Heterobicyclic compound, pharmaceutical composition, methods of obtaining heterobicyclic connection

 

(57) Abstract:

Describes compounds of General formula I. Heteroatom X represents oxygen, but can be others. The group W is preferably a carbonyl group, but may have other values. Preferred heterocyclic ring is a 4-oxo-4H-1-benzopyrane ring. It may have a wide range of substituents R2, R3, R6and R7. Y represents a related group selected from a wide range, but include-COO -,- CONH, -O-, -SO2and SO2NH-. Z represents alkylenes chain, and In - amine complex. These compounds and their prodrugs, enantiomeric and diastereoisomeric, N - oxides and pharmaceutically acceptable salts useful for the treatment of hypertension and disorders of the urinary tract associated with benign prostatic hypertrophy, and for treatment of other diseases. Method for obtaining compounds of formula I consists in the fact that the compound of General formula II F1-Y-Z-L, where F1represents the formula III in which X, W, R2, R3, R6and R7have the above values, L is a halogen atom or tsepliaeva group, is subjected to condensation with the compound of the formula IV, N V, where the Invention relates to the field of organic chemistry and pharmaceuticals, namely heterobicyclic compounds and pharmaceutical compositions based on them, as well as methods of producing these compounds.

Know the use of flavoxate, representing 8-(2-piperidinylcarbonyl)-3-methyl-4-oxo-2-phenyl-4-1-benzopyran as pharmaceutical agents in the treatment of urinary tract infections because it has the relaxation activity of smooth muscles due to the activity of a calcium antagonist. This activity has an effect on smooth muscles of the arch bladder as well as urinary, Central nervous system (CNS).

Compounds characterized by the present invention, contain more complex amine fragments instead piperidino group. In addition, they contain ethoxycarbonyl group, located in the space between aminoven fragment benzopyrano rings and other groups, standing in 2-, 3 - and 7-substitutions in benzopyrylium ring, the substitution of a heteroatom ring atom of sulfur or sulfinil, sulfonyl or aminogroup, and/or 2,3-digidrive benzopyrano rings. These structural changes give new compounds ability to interact with various biological systems.

Connection, the ary or double bond,

X is sulfur atom or oxygen;

W is a valence bond or a carbonyl-, methylene or hydroxymethylene group;

R2is a hydrogen atom, a C1- C6-alkyl, unsubstituted or substituted phenyl C1- C6alkenyl, C3- C6-carbonyl, pyridyl, furyl, thienyl, benzoyl, phenyl, unsubstituted or substituted by phenoxypropane, phenyl, trifluoromethyl, C1- C6-alkoxy-, hydroxy-, amino-, C1- C6-acylamino - or nitro-group;

R3is a hydrogen atom or halogen, C1- C6-alkyl or hydroxy-C1- C6-alkyl;

R6is a hydrogen atom or halogen, nitro-, amino-, C1- C6-alkylamino-, di(C1- C6)alkylamino-, C1- C6-acylamino, C1- C6-alkylsulfonyl-, hydroxy-, C1- C6-alkoxygroup or C1- C6-alkyl,

R7is a hydrogen atom or a C1- C6-alkoxygroup,

Y has a value of:

Y1- -CO-,

Y2- -COO-,

Y3- -CONH-,

Y4- -CON(CH3)-,

Y5- -SON(OH)-,

Y6- -CH(OH)-,

Y7- -CH(OAlkyl)-,

Y8- -CH=CH-,

Y10- CH=CH-CONH-,

Y11CN=NO-,

Y12- CH2-,

Y13- CH2/SUB> - CH2N(COCH3)-,

Y18- CH2N(CONH2)-,

Y19- CH2NHCO-,

Y20- CH2N(CH3)CO-,

Y21- CH2NH-CONH-,

Y22- CH2NHSO2-,

Y23- CH2O-,

Y24- CH2S-,

Y25- CH2SO-,

Y26- CH2SO2-,

Y27- CH2SO2NH-,

Y28- CH2SO2N(CH3)-,

Y29- NH-,

Y30- N(CH3)-,

Y32- N(CONH2)-,

Y33- NHCO-,

Y34- N(CH3)CO-,

Y35- NH-CO-NH-,

Y37- -O-,

Y42- -SO2N(CH3)-,

Y45- -CSNH-,

Y47-

< / BR>
Z is a linear or branched C1- C6-Allenova group;

B represents one of the following groups

< / BR>
in which Q represents a methylene group, and A represents one of the following groups

A1is phenyl, substituted by one or two halogen atoms and/or one or two C1- C6-alkyl, C1- C6-alkoxy - or hydroxy-group,

A22-pyrimidinyl group

< / BR>
(B2)

< / BR>
in which each of the L1and L2is independently from each atom vremenno are not hydrogen atoms,

(B3)

< / BR>
in which each of R10and R11independently represents a hydrogen atom or a C1- C6-alkoxy;

R12represents a hydrogen atom or a C1- C6is an alkyl group;

n = 2 or 3,

< / BR>
in which R12defined above.

When is a double bond, W represents a carbonyl group, and X represents aminogroup, the ring may undergo tautomerization, resulting in the structure of 4-hydroxy-quinoline.

The invention relates to enantiomers, diastereomers, N - oxides, pharmaceutically acceptable salts, and compounds of the formula I, in which the amino and/or imino-and/or hydroxy-group-protected. The compounds of formula I, in which the amino and/or imino-and/or hydroxy-group-protected, can be used as drugs prolonged action.

Group

< / BR>
in the future, will be denoted as F1. Preferred for this group, the following meanings of the substituents

double bond, X is an oxygen atom, W is a carbonyl group, R2is a phenyl group, R3is a methyl group, R6is a hydrogen atom, R7- atom-benzopyran-8-yl group.

Z preferably represents trimethylene or tetramethylene group. Y preferably represents one of the groups B1or B3preferably, 1-(2-methoxyphenyl)-piperazinyl. The text uses the generally accepted abbreviation: Me is methyl, Et is ethyl, Ac is acetyl, Alk is alkyl, THF is tetrahydrofuran, DMF is dimethylformamide, and DMSO - dimethyl sulfoxide.

Compounds described by the present invention, can be generally synthesized (except when R6and the substituents at R2represent OH or aminoalkyl, Y15and Y29as follows.

a) condensation of the parent compounds with obtaining compounds of F1-Y-Z-B6with the removal of tailorshop. It is preferable to conduct the reaction at 20 to 140oC in a polar solvent (dimethylformamide, methanol) in the presence of calcium carbonate.

b) an alternative method of preparing compounds of the formula I is condensation (under the same conditions) connection F1-Y-H with a compound L-Z-B, where L represents a halogen atom or tsepliaeva group

C) the compounds of formula I, with a group NH2in R6or R2can be obtained restore is nitrogroup. This recovery you can perform the following ways:

using as catalyst Raney Nickel in proton solvent (methanol, ethanol, isopropanol, water or a mixture),

using an aqueous solution of chloride of divalent tin in the optional presence of hydrochloric acid using proton solvent (methanol, ethanol, isopropanol or their mixtures with water or an aprotic solvent (ethyl acetate),

using iron and an aqueous solution of hydrochloric acid in proton solvent (methanol, ethanol, isopropanol or their mixtures with water).

The temperature of the above reaction should be selected in the range of 20 - 100oC.

d) the compounds of formula I, having NHAlk group as a substituent at R6you can obtain when monoalkylated compounds similar to compounds of the formula I, but having as a substituent an amino group. For example, this can be accomplished by the reaction of amino compounds I with an excess triperoxonane anhydride and subsequent interaction triperoxonane derived from L-alkyl reagent with subsequent removal of the protection thus obtained triperoxonane alkyl derived during the processing of carbonate to the holding group NHAlk or N(Alk)2as substituents at R6or as a substituent in the phenyl group, R2can be obtained by alkylation of the corresponding compounds containing amine substituents, the corresponding alkanes in the presence of a reducing agent, in particular cyanoborohydride sodium,

e) compounds containing OH-group as R6or as a substituent in the R2can be obtained by using as starting substances of the relevant related compounds containing alkoxysilane in the relevant provisions. In this case, it is preferable to handle them tribromide boron in dichloromethane at 0 - 40oC,

g) compounds of General formula I, with the single bond can be obtained or by selective hydrogenation of the corresponding compounds with a double bond, or by transformation of a suitable source which connection is 2,3 - already saturated. The second variant is particularly preferred if the compound contains a nitrogroup, since the hydrogenation is able to turn it into the amino group. Selective hydrogenation can be carried out or using hydrogen in the presence of a metal catalyst or catalyst oxide IU what igeria in an aprotic solvent (tetrahydrofuran, and/or dichloromethane) at a temperature of from -70 to 0oC,

C) compounds in which W represents hydroxymethylene group and the relationship 2,3 - saturated, can be obtained by restoring using sodium borohydride corresponding compounds in which W represents a carbonyl group, and the relationship 2,3 - saturated.

In some cases, compounds of General formula I can be obtained by transformation related compounds. Such transformations include:

a) F1- CO - Z - B-F1- CH(OH) - Z - B when restoring,

b) F1- CH(OH) - Z - B-F1- CH(OAlkyl) - Z - B by esterification,

c) F1- (CH2)n-NH - Z - B-F1- (CH2)n-N(CH3) - Z - B, where n = 0 or 1, when N - methylation,

d) F1- (CH2)n- NH - Z - B-F1- (CH2)n- N(COCH3) - Z - B, where n = 0 or 1, when N - acetylation,

(e) (F1- (CH2)n- NH - Z - B-F1- (CH2)n- N(CONH2) - Z - B, where n = 0 or 1, by the reaction with the isocyanate calcium,

f) F1- CH(OHO) - Z - B-F1- CO - Z - B during oxidation

g) F1- Y - Z - B-F1- Y - Z - B(N-oxide) during oxidation

h) H2N - F1- Y - Z - B-CH3- CONH - F1- Y - Z - B (where H2N - F1is a group of F1in which R/P>The preferred method of synthesis depends on the synthesized substances.

The raw materials used for synthesis, commercially available or can easily be synthesized from available materials.

Adrenergic antagonistic activity of the above compounds makes them useful as a means of influencing the body's tissues, such as blood vessels, prostate and uretta. Therefore, antiadrainergicakimi compounds can be used as therapeutic agents for the treatment of hypertension and urinary disorder associated with impaired patency of the lower sections urinary tract infections, including those caused by benign prostatic hypertrophy, but is not limited to it.

Serotonina activity of these compounds makes them useful as a means of effects on tissues of the Central nervous system. These compounds have biological activity in blocking relationships between receptors and their various specific ligands. They can be useful therapeutic tools for the treatment of depression and anxiety.

Surprisingly, the compounds of the present isolationalism receptor) show high selectivity in the lower part of the urinary tract of mammals, i.e., they are much more active in combating urethral contractions than at lowering blood pressure. For example, a known alpha1-antagonists, such as prazosin, which is 1-(4-amino-6,7-dimethoxy-2-hintline)-4-(2-furoyl)-piperazine (GB 1156973) do not have such selectivity (and in fact cause hypotension as the main side effects), whereas flavone derivatives, structurally similar to flavoxate, such as tetraploid, which is a 8-(1,1-dimethyl-2-piperidino-etoxycarbonyl)-3-methyl-4-oxo-2-phenyl - 4H-1-benzopyran hydrochloride (EP 0072620), have no effect on urethral contraction. Of course, those compounds of the present invention, which are not selective for the lower urinary tract, preferred as antihypertensive agents, but it is the electoral connection due to its low toxicity can often be used as antihypertensive agents.

Compounds of the present invention demonstrate good antagonistic effect against contractions of the urinary bladder of rats, which were caused by the calcium chloride. This effect may be PrepCom lower sections urinary tract (i.e., useful for treatment of urinary incontinence, syndrome urge to urinate, and other similar violations).

The main feature of the compounds of the present invention is their low toxicity. So you can use them in large quantities; this advantage is often more than compensates for the relatively low level of activity, which is typical of some of these compounds. Naturally, the preferred those compounds that have both high activity and low toxicity.

The invention also provides a pharmaceutical composition containing the compound according to the present invention, or a prodrug, enantiomer, diastereoisomer, N-oxide or pharmaceutically acceptable salt of such a compound in a mixture with a pharmaceutically acceptable diluent or carrier.

The synthesis of compounds of the present invention.

Compounds according to the present invention can be mainly obtained (except in those cases where the group R6and the substituents at R2represent OH or aminoalkyl and Y - Y15or Y29as follows.

Path a:

The condensation of compounds F1-Y-Z-B, in which L represents a halo atom is rowedit condensation at 20 140oC in a polar solvent such as dimethylformamide or methanol, usually in the presence of a base type of calcium carbonate. Condensation of this type is given below in the examples 1 - 3, 7 - 9, 11, 13 - 16, 21, 23 - 31, 38 - 42, 46 - 49, 54 - 59, 69, 73, 77, 78 and 84. (See also Patai, The Chemistry of The Amino Group, p. 45 et seq., Wiley Interscience, New York, 1968).

An alternative method of preparing compounds of the present invention is the condensation of (under the same conditions described in the previous paragraph) connection F1-Y-H with a compound L-Z-B, in which L was defined above. This condensation is illustrated below by examples 5, 6, 66, 79 and 81. According to this path can be also obtained compounds having Y - Y15or Y29(see previous citation).

The compounds of formula I, with a group NH2in R6or as a substituent in the R2can be obtained by reduction of corresponding compounds I, in which R6or the substituents in the R2represent NH2-group. Such recovery can be carried out:

using the catalyst of the Raney Nickel in proton solvent selected from methanol, ethanol, isopropanol, water or mixtures thereof; or

using SnCl2H2O when neobiota, acetic acid and their mixture, or in an aprotic solvent, such as ethyl acetate; or

using Fe and aqueous hydrochloric acid in proton solvent such as methanol, ethanol, isopropanol, water and mixtures thereof.

Temperature above reactions should be selected in the range of 20 - 100oC (J. March, Advanced Organic Chemistry, third Ed., p. 1103, Wiley Interscience, 1985). Examples of these reactions are given in the examples of the invention 94 - 124.

The compounds of formula I, having NHAlk-group as substituent R6you can obtain when monoalkylamines, since the relevant related compounds I, in which R6=NH2. For example, this can be accomplished by the reaction of amino compounds I first excess triperoxonane anhydride, and then thus obtained triperoxonane derived interacts with L-alkyl reagent and, finally, removal of the protection thus obtained triftoruranmetilidina derived during the processing of calcium carbonate in methanol or when treatment with sodium borohydride in methanol or dimethyl sulfoxide. These reactions are described in examples 32 and 33, in which they were carried on the Y-groups.

Or the compounds of formula I containing groups NHAlk or N(Alk)2in the cation of the relevant related compounds I, in which R6=NH2suitable alkanes in the presence of a reductive agent such as cyanoborohydride sodium. Descriptions of these reactions are shown below in examples 96 and 97.

Compounds having OH group as R6or as the substituent in the R2can be obtained by using as starting substances of the relevant related compounds I, alkoxy-substituted in these positions. This can be completed processing related compounds, for example you can try here3in dichloromethane at 0 - 40oC (T. W. Greene, Protective Groups in Organic Synthesis, p. 87, Wiley Interscience, 1981) or according to other methods described in this work.

