg, 75%) was obtained as yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-methoxyphenylacetyl)-2H-1,2,3-triazole-4-carboxylate (175 mg) obtained in stage (16b).

1H NMR (DMSO-d6): 3,71 (3H, s), 3,74 (3H, s), 3,85 (3H, s), 6,56 N, C), 6,85 (2H, d), 7,18 (1H, s), 7,18 (2H, d), the 7.65 (1H, s), 11,17 (1H, Shir. C).

Mass spectrum by fast atom bombardment: m/z 453 (M++1)

Example 17

7,8-Dimethoxy-2-(N-(2-(N, N-dimethylamino)ethyl)carbamoylaspartate (806 mg) is used instead atilhan-formate, obtain ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(4-nitrophenoxyacetic)-2H-1,2,3-triazole-4-carboxylate (778 mg, 71%) of ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (700 mg).

1H NMR (CDCl3): of 1.46 (3H, t) to 4.01 (3H, s), a 4.03 (3H, s) to 4.52 (2H, HF), 6,34 (2H, s), 7,05 (1H, s), 7,40 (2H, d), to 7.64 (1H, s), 8,30 (2H, d).

(17b) N, N - dimethylethylenediamine (0,02 ml) was added to a solution of ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(4-nitrophenoxyacetic)-2H-1,2,3-triazole-4-carboxylate (83 mg) obtained in stage (17A), in methylenechloride solution (1.5 ml) under cooling with ice. The resulting mixture is stirred for 2 hours. The reaction solution is then treated in the usual way, separate and purify, getting ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(N-(2-(N, N-dimethylamino)ethyl)-carbamoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate (64 mg, 85%).

1H NMR (CDCl3): USD 1.43 (3H, t), 2,21 (6N, C) to 2.41 (2H, t), 3,20-of 2.30 (2H, m) 4,00 (3H, s), 4,03 t (3H, s), of 4.49 (2H, HF), 5,49 (1H, s), 6,18 (2H, s), 7,02 (1H, s), the 7.65 (1H, s).

(17c) According to the method of example 3 (3b), ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(N-(2-(N, N-dimethylamino)ethyl)carbamoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate (56 mg, 100%) is obtained from ethyl 5-(4,5-dimethoxy-2-nitrophenyl)-2-(N-(2-(N, N-dimethylamino)ethyl)UB>) : a 1.25 (3H, t), 2,75 (6N, (C), 3,05 is 3.15 (2H, m), to 3.58-3,68 (2H, m) to 3.67 (3H, s), 3,90 (3H, s), 4,32 (2H, q), x 6.15 (1H, s), 6, 37 (2H, s), 6,50 (2H, Shir.C) to 6.75 (1H, s).

Mass spectrum by fast atom bombardment: m/z 465 (M++1).

(17d) According to the method of example 3 (3C) specified in the title compound (28 mg, 56%) was obtained as white powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(N-(2-(N, N-dimethylamino)-ethyl)carbamoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate (56 mg) obtained in stage (17c).

1H NMR (DMSO-d6) : 2,77 (6N, (C), of 3.10-3.20 (2H, m), 3,35 is-3.45 (2H, m), of 3.84 (3H, s), 3,86 (3H, s), 4,32 (2H, q), of 6.49 (2H, s), 7,20 (1H, s), the 7.65 (1H, s), 7,98 (1H, t), 11,16 (1H, s).

The mass spectrum with electron impact: m/z 418 (M++1).

Example 18

2-(Diethoxyphosphoryloxy)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(18a) According to the method of example 3 (3A), provided that diestelhorst (0,12 ml) is used instead of ethylchloride get the crude product, ethyl 2-(diethoxyphosphoryloxy)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (205 mg) of ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2)(255 mg).

(18b) By the method of example 3 (3b) get the crude product, ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(diethoxyphosphoryl is hydroxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (205 mg), obtained at the stage of (18a).

(18C) By the method of example 3 (3C), gets mentioned in the title compound (73 mg, yield after three stages 41%) of crude product ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(diethoxyphosphoryloxy)-2H-1,2,3-triazole-4-carboxylate (179 mg) obtained in stage (18b).

1H NMR (DMSO-d6) 1,20 (6N, t) of 3.84 (3H, s), 3,86 (3H, s), 4,00-4,10 (4H, m), 6, 41 (2H, d), 7,19 (1H, s), 7,66 (1H, s), 11,18 (1H,s).

Mass spectrum by fast atom bombardment: m/z 441 (M++1).

Example 19

7,8-Dimethoxy-4 (5H), 10-dioxo-2-(1-(3 - ventilatsioonile)-propyl)-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(19a) Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2)(2.1 g) and the monohydrate paratoluenesulfonyl acid (23 mg) is suspended in methylene chloride (60 ml) in an argon atmosphere. To the suspension is added Propionaldehyde (0,48 ml). The resulting mixture was stirred at room temperature for 10 minutes. To it was added 1,1'-carbonyldiimidazole (1.07 g) and the resulting mixture was stirred at room temperature for 10 minutes. The mixture is then treated in the usual way, and then separate and purify, getting ethyl 2-(1-imidazoledicarbonitrile)propyl-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-Carbo(3H, C) of 4.05 (3H, s), 4,50 (2H, kV) 6,94 (1H, t), was 7.08 (1H, m), to 7.09 (1H, s), 7,39-7,40 (1H, m), 7,60 (1H, s) to 8.12 (1H, m).

(19b) Ethyl 2-(1-(imidazoledicarbonitrile)propyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (377 mg) obtained in stage (19a), dissolved in toluene (12 ml). To the solution was added 3-pentanol (1.6 ml). The resulting mixture is refluxed for 20 hours. Then this mixture is treated in the usual way, separate and purify, getting ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(1-(3-ventilatsioonile)propyl)-2H-1,2,3-triazole-4-carboxylate (280 mg) as a pale yellow oil.

1H NMR (CDCl3): 0,82-0,99 (N, m) of 1.44 (3H, t), 1.56 to to 1.79 (4H, m), 2,18-to 2.29 (2H, m) 4,00 (3H, s), a 4.03 (3H, s), 4,50 (2H, HF), 4,54-4,60 (1H, m), 6,62 (1H, t)),? 7.04 baby mortality (1H, s), a 7.62 (1H, s).

Liquid chromatography-mass spectrometry: m/z 522 (M++1).

(19s) According to the method of example 3 (3b), ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-(3-ventilatsioonile)propyl)-2H-1,2,3-triazole-4-carboxylate (185 mg, yield after two steps of 50%) was obtained as pale-yellow oil from ethyl 5-(4, 5-dimethoxy-2-nitrobenzoyl)-2-(1-(3-ventilatsioonile)-propyl)-2H-1,2,3-triazole-4-carboxylate (270 mg) obtained in stage (19b).

1H NMR (CDCl3) : of 0.85 (3H, t), of 0.91 (3H, t), of 0.97 (3H, t), of 1.28 (3H, t), 1,57-1,67 dcosta chromatography-mass spectrometry: m/z 493 (M++1).

(19d) By the method of example 3 (3C) specified in the title compound (135 mg, 83%) was obtained as pale-yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-(3-ventilatsioonile) propyl)-2H-1,2,3-triazole-4-carboxylate (180 mg) obtained in stage (19s).