Compounds of General formula I in which a represents a single bond, can be obtained or by selective hydrogenation of the corresponding compounds in which a represents a double bond, or a suitable transformation of the original, in which the connection of 2,3 - already saturated; these source materials can be applied in accordance with the scheme of the reaction of 4, 6, 9, 11, 12, and 14 below. This last path is illustrated below in example 87, it is preferred, especially if the compound contains a nitrogroup, as the hydrogenation capable pravr the
hydrogen in the presence of a metal catalyst or a catalyst based on a metal oxide (for example, palladium on coal or platinum dioxide) in proton solvent at 20 to 120oC (E. H. Rodd, Chemistry of Carbob Campounds, vol. IVB, p. 903, Elsevier,. 1959); or

di(isobutyl)aluminium hydride in an aprotic solvent (such as tetrahydrofuran and/or dichloromethane) at a temperature of from -70 to 0oC (H. Sarges et al, J. Med. Chem., 33, 1859, 1990).

Compounds in which W represents hydroxymethylene group and the relationship 2,3 - saturated, can be obtained when restoring using sodium borohydride corresponding compounds in which W represents a carbonyl group, and the relationship 2,3 - saturated; this is reported below in example 123.

In some cases, compounds of General formula I can be obtained by transformation of other (related) compounds of the present invention. Such transformations include:

Path b: F1-CO-Z-B ---> F1-CH(OH)-Z-B

when restoring, as illustrated below in examples 17-20.

C: F1-CH(OH)-Z-B ---> F1-CH(OAlkyl)-Z-B

when the esterification, as illustrated below in example 22.

Path: d: F1-(CH2)n-NH-Z-B ---> F1(CE 35.

Path e: F1-(CH2)n-NH-Z-B ---> F1(CH2)n-N(COCH3)-Z-B

where n = 0 or 1, when N-acetylation, as illustrated below in example 36.

Path f: F1-(CH2)n-NH-Z-B ---> F1(CH2)n-N(CONH2)-Z-B

where n = 0 or 1, by the reaction with the isocyanate calcium, as illustrated in example 50 below.

Path g: F1-CH(OH)-Z-B ---> F1-CO-Z-B

during oxidation, as illustrated below in example 51.

Path h: F1-Y-Z-B ---> F1-Y-Z-B (N-oxide)

during oxidation, as illustrated below in examples 43 and 122.

Path i: H2N-F1-Y-Z-B ---> CH3-CONH-F1-Y-Z-B

(where H2N-F1are a group of F1in which R6- amino group, or R2includes the amino group) using the method of N-acylation, as described below in examples 36 and 95.

Path j: F1(R6=NH2)-Y-Z-B ---> F1(R6=CH3SO2NH)-Y-Z-B

when amidation using the method described in example 112.

Path k:

< / BR>
or

< / BR>
or

< / BR>
for N-alkylation using the method described below in examples 35 and 62.

Path l:

< / BR>
as illustrated in example 45.

It is also possible cross-connection double bond, for example:

Path m: F1-Y-CH=CH2+ H-B ---> F1-Y-CH2-CH2-B

as illustrated below in examples 37, 63 and 82.

Other schemes of synthesis include the education of Y, Z or B in the reaction, for example:

Path n: F1(X)-(Q)-Cl + A-HN-Z-B ---> F1(X)-(Q)-N(A)-Z-B

where X is a bond, CH2or CH=CH, Q=CO or SO2, A=H, alkyl or OPrwhere Pris a protective group, as described in example 12 (which is especially preferred) and in the examples 60, 61, 64, 67, 68, 72, 87, 88, 93, 98, 116, 129, 130.

These same compounds can be obtained in other ways, including:

F1(X)-COOH + A-NH-Z-B in the presence of a chip off the agent (for example, dicyclohexylcarbodiimide, N, N'-carbonyl-diimidazole or diethylthiophosphate) when the optional presence of a promoting agent (e.g., 4-dimethylaminopyridine or N-gidroekstruziya) in an aprotic solvent (e.g. dimethylformamide, chloroform) at -10/140oC (Albertson, Org. React., 12, 205-218, 1962; Doherty et al., J. Med. Chem., 35, 9, 1992; Staab et al., Newer M and 128.

F1(X)-COOH + A-NH-Z-B without the use of solvent at 150 - 220oC (Mitchell et al. , J. Am. Chem. Soc., 53, 1879, 1931) or in high-boiling ether solvents (for example, diglyme);

F1(X)-COO-Alk + A-NH-Z-B, with the optional presence of a chip off the agent (e.g., trimethylaluminum) in an aprotic and/or chlorinated solvent (for example, hexane, dichloromethane) at -10/80oC, or without solvents at 80 - 180oC (S. M. Weinreb et al., Tetrahedron, 4171, 1977; M. F. Lipton et al., Org. Synth., 59, 49, 1979);

F1(X)-COOH + alkylchloride in the presence of tertiary amine (e.g. triethylamine) followed by the addition of A-NH-Z-B at 0 - 80oC; with the optional addition of the promoting agent (e.g., 1-hydroxypiperidine) before the addition of amine (Albertson, Org. React., 12, 157, 1962).

Path o: F1-COCl + HS-Z-B ---> F1-Y49-Z-B.

Path p: F1-COCl + HO-Z-B ---> F1-Y2-Z-B

as illustrated in example 10.

Path g: F1CHO + H2NO-Z-B ---> F1-Y11-Z-B

as illustrated below in example 70.

The path r: F1-CHO + A-HN-Z-B ---> F1-CS-N(A)-Z-B

(where A=H or CH3in the presence of sulfur in an aprotic solvent, such as DMF or pyridine at 60 to 120oC (M. frmack et al., OUB>-NH2+ HCO-Z-B ---> F1-Y29-Z-B

as illustrated below in example 34.

The path t: F1-Y-CH3+ HO-CH2-B ---> F1-Y-CH2-CH2-B

as illustrated below in example 4.

The path u: F1-CH=CH-CONH2+ HOCH2-B ---> F1-Y10-CH2-B.

Path v:

< / BR>
in terms of recovery, as illustrated below in example 44.

The path w:

,

as illustrated below in examples 74 to 76.

,

as illustrated below in example 52.

Path x:

,

as illustrated below in example 65.

The path y: F1-Y-Z-CHO + HB ---> F1-Y-Z-B

as illustrated below in example 53.

People skilled in this field should understand that all the above mentioned ways of synthesis from b to y) should be simplified so that reacts intermediate compounds would not have further groups that are sensitive to the same reagents (e.g., CO, NH2-, NHAlk or OH-groups). The compounds of formula I having such reactive groups can be obtained by ways of synthesis from b to y), provided that the reactive groups present in the source connection before. what some examples of protection and removal for different reactive groups can be found in T. W. Green, Protective Groups in Organic Synthesis, Wiley Interscience, 1981.

Or non-reactive group (for example, NO2during the first reaction may not have transformations, and then transformed into the reactive group (for example, NH2) at the final stage of the synthesis (See, for example, path a).

The preferred method of synthesis will depend on what connection you want to get, but the path n) is mostly preferred for those compounds that can be obtained with its help. Additional methods of synthesis are obvious for people skilled in this field.

Source materials.

Source materials (F1-Y-Z-L, F1-Y-H and others) used in the methods of obtaining, described above, can be obtained from simple compounds such as F1-COOH, F1-CHO, F1-COCl, F1-NH2and F1OH-by transformations known to people skilled in this field. Many of these simple compounds (F1-COOH, F1-CHO, F1-COCl, F1-NH2and F1-OH) are commercially available or their synthesis are known in the literature. Those modifications is given below.

Scheme 1 reaction (see end of description) gives compounds in which W represents a carbonyl group, and X represents an oxygen atom.

Stage 1a. Method without isolation of intermediate phenyl ether:

- R3CH2COCl or (R3CH2CO)2O and the Lewis acid (e.g., AlCl3or ZnCl2), without solvent or in an aprotic solvent (e.g. nitrobenzene or a chlorinated solvent) at 20 - 180oC.

The method of allocating the intermediate phenyl ether:

R3CH2COCl or (R3CH2CO)2O, is heated with raw materials or other methods of esterification, such as the method of Schotten's-Bauman. Selected ether and then heated in nitrobenzene or other aprotic solvent (e.g., chlorinated solvent or without any solvent at 20 to 180oC in the presence of Lewis acid type AlCl3or ZnCl2(A. M. Blatt, Org. React., 1, 342, 1942).

Stage 1b.

R2COCl or (R2CO)2O and R2COONa separately or in high-boiling aprotonin solvent (such as o-dichlorobenzene) at 150 - 220oC; this reaction also allows the direct conversion of compounds (2) in connection (6) if Conn is under piperidine in 60 - 80oC;

R2COCl or (R2CO)2O in a chlorinated solvent at a temperature of from -10 to 120oC in the presence of a base type 1.8-diazabicyclo (DBU).

Stage 1c.

R2COCl in pyridine at 20 - 100oC or aprotonin solvent at 0 - 80oC when the optional presence of a base type NEt3or 4-dimethylaminopyridine.

Stage 1d.

K2CO3in acetone or methyl-ethyl ketone at 20 - 80oC;

NaH and DMSO or THF at 0 - 40oC;

KOH or t-piperonyl calcium in pyridine at 20 - 100oC.

Stage 1e.

HCl or H2SO4in AcOH at reflux distilled or alcohol (MeOH, EtOH, isopropanol) at a temperature of 20oC to the temperature of reflux distilled.

Stage 1f.

R2COCl and K2CO3or KOH in water and phase catalyst in benzene or toluene at reflux distilled;

R2COOAlk and bis(trimethylsilyl)amide lithium or diisopropylamide lithium THF at a temperature of from -78 to 0oC.

Stage 1g.

If A is a COOCH3or COOC2H5group:

NaOH in aqueous EtOH at 0 - 75oC;

LiOH in aqueous DMF, MeOH or THF, or a mixture thereof with a 10 - 100oC;

HCl in protonirovanie using the catalyst of the Raney Nickel in proton solvent (for example, isopropanol) or in a mixture of proton solvents at 20 - 100oC;

restore using hydrogen and a catalyst (for example, Raney Nickel or Pd/C) in proton solvent (such as MeOH, EtOH, isopropanol or a mixture thereof) at 20 - 100oC;

restore using SnCl2in the presence of HCl in water proton solvent (e.g., AcOH) at 20 - 100oC;

recovery in the presence of Fe and HCl in water proton solvent at 20 - 100oC;

If A is CH=CHCH3group:

oxidation using Na2Cr2O7or other oxidizing agents, such as KMnO4in acetone/H2SO4if 0 - 100oC.

Scheme 2 reaction (see below) leads to compounds in which X represents a sulfur atom or sulfinil or sulfonylurea, and W represents a carbonyl group. The original o-mercaptobenzoic (1) are commercially available or can be obtained by known methods, for example by conversion of the corresponding o-alkylaryl-benzodiazines salts when they are processed by ethylxanthate potassium (M. S. Cohen et al., J. Org. Chem., 18, 1394, 1953).

Stage 2a.

R2COCH(R3)CN, or R2COCH(R3)COOAlk in polyphosphoric 0 - 40oC;

R2CCOOAlk and base in an aprotic solvent (such as THF or DMF) at 20 - 140oC.

The last both options provide for subsequent processing of polyphosphoric acid at 50 - 120oC.

Stage 2b.

NaOH in aqueous EtOH at 40 - 75oC;

LiOH in aqueous DMF at 40 - 100oC.

Stage 2c.

The stoichiometric amount of 30% H2O2in AcOH at 25 -60oC;

Stage 2d.

30% H2O2in AcOH at 50 - 80oC.

Scheme 3 reactions leads to the compounds (2) in which R7represents a methoxy group, W represents a carbonyl group, and X is a sulfur atom or oxygen. Compounds (1) can be obtained according to schemes 1 and 2 reactions, using as source the appropriate phenols or thiophenol (not substituted in position 2 or 6 on COOAlk or NO2).

Scheme 3.

< / BR>
Stage 3a.

HCHO and gaseous HCl in AcOH containing aqueous HCl (d = 1.18) at 50 - 100oC (P. Da Re et al., Ann. Chim., 46, 904, 1956). You can use this method if R3different from H or CH2OH.

Simple intermediate 2,3-dihydrocodeinone ( represents a single bond) can be obtained Salaspils, NH2, OH), were previously protected as described above. Thus obtained compound (4) can be converted into the corresponding derivatives, where A=COOH or NH2according to the method described in stage 1g.

Stage 4a.

R2-CHO, aqueous NaOH in EtOH or other proton solvent;

R2-CHO, NaH or t-piperonyl potassium in THF (or other bipolar aprotic solvent) at 0 - 150oC.

Stage 4b.

Mineral acid (such as HCl or H2SO4) in water or other proton solvent (such as EtOH, Asón) at 0 - 100oC.

Stage 4c.

R2CHO, 0.1 N. - 1 N. aqueous NaOH or other suitable base in the proton solvent;

R2CHO, pyrrolidin in proton (e.g., MeOH) or polar aprotic solvent at 0 - 100oC (H. J. Kabbe, Synthesis, 1978, p. 886).

Stage 4d.

Diisopropylamide lithium in THF at 0 - 20oC; then trimethylsilane and organic base (for example, NEt3) (S. E. Kelly et al., J. Org. Chem., 56, 1325, 1991).

Stage 4e.

R2-CHO in a chlorinated solvent (e.g. dichloromethane) at -78oC, then TiCl4or another Lewis acid (S. E. Kelly et al., J. Org. Che et al., Tetrahedron Letter, 1979, 3685).

Stage 4g.

R2-CH= CR3COCl, Lewis acid (e.g., AlCl3) in a suitable solvent (e.g. nitrobenzene) or without solvent at 20 to 180oC.

Stage 4h.

R2-CH= CR3COOAlk, the hydroxide of triethylenediamine in an aprotic solvent (e.g. benzene or without solvent) at 50 - 150oC; then aqueous NaOH in MeOH at 20 - 50oC or LiOH in aqueous DMF. (In this case, compounds in which A - COOCH3or COOC2H5also hydrolyzed to compounds with A = COOH).

Stage 4i.

Concentrated H2SO4or P2O5or polyphosphoric acid, or a Lewis acid in nitrobenzene or toluene, or without solvent at 0 - 180oC. (In this case, the hydrolysis of A = COOAlk to A = COOH).

A simple starting materials containing R3- OH or or8where R8represents an alkyl or aralkyl, can be obtained according to scheme 5 reaction (see the end of the description), in which A has the same meaning as in the reaction scheme 1. Compounds (1) and (2) (which are the same as (2) and (4) in reaction scheme 4, but in which R3- H) can be obtained according to scheme d is Lithuania in the reaction scheme 5, can be obtained by known methods from the corresponding salicylates or thiosalicylate (see J. March, Advanced Organic Chemistry, 486, John Wiley and Sons, New York, 1985, Rene L. et al., Eur. J. Med. Chem.-Chim. Ter., 4, 385, 1977, and references referred to therein). Deputy A in compounds (3) and (6) reaction 5 can be turned into a Deputy B using processes stage 1 scheme of reactions 1.

Stage 5a.

Aqueous NaOH in an alcohol solvent (such as MeOH or EtOH), then processing 30% H2O2at a temperature of from -10 to -78oC. (N. D. Meyer et al., J. Med. Chem. , 34, 736, 1991, and references cited in this work). (If A is CH=CH3; if A = COOR, he becomes simultaneously COOH).

Stage 5b.

If is a single bond:

amyl nitrate or other alkylated without solvent or in a suitable solvent (such as EtOH or benzene) in the presence of a catalyst, such as 37% HCl (Org. React., 7, 327, 1953 and references in this work); then water (H2SO4in proton solvent (e.g., AcOH) at 10 - 100oC (Acheson, R. M. An Introduction to the Chemistry of Heterocyclic Compounds, 347, John Wiley and Sons, New York, 1976).

If is a double bond:

diisopropylamide lithium in dry THF at -78oC; then AcOH and 30% H2OoC (Rene L. and T. Sakakibara et al., Bull. Chem. Soc. Jpn., 51, 3095, 1978).

Stage 5d.

15% H2O2, NaOH or other base (for example, NEt3in proton solvent such as MeOH at 20 - 100oC (S. R. Deshpande et al., Synthesis, 835, 1983) or photolysis and alkaline hydrolysis (Rao T. S. et al., Heterocycles, 22, 1377, 1984) or KO2in benzene, containing 18-crown-6 ether at 20 - 100oC (Rao T. S., Heterocycles, 26, 2117, 1987). (If A is not a CH= CH-CH3; if A = COOR, he simultaneously becomes COOH).

Stage 5e.

R8L, where L is tsepliaeva group (for example, alkylsulfate, halogen, tosyl) and base (e.g., K2CO3, NaH, KOH, NaOH or LiOH in a suitable solvent (such as THF, DMSO, benzene) in the presence of phase catalyst (for example, bromide of benzyltriethylammonium) at 0 - 180oC.

Stage 5f.

According to the methods of stage 1b.

Scheme 6 reaction (see the end of the description), in which A has the same meaning as in the reaction scheme 1, leads to compounds in which W represents a thiocarbonyl group. Compounds (1) and (2) schemes which may be converted according to the process stage 1g in Deputy B, as it was defined in the reaction scheme 1.

Stage 6a.

P2S5in pyridine at 50 - 100oC (Stavaux et al., Bull, Soc Chim. Fr., 2082, 1967).

Stage 6b.

P2S5or B2S3or SiS2or the reagent Lawesson in a chlorinated solvent (e.g. chloroform) or other aromatic solvent (e.g. benzene, toluene, xylene) at reflux distilled (Dean et al., J. Chem. Soc. C, 2192, 1963, R. K. Razdan et al., J. Med. Chem., 21, 643, 1978, K. Clausen et al., Tetrahedron, 37, 3635, 1991).

Stage 6c.

COCl2without solvent or in an inert solvent (e.g. benzene) at 40 - 90oC (A. Schonberg et al., Chem. Ber., 101, 701, 1968).

Stage 6d.

Teoksessa or diamentina acid or teachercentered calcium in a suitable solvent (e.g. benzene) at reflux distilled (see previous link).

A reaction scheme 7 (see the end of the description), in which A has the same meaning as in the reaction scheme 1, leads to compounds in which W represents a methylene or hydroxymethylene group. Compounds (1), (2) and (4) of the schemes of reactions 7 can be obtained according to reaction schemes 1, 2, 5 and 6. Deputy A in the compounds (7) of the schemes of reactions 7 can be converted to SIP the>1,2-Acondition or 1,3-propanedithiol in an aprotic solvent (e.g. dichloromethane or benzene, or toluene) at 0 - 110oC in the presence of a catalyst (e.g. p-toluensulfonate acid).

Stage 7b

R2COCH2R3in a suitable solvent mixture (for example, EtOAc or dichloromethane together with EtOH or MeOH), saturated with gaseous HCl or 0 - 40oC; then the aqueous HClO4in acetone at 20 - 100oC (L. Jurd, Tetrahedron, 28, 493, 1972).

Stage 7c.

LiAlH4in THF at reflux distilled (if A is different from the COOR and NO2);

ZnI2and cyanoborohydride sodium (6 equivalents) in a chlorinated solvent (for example 1,2-dichloroethane) at a temperature of from room temperature to the temperature of reflux distilled (C. K. Lau et al., J. Org. Chem., 51, 3083, 1986).

Stage 7d.

The Raney-Nickel in an alcohol solvent (e.g. isopropanol) at a temperature of from room temperature to the temperature of reflux distilled (Hilton et al., J. Am. Chem. Soc., 90, 6887, 1968).

Stage 7e.

NaHB4in a suitable solvent (such as MeOH or EtOH or DMSO) at a temperature of -10 to 50oC (see link in paragraph 7b).

LiAlH4in THF (or any other suitable solvent) at 0 - 50oC (if A is different from COOR or NO2) (Degani et is at room temperature (see the previous reference).

Stage 7g.

Melting with P2O5at 80 - 180oC (Hortmann et al., J. Am. Chem. Soc., 96, 6118, 1974).

Stage 7h.

NaBH4in EtOH or other suitable solvent at a temperature of from 0oC to the temperature of reflux distilled (K. Anaya, Bull. Chem. Soc. Jpn., 40, 1884, 1967);

hydrogen (1 - 10 ATM) in EtOH (or other suitable solvent) in the presence of a catalyst such as 5% or 10% Pd/C or Raney Nickel, or PtO2at a temperature of from room temperature up to 80oC (see previous link) if A is different from CH=CH-CH3. If A = NO2he simultaneously restored to the NH2);

triisopropoxide aluminum in isopropanol at a temperature of from room temperature up to 92oC.

In scheme 8 reaction (see below) indicated receiving a simple starting materials, such as(4), (5), (6) and (9) in which A has the same meaning as in the reaction scheme 1. Connection(1), (2), (3), (7), (8) can be obtained by the reaction schemes 1, 2, 4, 5, 7, 9, 11. Deputy A connection (4) - (6) and (9) scheme of reactions 8 can be converted according to the stage of 1g in the Deputy indicated in the reaction scheme 1.

Stage 8a.

Pb(OAc)4in a suitable solvent (e.g. benzene, toluene) PR the capabilities of 7, stage 7a), then alkaline hydrolysis (if A - COOR, then it can be converted to COOH);

isopropoxide aluminum, as described in reaction scheme 7, step 7f;

DIBORANE in THF at temperatures from -10oC to room; then water (H2O2in the presence of NaOH (if different from A CH=CH-CH3; if A = COOR, he simultaneously becomes COOH). (Kirkiacharian et al., C. R. Hebd. Seances Acad. Ser. C, 289, 227, 1979);

LiAlH4and AlCl3in a suitable solvent (such as THF) at 0oC at reflux distilled (if A is different from the COOR and NO2) (Bokadia et al., J. Chem. Soc., 4663, 1961).

Stage 8c.

Hydrogen (100 ATM), chromite copper in EtOH at 140oC (M. A. Vickars, Tetrahedron, 20, 2873, 1964). If A= NO2he simultaneously becomes NH2group.

Stage 8d.

KMnO4in t-butanol (or other suitable solvent) in the presence of aqueous NaOH at a temperature of from -10 to 0oC (K. Hanaya, Bull. Chem. Soc. Jpn., 40, 1884, 1967). (If A is different from CH=CH-CH3). (See also A. H. Haines, Methods for Oxidation of Organic Compounds, Academic Press Inc. (London), 1985, chapter 3.2.2).

the osmium tetroxide (see the previous reference, Chapter 3.2.1) in a suitable solvent (for example, Et2O) at room temperature (Baranton et al., Bull. Soc. Chim. Fr., 4203, 1968) (in case A GRT -50oC; then NaOH, H2O, 45oC (see Baranton et al. above and A. H. Haines above, Chapter 3.2.7) (if A is different from CH=CH-CH3; if A = COOR, he simultaneously becomes COOH);

the silver acetate and iodine in wet AcOH at 0 - 20oC (see K. Hanaya higher and A. H. Haines Chapter 3.2.3, 3.2.4, 3.2.9) if A is different from CH=CH-CH3.

Stage 8e.

30% H2O2in the presence of NaHCO3in benzonitrile at 0 - 110oC, then LiAlH4in THF at 0 - 40oC (if A is different from the COOR and CH=CH-CH3(Clark et al., Austr. Journ. of Chem., 27, 865, 1974).

Stage 8f.

Hydrogen (1 to 50 ATM) in a suitable solvent (such as EtOH) in the presence of a metal catalyst (for example, PdCl2) at a temperature of from room temperature to 78oC (if A = NO2he simultaneously becomes NH2). (Bolger et al., Tetrahedron, 23, 341, 1967).

Stage 8g.

Cm. stage 8b (Clakr et al, see above).

Stage 8h.

0.4 M heptahydrate of trichloride cerium in MeOH in a suitable solvent (such as MeOH); then NaHB4at a temperature of 0 - 78oC (WO 89/06650);

NaBH4in diglyme at a temperature of from 0oC to the temperature of reflux distilled (G. P. Thakar, Indian J. Chem., 3, 74, 1965) (if A = NO2then it turns into NH2);

NaBH4
DIBORANE in THF at room temperature (if A is different from CH= CH-CH3(see previous link).

A simple starting materials, in which W is CH2and a single bond is in position 2, 3 can be obtained according to reaction scheme 9, in which A has the same value as in reaction scheme 1. Compounds (1) of scheme 9 reaction (see the end of the description) can be obtained according to reaction scheme 6. These same compounds can also be obtained the outcomes of the compounds (2) the transformation of the latter into the ether 4-toluensulfonate acid or ester methanesulfonic acid, or one that can be turned into a derived tiefer (1) by nucleophilic substitution of the thiol. These simple transformations can be carried out by methods known to people skilled in this field. Compounds (2) of the schemes of reactions 9 can be obtained according to reaction scheme 7. Connection (3) from the scheme of reactions 9, in which P= OC(S)-aryl or OC(S)-heteroaryl, or OC(S)O-alkyl, or OC(S)O-alkyl, or OC(S)O-aryl, or OC(S)S-alkyl, can be obtained by the reaction of compounds (2) with a suitable chlorothioformate or chlorothioformate or 1-1'-thiocarbonyl-diimidazole is 4) can be obtained from compounds (1) or (3) simple reactions of elimination with bases. Deputy A in the compounds (6) schema reactions 9 can be converted according to the processes specified in stage 1g, Deputy B, as defined in reaction scheme 1.

Stage 9a.

The Raney-Nickel in a suitable solvent (e.g. isopropanol) at a temperature of from room temperature to 100oC. If A represents the NO2he simultaneously becomes NH2;

hydride teatralova in benzene or other aromatic solvent at 30 - 150oC. Description of other methods, such as Nickel chloride and NaBH4in MeOH or bropirimine complex in triperoxonane acid or dichloromethane in the presence of AlCl3, see J. March, Advanced Organic Chemistry, p. 728, J. Wiley and Sons, New York, 1992 and the references given there. (In the case when A is different from CH=CH-CH3).

Stage 9d.

Hydrogen with a catalyst according to reaction scheme 8, step 8f. If A represents the NO2then it turns into NH2at the same time.

Stage 9c.

The anti-hydride or Tris(trimethylsilyl)silane in the presence of azoisobutyronitrile in a suitable solvent (e.g. toluene) at 80 - 150oC (M. Drescher, Synthesis, 362, 1992, M. Sekine J. Org. Chem. 55, 924, 1990);

silane (for example, Treaty the temperature of reflux distilled in the presence of CF3COOH or BF3(F. M. Mauser, J. Org. Chem., 55, 555, 1990);

triethylchlorosilane, sodium iodide in acetonitrile, and then zinc powder in AcOH and acetonitrile at a temperature from room temperature up to 80oC (T. Morita et al., Synthesis, 32, 1981).

If P is a halogen or O-S-derivative:

recovery agent (for example, cyanoborohydride sodium hexamethylphosphoramide or NaBH4in DMSO), which are selected from those described in J. March, Advanc. Org. Chem., J. Wiley, New York, 1992, Chapter 0-76, 0-77.

Stage 9d.

Hydrogen (1 - 5 ATM) in a suitable solvent (such as EtOH) in the presence of a catalyst (for example, 10% Pd/C at 50 - 78oC) (Sarcevic, Helv. Chim. Acta, 56, 1457, 1973). (If A = NO2simultaneously, it turns into NH2);

Zn and gaseous HCl in Et2O or Ac2O in toluene at 0 - 80oC (Todah, Bull Chem. Soc. Jpn., 45, 264, 1972) (if A is different from the NO2).

Stage 9e.

Zn and aqueous HCl in a suitable solvent (such as EtOH) at 0 - 78oC;

according to the stage 9d above (if A = NO2he simultaneously becomes NH2);

hydrazine, NaOH in ethane-1,2-diole at 200oC (Chemical Abstracts, 74, (1971): 22699) (if A is different from COOR, NO2or other methods listed above in the work of J. March ( 10 reactions (see at the end of the description) specifies ways to produce compounds in which W is a valence bond, and X is oxygen atom or sulfur

Stage 10a.

According to stage 1a, but using R3COCl or (R3CO)2O instead of R3CH2COCl or (R3CH2CO)2O emitting or without the isolation of intermediate phenyl ether;

hexamethylenetetramine in CF3COOH at reflux distilled followed by the addition of aqueous HCl. If A = COOAlk, in such a strongly acidic environment, it can be hydrolyzed to COOH, and then need to re-distillation with a suitable alcohol (for example, using thionyl chloride at the temperature of reflux distilled) before stage 10c;

Stage 10b.

R3COCH(R2)Hal in acetone or methylethyl ketone or dichloromethane or chloroform in the presence of a suitable base, such as K2CO3NEt3or NaH in 20 - 80oC.

Stage 10c.

R2CH(Hal)COOAlk in an aprotic solvent, such as DMF, in the presence of a base, such as K2CO3at 70 - 100oC, followed by hydrolysis of the crude intermediate compounds in a strong base (such as KOH) in proton solvent such as EtOH at reflux distilled, enclosed is lol) and acid catalysis (for example, p-toluensulfonate) at reflux distilled or simple heating at 240oC quinoline;

R2CH2Hal and KOH at reflux distilled EtOH followed by cyclization of the selected intermediate phenyl(thio)ether with sodium methoxide in a boiling mixture of DMF/MeOH. If A is a COOAlk, can be obtained intermediate compound (4) containing A = COOH;

Stage 10d.

Vigorous stirring in a heated pre polyphosphoric acid at 90 - 140oC;

the Lewis acid (e.g., AlCl3) in chlorobenzene at 70 - 90oC. Cyclization of the compounds (3) with R3- Cl, using a Lewis acid (for example, AlCl3) in o-dichlorobenzene at 45oC or using BF3in Et2O at 20 - 25oC result in compounds (4), in which R3- OH, as reported by K. Davies, J. Chem. Soc. P. T., 1, 2624, 1957, if X=S and R2=H.

Stage 10e.

The sodium alcoholate (1 equivalent) in the same alcohol at 0 - 90oC; if A = COOAlk, the corresponding AlkOH can be used as the reaction solvent;

if R2= COOAlk and X - S, compound (4) can be hydrolyzed with a mixture of sulfuric and acetic acids corresponding to R2=COOH (if you have A = COOAlk, he then can the P>C, giving the compound (4) in which R2=H according to J. Cooper et al., J. Chem. Soc. (C), 1971, 3405.

Stage 10f.

R2CH2XH and one equivalent of sodium in EtOH at reflux distilled or with NaHCO3in a mixture of Et : water at 60 - 90oC.

Stage 10g.

If A = COOAlk or NO2there may be used the methods outlined in stage 1g. It should be noted that the recovery group NO2in NH2group at the catalytic hydrogenation may cause simultaneous hydrogenation of the double bond in position 2, 3; this was reported in the works of S. L. Meisel et al., Heterocyclic Compounds, Ed. Interscience Publ. : "Compounds with Condensed Thiophene Rings", p. 34(1954) and M. Ahmed, Ed. Wiley Interscience: "Benzofurans", p. 56 (1974).