1H NMR (CDCl3) : 0,84 (3H, t) to 0.92 (3H, t), and 0.98 (3H, t), 1,55-to 1.67 (4H, m), 2,39-of 2.50 (2H, m) 4,00 (3H, s), of 4.05 (3H, s), 4,60 (1H, quintet), to 6.75 (1H, s), 6,92 (1H, t), 7,88 (1H, s), 9,54 (1H, s).

Liquid chromatography-mass spectrometry: m/z 447 (M+).

Example 20

2-(1-Isopropoxycarbonyl-2-methylpropyl)-7,8 - dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(20A) Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (1.07 g) and monohydrate paratoluenesulfonyl acid (53 mg) is suspended in methylene chloride (10 ml) in an argon atmosphere. To the suspension is added Isobutyraldehyde (330 mg). The resulting mixture was stirred at room temperature for 25 minutes. To it was added 1,1'-carbonyldiimidazole (744 mg) and methylene chloride, the resulting mixture was stirred at room temperature for 25 minutes. To the mixture is added isopropyl alcohol (920 mg), the mixture was stirred at room temperature for 3 hours, and sateia, getting ethyl 2-(1-isopropoxycarbonyl-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate as a pale yellow foam (520 mg, 34%).

1H NMR (CDCl3) : to 0.72 (3H, d), of 1.05 (3H, d), 1,25 (3H, d), of 1.28 (3H, d), the 1.44 (3H, t), of 2.56 (1H, m) 4,00 (3H,s) 4,08 (3H, s), of 4.49 (2H, q), is 4.85 (1H, m), 6.35mm (1H, d), 7,06 (1H, m), a 7.62 (1H, s).

(20A') Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2)(50 g) is suspended in ethyl acetate (500 ml). To the suspension is added at a temperature of 25oC in an atmosphere of argon Isobutyraldehyde (20 ml). The resulting mixture was stirred at this temperature for 20 minutes.

Then to the mixture is added sodium iodide (21,4 g) and potassium carbonate (78,9 g). Then add 50 ml of isopropylcarbamate, reactions provide an opportunity to proceed under stirring at 60oWith over 45 hours.

To the reaction solution was added ethyl acetate (100 ml). The resulting mixture was washed twice with 750 ml of water, and then washed with 20% sodium chloride solution (500 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The residue is crystallized from aqueous methanol, getting ethyl 2-(1-isopropoxycarbonyl-2-methylpropyl)-5-(4,5-dimethoxy-2-Narnia, obtained at the stage of (20A).

(20A) Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (5,00 g) is suspended in ethyl acetate (50 ml). To the suspension is added at a temperature of 25oC in nitrogen atmosphere 1-chloro-2-methylpropiophenone (a 8.34 g), sodium iodide (2.14 g) and potassium carbonate (7,89 g). Reactions provide an opportunity to proceed under stirring at 60oC for 96 hours.

To the reaction solution was added ethyl acetate (10 ml). The resulting mixture was washed twice with 75 ml of water, and then washed with 20% sodium chloride solution (50 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The residue is purified on a chromatographic column with silica gel (n-hexane: ethyl acetate) to give ethyl 2-(1-isopropoxycarbonyl-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (0,89 g, 12.3 per cent).1H NMR spectrum of this compound is identical to the spectrum of the compound obtained in stage (20A).

(20b) According to the method of example 3 (3b), ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-isopropoxycarbonyl-2-methylprop-saws)-2H-1,2,3-triazole-4-carboxylate (485 mg, 99%) was obtained as light yellow foam from ethyl 2-(1-isopropoxycarbonyl-or SIG>
1H NMR (Dl3) : of 0.85 (3H, d), to 1.14 (3H, d), of 1.26 (3H, d), of 1.28 (3H, t) is 1.31 (3H, d), a 2.75 (1H, m), 3,81 (3H, s), 3,90 (3H, s), 4,34 (2H, HF), a 4.86 (1H, m), 6,14 (1H, s), of 6.49 (2H, Shir.C) 6,51 (1H, d), 6,77 (1H, s).

(20C) According to the method of example 3 (3C) specified in the title compound (273 mg, 62%) was obtained as pale-yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-isopropoxycarbonyl-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate (485 mg) obtained in stage (20b).

1H NMR (Dl3) : of 0.85 (3H, d) and 1.15 (3H, d), 1,25 (3H, d), is 1.31 (3H, d), 2,80 (1H, m) 4,00 (3H, s), of 4.05 (3H, s), a 4.86 (1H, m), of 6.68 (1H, d), of 6.73 (1H, s), 7,88 (1H, s), for 9.47 (1H, Shir. C).

Liquid chromatography-mass spectrometry: m/z 433 (M++1).

Example 21

2-(Acetoxymethyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-C] [1]benzazepin

(21a) According to the method of example 19 (a), provided that paraformaldehyde (45 mg) and acetic anhydride (0.3 ml) are used, respectively, instead of Propionaldehyde and 1,1'-carbonyldiimidazole, obtain ethyl 2-(acetoxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (618 mg, 98%) as a pale yellow foam from ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2)(525 mg).

1H NMR (Dl3) : of 1.45 (3H, t), 2,12 (3H, s) to 4.01 (3H, s), a 4.03 (3 is 2">

(21b) According to the method of example 3 (3b) to obtain ethyl 2-(acetoxymethyl)-5-(2-amino-4,5-dimethoxybenzoyl)-2H-1,2,3-triazole-4-carboxylate (510 mg, 90%) as a yellow oil from ethyl 2-(acetoxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (610 mg) obtained in stage (21A).

1H NMR (Dl3) : of 1.27 (3H, t), of 2.15 (3H, s), 3,66 (3H, s), 3,91 (1H, s), 4,34 (2H, q), x 6.15 (1H, s), 6.35mm (2H, s), 6,50 (2H, Shir.C) to 6.75 (1H, s).

The mass spectrum with electron impact: m/z 392 (M+).

(S) According to the method of example 3 (3C), gets mentioned in the title compound (360 mg, 84%) as a yellow powder from ethyl 2-(acetoxymethyl)-5-(2-amino-4,5-dimethoxybenzoyl)-2H-1,2,3-triazole-4-carboxylate (492 mg) obtained in stage (21b).

1H NMR (DMSO-d6) : 2,12 (3H, s), 3,83 (3H, s), of 3.84 (3H, s), of 6.52 (2H, s), 7,14 (1H, s), 7,63 (1H, s), 11,12 (1H, s).

The mass spectrum with electron impact: m/z 346 (M+).

Example 22

2-(Isobutyryloxy)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(22A) By the method of example 19 (19a), provided that paraformaldehyde (12 mg) and somerley anhydride (0.17 ml) are used, respectively, instead of Propionaldehyde and 1,1'-carbonyldiimidazole, obtain ethyl 2-(isobutyryloxy)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3--4-carboxylate (example obtaining 2)(140 mg).

1H NMR (Dl3) : to 1.15 (3H, d), to 1.21 (3H, d), a 1.45 (3H, t), 2.57 m) of 2.68 (1H, m) to 4.01 (3H, s), a 4.03 (3H, s), 4,50 (2H, q), of 6.20 (2H, s), 7,03 (1H, s), 7, 65 (1H, s).