If A = NO2and R2= COAr, the restoration carried out using hydrogen in the presence of Pd/C catalyst, gives compounds (5), in which B-NH2and R2= CH2Ar; this is reported in WO 86/07056;

If A = CH3and R2, R3, R6other than CH3or R2no CH3group, the compounds may be converted respectively to:

A = CH2Br interaction with N-bromosuccinimide in CCl4when using 2,2'-azobisisobutyronitrile or benzoyl peroxide as catalysts in hloroform with subsequent acid hydrolysis of the salt in boiling AcOH or interaction of the compounds, containing A = CH3with bichromate of tetrabutylammonium at reflux distilled in chloroform according to Valeri et al. , Arzneim. Forsch., 40, 122 (1990);

A = COOH in the oxidation of the above compounds (A = CHO) with silver oxide in a mixture of water proton solvent (such as EtOH-DMF) at 0 - 70oC according to H. R. Rodrigues et al., Tetrahedron, 24, 6587, 1968) or by using KMnO4in t-butanol in the presence of aqueous solution of NaH2PO4at 70 - 75oC according to S. Maruzama et al., Tetrahedron Letters, 27, 4537 (1986).

Compounds (4) the above reactions 10 containing R3= C6H5or t-butyl, R2= H and X = O, can be converted into the corresponding intermediate compounds containing R2= C6H5or t-butyl and R3= H interaction with polyphosphoric acid at 132oC according to Davies et al., J. Chem. Soc., 1958, 822.

If X is an imino or alkylamino, and W the same meaning as above, with the exception of valence bonds, simple starting materials can be obtained according to the following reaction scheme 11 (see below):

Stage 11a.

EtOC(R2)= C(COOEt)2at 80 - 140oC without solvent and polar solvent (for example, sophonow acid in a chlorinated solvent (for example, chloroform or dichloromethane) or an aprotic solvent (e.g. benzene) at reflux distilled in azeotropic conditions.

Stage 11c.

Heating at Ph2O in the presence of p-toluensulfonate acid, or phosphoric acid, or ZnO as catalysts at 245 - 255oC according to Hung, Teljies 6251 (Chemical Abstracts, 79, 92026v, 1973):

heating in a high boiling solvent (e.g., Ph2O) with subsequent hydrolysis of the unselected compounds (4) (R3= COOEt) a strong acid (such as HCl) in proton solvent (e.g. acetic acid) at reflux distilled to obtain compound (4) in which R3=COOH. Previously allocated acid can be dekarboksilirovanie when heated in a high boiling solvent (e.g., Ph2O), giving compound (4) in which R3= H according to R. Albrecht et al., Ber., 105, 3118 (1972).

Stage 11d.

Heating in a high boiling solvent (e.g., Ph2O) at 255oC;

if R = Alk, connections (4) is obtained directly from compounds (1) without isolating the compound (3) by condensation with R2COCH(R3)COOAlk in polyphosphoric acid at 90 - 150oC according to F. Piozzi et al., Gazz. Chim. It., 100, 678, 1970.

Stage 11e.

and processing FeCl3at reflux distilled according to W. A. Denny et al., J. Med. Chem., 32, 396, 1989;

if A = COOAlk, connections (4) it is necessary to hydrolyze to the corresponding A-COOH before implementation stage 11e,

if A = NO2I receive the intermediate compounds with A = NH2;

Stage 11f.

R2CH= CHCHO and arsenic acid in strongly acidic medium (for example, concentrated H2SO4and water at 105 - 115oC according to EP 0206802.

If A = COOAlk, connections (1) it is necessary to hydrolyze to the corresponding A = COOH before implementation stage f. All connections (1), we have R = H, and all of the obtained compound (5), we have R3= H.

Stage 11g.

R2CH(Hal)-CH(R3)COOH in proton solvent (e.g. water) in the presence of strong bases NaOH at 100 - 125oC followed by cyclization of the selected compounds beta-anilinophenol acids using pre-warmed polyphosphoric acid at 120 - 125oC or with phosphorus pentoxide in a high-boiling aprotic solvent (e.g. xylene) at 120 - 140oC. In some cases it is useful to proceed from compounds (1), in which R represents tosyl or other suitable protective group; poluchenii acid (for example, HCl) in proton solvent (e.g., AcOH) at reflux distilled.

If A = COOAlk, I get the connection (6) where A = COOH.

Stage 11g.

R2CHO and ethylene in AcOH and HCl at 25 - 30oC according to K. D. Hess, Liebig., Ann. Chem., 741, 117 (1970). If in the compounds (1) R = H, you get the raw materials (7) where R=R3= H;

the epichlorohydrin followed by cyclization of the selected derivatives anilinophenol at reflux distilled N, N-diethylaniline or o-dichlorobenzene in the presence of a proton acceptor (for example, NEt3according to the work of S. D. Boyd et al., J. Org. Chem., 30, 2801(1965). In this case, the receive connection (7) where R=R2=H and R3= OH.

Stage 11i.

Hydrogenation in the presence of a catalyst (e.g. platinum oxide) in proton solvent (such as EtOH) at 20 - 30oC and 2 - 4 ATM according to G. M. Coppola,. J. Heter. Chem., 15, 645, 1978.

If A = NO2then get a connection (7) where A = NH2.

Thus obtained compounds(4), (6), (7) can be converted into the corresponding derivatives in which A = COOH or NH2according to the methods of scheme of reactions 1, step 1g.

Synthesis of simple compounds (7) of scheme 11 reactions, in which R = H and A = COOH can be aswell chloride in a polar solvent (for example, THF) at reflux distilled with subsequent internal acylation according to the Friedel - Crafts crude chlorosilane Lewis acid (e.g., AlCl3in a non-polar solvent (e.g., CS2) at reflux distilled according to EP 0402859.

Stage 12b

30 - 35% water (H2O2and a strong base (such as NaOH) in a polar solvent (e.g. water) at 20 - 30oC followed by the addition of a strong acid (such as HCl), as described in EP 0402859.

The scheme of reactions 13 and 14 (see below) leads to a simple starting materials, in which X represents aminogroup, and W is a valence bond. In both these schemes, A has the same meaning as in reaction scheme 1.

Stage 13a.

ClCH2(Cl)= CH2in the presence of K2CO3at 40 - 80oC according to L. Purdie, J. Chem. Soc., (C) 1970, 1126.

Stage 13b.

R2COHal in pyridine or in a chlorinated solvent (e.g. dichloromethane) in the presence of a proton acceptor (for example, NEt3) at 20 - 100oC or in a polar solvent (e.g. acetone) in the presence of K2CO3at 20 - 80oC.

Stage 13c.

BF3in MeOH at 130 - 155oC;
3
.

Stage 13d.

R2COCH(OAlk)2in nonpolar solvent (such as toluene) in the presence of iodine as a catalyst at reflux distilled in azeotropic conditions with the subsequent restoration of the selected (or unselected) aminosidine using NaBH4in polar solvent (such as MeOH) in the presence as catalyst NaOH at reflux distilled. If A = COOAlk, it will be hydrolyzed to COOH.

Stage 13e.

Amide sodium in a high-boiling solvent (e.g. N,N-diethylaniline) at 220 - 250oC according to F. Piozzi et al., Gazz. Chim. It., 93, 1382, 1963;

t-piperonyl calcium in polar solvent (such as DMF) at 20 - 100oC according to EP 0042298.

Stage 13f.

BF3in apolar solvent (e.g. benzene) at 5 - 10oC.

Stage 13g.

Zn or Fe dust in an acidic environment (e.g., AcOH) and water at 70 - 100oC. If A = NO2it will be restored to the NH2.

Stage 13h.

Thionyl chloride at reflux distilled. The resulting acylchlorides produce, and they interact with sodium azide in acidic medium (for example, AcOH) at 10 - 20oC, on subsequent heating at 50 - 70oC.

m by addition of an aqueous ZnCl2when 5 - 10oC and interaction of selected salts of the page with CH2=C(R2)COOH in polar solvent (e.g. acetone) in the presence of a copper salt (e.g., CuCl2) at 25 - 30oC. Examples of stages 13g, 13h, 13i are given in the work of A. Allais et al., Eur. J. Med. Chem., 10, 187, 1975.

Stage 13j.

R2CH2NO2in polar solvent (such as EtOH) in the presence of a base (e.g. n-butylamine) and catalytic amounts of acid (e.g., AcOH) at reflux distilled.

Thus obtained compound (5) can be converted into the corresponding derivatives containing A=COOH or NH2according to the methods outlined in reaction scheme 1, step 1g.

With regard to the scheme of reactions 14, it is intended for compounds (4), with R3= H, which correspond to the compounds (5) of the schemes of reactions 13.

Stage 14a.

NaNO2in aqueous acidic medium (e.g., HCl) at a temperature of from -5 to 5oC;

soliditet in polar solvent (such as EtOH) at 5 - 10oC.

Stage 14b.

An aqueous solution of SO2at 0 to 10oC according Pfannstiel et al., Ber. 75, 1096, 1942;

triphenylphosphine and heated highlighted postnasal salt in water SUB>3)Hal in a high-boiling solvent (e.g. N,N-diethylaniline) at 160 -0 180oC or simply by heating without solvent at 180oC;

R3COCH(R2)Hal in polar solvent (e.g. acetone) in the presence of a suitable proton acceptor (for example, K2CO3) at reflux distilled with subsequent cyclization of the selected intermediate beta-anilinomethyl using svezheraspilennaya ZnCl2in proton solvent (such as EtOH) at reflux distilled;

R2CH(Hal)CN in the presence of BCl3and Lewis acid (e.g., TiCl4in apolar solvent (e.g. benzene) at reflux distilled followed by cyclization of 2-amino-alpha-galazutdinov using a suitable reductive agent (e.g., NaBH4in the polar environment (for example, dioxane-water) at reflux distilled according to T. Sagusawa et al., J. Org. Chem., 44, 578, 1979. The above-described method receive connections (4) in which R3= H;

R2COCH(R3)Hal (0.5 equivalent) in a polar solvent (such as MeOH) at reflux distilled with subsequent cyclization of the selected Schiff bases strong acid (for example, CF3COOH) at 20 - 30oC.

Stage 14d.

R2COCH2R3when on the processes selected by cyclization of hydrazones with polyphosphoric acid at 100 130oC or followed by heating with ethylene glycol and aqueous formic acid or ethanol formic acid;

the cyclization can also be accomplished by heating in ethanolic HCl at reflux distilled or in a mixture of AcOH/HCl at reflux distilled, or phosphoric acid at 95 - 105oC, or by simply heating with anhydrous ZnCl2at 100 220oC. If A = COOAlk, can be obtained compound (4) in which A = COOH.

Stage 14e.

Bropirimine complex at 0 - 30oC followed by the addition of protonation agent (e.g., HCl);

tin or zinc and aqueous HCl at 50 - 100oC;

NaBH4in the presence of a Lewis acid (for example, AlCl3) in pyridine at 0 - 30oC or in the presence of salt type of cobalt chloride or chloride of zinc;

biocenotic sodium in AcOH at 20 - 80oC;

hydrogen in the presence of a catalyst (such as Pt) in a polar solvent (e.g., EtOH) at 20 - 80oC.

Other basic methods described in the paper by Houlihan, Heterocyclic Compounds, part 1, Ed. Wiley Interscience: "Indols", p. 462 (1972). If A = NO2then the compound (4) can be restored to the corresponding compounds (5) where A = NH2.

Stage 14f.

NaH and RHal in anhydrous the (for example, THF) at low temperature (-70oC).

Compound (4) having other reactive groups such as NH2or OH, must be protected using suitable protective group which can be selectively destroyed using methods of removing the protection.

Stage 14g.

RHal in the presence of carbonates of alkali metals (e.g. potassium carbonate) according to Houlihan, Heterocyclic Compounds, part 2, Ed. Wiley Interscience: "Indoles", p. 90 (1972) and the links in it;

compound (5) having other reactive groups such as NH2or OH, must be protected as outlined above.

Stage 14h.

Tetrachloro-(1,4-benzoquinone in a polar solvent (for example, onomatology ether of ethylene glycol) at reflux distilled;

chloride copper (II) in pyridine at reflux distilled according Kikugawa et al., J. Heter. Chem., 16, 1325, 1979.

Compounds (6), in which R2and R3other than H, can be restored to their respective source materials (7) with lithium aluminum hydride according to H. C. Printy et al., J. Am. Chem. Soc., 71, 3206, 1949.

Connection (4) from the scheme of reactions 14, with R2=H and R3=OH can be produced from compound (7) scheme of reactions 11, in which R=R2=H and R3the m EtOH at reflux distilled according to S. D. Boyd et al., J. Org. Chem., 30, 2801, 1965.

Raw materials(4), (5), (6) and (7) can be transformed into the corresponding A = COOH or NH2according to the method of scheme of reactions 1, step 1g, and in the alternative end products. If there is NH and possibly its effect on the subsequent reaction, it can be protected as described in T. W. Green, Protective Groups in Organic Synthesis, Wiley Interscience, 1981. Or non-reactive group (for example, NO2) can be transformed into the reactive group (for example, NH2) at the final stage of the synthesis.

Raw materials, in which W is a valence bond, X represents aminogroup, and the substituent in position 7 represents carboxymethyl group can be obtained according to reaction scheme 15 (see the end of the description).

Stage 15a.

Hydrogen in the presence of 10% Pd/C as catalyst and 45 pounds of water containing one equivalent of NaOH, followed by diazotization with sodium nitrite in HCl at 0 - 5oC and tin chloride (II). The cyclization is carried out upon acidification of the salt of tin using H2S and ends at reflux distilled xylene, see H. E. Baumgarten et al., J. Am. Chem. Soc., 82, 3977, 1960.

Stage 15b.

R3CH2COR2the ACLs work W. J. Welstead et al., J. Med. Chem., 22, 1074 (1979) when R2= CH2and R3=C6H5outlining also the stage 15c and 15d.

Stage 15c.

The lower alkanol (e.g., MeOH, EtOH) at reflux distilled in the presence of a current of hydrogen chloride.

Stage 15d.

A strong base (such as KOH) in a polar solvent (e.g. water) at reflux distilled.

Receiving a simple starting materials, in which R3is hydroxyalkyl, and/or the corresponding esters can be done or by reacting compounds (3) of the schemes of reactions 1, compounds (2), (4) or (5) of the schemes of reactions 2, compounds (4) of the schemes of reactions 6, 10, 11, and 15, compounds (5) of the schemes of reactions 13 and compounds (4) and (6) of the schemes of reactions 14, in which R3= H, CH3according to the reaction scheme 16 (see the end of the description), in which A and B have the same values as in the reaction scheme 1, R4represents an alkyl or arakalgudu, and R5represents H or alkyl group.

Stage 16a.

R3= H, W = CO, CS (and no activated phenyl ring):

formaldehyde and HCl in water, EtOH or AcOH at 50 - 100oC;

chloromethyl methyl ether and fuming sulfuric acid at 50 - 70o<ü; in the molecule there is no methyl groups:

N-bromosuccinimide in the presence of benzoyl peroxide or 2,2'-azobisisobutyronitrile in CCl4at 50 - 80oC.

Stage 16b.

R3= H, W is a chemical bond, X =O, S, NH or N = Alk and other rings of the molecule no donor groups:

the phosphorus oxychloride and DMF at 50 - 140oC or other reagents (see Jutz, Adv. Org. Chem., 9, 225, 1976);

R3= CH3W represents a chemical bond, X = O, S, NH or N = Alk and there were no groups CH3;

irradiation with a mercury lamp high pressure proton solvent (e.g., AcOH) at 20 - 100oC according flask et al., Tetrahedron, 23, 603, 1973.

Stage 16c.

Sodium acetate or potassium in an aprotic solvent (such as acetone, DMF) at 40 - 120oC.

Stage 16d.