(22b) According to the method of example 3 (3b) to obtain ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(isobutyryloxy)-2H-1,2,3 - triazole-4-carboxylate (510 mg, 90%) as a yellow oil from ethyl 2-(isobutyryloxy)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (610 mg) obtained in stage (22A).

1H NMR (Dl3) : 1,18 (6N, e), of 1.28 (3H, t), 2,61-of 2.66 (1H, m), the 3.65 (3H, s), 3,90 (1H, s), 4,34 (2H, q), x 6.15 (1H, s), 6,36 (2H,s), 6,50 (2H, Shir.C) to 6.75 (1H, s)

The mass spectrum with electron impact: m/z 420 (M+).

(22 ° C) According to the method of example 3 (3C), gets mentioned in the title compound (360 mg, 84%) as a yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(isobutyryloxy-methyl)-2H-1,2,3-triazole-4-carboxylate (492 mg) obtained in stage (22b).

1H NMR (DMSO - d6) : 1,10 (6N, e), 2,62-2,69 (1H, m), of 3.84 (3H, s), 3,85 (3H, s), is 6.54 (2H, s), 7,18 (1H, s), to 7.64 (1H, s), 11,16 (1H,s).

The mass spectrum with electron impact: m/z 374 (M+).

Example 23

2-(n-Butyryloxy)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(23a) By the method of example 19 (19a), provided that paraformaldehyde (12 mg) and oil anger relaxometer)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (178 mg, 99%) as a pale yellow foam from ethyl 5-(4, 5-dimethoxy-2-nitrobenzoyl)-1H-1,2, 3-triazole-4-carboxylate (example obtaining 2) (140 mg).

1H NMR (CDCl3) : to 0.92 (3H, t), of 1.44 (3H, t), 1,61-1,71 (2H, m) 2,44 (2H, t) to 4.01 (3H, s), a 4.03 (3H, s), 4,50 (2H, q), of 6.20 (2H, s), 7,03 (1H, s), 7, 65 (1H, s).

The mass spectrum with electron impact: m/z 450 (M+).

(23b) According to the method of example 3 (3b) to obtain ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(n-butyryloxy)-2H-1,2,3-triazole-4-carboxylate (126 mg, 83%) as a yellow foam from ethyl 2-(n-butyryloxy)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (160 mg) obtained in stage (23a).

1H NMR (Dl3) : of 0.95 (3H, t), of 1.27 (3H, t), 1,64 is 1.70 (2H, m), is 2.37 (2H, t), the 3.65 (3H, s), 3,91 (1H, s), 4,34 (2H, q), x 6.15 (1H, s), 6,36 (2H, s), 6,50 (2H, Shir.C) to 6.75 (1H, s).

The mass spectrum with electron impact: m/z 420 (M+).

(23 ° C) According to the method of example 3 (3C), gets mentioned in the title compound (86 mg, 80%) as a yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(n-butyryloxy)-2H-1,2,3-triazole-4-carboxylate (120 mg) obtained in stage (23b).

1H NMR (DMSO-d6) : of 0.87 (3H, t), 1,51 is 1.60 (2H, m), 2,43 (2H, t), of 3.84 (3H, s), 3,85 (3H, s), is 6.54 (2H, s), 7,17 (1H, s), to 7.64 (1H, s), and 11.2 (1H, s).

The mass spectrum with electron impact: m/z 374 (M
(24A) By the method of example 19 (19a), provided that paraformaldehyde (15 mg) and methylenechloride solution of the acid chloride obtained from monobenzylether of ester of succinic acid (520 mg) and thionyl chloride (0,91 ml), used respectively instead of Propionaldehyde and 1,1'-carbonyldiimidazole, obtain ethyl 2-(3-(benzyloxycarbonyl)propionyloxy)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (148 mg, 58%) from ethyl 5-(4,5-Dimetcote-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (175 mg).

1H NMR (CDCl3) : the 1.44 (3H, t), 2,69 (4H, s) to 3.99 (3H, s), was 4.02 (3H, s), of 4.49 (2H, q), of 5.11 (2H, s), to 6.19 (2H, s), 7,03 (1H, s), 7,30-7,40 (5H, m), 7,63 (1H, s).

(24b) By the method of example 3 (3b) and (3C) get mentioned in the title compound (7 mg, 26%) from ethyl 2-(3-(benzyloxycarbonyl)propionyloxy)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (100 mg) obtained in stage (24A).

1H NMR (DMSO-d6) : 2,60 (4H, m), 3,83 (3H, s), 3,85 (1H, s), is 6.54 (2H, s), 7,17 (1H, s), to 7.64 (1H,s), 11,16 (1H, s), 12,54 (1H, Shir.C).

Mass spectrum by fast atom bombardment: m/z 405 (M++1).

Example 25

2-(Cyclohexylcarbonyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(25A) By way of the use is but instead of Propionaldehyde and 1,1'-carbonyldiimidazole, obtain ethyl 2-(cyclohexylcarbonyl)-5-(4,5-dimethoxy-2 - nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (416 mg) of ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate example of obtaining 2) (175 mg).

1H NMR (CDCl3) : 1,20-2,00 (10H, m) of 1.44 (3H, t) to 2.35 (1H, m) 4,00 (3H, s), a 4.03 (3H, s), of 4.49 (2H, HF), to 6.19 (2H, s), 7,03 (1H, s), the 7.65 (1H, s).

Mass spectrum by fast atom bombardment: m/z 491 (M++1)

(25b) By the method of example 3 (3b) and (3C) get mentioned in the title compound (32 mg, 18%) from ethyl 2-(cyclohexylcarbonyl)-5-(4,5-dimethoxy-2 - nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (200 mg) obtained in stage (25A).

1H NMR (DMSO-d6) : 1,16-1,90 (10, m) of 2.45 (1H, m), 3,83 (ZN, C), 3,85 (1H, s), 6,51 (2H, s), 7,16 (1H, s), to 7.64 (1H, s), of 11.15 (1H, s).

Mass spectrum by fast atom bombardment: m/z 415 (M++1).

Example 26

7,8-dimethoxy-2-(3-methoxyphenyl-3-yl)-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(26a) Monohydrate paratoluenesulfonyl acid (20 mg) are added to a solution of 3-pentanone (3.1 ml) and triethylorthoformate (3.3V. ml) in methylene chloride (10 ml). The resulting mixture was heated for 1 hour under stirring. This solution (4 ml) was added to a solution of ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2 anatoy temperature for 1 hour, it added triethylamine (0.05 ml). The mixture is then treated in the usual way, separate and purify, getting ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(3-methoxyphenyl-3-yl)-2H-1,2,3-triazole-4-carboxylate (140 mg, 78%) as yellow powder.

1H NMR (Dl3) : 0,75-0,79 (6N, m) of 1.45 (3H, t), 2,19 was 2.25 (4H, m), of 2.97 (3H, s) to 4.01 (3H, s), Android 4.04 (3H, s), of 4.49 (2H, HF), 7,10 (1H, s), 7,60 (1H, s)

Mass spectrum by fast atom bombardment: m/z 451 (M++1).

(26b) According to the method of example 3 (3b) ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(3-methoxyphenyl-3-yl)-2H-1,2,3-triazole-4-carboxylate (110 mg, 91%) was obtained from ethyl 5-(4,5-dimeth-hydroxy-2-nitrobenzoyl)-2-(3-methoxyphenyl-3-yl)-2H-1,2,3-triazole-4-carboxylate (130 mg) obtained in stage (26a).

1H NMR (Dl3) : 0,87 (6N, t) of 1.26 (3H, t), 2,33 at 2.45 (4H, m), of 3.13 (3H, s), 3,61 (3H, s), 3,90 (3H, s) to 4.33 (2H, q), x 6.15 (1H, s), of 6.49 (2H, Shir.C) 6,74 (1H, s).

Mass spectrum by fast atom bombardment: m/z 421 (M++1).

(26C) Ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(3-methoxyphenyl-3-yl)-2H-1,2,3-triazole-4-carboxylate (80 mg) is dissolved in isopropyl alcohol (1.5 ml) in an argon atmosphere. To the solution was added tert-piperonyl potassium (25 mg). The resulting mixture was stirred at room temperature for 15 minutes. Then mix obrabecim logo color.

1H NMR (Dl3) : 0,87 (6N, t), 2,42 (2H, q), of 2.53 (2H, q), of 4.00 (3H, s), a 4.03 (3H, s), of 6.66 (1H, s), of 7.90 (1H, s), 9,14 (1H, Shir).

Mass spectrum by fast atom bombardment: m/z 374 (M+).

Example 27

2-(4-Etexilate-4-yl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(27A) Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2) (140 mg) and the monohydrate paratoluenesulfonyl acid (2 mg) is suspended in methylene chloride (2 ml) in an argon atmosphere. To the suspension is added 4-heptane (0, 14 ml) and triethylorthoformate (0.17 ml).

The resulting mixture was stirred at room temperature for 2 hours. Then add monohydrate paratoluenesulfonyl acid (4.5 mg). This mixture was stirred at room temperature for 2 hours. The mixture is then treated in the usual way, separate and purify, getting ethyl 2-(4-etexilate-4-yl)-5-(4,5-dimethoxy-2-nitroben-zoilus)-2H-1,2,3-triazole-4-carboxylate (160 mg, 82%) as yellow powder.

1H NMR (Dl3) : 0,90 (6N, t), and 1.00-to 1.15 (2H, m), was 1.04 (3H, t), 1.26-1.28 (in 2H, m) of 1.44 (3H, t), 2,05-of 2.21 (4H, m), 3,10 (2H, kV) to 4.01 (3H, s), Android 4.04 (3H, s), 4,48 (2H, HF), was 7.08 (1H, s), to 7.61 (1H, s).

The mass spectrum with electron impact: m/z 492 (M+).

(27b) On the%) are obtained in the form of a yellow oil from ethyl 2-(4-etexilate-4-yl)-5-(4,5-dimethoxy-2 - nitrobenzoyl) -2H-1,2,3-triazole-4-carboxylate (190 mg), obtained at the stage of (27A).

1H NMR (CDCl3) : 0,95 (6N, t), 1,10-1,19 (2H, m), is 1.11 (3H, t), of 1.25 (3H, t), 1,35-to 1.38 (1H, m), 2,24-to 2.42 (4H, m) of 3.25 (2H, HF), 3,61 (3H, s), 3,90 (3H, s), 4,32 (2H, q), x 6.15 (1H, s), 6,50 (2H, Shir.C) 6,74 (1H, s).

The mass spectrum with electron impact: m/z 462 (M+).

(27) According to the method of example 26 (26C) specified in the title compound (75 mg, 60%) was obtained as a crystalline yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-etexilate-4-yl)-2H-1,2,3-triazole-5-carboxylate (143 mg) obtained in stage (27b).

1H NMR (Dl3) : 0,96 (6N, t), 1,11-1,19 (2H, m) of 1.13 (3H, t), 1,34 was 1.43 (2H, m), 2,30-of 2.38 (2H, m), 2,44-2,52 (2H, m), or 3.28 (2H, q), of 4.00 (3H, s), of 4.05 (3H, s), to 6.80 (1H, s), of 7.90 (1H, s) 9,68 (1H, Shir.C).

Mass spectrum by fast atom bombardment: m/z 417 (M+).

Example 28

2-(Ethoxymethyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo [4,5-C] [1]benzazepin

(28a) Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtaining 2)(210 mg) and the monohydrate paratoluenesulfonyl acid (62 mg) is suspended in methylene chloride (5 ml) in an argon atmosphere. To a suspension add diethoxymethane (0.5 ml). The resulting mixture was stirred at 80oC for 2 hours. The mixture is then treated in the usual way, the section is the form of yellow powder.

1H NMR (CDCl3) : of 1.17 (3H, t), of 1.45 (3H, t), 3,55 (2H, q), of 4.00 (3H, s), a 4.03 (3H, s), of 4.49 (2H, HF), 5,62 (2H, s), 7,05 (1H,s), to 7.64 (1H, s).

The mass spectrum with electron impact: m/z 408 (M+).

(28b) By the method of example 3 (3b) ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(ethoxymethyl)-2H-1,2,3-triazole-4 - carboxylate (178 mg, 88%) are obtained in the form of a yellow oil from ethyl 2-(ethoxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (220 mg) obtained in stage (28a).

1H NMR (Dl3) : to 1.21 (3H, t), of 1.26 (3H, t), 3,63 (3H, s), 3,70 (2H, HF), 3,90 (3H, s), 4,43 (2H, HF), 5,78 (2H, s), x 6.15 (1H, s), 6,50 (2H, Shir. C) of 6.73 (1H, s).

The mass spectrum with electron impact: m/z 378 (M+).

(28C) According to the method of example 26 (26C) specified in the title compound (116 mg, 92%) was obtained as a crystalline yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(ethoxymethyl)-2H-1,2,3-triazole-5-carboxylate (142 mg) obtained in stage (28b).

1H NMR (Dl3) : 1.12 (3H, t), of 3.64 (2H, HF), 3,83 (3H, s), 3,85 (3H, s) 5,94 (2H, s), 7,13 (2H, s), the 7.65 (1H, s), and 11.2 (1H, Shir.C).

The mass spectrum with electron impact: m/z 332 (M+).

Example 29

2-(Isopropoxyphenyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-C][1]benzazepin

(29A) According to the method of example 19 (19a) and is carbonyldiimidazole. Thus obtained ethyl 2-(isopropoxyphenyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (215 mg, 85%) as a pale yellow oil from ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example obtain 2 (210 mg).

1H NMR (Dl3) : 1,17 (6N, e), a 1.45 (3H, t), 3,74-of 3.80 (1H, m) 4,00 (3H, s), a 4.03 (3H, s), of 4.49 (2H, HF), 5,63 (2H, s),? 7.04 baby mortality (1H, s), to 7.64 (1H, s).

The mass spectrum with electron impact: m/z 422 (M+).

(29b) By the method of example 3 (3b) ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(isopropoxyphenyl)-2H-1,2,3-triazole-4-carboxylate (190 mg) are obtained in the form of a yellow oil from ethyl 2-(isopropoxyphenyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (200 mg) obtained in stage (29A).