R5in the compounds (5) is H:

regenerative hydride (e.g., NaBH4) in a polar solvent (such as MeOH or EtOH, or dioxane) at 0 - 80oC;

R5in the compounds (5) represents alkyl:

magnesium allylbromide in aprotic solvents (for example, Et2O, THF) at 0 - 60oC.

Stage 16e.

what if A = COOAlk, it can be hydrolyzed to COOH.)

Stage 16f.

The same methods that are described in the stage 1 scheme of reactions 1, but for compounds (5) is the oxidation of CH=CHCH3to COOH.

Stage 16g.

A strong base (such as NaH) in reagent R4-L (where L represents a halogen atom or tosyloxy) in anhydrous aprotic solvents such as DMF or THF) at 20 - 140oC.

Stage 16h.

R4OH and the basis (e.g., Na, NaH) in excess of R4OH, or in an aprotic solvent (such as DMF or THF) at 20 - 140oC.

Simple connection (6) containing a hydroxyalkyl group in position 3 and thus obtained can interact in the same way, or can give derivatives hydroxymethylene group with known reagents and methods, so that the specified group is not a barrier to further reaction stages, which are necessary to obtain the compounds of formula I that contain protected hydroxyalkyl group of type R3. Protected final connection eventually become using the methods of removing protection in the compounds of formula I in which R3represents a hydroxyalkyl group.

Method 1.

Interaction with chloroformate, isocyanate or isothiocyanato, chloride or bromide, carbonyl or other derivative activated acid (e.g., anhydride) in a suitable solvent (for example, chlorinated solvent, DMF, THF, dioxane, acetonitrile, pyridine) in the presence of a base (for example, NEt3, pyridine, 4-dimethylaminopyridine, NaOH, potassium carbonate or 1,10-diazabicyclo or others not specifically mentioned) or in the absence of base at -20/100oC;

interaction with the carboxylic acid in the solvents mentioned above, in the presence of a condensing agent type N,N'-carbonyldiimidazole, carbodiimides or other agents known to people skilled in this field;

interaction with dialkyl - or diarylphosphino or dialkylanilines in the same conditions that were described above (see below for an example 114 and S. O. Thorberg et al., J. Med. Chem., 30, 2008, 1987).

Method 2.

Derivative prodrugs "sour" NH-group, as discussed above, can be synthesized from compounds of formula I to obtain N-hydroxy(replaced the s derivatives.

The intermediate N-hydroxy(substituted)methyl derivative can be selected or can respond directly, giving the target compound.

N-hydroxy(substituted)methyl derivative type Ny-CH(R1)OH, where R1= H or CCl3can be obtained by the interaction of suitable compounds of formula 1 with formaldehyde or CCl3CHO, as described in the work of H. E. Zaugg, Organic Reactions, 14, CHapter 2, 52; J. Wiley and Sons, New York, 1965, or J. P. Chup, J. Org. Chem., 28, 2592, 1965.

If R1represents phenyl, these compounds can be synthesized by the reaction of benzaldehyde and a cyclic amine (e.g., research) in MeOH or in a mixture of dichloromethane:MeOH 1:1 at a temperature of from 0oC to the temperature of reflux distilled and hydrolysis of the intermediate of 0.1 N. HCl at pH 4 (O. Jacobseen, Annalen, 157, 243, 1884; Y. Bundgaard et al., Int. J. Pharm., 22, 45, 1984).

All of the above ways of reactions and their stage should be considered as examples, they do not limit the ability of the present invention. People skilled in this field, know that these chemical transformations are carried out in polyfunctional substrates and that the reagents can actually snag, interacting with the group in the amino group, as required, however, and isolated double bonds can gidrirovaniya and can stand different halogen atoms; lithium aluminum hydride can restore conjugated ketones to alkanes, as required (for example, stage 7c in reaction scheme 7), but he can restore COOAlk group to CH2OH or NO2group to the-N=N -, etc. Undesirable side reactions can be avoided or minimized by choosing the appropriate conditions or the use of alternative reagents or different ways of synthesis. If this "alternative" way to give negative results, we obtain the undesirable intermediate compounds must be converted into the desired compounds using methods known to a skilled in this area people.

The production of intermediate compounds.

8-(3-Bromopropionyl)-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran (intermediate compound (I).

30 g of 1,3-dibromopropane added dropwise to a suspension of 30 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate sodium in 150 ml of dimethylformamide and 35 ml of water at room temperature. The reaction mixture was shaken at room temperature for 5 days. Add 100 ml of water and continue is the use of thin-layer chromatography on silica gel, elwira a mixture of chloroform:ethyl acetate in a ratio of 95: 5. The collected fractions evaporated in vacuum to dryness, and the residue will recrystallized from ethanol; this gives 27.7 g of target compound with a melting point 114 - 115oC.

Benzopyran-carboxylate salt used in the previous synthesis, was obtained by dissolving 104 g of the corresponding acid in 560 ml of hot methanol and add 280 ml of an aqueous solution containing 31 g of acid sodium carbonate. To this solution was added to 850 ml of acetone to precipitate the target salt, which was collected during the filtration with suction (62 g, melting point 280oC). The corresponding acid was obtained according to Da Re, P et al., J. Med. Pharm. Chem., 2, 263, 1960.

8-Hydroxymethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound II).

467 ml 1,48 N. solution of sodium borohydride in anhydrous dimethylformamide was added after 30 min with shaking at room temperature to a solution of 100 g of 3-methyl-4-oxo-2-phenyl-4H-benzopyran-8-carbonyl chloride in 1 l of anhydrous dimethylformamide. The reaction mixture was shaken for 2.5 h at room temperature; 88 ml of 2 N. HCl was added while maintaining a temperature in the range of 0 to 5ooC.

E-8-(2-Carboxyvinyl)- 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound III).

A mixture containing 7.92 g 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared according to K. Uneyama et al., Bull. Chem. Soc. Jap., 58, 2361, 1985), 3.75 g of malonic acid and 0.46 ml of piperidine in 15 ml of anhydrous pyridine was dissolved in 100oC for 3 hours After cooling to 20 to 25oC the reaction mixture was poured into a mixture of 90 g of crushed ice and 33 ml of HCl (d = 1.18). The resulting precipitate was collected with filtration with suction, washed with water and crystallized twice from 95% ethanol; the result was obtained 5.5 g of compound indicated in the title, with a melting point 226 - 229oC.

E-8-(2-Chlorocarbonyl)-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran (intermediate compound IV).

A solution of 9.2 g of the intermediate compound III and 7.8 g of thionyl chloride in 75 ml of toluene was subjected to reflux distilled for 3 hours After cooling to 20 to 25oC the resulting Chris is 8 g connection specified in the header, with a melting point after recrystallization from toluene 196 - 198oC.

8-Acetyl-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran (intermediate compound (V).

1.17 g of magnesium turnings, 7.4 ml of anhydrous ethanol and 0.2 ml of anhydrous carbon tetrachloride was placed in a round bottom flask under a stream of nitrogen. When the temperature began to rise, was added 7.5 ml of anhydrous chlorobenzene followed by a slow precapitalism (25 min) solution of 5.28 ml of anhydrous diethylmalonate and 375 ml of anhydrous chlorobenzene in 16 ml of anhydrous ethanol. The reaction flask was heated to 75oC for 2 h, then was cooled to 25oC and slowly added a solution of 8.8 g of 3-methyl-4-oxo-2-phenyl-4H-benzopyran-8-carbonyl chloride in 88 ml of anhydrous chlorobenzene, the temperature does not exceed 35oC. Then the reaction mixture was shaken for 2 h at 35oC, and then cooled to 0oC. was Added 13 ml of water and 1.9 ml of sulfuric acid (d = 1.84). The resulting solution decantation from insoluble inorganic substances and shook in a vacuum.

The resulting crude allalone was subjected to reflux distilled for 6 h with 10.4 ml of acetic acid, 7 ml of water and 1.3 ml of sulfuric acid (d = 1.84). P is dnim sodium carbonate. During crystallization from 90% ethanol was obtained 6.5 g of compound indicated in the title, with a melting point 159 - 161oC.

8-Bromoacetyl-3-methyl-4-oxo-2-phenyl-4H-benzopyran (intermediate compound VI).

After 2 hours at 20 - 25oC to a solution of 19.5 mg of the intermediate V in 700 ml of chloroform, add a solution of 11.2 g bromine in 250 ml of chloroform. After shaking for 1 h at 20 - 25oC the solution was washed with 400 ml of 2 N. aqueous sodium hydroxide solution and then again with water, dried with anhydrous sodium sulfate and evaporated in vacuum. The crude product is treated with diethyl ether, collected by filtration with suction and crystallized from acetone, resulting in the 16 g of compound indicated in the title and having a melting point 134 - 135oC.

8-(2-Hydrooximethylcarbamil)-3-methyl-4-oxo-2-phenyl-4H-benzopyran (intermediate compound (VII).

The specified connection receive as an intermediate compound XXXVI, using 2-aminoethanol instead of 3 aminoethanol. The melting point of 206 to 208oC.

3-Methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-sulfonyl chloride (intermediate compound (VIII).

A solution of 4.55 g of sodium nitrite in 12 ml of water would is described in the work of Da Re, p et al., 11. Farmaco (Ed. Sci), Il, 670, 1956) in 150 ml of HCl (d = 4.18) under - 5oC. Stirring was continued at 0oC for 30 min After 10 min at a temperature of from -5 to 0oC the solution was poured into 120 ml of 30% solution of sulfur dioxide in acetic acid containing 1.53 g of dihydrate of copper chloride and 13 ml of water. To this mixture was added 300 ml of ice water after 1 h at 0oC and after another 1 h at 20 - 25oC. the Resulting precipitate was collected by filtration with suction, washed with water and dried in a desiccator over sodium hydroxide to a constant weight. Obtained 18 g of the crude product indicated in the title, with a melting point of 165 - 170oC and ready for use without further purification.

8-(3-Chloropropoxy)-3-methyl-4-oxo-2-phenyl-H-1-benzopyran (intermediate compound (IX).

This connection receive as an intermediate compound XI, but using 1-bromo-3-chloropropane instead of 1-bromo-2-chlorethane; after washing with a mixture of petroleum ether: diethyl ether in the ratio 7:3 melting point was 98 - 102oC.

8-Acrylamide-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound X).

A solution of 1.75 ml of chloride of acryloyl in 15 ml of anhydrous tetrahydrofuran was added in drops to Stakhiv the Ana at -10oC. After shaking at 0oC for 1 h and at room temperature for the same time, the reaction mixture was poured into water and filtered when easymoney. The filtrate was washed with water. Drying gave 5.5 g of compound indicated in the title, with a melting point 229 - 230oC.

8-(2-Chloroethoxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound (XI).

A mixture of 7.52 g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described Da Re, P et al., Ann.Chim., 1962, p. 506), 6.22 g of anhydrous potassium carbonate and 25.5 ml of 1-bromo-2-chlorethane in 70 ml of dimethylformamide was shaken for 25 h at 60oC. the Mixture was cooled to 20 to 25oC and poured into 600 ml of water. The organic solution obtained by extraction with dichloromethane, washed with an aqueous solution of sodium chloride and dried on anhydrous sodium sulfate. The solvent and excess 1-bromo-2-chlorethane evaporated in vacuum to obtain 8.8 g of compound indicated in the title, with after crystallization from chloroform: hexane melting point 141 - 142oC.

8-(2-Azidoethoxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound XII).

A mixture of 15.2 g of intermediate compounds XI and 6.24 what I'm up to 20 25oC the reaction mixture was poured into 1.5 l of water and was extracted with dichloromethane. The organic solution was washed with an aqueous solution of sodium chloride and dried on anhydrous sodium sulfate. The solvents were evaporated in vacuum. The residue was transferred into water, collected by filtration with suction and dried; this gave 14 g of compound indicated in the title, with a melting point 119 - 120oC.

8-[N-(2-Hydroxyethyl)-N-methyl-carbarnoyl] -3-methyl-4-oxo-phenyl-4H - 1-benzopyran (intermediate compound XIII).

A solution of 1.6 ml of 2-methylamino-ethanol in 10 ml of water was added dropwise in 5 min to a suspension of 6 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-benzopyran and 1.52 g of sodium carbonate in 60 ml of acetone. After shaking for 2.5 hours at 20 - 25oC the solvent was removed in vacuo, and the residue was transferred into 150 ml of acetone. The mixture was subjected to reflux distilled for 15 min, and then filtered. The solvent is evaporated from the filtrate, and the residue was dissolved in 20 ml of dimethylformamide, and treated with 14 ml of a 1.4% solution of sodium carbonate, were shaken for 30 min at 20 - 25oC and was diluted by adding 150 ml of water. The mixture was extracted with chloroform, the organic layer was washed with 0.5 N. HCl and then with water. The solution missisauga ether and shaken for 2 h at 20 25oC. the solids were collected by filtration and was led from ethyl acetate to obtain 4.97 g of compound indicated in the title, with a melting point 128 - 130oC.

8-(2-Chlorocinnamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound (XIV).

The specified connection was obtained in the same manner that the intermediate compound XXXVII, only intermediate compound VII was used instead of compound XXXVI and the reaction was conducted at room temperature. Melting point 181 - 182oC (ethyl acetate).

8-(N-Methyl-2-chloro-ethylcarbamate)-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran (intermediate compound XV).

A solution of 1.1 ml of thionyl chloride in 2 ml of dichloromethane was added to a solution of 3.37 g of intermediate compound XIII in 20 ml of dichloromethane and the mixture was shaken for 4 h at room temperature. Upon removal of solvent received the oil, which moved in diethyl ether. The connection specified in the title, was precipitated in the form of white solids collected for use by filtering without further purification. Melting point (118) 126 - 128oC (diethyl ether).

8-(4-Bromobutoxy)-3-methyl-4-oxo-2-phenyl-4H-1-bezoplatnogo potassium carbonate and 43.6 g of dimethylformamide was dissolved in 75oC for 2 h the Mixture was cooled to 20 to 25oC, was poured into 100 ml of water and was extracted with chloroform. The organic layer was washed with an aqueous solution of sodium chloride and dried on anhydrous sodium sulfate. The solvents and excess 1,4-dibromobutane evaporated in vacuum. The residue was washed with 55 ml of a mixture of petroleum ether : diethyl ether 7:4 and collected during the filtration with suction to obtain 5.6 g of compound indicated in the title, with a melting point of 91 - 92oC.

8-(5-Bromopentane)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound (XVII).

This compound was obtained by the method described for intermediate compounds XVI, but instead of 1,4-dibromobutane used the 1.5-dibromethane and the crude product was purified by chromatography on columns on silica gel (elwira a mixture of dichloromethane : ethyl acetate 99:1). The melting temperature after washing with a mixture of petroleum ether : diethyl ether 30:4 was 75 - 76oC.

8-(2-Chloridometer)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound XVIII).

6 ml of thionyl chloride in 18 ml of chloroform was added at 0oC to shake a solution of 23 g of intermediate compounds XXII and 11 ml tritium to room temperature it was poured into water. The organic layer was separated, washed with sodium chloride solution, dried on anhydrous sodium sulfate and evaporated to dryness in vacuum. Yield: 24 g of compound indicated in the title. A sample, crystallized from ethanol, had a melting point of 102 - 103oC.

8-Chloromethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound XIX).