1H NMR (Dl3) : 1,17 (6N, e), of 1.26 (3H, t), 3,63 (3H, s), 3,80-are 3.90 (1H, m), 3,90 (3H, s), 4,43 (2H, HF), 5,80 (2H, s), 6,16 (1H, s), 6,50 (2H, Shir.C) 6,72 (1H, s).

The mass spectrum with electron impact: m/z 392 (M+).

(29s) According to the method of example 26 (26C) specified in the title compound (110 mg, 70%) was obtained as yellow powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(isopropoxyphenyl)-2H-1,2,3-triazole-5-carboxylate (180 mg) obtained in stage (29b).

1H NMR (DMSO-d6) : 1,12 (6N, e), of 3.84 (3H, s), 3,85 (3H, s), 3,93-3,95 (1 is ptx2">

Example 30

2-(1-(1,3-Diethoxy-2-propoxycarbonyl)-2 - methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-C][1]-benzazepin

(30A) By the method of example 19 (19a), provided that Isobutyraldehyde (0,078 ml) is used instead of Propionaldehyde, obtain ethyl 2-(1-(1-imidazoledicarbonitrile)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (252 mg, 61%) of ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (example getting 2) (280 mg).

1H NMR (Dl3) : of 0.82 (3H, d), of 1.12 (3H, d), the 1.44 (3H, t), 2,64-of 2.81 (1H, m) to 4.01 (3H, s), a 4.03 (3H, s), 4,50 (2H, HF), to 6.67 (1H, d), was 7.08 (2H, m), 7,41 (1H, s), to 7.59 (1H, s) to 8.14 (1H, m).

Liquid chromatography-mass spectrometry: m/z 517 (M++1).

(30b) According to the method of example 19 (19b), provided that 1,3-diethoxy-2-propanol (0.6 ml) is used instead of 3-pentanol, ethyl 2- (1-(1,3-diethoxy-2-propoxycarbonyl)-2 - methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (165 mg, 44%) get the oil light yellow color from ethyl 2-(1-(1-imidazoledicarbonitrile)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (325 mg) obtained in stage (30A).

1H NMR (Dl3) : of 0.71 (3H, d), 1,08-1,25 (N, m) of 1.45 (3H, t), 2,49-2,61 (1H, m), 3,38-3,63 (8H, m) to 4.01 (3H, s), 4.04 the: m/z 597 (M++1).

(30C) By the method of example 3 (3b), ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-(1,3-diethoxy-2-propoxycarbonyl)-2-methylpropyl)-2N, 1,2,3-triazole-4-carboxylate (177 mg, 78%) are obtained in the form of oil is light yellow in color from ethyl 2-(1-(1,3-diethoxy-2-propoxycarbonyl)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazol-5-carboxylate (240 mg) obtained in stage (30b).

1H NMR (CDCl3) : of 0.85 (3H, d), 1,08-1,21 (N, m) of 1.29 (3H, t), 2,75-of 2.81 (1H, m), 3,40-3,72 (11N, m), 3,91 (3H, s), 4,34 (2H, HF), 4,92 is equal to 4.97 (1H, m), x 6.15 (1H,s), 6,50 (2H, Shir.C) is 6.54 (1H, d), 6,79 (1H, s).

Liquid chromatography-mass spectrometry: m/z 567 (M++1).

(30d) By the method of example 3 (3C) specified in the title compound (65 mg, 40%) was obtained as a light yellow crystalline powder from ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-(1,3-diethoxy-2-propoxycarbonyl)-2-methylpropyl)-2N, 1,2,3-triazole-4-carboxylate (175 mg) obtained in stage (30C).

1H NMR (Dl3) : of 0.85 (3H, d), of 1.09 (3H, t), 1,16-1,19 (6N, m), of 2,75 2,85 (1H, m), 3,38-3,66 (8H, m) 4,00 (3H, s), Android 4.04 (3H, s), 4,88-is 4.93 (1H, m), of 6.68 (1H, d), 6,70 (1H, d), 7,88 (1H, s), 9,31 (1H, s).

Mass spectrum by fast atom bombardment: m/z 521 (M++1).

Example 31

7,8-dimethoxy-2-(2-(2-methoxyethoxy)ethoxycarbonyl)- 2-methylprop the new ether of diethylene glycol (3.6 ml) is used instead of 3-pentanol, add triperoxonane acid (3.8 ml), ethyl receive 2-(-(2-(2-methoxyethoxy)ethoxycarbonyl)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (8,82 g, 52%) of ethyl 2-(1-(1-imidazoledicarbonitrile)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (13,0 g) obtained in stage (30A)

1H NMR (Dl3) : to 0.72 (3H, d), with 1.07 (3H, d), the 1.44 (3H, t), 2,50-to 2.65 (1H, m) to 3.36 (3H, s), 3,50-3,55 (2H, m), 3,60-the 3.65 (2H, m), 3,65 of 3.75 (2H, m) to 4.01 (3H, s), Android 4.04 (3H, s), 4,20 is 4.35 (2H, m), of 4.49 (2H, HF), 6.35mm (1H, d), 7,07 (1H, cm), a 7.62 (1H, s).

(31b) According to the method of example 3 (3b), ethyl 5-(2-amino-4,5-dimethoxy)-2-(1-(2-(2-methoxyethoxy)ethoxycarbonyl)-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate (1,14 g, 100%) is obtained from ethyl 2-(1-(2-(2-methoxyethoxy)ethoxycarbonyl) -2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (1,15 g) obtained in stage (31A).

1H NMR (Dl3) : of 0.85 (3H, d) and 1.15 (3H, d), of 1.29 (3H, t) 2,70-to 2.85 (1H, m) to 3.36 (3H, d), 3,50-3,55 (2H, m), 3,60-the 3.65 (2H, m) to 3.64 (3H, s), 3,69 of 3.75 (2H, m), 3,90 (3H, s), 4,35 (2H, HF), 4,20-and 4.40 (2H, m), 6,14 (1H, C) of 6.49 (2H, s), 6,53 (1H, d), is 6.78 (1H, s).

(S) According to the method of example 3 (3C) specified in the title compound (750 mg, 75%) was obtained as a crystalline light yellow colour powder from ethyl 5-(2-amino-4,5-dimethoxy)-2-(1-(2-(2-UP>1
H NMR (Dl3) : 0,86 (3H, d), of 1.17 (3H, d), of 2,75 2,90 (1H, m) to 3.35 (3H, d), 3,50-3,55 (2H, m), 3,60-the 3.65 (2H, m), 3,71 (2H, t), of 4.00 (3H, s) 4,07 (3H, s), 4.26 deaths (1H, dt ), 4,34 (1H, dt), of 6.68 (1H, d), 6,85 (1H, s), 7,88 (1H, s), 9,94 (1H, s).

Example 32

2-(1-(1,3-Diethoxy-2-propoxycarbonyl)-2 - methylpropyl)-8-isopropoxy-7-methoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-C][1]-benzazepin

(32A) By way of example getting 2, ethyl 5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (1.47 g, 78%) is prepared from a mixture of approximately 1: 1 (2,49 g), ethyl 4-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate (example of getting a 3, b-1) and ethyl 5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate (example of getting a 3, b-2).

1H NMR (Dl3) : 1,43 (N, d), of 4.00 (3H, s), 4,47 (2H, HF), 4,65-4,80 (1H, m), 7,00 (1H, s), 7,66 (1H, s).