53.4 g of the intermediate compound (II) and 38.8 ml of anhydrous triethylamine were dissolved in 440 ml of chloroform. In this solution at temperatures from -10 to -2oC dropwise added a solution of 19.8 ml of thionyl chloride in 80 ml of anhydrous chloroform. The reaction mixture was shaken at room temperature for 4 h, and then diluted with 400 ml of water. The aqueous phase was extracted with chloroform, and the extracts added to CHLOROFORMATES phase. A solution of chloroform was washed with salt solution, dried on anhydrous sodium sulfate and evaporated in vacuum to dryness. Yield: 56 g of compound indicated in the title, by recrystallization from ethanol to its melting point was 112 - 113oC.

8-Methylaminomethyl-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran (intermediate compound XX).

A solution of 15.1 g of anhydrous zinc chloride and 14.5 g of cyanoborohydride nutrientpoor, 60 g of methylamine hydrochloride and 125 ml of triethylamine in 600 ml of anhydrous ethanol; the addition was carried out at 0oC. After shaking for 5 h at 20 - 25oC the solvent is evaporated in vacuo, and the residue was transferred into 200 ml of water and collected by filtration with suction. The crude product was dissolved in aqueous acetic acid, washed with ethyl acetate and precipitated by the addition of a cold solution of 6 n sodium hydroxide. Received 49 g of compound indicated in the title; its melting point after crystallization from 75% ethanol was 97 - 99oC

8-(2-Chloroethylthiomethyl)-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran (intermediate compound XXI).

A solution of 37 g of intermediate compounds XIX and 10.5 g of thiourea in ethanol was subjected to reflux distilled for 1 h, the Reaction mixture was cooled to room temperature and 42 g of 8-amylinomimetic-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran secretaryshall spontaneously. A sample, recrystallized from ethanol, had a melting point of 233 - 235oC. 48 ml of 35% aqueous sodium hydroxide solution was added to vigorously shake a suspension of 35 g of the previously obtained compound and 1.05 g of benzyltriethylammonium chloride in 440 ml of 1,2-dichloroethane. The mixture strjahivaj to the organic layer, which was washed with sodium chloride solution, dried on anhydrous sodium sulfate and evaporated to dryness in a vacuum. The residue was led from methanol; received 22 g of compound indicated in the title, with a melting point of 82 83oC.

8-(2-Hydroxyethoxymethyl)-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran (intermediate compound XXII).

Was prepared solution of 2.5 g of intermediate compound XIX in 25 ml of xylene and 3 ml of dioxane. 0.15 g of sodium was dissolved in a 3.10 ml anhydrous ethylene glycol and this solution was added dropwise to a solution of intermediate compound XIX at room temperature. After reflux distilled for 5.5 h, the reaction mixture was cooled to room temperature and poured into 150 ml of water. Carried out the extraction with dichloromethane, and the extract was washed with sodium chloride solution, dried on anhydrous sodium sulfate and evaporated to dryness in a vacuum. The solid residue was led from ethanol, thus obtaining 2.1 g of compound indicated in the title, having a melting point 132 - 133oC.

8 Trifurcated-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran (intermediate compound XXIII).

A solution of 9.5 ml triperoxonane anhydride in 20 ml of anhydrous who methyl-4-oxo-2 - phenyl-1H-1-benzopyran in 50 ml of anhydrous dichloromethane. The reaction mixture was shaken for 2 hours at 20 - 25oC, and then poured on crushed ice. The organic solution obtained by extraction with dichloromethane, washed with cold 5% sodium bicarbonate solution, and then dried on anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was led from ethanol to obtain 5.2 g of compound indicated in the title and having a melting point 175 - 176oC.

8-Aminomethyl-3-methyl-4-2-phenyl-4H-1-benzopyran (intermediate compound XXIV).

A mixture of 21 g of intermediate compound XXIX and 19 g of triphenylphosphine in 160 ml of tetrahydrofuran was shaken at room temperature for 8 hours Thin layer chromatography indicated the disappearance of the intermediate XXIX. Was added 3 ml of water and shaking was continued for another 24 h the Solvent was removed with rotary evaporator, and the residue was dissolved in water. The aqueous solution was washed with ethyl acetate, making the solution basic with 37% solution of sodium hydroxide, and then filtered on a Buechner funnel. The filtrate was washed with water and dried to obtain 18 g of compound indicated in the title. Hydrochloride, recrystallized from ethanol, had Tampere connection XXV).

41.6 ml of aqueous 30% hydrogen peroxide was added dropwise over 20 min to a solution of 26.2 g of intermediate compound XXI in 300 ml of glacial acetic acid at 40oC. the Mixture was heated to 60oC, shaking at this temperature for 4.5 h, cooled to room temperature and poured into 60 ml of water. When filtering on a Buechner funnel was obtained filtrate, which was washed with water and dried. The result was obtained by 29.4 g of compound indicated in the title. The sample was led from ethanol, melting point was $ 159 - 161oC.

8-(2-Chloroethylthiomethyl)-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran (intermediate compound XXVI).

36 ml of aqueous 30% hydrogen peroxide was quickly added dropwise to a solution of 12 g of intermediate compound XXI in 84 ml of glacial acetic acid at 10oC. the Reaction mixture was shaken for 4 h at room temperature, and then poured into 220 ml of water. The connection specified in the title, were collected during the filtration with suction, washed with water and dried. Yield 12.4 g, melting point 142 - 145oC (methanol).

8-[N-Methyl-N-(2-chloroethyl)-aminomethyl] -3-methyl-4-oxo-2-phenyl - 4H-1-benzopyran (intermediate compound XXVII).

oC. Then the reaction mixture was poured into 600 ml of water and was extracted with dichloromethane. The organic layer was washed with water, dried on anhydrous sodium sulfate and acidified ethanolic hydrogen chloride. The solvent and excess 1-bromo-2-chlorethane was distilled in vacuum at 70 - 80oC. the Residue was placed in a cold 1 N. aqueous sodium hydroxide solution and was extracted with dichloromethane. The organic layer was washed with water, dried on anhydrous sodium sulfate and evaporated to dryness in vacuum at 25 - 30oC. the Crude product is indicated in the title, was purified by thin-layer chromatography on silica gel, elwira a mixture of ethyl acetate : petroleum ether 7 : 3. There was obtained 18 g of compound indicated in the title, with a melting point after crystallization from ethanol 118 - 120oC.

1-(2-Hydroxy-2-methylpropyl)-4-(2-methoxyphenyl)-piperazine (intermediate compound XXVIII).

A mixture of 7 g of 1-(2-methoxyphenyl)piperazine, 7.33 g of anhydrous potassium carbonate, 1.75 g of potassium iodide and 5.6 ml of 1-chloro-2-methyl-2-propanol was shaken for 90 min at 70oC and then for 6 h at 90oC. the Reaction mixture was poured into a mixture of ice water and was extracted with ethyl acetate. The organic layer was washed water RA the config in the title, was obtained in the form of oil and identified as its dihydrochloride, crystallized from ethanol and melted at 225 - 227oC.

8-Azidomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound XXIX).

A mixture of 22.8 g of intermediate compound XIX and 6.8 g of sodium azide in 110 ml of dimethylformamide was shaken for 3 h at 100oC. After cooling to room temperature, to the reaction mixture was added 130 ml of water and 88 ml of ethanol. After 1 h the crystals were collected by vacuum filtration, washed with water and dried. Yield: 22 g of the product specified in the title. A sample, recrystallized from ethanol, had a melting point of 132 - 134oC.

8-[N-(2-Hydroxyethyl)-aminomethyl] -3-methyl-4-oxo-2-phenyl - 4H-1-benzopyran (intermediate compound XXX).

A solution of 2.38 g of anhydrous zinc chloride and 2.30 g of lamborginid sodium in 71 ml of anhydrous ethanol was added dropwise with shaking to a mixture of 9.24 g 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 9.12 g of ethanolamine in 90 ml of anhydrous methanol. Shaking was continued for 5 h at 20 - 25oC, then the solvent was removed in vacuum. To the residue was added 250 ml of water, and the undissolved substance was SWAT is washed with ethyl acetate. This aqueous solution was podslushivaet by adding 2 n sodium hydroxide solution, and the precipitate was collected with filtration with suction. After washing with water, there was obtained 8.5 g of compound indicated in the title, having after drying at 60oC melting point 117 - 121oC.

8-(N-Methyl-N-chloroacetyl-aminomethyl)-3-methyl-4-oxo-2-phenyl - 4H-1-benzopyran (intermediate compound XXXI).

A solution of 6 ml of chloroacetyl chloride in 60 ml of 1,2-dichloroethane was dropwise added to a solution of 20 g of intermediate compound XX and 10 ml of triethylamine in 200 ml of 1,2-dichloroethane at a temperature between -5 and 0oC. After shaking for 2 h at 20 - 25oC to the reaction mixture was added 150 ml of water and separation of the phases. The organic phase is washed with water and dried on anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was led from ethanol was obtained 22.5 g of compound indicated in the title, with a melting point of 146 to 148oC.

8-Chloroacetamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound XXXII).

A solution of 3.2 ml of chloroacetanilide in 32 ml of 1,2-dichloroethane was added dropwise with shaking to a mixture of 10 g of promezutocnie 1 h at room temperature and then added to 150 ml of water. Conducted phase separation, the aqueous phase was extracted with 1,2-dichloroethane, the extracts were added to the organic phase, which was then washed with cold saturated sodium bicarbonate solution. Then washed with water, dried on anhydrous sodium sulfate and evaporated in vacuum to dryness. The residue was led from ethanol, having obtained 10.7 g of compound indicated in the title, with a melting point 152 - 155oC.

8-[N-Acetyl-N-(2-chloroethyl)-aminomethyl] -3-methyl-4-oxo-2-phenyl - 4H-1-benzopyran (intermediate compound XXXIII).

8.65 g of intermediate compound XXX and 4.15 ml of triethylamine were dissolved in 70 ml of tetrahydrofuran. To this solution at -10oC was added dropwise over 40 minutes a solution of 2.35 ml of acetylchloride in 23 ml of tetrahydrofuran. After shaking for 3 h at 0 to 10oC and for 2 h at 20 - 25oC the solvent evaporated in vacuum. To the residue was added 100 ml of water and the extraction with dichloromethane. The organic extracts were combined and then evaporated under vacuum of the solvent. The residue was dissolved in 50 ml of methanol, and thereto was added 3 g of potassium carbonate and 10 ml of water. After shaking for 20 min at 50oC, held for hydrolysis treatment is tan so as was described above. The dichloromethane solution was again evaporated to dryness; the result obtained 5.9 g of 8-[N-acetyl-N-(2-hydroxyethyl)-aminomethyl] -3-methyl-4 - oxo-2-phenyl-4H-1-benzopyrane with a melting point 171 - 172oC. 3.6 ml of thionyl chloride in 30 ml of dichloromethane was added dropwise at 0oC to a solution of 6.1 g of the above compound in 70 ml of dichloromethane. After shaking for 90 min at 20 - 25oC the reaction mixture was washed with water and dried. The solvent was removed in vacuo to yield the crude product indicated in the title, was ready for use without further purification.

8-(3-Chlorpropyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound XXXIV).

A solution of 20.1 g of dihydrate of tin chloride (II) in 18 ml of HCl (d = 1.18) was added within 5 min at 65oC to a solution of 6 g of intermediate compound VIII in 70 ml of acetic acid. After 10 min the reaction mixture was cooled to 30 - 35oC, and the solvent was removed in vacuum. The residue was transferred into the water, and the undissolved substance was collected during the filtration with suction, washed with water and dried. Exit 8-mercapto-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran was 3.2 g, melting point after crystallization from ethanol the m-3-chloropropane, 0.2 g of tetrabutylammonium bromide and 6.2 ml of 35% sodium hydroxide in 80 ml of benzene was shaken vigorously for 4 h at 20 - 25oC. Was added 100 ml of water and 40 ml of dichloromethane. The organic layer was separated, washed with water and dried on anhydrous sodium sulfate. The solvent and excess 1-bromo-3-chloropropane was removed in vacuum. The residue was purified column chromatography on silica gel, elwira a mixture of petroleum ether : ethyl acetate in the ratio of 9:1 was obtained 5.7 g of compound indicated in the title. After crystallization from methanol his melting temperature was 84 - 86oC.

8-(3-Chloropropanesulfonyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound XXXV).

7 ml of 30% hydrogen peroxide was added to a solution of 3.45 g of intermediate compound XXXIV in 35 ml of acetic acid at 20 - 25oC. After shaking for 4 h at 60oC the reaction mixture was cooled to 20 to 25oC and added 30 ml of water. The resulting precipitate was collected with filtration with suction, washed with water and dried. The result was obtained 3.4 g of compound indicated in the title, which after crystallization from acetone had a melting point of 160 to 163oC.

8-(3-Hydroxypropylamino in 50 ml of water was added dropwise within 30 min to a suspension of 30 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride and 15.2 g of potassium carbonate in 400 ml of acetone. This viscous suspension was shaken for 3 h at 20 - 25oC. the Solvents were removed in vacuo and the residue was transferred into 300 ml of water. After shaking for 1 h the precipitate was collected by filtration with suction and washed with water. The crude product was purified by crystallization from 95% ethanol; received 23.8 g of compound indicated in the title and having a melting point 191 - 193oC. concentration in vacuo of the filtrate was obtained separately 4.7 g of the same connection.

8-(3-Chloropropionyl)-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran (intermediate compound XXXVII).

A solution of 1.1 ml of thionyl chloride in 2 ml of chloroform was added to the boiling solution of 3.37 g of intermediate compound XXXVI in 20 ml of chloroform. After shaking at reflux distilled over 90 min the solvent was removed in vacuo, and the residue was led them acetonitrile. Received 3 g of pure compound indicated in the title and having a melting point 193 - 194oC.

8-[1-Hydroxy-4-(4-methylphenylsulfonyl)-butyl] -3-methyl-4 - oxo-2-phenyl-4H-1-benzopyran (intermediate compound XXXVIII).

1.12 g of sodium cyanide in 3 ml of water was added to stirred up a mixture of 3.96 g 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzop the 5oC. the Reaction mixture was subjected to reflux distilled for 4 h, then was added 10 ml of cold water. Tetrahydrofuran was distilled at normal pressure and added 10 ml of 1,2-dichloroethane and 10 ml of chloroform. The organic phase was separated, washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated in vacuum to dryness. The residue suspended in diethyl ether, was filtered and was led from a mixture of chloroform : ethyl acetate. Output: 3.55 g of 8-(morpholino-cyanomethyl)-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyrane; melting point 236 - 238oC.

To a suspension of 22.8 g of the thus prepared compounds in 520 ml of anhydrous tetrahydrofuran was added at room temperature and shaking 3.5 ml of 30% solution of potassium hydroxide in anhydrous ethanol. To this suspension was added dropwise 6.3 ml of Acrylonitrile in 20 ml of tetrahydrofuran, and the reaction mixture was shaken for 1 h at room temperature. The solvent was evaporated in vacuum. Crystallization of the residue from methanol gave 23.22 g of 8-(1,3-dicyano-1 morpholino-propyl)-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran.

23.2 g of the thus obtained compound was dissolved in 250 ml of dioxane. Was added to the URS and the mixture was poured into 700 ml of an aqueous solution of sodium chloride and was extracted with ethyl acetate. The extracts were washed with an aqueous solution of sodium chloride and was treated with 700 ml of 1 M sodium hydroxide solution. The aqueous layer was washed with ethyl acetate and acidified with 37% HCl. The precipitate was collected with filtration with suction and was led from ethanol, gave 10.2 g of 8-(3-carboxy-1-hydroxy-propyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyrane with a melting point 191 - 192oC.