(32b) Monohydrate paratoluenesulfonyl acid (57 mg) and isobutylamine aldehyde (0,41) are added to a solution of ethyl 5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (1,14 g) obtained in stage (32A), in a solution of methylene chloride (17 ml) at -20oC. the resulting mixture was stirred at this temperature for 1 hour. To the reaction solution was added 1,1'-carbonyldiimidazole (732 mg). Then, cerewet to room, continuing to stir for 25 hours. To the reaction solution was added 0.5 M hydrochloric acid while cooling with ice to stop the reaction, then carry out the separation. The organic layer is washed five times with 7% aqueous solution of sodium bicarbonate. The solvent is evaporated under reduced pressure. To the residue is added diethyl ether and water. The organic layer after separation, washed twice with water, 0.5 M hydrochloric acid, twice with water and then with 20% saline solution in this order. The solvent is evaporated under reduced pressure. The residue is purified on a chromatographic column with silica gel (ethylacetate) give crude product, ethyl 2-(1-(1,3-diethoxy-2-propoxycarbonyl)-2-methylpropyl)-5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (1,15 g).

1H NMR (Dl3) : of 0.71 (3H, d), with 1.07 (3H, d), of 1.10 (3H, d) and 1.15 (3H, t), of 1.41 to 1.47 (N, m), 2,54-to 2.65 (1H, m), 3,40-of 3.64 (8H, m) to 4.01 (3H, s), of 4.49 (2H, HF), 4,68 was 4.76 (1H, m), 4,90-4,96 (1H, m), to 6.39 (1H, d), 7,03 (1H, cm) to 7.61 (1H, s).

The mass spectrum with electron impact: m/z 624 (M+).

(32C) According to the method of example 3 (3b), ethyl 5-(2-amino-5-isopropoxy-4-methoxybenzoyl-2-(1-(1,3-diethoxy-2-propoxycarbonyl)-2-methylpropyl)-2H-1,2,3-triazole-4-metoxi-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (1/12 g), obtained at the stage of (32b).

1H NMR (Dl3) : of 0.85 (3H, d), of 1.13 (3H, d), of 1.18 (3H, t), 1,23 (6N, 2D), of 1.26 (3H, t), for 1.49 (3H, d), 2,73-2,82 (1H, m), 3,40-3,68 (8H, m), 4.09 to to 4.17 (1H, m) to 4.33 (2H, q), is 4.93-5,00 (1H, m), 6,13 (1H, s), 6,46 (2H, s), 6,56 (1H, d), 6,83 (1H, s).

The mass spectrum with electron impact: m/z 594 (M+).

(32d) According to the method of example 3 (3C) specified in the title compound (634 mg, 65% after two steps) is obtained from ethyl 5-(2-amino-5-isopropoxy-4-methoxybenzoyl)-2-(1-(1,3-diethoxy-2-propoxycarbonyl)-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate, obtained in stage (32C).

1H NMR (Dl3) : of 0.85 (3H, d), a 1.08 (3H, t), of 1.17 (3H, d), of 1.18 (3H, t), 1,42 (6N, e), 2,78-2,90 (1H, m), 3,36-3,66 (8H, m), a 4.03 (3H, s), 4,68-rate 4.79 (1H, m), 4,90-5,00 (1H, m), 6,70 (1H, d), 6,79 (1H, s), of 7.90 (1H, s), 9,74 (1H, s).

The mass spectrum with electron impact: m/z 548 (M+).

Example 33

8 Isopropoxy-2-(1-isopropoxycarbonyl-2 - methylpropyl)-7-methoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-C][1]-benzazepin

(33a) Isobutyraldehyde (2,9 ml), sodium iodide (3,18 g), potassium carbonate (of 11.69 g) and isopropylcarbamate (7.2 ml) are added in the order specified in the atmosphere of argon at room temperature to a solution of ethyl 5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (8, 01 g) obtained in stage (32A)dobavlaut water, to stop the reaction. The resulting mixture was extracted with ethyl acetate. The organic layer is washed with 20% brine and dried over anhydrous magnesium sulfate. The solvent is evaporated. The resulting mixture was purified through column chromatography with silica gel (hexane:ethyl acetate) to give ethyl 2-(1-isopropoxycarbonyl-2-methylpropyl)-5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (10,12 g, 89%).

1H NMR (Dl3) : to 0.72 (3H, d), of 1.05 (3H, d), of 1.26 (3H, d), of 1.28 (3H, d), the 1.44 (3H, d), to 2.57 (1H, m) 4,00 (3H, s), of 4.49 (2H, HF), 4,72 (1H, m), is 4.85 (1H, septet), 6,36 (1H, d), 7,01 (1H, s), 7,60 (1H, s).

The mass spectrum with thermocream (TSPMS): 537 (M++1).

(33b) According to the method of example 3 (3b), ethyl 5-(2-amino-5-isopropoxy-4-methoxybenzoyl)-2-(1-isopropoxycarbonyl-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate is obtained from ethyl 2-(1-isopropoxycarbonyl-2-methylpropyl)-5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (10,12 g) obtained in stage (33a).

1H NMR (Dl3) : of 0.85 (3H, d) and 1.15 (3H, d), 1,22 (6N, e), 1,2-1,4 (N, m), was 2.76 (1H, d), a 3.87 (3H, s), 4,10 (1H, m), 4,30 (2H, HF), 4,88 (1H, septet), 6,13 (1H, s), 6,53 (1H, d), for 6.81 (1H,s).

The mass spectrum with thermocream TSPMS: 507 (M+1)

(33) a Solution of ethyl 5-(2-amino-5-isopropoxy-4-methoxybenzoyl)-2-(1-isopropol) was stirred at 90oC for 3.5 hours in an argon atmosphere. The reaction mixture was concentrated. To the concentrate is added toluene, the resulting solution was again concentrated. The concentrate is extracted with methylene chloride, twice washed with 7% aqueous sodium bicarbonate solution and once with 10% salt solution. The organic layer is concentrated. The solvent is evaporated. The resulting mixture was washed twice with isopropyl alcohol, purified through column chromatography (chloroformate), receiving specified in the header of the connection (as 4.02 g, 45% after two steps).

1H NMR (Dl3) : of 0.85 (3H, s) of 1.16 (3H, d), of 1.26 (3H, d), is 1.31 (3H, d), 1,42 (6N, e), of 2.81 (1H, m), a 4.03 (3H, s), 4,74 (1H, septet), a 4.86 (1H, septet), of 6.68 (1H, d), 6,76 (1H, s), of 7.90 (1H, s), for 9.64 (1H, Shir.C).

Mass spectrum by fast atom bombardment: m/z 461 (M++1).

The connections defined in the headers of examples 1-33 have the following chemical formulas (see table 1-4).

Example of getting 1. Obtaining tablets

The compound of example 20 (50.0 g), lactose (139,0 g), hydroxypropylcellulose (HPC-SL: 6.0 g), calcixerollic (4.0 g) and purified water (9.0 g) are thoroughly mixed. This mixture granularit, dried and separated grain size. To the pellet add magnesium stearate (1.0 g), tately 20 in each tablet.

Example of getting a 2. Obtaining pellets

The compound of example 20 (50.0 g), lactose (420 g), hydroxypropylcellulose (HPC-SL:15.0 g), calcixerollic (10 g) and purified water (30 g) are thoroughly mixed. This mixture granularit, dried, split grain size, sift. To the pellet add magnesium stearate (5.0 g), thoroughly mix, receiving fine granules containing 100 mg of the compound of example 20 grams of the drug.

An example of pharmacological tests

Connection example of obtaining 1, the compound of example 7 and the compound of example 20 is suspended or dissolved in 0.5% aqueous solution of methylcellulose. The resulting solution was orally administered in equimolar quantities dogs and rats. After the introduction, using HPLC quantitatively determine the amount of each of the compounds in the plasma of each animal. The results obtained are summarized in table 5. The absorption of each sample is determined by the area under the curve: level of drug in the plasma depending on time (AUC). In the AUC values obtained for the compounds of examples 7 and 20, as prodrugs, was 3-4 times higher for dogs, 3-7 times higher in rats compared with the values obtained for the compounds is: introduction

The compound of example 20 is homogeneous suspended in 0.5% aqueous solution of methylcellulose. Suspension forcibly administered orally to male mice IRC (aged 5 weeks). As a result, all mice survived and no abnormalities were observed at a dose of 2 g/kg for the compound of example 20.

1. Derivatives of tricyclic triazolobenzodiazepine represented by the formula (I), their pharmacologically acceptable salt or MES

< / BR>
where R1represents a hydrogen atom or a C1-4alkyl;

R2and R5that may be the same or different, represent a hydrogen atom, a C1-4alkyl or methoxy;

R3and R4that may be the same or different, represent: (a) hydrogen atom; (c) a hydroxyl group; (d) formyl, (e)1-12alkyl which may be substituted by a halogen atom; (f)2-12alkenyl, which may contain one carbon-carbon double bond and may be substituted by (1) halogen atom, (2) cyano, (3) -COR9where R9represents C1-6alkyl, (4) -COOR10where R10represents a hydrogen atom or a C1-6alkyl, (5) -CONR11R12where R11and R12that may be the same or different, represent (i) atom in the s1-4the alkyl, which is substituted six-membered saturated heterocyclic ring containing two nitrogen atom (the nitrogen atoms substituted C1-4by alkyl), or unsaturated six-membered heterocyclic ring, (iii) phenyl, which is substituted by carboxyla, or (iv) unsaturated five - or six-membered heterocyclic ring; (6) unsaturated six-membered heterocyclic ring which may be substituted WITH1-4the alkyl, or ethanolism; (g)1-12alkoxy which may be substituted: (2) hydroxyl group, (3) cyano, (5) phenyl, (6) WITH1-4alkoxy, (7) phenoxy, (8) amino which may be substituted1-4the alkyl, (9) -COR13where R13represents C1-6alkyl, phenyl, substituted by halogen atom or WITH1-4alkoxy, or phenyl WITH1-4alkyl, (10) -COOR14where R14represents a hydrogen atom or a C1-6alkyl, (11) -CONR15R16where R15and R16that may be the same or different, represent a hydrogen atom or a C1-6alkyl which may be substituted unsaturated six-membered heterocyclic ring, or (12) a saturated six-membered heterocyclic ring which may be substituted WITH1-4the alkyl or phenyl WITH1-4by alkyl; (h) -C=N-OR/SUB>OR17where m is an integer from 0 to 4, and R17is1-6alkyl; (k) -(CH2)jCOOR19where j is an integer from 0 to 4, and R19represents C1-6alkyl; (l) -(CH2)p-NR20R21where p is an integer from 1 to 4, and R20and R21that may be the same or different, represent (1) hydrogen atom, (2) C1-6alkyl which may be substituted amino, substituted C1-4the alkyl, (3) phenyl1-4alkyl, (4) -COR22where R22is1-4alkyl which may be substituted by carboxyla, or (5) -SO2R23where R23is1-4alkyl or phenyl which may be substituted by a halogen atom; (m) -(CH2)q-CONR24R25where q is an integer from 0 to 4, and R24and R25that may be the same or different, represent a hydrogen atom, an unsaturated six-membered heterocyclic ring, or C1-6alkyl which may be substituted unsaturated six-membered heterocyclic ring, or, in another embodiment, R24and R25may form a saturated six-membered heterocyclic ring together with the nitrogen atom to which they Presidio); and (n) -NR26R27where R26and R27that may be the same or different, represent a hydrogen atom or-COR28where R28represents C1-6alkyl, or phenyl, which is substituted WITH1-4the alkyl or C1-6alkoxy substituted by phenyl;

R31and R32that may be the same or different, represent a hydrogen atom or a C1-6alkyl; and

Q represents a group selected from the following groups (i) to(iv), or halogen atom, or WITH1-6alkoxy:

< / BR>
< / BR>
where R33represents C1-6alkyl, substituted C1-6alkoxy, optionally substituted C1-6alkoxy; phenyl, which is substituted WITH1-6alkoxy or nitro;

R34is1-16alkyl which may be substituted by a halogen atom, carboxyla or phenyl, substituted C1-6alkoxy, phenyl which may be substituted amino, or unsaturated six-membered nitrogen-containing heterocyclic ring;

R35represents hydrogen;

R36represents C1-6alkyl, which is substituted di1-4alkylamino; R37and R38that may be the same or different, represent a C1-6alkyl, provided that the group-CR32the Association under item 1, where R1represents a hydrogen atom, R2, R3, R4and R5represent a hydrogen atom or (g)1-12alkoxy.

3. Connection on p. 1, where R1, R2and R5represent a hydrogen atom, R3and R4represent a hydrogen atom or (g)1-12alkoxy.

4. Connection on p. 1, where R1, R2, R4and R5represent a hydrogen atom, R3is (g)1-12alkoxy.

5. Connection on p. 1, where R1, R2, R3and R5represent a hydrogen atom, R4is (g)1-12alkoxy.

6. Connection on p. 1, represented by formula (Ia), or its pharmacologically acceptable salt or MES

< / BR>
where R41and R42that may be the same or different, represent a hydrogen atom, hydroxyl, C1-6alkoxy or C1-6alkyl which may be substituted by a halogen atom;

R31, R32and Q are specified in paragraph 1 values, provided that the group-CR31R32Q represents C1-6alkyl, substituted by a halogen atom or C1-6alkoxy.

7. Connection on p. 6, where R41and R42submit C1-6-alkoxy and Q represents a group (i).
2-(1-{ 1,3-diethoxy-2-propoxycarbonyl)-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-C]-[1]benzazepin

2-(1-(1,3-diethoxy-2-propoxycarbonyl)-2-methylpropyl)-8-isopropoxy-7-methoxy-4(5H),10-dioxo-2H-1,2,3-tri-azolo[4,5-C][1]benzazepin, or

8 isopropoxy-2-(1-isopropoxycarbonyl-2-methylpropyl)-7-methoxy-4(5H),10-dioxo-2H-1,2,3-tremolo[4,5-C][1]-benzazepin,

or its salt or solvate.

9. Pharmaceutical composition for treatment of allergic diseases, comprising the compound according to any one of paragraphs.1-8, or its pharmacologically acceptable salt, or MES.