DIBORANE obtained when prikatyvanie in 19 ml of a 0.66 M solution of sodium borohydride in diglyme solution of 2.1 ml of fresh diethyl ether boron TRIFLUORIDE in 10 ml of anhydrous diglyme, barbotirovany in a suspension of 2.28 g of the above compound in 23 ml of anhydrous tetrahydrofuran was shaken under a stream of nitrogen at 0oC. the Shaking continued for 20 min at 0oC and then for 20 min at room temperature. To the mixture at 0oC was carefully bury methanol to quench the reaction. The solvents were removed by evaporation in a vacuum. The residue was purified by thin-layer chromatography on silica gel, elwira a mixture of petroleum ether : ethyl acetate 3:7. The collected fraction was evaporated in vacuum, the result was 2 g of 8-(1,4-dihydroxybutyl)-3-methyl - 4-oxo-2-phenyl-4H-1-benzopyrane with a melting point of 133 - 134oC.

oC and left overnight without shaking at a temperature of -4oC. Then it was poured into 200 ml of an aqueous solution of sodium chloride, acidified with 10 ml 12 N. HCl and filtered with suction. The filtrate was dissolved in chloroform, and the solution was washed with an aqueous solution of sodium chloride and dried on anhydrous sodium sulfate. The solvent is kept on a rotary evaporator. The residue was purified by thin-layer chromatography on silica gel, elwira a mixture of petroleum ether : ethyl acetate 1:1. The collected fractions were evaporated to dryness in vacuo; the resulting 3.04 g of the product specified in the title, with a melting point of 123 - 124oC.

4-[4-(2-Methoxyphenyl)-1-piperazinil]-Butyraldehyde (intermediate compound XXXIX).

A solution of 5.4 g of 2-(3-chloropropyl)-dioxolane and 15.9 g of 1-(2-methoxyphenyl)-piperazine in 60 ml of dimethylformamide was shaken for 4 h at 80oC. After cooling to 20 to 25oC the reaction mixture was poured into 500 ml ice 0.5 n sodium hydroxide solution and was extracted with dichloromethane. The organic phase is washed with water and dried on anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified thin-layer chromatograph is)-1-piperazinil]-propyl}-dioxolane in the form of butter.

NMR CDCl3()

1.5 - 2.0 (4H, m, CH2CH2CH)

2.2 - 3.2 (10H, m, 5CH2N)

3.7 - 4.0 (7H, m, OCH3and 2OCH2)

4.8 (1H, t, OCHO)

6.7 - 6.9 (4H, m, aromatic protons).

A solution containing 12.8 g of thus obtained compound in 200 ml of tetrahydrofuran and 420 ml of 1 N. HCl, was kept for 24 h at 20 - 25oC. Then it was podslushivaet 5 N. solution of sodium hydroxide and immediately was extracted with dichloromethane. The organic layer was washed with water and dried on anhydrous sodium sulfate. The solvent is evaporated in vacuo, and the residue was purified by thin-layer chromatography on silica gel, elwira a mixture of dichloromethane : methanol in the ratio of 97 : 3. There was obtained 6.4 g of compound indicated in the title, in the form of butter.

NMR CDCl3()

1.5 - 2.0 (2H, m, CH2CH2CH2)

2.2 - 2.8 (8H, m, 3CH2N and CH2CHO)

2.9 - 3.2 (4H, m, 2CH2NAr)

3.8 (3H, s, OCH3)

6.8 (H, s, aromatic protons)

9.3 (1H, s, CHO).

8-(2,3-Epoxypropoxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound XL).

7 ml of 2,3-epoxypropane was added dropwise at 20 - 25oC to shake a mixture of 5 g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 9.7 ml of 2 N. g is lively in 100 ml of water and the precipitate was collected by filtration with suction. After drying and purification by thin-layer chromatography on silica gel (eluate - petroleum ether : ethyl acetate 65:35) was obtained 4.45 g of compound indicated in the title, with a melting point 128 - 129oC.

8-[N-Methyl-2-(4-methylphenylsulfonyl)-ethylsulfanyl] -3 - methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound XLI).

A solution of 5 g of intermediate compound VIII in 60 ml of dichloromethane and 20 ml of tetrahydrofuran was added dropwise to a mixture of 275 ml of 2-methylaminoethanol and 2.1 ml of triethylamine in 20 ml dichloromethane at 0oC. After shaking for 2 h at 20 - 25oC to the reaction mixture was added 100 ml of water and 100 ml dichloromethane. The phases were separated and the organic layer was dried on anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified column chromatography on silica gel, elwira a mixture of petroleum ether: ethyl acetate 3: 7. There was thus obtained 4.5 g of 8-(N-methyl-2-hydroxyethylsulphonic)-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyrane with a melting point after crystallization from ethanol 146 - 147oC.

The compound obtained was converted into the compound indicated in the title, in the p-toluensulfonate according to the second stage percent is owano without further purification.

8-[2-(4-Methylphenylsulfonyl)-ethylsulfanyl] -3-methyl-4 - oxo-2-phenyl-4H-1-benzopyran (intermediate compound XLII).

A solution of 5 g of intermediate compound VIII in 37 ml of tetrahydrofuran at 0oC was added dropwise to a mixture of 2.5 ml of ethanolamine and 275 ml of triethylamine in 25 ml of tetrahydrofuran. After shaking at 20 - 25oC the reaction mixture was poured into 400 ml of water. The precipitate was collected with filtration with suction, washed with water and dried with air. The result was obtained 4.6 g of 8-(2-hydroxyethylsulphonic)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyrane, melting at 186 - 187oC after crystallization from ethyl acetate.

2.1 g of p-toluensulfonyl chloride was added in portions at 0oC to a solution of 3.6 g of the above compound in 25 ml of pyridine. After exposure for 6 h at 20 - 25oC the mixture was slowly poured onto crushed ice containing a slight excess of hydrochloric acid. Formed precipitate, which was collected by filtration with suction and washed with water. There was obtained 4.9 g of the compound indicated in the title, which melts at 166 - 169oC after crystallization from ethyl acetate.

8-(3-Aminopropylsilyl)-3-methyl-4-oxo-2-phenyl-4H-1-banter bonyl chloride in 250 ml of anhydrous tetrahydrofuran was bury at 0oC to shake a solution of 17 g of 3-(2-methyl-2-propoxycarbonyl)Propylamine (prepared according to Saari, W. S. et al., J. Med.Chem., 33, 97. 1990) in 13 ml of triethylamine. After shaking for 2 h at room temperature the reaction mixture was poured into water and filtered to highlight 12.3 g of 3-(2-methyl-2-propoxycarbonyl)-propyl-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran-8-carboxamide, which was recrystallized from ethanol. Melting point 178 - 180oC.

A solution of 4.3 ml triperoxonane acid in 15 ml of anhydrous dichloromethane was added dropwise at -5oC with shaking to a solution containing 3.3 g of compound prepared above, and 35 ml of anhydrous dichloromethane. After heating to room temperature the mixture was shaken for 8 hours Dichloromethane and excess triperoxonane acid evaporated at 20 - 25oC using rotary evaporator. Oily residue was dissolved in dichloromethane and added 1 n sodium hydroxide solution. The organic layer was washed with water, dried on anhydrous sodium sulfate and filtered. To the filtrate was added excess ethanolic HCl and the solvent was removed in vacuum. The residue was led from ethanol was obtained 1.5 g of the compound of the decree is-1-benzopyran (intermediate compound XLIV).

4 ml of 2-chlorotriazine was added with shaking at room temperature to a solution of 3.9 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 52 ml of anhydrous dimethylformamide. Shaking was continued for 5 h at 70oC. To the reaction mixture were added water and then extraction was performed with ethyl acetate. The organic phase is evaporated to dryness in a vacuum. The residue is suspended by shaking in diethyl ether. The product that is listed in the title, was filtered and was recrystallization from methanol. Output 3.74 g, melting point 213 - 214oC.

(Z, E-8-{ 4-[2-(1,3-Dioxane)] -1-butenyl}-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran (intermediate compound XLV).

1.6 ml of 2.5 n utility in hexane was added dropwise at -20oC to a solution of 1.53 g of 2-[2-(1,3-dioxane)]-ethyl triphenylphosphine bromide in 10 ml of anhydrous tetrahydrofuran. The mixture was shaken for 20 min at -20oC. this mixture was priceman solution of 0.8 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 11 ml of anhydrous tetrahydrofuran. Then for 90 min was performed to heat up to the 0oC and then for 30 min to room temperature. The solvent was evaporated in vacuum and the residue was purified by thin-layer chromatography on silica gel, diastereoisomers, with a melting point of 98 - 100oC. the Ratio of these two isomers was determined by NMR-spectroscopy and amounted to E:Z = 65:35.

NMR, CDCl3():

8.1 - 8.2 (m, 1H, CH at position 5 in benzopyrano ring);

7.2 - 7.8 (m, 7H, aromatic CH groups benzopyranones and phenyl rings);

6.9 (dt, 1H, Fl-CH E-isomer);

6.8 (dt, 1H, Fl-CH Z-isomer);

6.4 (dt, 1H, Fl-CH=CH E-isomer);

5.9 (dt, 1H, Fl-CH=CH Z-isomer);

4.6 - 4.7 (m, 1H, OCHO);

3.6 - 4.2 (m, 4H, OCH2O from dioxane ring);

2.4 - 2.7 (m, 2H, CHCH2CH);

1.9 - 2.3 (m, 5H, CH3and CH2in position 5 in dioxane ring).

8-{ 4-[2-(1,3-Dioxane)]-butyl)-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran (intermediate compound XLVI).

A mixture of 0.2 g of 10% Pd/C catalyst and 1 g of intermediate compound XLV in 24 ml of methanol was first made in the Parr apparatus at room temperature under hydrogen pressure of 1.5 ATM. After all theoretical amount of hydrogen the catalyst was filtered, and the solvent was removed by evaporation in a vacuum. The residue was led from cyclohexane to obtain the connection specified in the title; its melting point was 118 - 119oC.

8-Carboxymethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (p - 10oC was added to a mixture of 2.76 g of 8-allyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (P. Da Re, US 3350411), 0.17 g of Aliquat 336, 1,12 ml of acetic acid, 56 ml of dichloromethane, 3.2 ml of sulfuric acid (d = 1.84) and 60 ml of water. Shaking was continued for 5 h at room temperature. At 0 - 5oC for 15 min portions was added 3.4 g of sodium metabisulfite. The organic layer was separated, washed with water and was extracted with 60 ml of 1 N. aqueous sodium hydroxide solution. The aqueous phase was acidified by adding diluted hydrochloric acid and was extracted with ethyl acetate. The organic phase is washed with water, dried on anhydrous sodium sulfate and after filtration was evaporated in vacuum to dryness. The residue was treated with carbon tetrachloride, and the solid substance was collected by filtration with suction. There was obtained 1 g of compound indicated in the title, with a melting point 191 - 192oC (acetonitrile).

8-(4-Chloroethylamino)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound XLVIII)

The connection specified in the title, was obtained in the same manner as the intermediate compound X, but instead of chloride of acryloyl used chloride 4-chlorobutyryl. The obtained solid residue filtered from the water and% aqueous ethanol and washed with diethyl ether, melted at 162 - 164oC.

8-Methylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound XLIX).

A solution of 0.5 g of intermediate compound XXIII in 1.5 ml of anhydrous dimethylformamide was added dropwise with shaking at -5oC to a suspension of 0.045 g of sodium hydride (80% in mineral oil). After shaking for one hour at room temperature was added dropwise 0,092 ml under the conditions in 0.6 ml of anhydrous dimethylformamide. Then the reaction mixture was shaken for 1 h at 50oC, cooled to 20oC, poured into water, filtered with suction and dried for 3 h at 60oC. there Was obtained 0.6 g of 8-(N-methyltrifluoroacetamide)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

NMR (CDCl3, ):

8.15 (dd, 1H, benzopyranyl CH at position 5);

7.10 - 7.60 (m, 7H, other benzopyranones and phenyl CHs);

3.30 (s, 3H, CH3N);

2.10 (s, 3H, benzopyranyl CH3in position 3).

A mixture containing 0.44 g of the above compound and 0.05 g of sodium borohydride in 4 ml ethanol and 1 ml of dimethyl sulfoxide was shaken for 1 h at room temperature, and then treated with excess 4 N. hydrochloric acid. After removal of ethanol by evaporation in vacuum ostatni water, dried on anhydrous sodium sulfate and evaporated in vacuum to dryness. The solid residue was led from ethanol; obtained 0.22 g of compound indicated in the title, melting at 143 - 146oC.

8-(N-Methylacrylamide)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound L).

This compound was obtained in the same way as the intermediate compound X, but instead of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound XLIX. Instead of diluting it with water, THF was removed by evaporation in vacuo, the crude residue was dissolved in ethyl acetate and washed with water. The organic layer was dried on anhydrous sodium sulfate and was evaporated to dryness in vacuo to obtain the compound indicated in the title. The sample, purified column chromatography on silica gel (suirable a mixture of ethyl acetate:petroleum ether 4:6) and crystallized from cyclohexane, melted at 136 - 137oC.

1-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindole-2-yloxy)-ethyl]-4-(2 - methoxyphenyl)-piperazine (intermediate compound LI).

The mixture 6.73 g of N-hydroxyphthalimide, 3.73 g of sodium acetate and 10 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine in 100 ml of anhydrous dimethyl sulfoxide in the control and were extracted with ethyl acetate. The collected organic layers were washed 1 N. sodium hydroxide, dried on anhydrous sodium sulfate and evaporated to dryness in a vacuum; it was obtained 7.58 g of compound indicated in the title. A sample, crystallized from cyclohexane, melted at 80 - 83oC.

1-(2-Aminoacetyl)-4-(2-methoxyphenyl)-piperazine hydrochloride (intermediate compound LII).

A solution of 6.59 g of intermediate compound LI and 1.10 ml of 85% hydrazine hydrate in 130 ml of 95% ethanol was subjected to reflux distilled for 4 hours, the Ethanol was removed by evaporation in a vacuum. The residue was washed with water, and then the excess of 37% HCl and filtered. The acidic aqueous solution was made alkaline with 5% sodium hydroxide, and then was extracted with chloroform. The organic layer was dried on anhydrous sodium sulfate and evaporated in vacuum to dryness, to obtain 4.3 g of the compound indicated in the title, in the form of oil. The sample was converted into hydrochloride by formation of a salt with ethanolic hydrogen chloride in dichloromethane. The solvents were removed by evaporation in vacuo, the crude residue was led from ethanol; received the connection specified in the title, with a melting point 208 - 209oC.

8-(4-Chloroethylthio)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran is then the intermediate compound XXXIV, but instead of 1-bromo-3-chloropropane used 1-bromo-4-chlorobutane. The melting point of 81 - 84oC (ethanol).

8-(4-CHLOROTHALONIL)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound LIV).

The connection specified in the title, was obtained in the same way as the intermediate compound XXVI, only intermediate compound LIII was used instead of compound XXI. A sample, crystallized from a mixture of cyclohexane : benzene 0.5:1, melted at 124 - 125oC.

8-Carboxy-4-oxo-3-phenyl-4H-1-benzopyran (intermediate compound LV).