10. A method of treating allergic diseases comprising administration to the mammal of a compound according to any one of paragraphs.1-8, or its pharmacologically acceptable salt, or MES, together with a pharmaceutically acceptable carrier.

11. The compound according to any one of paragraphs.1-8, or its pharmacologically acceptable salt, or MES, as the active agent for a therapeutic agent for the treatment of allergic diseases.

12. The compound represented by formula (II) or its salt or MES

< / BR>
where R51is nitro or amino;

R52>are specified in paragraph 1 values, provided that the group-CR31R32Q represents C1-6alkyl, substituted by a halogen atom or C1-6alkoxy.

13. The compound represented by formula (II'), or its salt or MES

< / BR>
where Q, R2- R5, R31, R32, R51and R52are specified in paragraph 1 and 12 values, provided that the group-CR31R32Q represents C1-6alkyl, substituted by a halogen atom or C1-6alkoxy.

14. The compound represented by formula (VI) or its salt or MES

< / BR>
where Q, R2- R5, R31, R32and R52are specified in the PP.1 and 12 values.

15. The compound represented by formula (VI'), or its salt, or MES

< / BR>
where Q, R2- R5, R31, R32and R52are specified in the PP.1 and 12 values.

16. The compound represented by formula (VII) or its salt, or MES

< / BR>
where R2-R5and R52are specified in the PP.1 and 12 the value.

17. The compound represented by formula (VIII) or its salt, or MES

< / BR>
where R61represents a protective group for triazole;

R2-R6and R52are specified in the PP.1 and Wiley group (i), as defined in paragraph 1;

R2- R5, R31, R32and R52are specified in the PP.1 and 12 values,

which involves the following stages: (1) interaction of the compounds represented by formula (V)

< / BR>
where R2- R5and R52are specified in the PP.1 and 12 values,

with the connection represented by R31R32C=O, where R31and R32are specified in paragraph 1 values; (2) interaction of the compound obtained in stage (1), with the compound represented by R71-C(=O)-R72where R71and R72each independently represents a chlorine atom, 4-nitrophenyl or 1-imidazolyl; and (3) interaction of the compound obtained in stage (2), with the compound represented by R33OH, where R33has specified in paragraph 1.

19. The method of obtaining the compound represented by formula (IIA')

< / BR>
where Q represents group (i), as defined in paragraph 1;

R2- R5, R31, R32and R52are specified in the PP.1 and 12 values,

which involves the following stages: (1) interaction of the compounds represented by formula (V)

< / BR>
where R2- R5and R52are specified in the PP.1 and 12 values,

with the connection represented by R31R32C=O, where R3133where Hal represents a halogen atom, and R33has specified in paragraph 1 values, in the presence of a carbonate of an alkali metal and the alkali metal iodide.

20. The method of obtaining the compound represented by formula (IIA')

< / BR>
where Q represents group (i), as defined in paragraph 1;

R2- R5, R31, R32and R52are specified in the PP.1 and 12 values,

which includes the stage of interaction of the compounds represented by formula (V)

< / BR>
where R2- R5and R52are specified in the PP.1 and 12 values,

with the compound represented by formula (IV)

< / BR>
where Hal represents a halogen atom;

Q represents group (i), as specified in paragraph 1,

R31and R32are specified in paragraph 1 values

in the presence of inorganic bases and alkali metal iodide.

21. The method of obtaining the compound represented by formula (VI')

< / BR>
where Q represents group (i), as defined in paragraph 1;

R2- R5, R31, R32and R52are specified in the PP.1 and 12 values,

which involves the following stages: (1) interaction of the compounds represented by formula (VII)

< / BR>
where R2- R5and R52UP>32
are specified in paragraph 1 values; (2) interaction of the compound obtained in stage (1), with the compound represented by R71-C(=O)-R72where R71and R72each independently represents a chlorine atom, 4-nitrophenyl or 1-imidazolyl; and (3) interaction of the compound obtained in stage (2), with the compound represented by R33HE, where R33has specified in paragraph 1.

22. The method of obtaining the compound represented by formula (VI')

< / BR>
where Q represents group (i), as defined in paragraph 1;

R2- R5, R31, R32and R52are specified in the PP.1 and 12 values,

which involves the following stages: (1) interaction of the compounds represented by formula (VII)

< / BR>
where R2- R5and R52are specified in the PP.1 and 12 values,

with the connection represented by R31R32C=O, R31and R32are specified in paragraph 1 values; and (2) interaction of the compound obtained in stage (1), with the compound represented HalCOOR33where Hal represents a halogen atom, and R33has specified in paragraph 1 values, in the presence of a carbonate of an alkali metal and the alkali metal iodide.

23. The method of obtaining compounds present is P>31
, R32and R52are specified in the PP.1 and 12 values,

which includes the stage of interaction of the compounds represented by formula (VII)

< / BR>
where R2- R5and R52are specified in the PP.1 and 12 values,

with the compound represented by formula (IV)

< / BR>
where Hal represents a halogen atom;

Q represents group (i), as specified in paragraph 1;

R31and R32are specified in paragraph 1 values

in the presence of inorganic bases and alkali metal iodide.

24. The method of obtaining the compound represented by formula (VIII)

< / BR>
where R2- R5, R52and R61are specified in the PP.1, 12 and 17 values,

which includes the stage of interaction of the compounds represented by formula (IX)

< / BR>
where R2- R5and R52are specified in the PP.1 and 12 values, with the compound represented by formula (X)

R61-N3(X)

where R61is specified in the letter of 17 values.

25. The method according to p. 24, characterized in that the starting compound represented by the formula (IX) is obtained by dehydrogenation of the compounds represented by formula (XI)

< / BR>
where R2-R5, R52are specified in the PP.1 and 12 SUP>, R52and R61are specified in the PP.1, 12 and 17 values,

which includes the stage of interaction of the compounds represented by formula (XII)

< / BR>
where M is lithium, magnesium chloride, magnesium bromide, magnesium iodide, zinc bromide, zinc iodide, bromide, cadmium iodide cadmium or copper;

R2-R5are specified in paragraph 1 values

with a compound represented by the formula (XIII)

< / BR>
where R52and R61are specified in the PP.12 and 17.

27. The method of obtaining the compound represented by the formula (XV)

< / BR>
where R2- R5, R52and R61are specified in the PP.1, 12 and 17 values,

which includes the stage of interaction of the compounds represented by formula (XVI)

< / BR>
where R2-R5and R52are specified in the PP.1 and 12 values,

with the compound represented by formula

(X) R61-N3(X)

where R61is specified in the letter of 17 values.

28. The method according to p. 27, characterized in that the starting compound represented by the formula (XVI) is obtained by dehydrogenation of the compounds represented by formula (XVII)

< / BR>
where R2- R5and R52are specified in the PP.1 and 12 values.

29. Audinarayana in PP.6 and 12 values, provided that R41and/or R42do not represent a hydrogen atom.

30. The compound represented by the formula (XVIa) or its salt, or MES

< / BR>
where R41, R42, R51and R52are specified in the PP.6 and 12 values.

Priority points:

29.09.1997 on PP.1-3, 6-11, 14-15 and 21-23;

04.03.1998 on PP.12-13, 16-17 and 24-30.

 

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< / BR>
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