The solution 38.22 g of silver nitrate in 75 ml of water was added in drops with shaking at 20 - 25oC to a solution of 22.5 g 8-formyl-4-oxo-3-phenyl-4H-1-benzopyran (prepared according to G. Atassi et al., Eur. J. Med. Chem. - Chim. Ter., 20, 393, 1985) in 150 ml of 85% ethanol and 450 ml of dimethylformamide. Then dropwise with shaking at 15 - 20oC was added a solution 32.67 g of 85% potassium hydroxide in 195 ml of water. After shaking at room temperature the reaction mixture was filtered with suction; the mother liquor was acidified with 37% hydrochloric acid and diluted with 1.2 l of water. After filtration with suction and washing with water until neutral was the Wali with 444 ml of 0.3 M acid sodium carbonate to obtain transparent layers. The aqueous layer was washed with 75 ml of ethyl acetate, then acidified with 37% hydrochloric acid, filtered and dried at 60 - 65oC. Was obtained 19.12 g of compound indicated in the title, melting at 218oC. Sample, crystallized from ethanol, had the same melting temperature.

8-Chlorocarbonyl-4-oxo-3-phenyl-4H-1-benzopyran (intermediate compound LVI).

The mixture at 15.97 g of intermediate compound LV and 15.6 g of thionyl chloride in 75 ml of anhydrous toluene was dissolved at 80 - 85oC within 4 hours After removal of the solvent in vacuo the residue was twice washed with 20 ml of toluene and evaporated to dryness in vacuum. After drying there was obtained 16 g of compound indicated in the title and melting at 138 - 140oC, which was used without further purification. Melting point 138 - 140oC (toluene).

8-(N-Acetylmuramyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound LVII).

A mixture of 3.5 g of 8-carbarnoyl-4-oxo-2-phenyl-4H-1-benzopyran (described in JP 61-238783), 4.8 ml of acetic anhydride and 0.25 ml of sulfuric acid (d = 1.098) was shaken for 3 min at 140oC. the Reaction mixture was cooled to room temperature, diluted with water and filtered with suction, which gave, after predny NH);

8.35 - 8.70 (m, 2H, CH in position 5 and 7 benzopyrrole ring);

7.45 - 8.00 (m, 6H, aromatic CHs);

2.60 (s, 3H, CH3CO);

2.20 (s, 3H, CH3in position 3 benzopyrrole ring).

2-(2-Methylthiophene)-acetaldehyde diethylacetal (intermediate compound LVIII).

A mixture of 15.2 ml of 97% 2-bromoacetaldehyde diethylacetal, 14 g of 2-(methylthio)-phenol, 13.7 g of anhydrous potassium carbonate and 3.13 tricaprylate chloride in 140 ml of anhydrous dimethylformamide was shaken for 38 h at 95oC. At the end of this time the reaction mixture was cooled to room temperature, poured into 1 l of water and was extracted with diethyl ether. The organic layer was washed with water, dried on anhydrous sodium sulfate and evaporated in vacuum to dryness. The oily residue was purified column chromatography on silica gel, elwira a mixture of petroleum ether : ethyl acetate 99:1. Evaporation in vacuo of the collected fractions gave 12.9 g of pure compound indicated in the title. A sample, crystallized from n-hexane, melted at 50 - 52oC.

2-(2-Methylthiophene)-acetaldehyde (intermediate compound LIX).

A mixture of 10.5 g of intermediate compound LVIII and 140 ml of 2 N. hydrochloric acid in 85 ml of anhydrous then it is carbonated is uume, and the aqueous residue was extracted with ethyl acetate. The organic layer was washed with water, dried on anhydrous sodium sulfate and was evaporated to dryness in vacuum. The result was obtained 9.5 g of compound indicated in the title, as dry matter, which was used without further purification. The sample was led from cyclohexane, getting a net connection specified in the title, with a melting point of 102 - 104oC.

8-(4-CHLOROTHALONIL)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound LX).

The connection specified in the title, was obtained using the same method as intermediate compound XXV, only instead of intermediate compound XXI was used intermediate compound LIII. It crystallized from diisopropyl ether and melted at 112 - 115oC.

8-Etoxycarbonyl-4-oxo-4H-1-benzopyran (intermediate compound LX).

4.35 g of metallic sodium was added pieces to a solution of 9.85 g of ethyl-3-acetyl-2-hydroxy benzoate (synthesized from 3-acetyl-2-hydroxybenzoic acid, obtained as described R. E. Ford, J. Med. Chem., 29, 538, 1986) at room temperature. Within 1.5 h were dephlegmation 6 N. ethanolic hydrogen chloride, evaporated doucett : petroleum ether 8:2) in 98 ml of ethylformate; melting point 47oC (hexane).

After spontaneous reflux distilled reaction mixture for 20 min, it was shaken at room temperature for 4 h, and ethyl formate was removed by evaporation in vacuo to dryness. The resulting crude product was washed with 120 ml of ethanol and 67 ml of 5.6 M ethanolic hydrogen chloride. The mixture was shaken at reflux distilled for 30 min, then cooled to room temperature and was evaporated to dryness in vacuum. The residue was purified column chromatography on silica gel, elwira a mixture of ethyl acetate : petroleum ether 3 : 7 to 6 : 4. Received 8.31 g of compound indicated in the title; sample, crystallized from cyclohexane, melted at 88 - 89oC.

8-Carboxy-4-oxo-4H-1-benzopyran (intermediate compound LXII).

30 ml of 6 N. hydrochloric acid was added to a solution of 4.0 g of intermediate compound LXI in 30 ml of dioxane, the mixture was dissolved at reflux distilled for 5 hours, the Reaction mixture was cooled to room temperature and poured into 200 ml of water. After incubation for 12 h at 0 to 5oC has received the connection specified in the title; it was filtered with suction. After washing with water and diethyl ether and drying there was obtained 2.8 g with the using acetonitrile : ethanol 25 : 1, was filtered and was led from acetic acid; sample melted at 253 - 254oC.

8-Carboxy-6-hydroxy-3-methyl-4-oxo-4H-1-benzopyran (intermediate compound LXIII).

A mixture of 175 g of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (obtained as described in JP 61-15880) and 28 ml of 57% idiscovered acid in 47 ml of acetic acid was dissolved at reflux distilled within 18 hours the Reaction mixture was cooled to room temperature and poured into water; to bring the pH to 4 to 5 was added 1 n sodium hydroxide. Was added 5.2 g of sodium thiosulfate and shaking continued for 15 minutes After this time, the crude product is indicated in the title, was filtered with suction and dissolved in 0.5 M sodium hydroxide. The solution was washed with ethyl acetate and acidified to pH 1 by addition of 37% hydrochloric acid. The connection specified in the title, was collected with suction and dried off. Yield: 1.12 g of compound indicated in the title, which was used without further purification; melted at 279 - 281oC after crystallization from 50% ethanol.

2-Hydroxy-5-nitro-3-propionyl benzoic acid (intermediate compound LXIV).

97.1 g of 2-hydroxy-3-propionyl benzoic acid, prepared ywaniem when - 25oC. To the reaction mixture for 40 min was added a mixture of 40 ml of 65% nitric acid and 100 ml of sulfuric acid (d = 1.84); at this temperature the reaction mixture was maintained between -20 -13oC. the Mixture was shaken additionally for 30 min at -18oC. then it was quickly poured into a mixture of 2.0 kg of crushed ice and 500 ml of water, shaken for 10 min and filtered to obtain the compound indicated in the title, after washing with water and drying at 50oC for 6 hours Crystallization of this dry matter of 50% ethanol gave 91.5 g of compound indicated in the title and melting at 186 - 189oC. the Compound was used without further purification; sample, recrystallized from 50% ethanol, melted at 189 - 191oC.

Ethyl 2-hydroxy-5-nitro-3-propionyl benzoate (intermediate compound LXV).

The solution 93.3 g of intermediate compound LXIV and 25 ml of sulfuric acid (d = 1.84) in 490 ml of ethanol was subjected to reflux distilled within 17 hours After cooling to room temperature was added in portions 47.7 g of potassium carbonate, and the ethanol evaporated in vacuo. The residue is washed with 1.2 l of water, was podslushivaet the addition of 37% aqueous sodium hydroxide solution and was shaken for 15 minutes To this suspension was added 37% Toroe used without further purification (melting point 75 - 77oC). A sample, crystallized twice from ethanol, melted at 76 - 77oC.

8-Etoxycarbonyl-3-methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound LXVI).

The mixture 48.1 g of intermediate compound LXV, 63 ml of benzoyl chloride and 85.6 g of sodium benzoate was dissolved in 180oC (bath temperature) for 8 hours Pasty mixture was cooled to 60 - 70oC, was added 700 ml of 50% ethanol and the resulting mixture was shaken again at the 50oC 30 min 60 ml of 35% sodium hydroxide was added at the 5oC, ensuring that the temperature did not rise above 15oC. Filtration with suction subsequent washing with 50% ethanol and water gave the crude product, which was purified by double passage through a chromatographic column filled with silica gel. The first elution was performed with a mixture of dichloromethane : petroleum ether in the ratio of 8 : 2 to 9 : 1, then suirable dichloromethane and finally - with a mixture of dichloromethane : ethyl acetate in a ratio of 95 : 5. Upon evaporation in vacuo of the collected fractions received the connection specified in the title, which was washed 140 ml of ethanol. Yield 43 g, melting point 132 - 133oC (ethanol).

8-Carboxy-3-methyl-6-nitro-4-oxo-2 - 1 N. sodium hydroxide in 320 ml of ethanol was dissolved at reflux distilled for 30 minutes the Organic solvent was removed by evaporation in vacuo, and the resulting suspension was diluted with 200 ml of water and acidified with 37% hydrochloric acid. Filtration and washing with diethyl ether gave a result of 11.1 g of compound indicated in the title and melting at 286 - 292oC, which was used without further purification. After crystallization from a mixture of dimethylformamide : water 6 : 4 this compound showed the same melting temperature.

8-Chlorocarbonyl-3-methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound LXVIII).

A mixture of 6.2 g of intermediate compound LXVII, 5.2 ml of thionyl chloride and 0.1 ml of anhydrous DMF (dimethylformamide) in 60 ml of toluene was shaken for 2 h at 90oC. Evaporation to dryness in vacuo and drying resulted in a 6.5 g of compound indicated in the title, with a melting point 161 - 162oC, which was used without further purification. The sample was led from toluene, and he had the same melting temperature.

8-Carboxy-7-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate compound LXIX).

216 ml of 0.3 M potassium permanganate solution in water was added according to the fact described Da Re et al., J. Org. Chem. , 25, 1097, 1960) and 54 ml of 5% sodium dihydrophosphate in 162 ml of t-butanol and shook at the 75oC. After 2.5 h of shaking at the same temperature, the reaction mixture was cooled to room temperature and slowly dropwise added 81 ml of 1 M dithionite sodium. The mixture was extracted with ethyl acetate, the organic layer was washed 4 times with 160 ml of 0.5 n sodium hydroxide; the collected aqueous layers washed with diethyl ether and acidified with 37% hydrochloric acid. The connection specified in the title, precipitated. It was filtered and washed with water, after drying, there was obtained 3.3 g of compound, which was used for subsequent reactions without further purification. After crystallization from 95% ethanol, the compound melted at 180 - 181oC.

Ethyl 3-propionyl 2-(4-triftormetilfosfinov)-benzoate (intermediate compound LXX).

A solution of 6.7 g of 4-triftormetilfullerenov (obtained from the corresponding benzoic acid and thionyl chloride in benzene at reflux distilled and used without purification) in 50 ml of chloroform was added dropwise to a solution of 7.13 g of ethyl 2-hydroxy-3-propenylbenzene and 4.9 ml of triethylamine in 50 ml of chloroform. The mixture was shaken for 2 h at room temperature, the solvent vapour is ethyl acetate 85 : 15. In the process of evaporation to dryness in vacuo of the collected fractions was obtained 7.4 g of compound indicated in the title, in the form of butter.

The NMR spectra at 60 MHz (CDCl3, ):

7.6 - 8.5 (m, 6H, aromatic CHs);

7.5 (t, 1H, phenolic ring CH in position 5);

4.2 (q, 2H, COOCH2);

2.9 (q, 2H, COCH2);

1 - 1.3 (2t, 6H, 2 CH3).

8-Etoxycarbonyl-3-methyl-4-oxo-2-(4-triptoreline)-4H-1-benzopyran (intermediate compound LXXI).

A mixture of 6.96 g of intermediate compound LXX and 2.58 g of t-butoxide potassium in 35 ml of pyridine were shaken for 2 h at 100oC. After this time the reaction mixture was cooled to room temperature, poured into a solution of 50 ml of acetic acid in 600 ml of water and was extracted with ethyl acetate. The organic layer was washed with 10% hydrochloric acid and water, dried on anhydrous sodium sulfate and evaporated in vacuum to dryness. Was obtained 6.9 g of 1-(2-hydroxy-3-etoxycarbonyl)-2-methyl-3-(4-triptoreline)- 1,3-propanedione. A solution of this compound and 2.2 ml of 37% hydrochloric acid in 35 ml of glacial acetic acid was shaken for 1.5 h at 100oC. After cooling to room temperature the mixture was poured in 630 ml of 1 n sodium hydroxide and was extracted with ethyl acetate. The organic layer industry is full by chromatography on silica gel, elwira a mixture of petroleum ether : ethyl acetate 85 : 15. Upon evaporation in vacuo to dryness was obtained 2.95 g of compound indicated in the title, melting after crystallization from cyclohexane at 111 - 113oC.

8-Carboxy-3-methyl-4-oxo-2-(4-triptoreline)-4H-1-benzopyran (intermediate compound LXXII).

A mixture of 2.95 g of intermediate compound LXXI and 0.43 g of the monohydrate of lithium hydroxide in 12.5 ml of methanol and 12.5 ml of tetrahydrofuran containing 8 ml of water was shaken for 1.5 h at room temperature. The mixture was poured into a solution of 30 ml of 1 N. hydrochloric acid in 300 ml of water and filtered with suction. Received 2.47 g of compound indicated in the title, which was used without further purification. A sample, crystallized from 60% ethanol, melted at 253 - 254oC.

8-Etoxycarbonyl-2-(4-benzoylphenyl)-3-methyl-4-oxo-4H-1-benzopyran (intermediate compound LXXIII).

The specified compound was synthesized according to the methods of obtaining the intermediate LXX and LXXI, only as the source used 4-benzoylbenzoate chloride instead of 4-trifloromethyl chloride and carried out the reaction in the presence of 4-dimethylaminopyridine instead of triethylamine. After the usual procedure is of paravane to dryness in vacuo of the collected fractions was obtained connection, specified in the title; it was used without further purification. A sample, crystallized from cyclohexane, melted at 125 - 136oC.

8-Carboxy-2-(4-benzoylphenyl)-3-methyl-4-oxo-4H-1-benzopyran (intermediate compound LXXIV).

The indicated compound was obtained as an intermediate compound LXXII, only as the source used intermediate compound LXXIII instead of connecting LXXI. The connection specified in the title, was purified by dissolving the crude product in 0.5 M sodium hydroxide, washing the aqueous layer with ethyl acetate and precipitation of pure compounds when added 37% hydrochloric acid. A sample, crystallized from acetic acid, melted at 260 - 262oC.

Ethyl 2-(4-phenoxybenzoyl)-3-propionyl benzoate (intermediate compound LXXV).

The connection specified in the title, was obtained by the method described for intermediate connection LXX, but instead of 4-triftormetilfullerenov as the source used 4-phenoxybenzoate. Mpariwa solvent received net product that is listed in the title.

The NMR spectra at 200 MHz (CDCl3, ):

8.17 (dd, 3H, phenyl CHs in anthopology relative to the carboxylate groups);

7.9 sustained fashion carboxylate groups);

7.25 (d, 1H, CH at position 4 phenoxyl ring);

7.05; 7.10 (2d, 4H, other CHs phenoxyl ring);

4.25 (q, 2H, CH2O);

2.90 (q, 2H, CH2CO);

1.05 - 1.20 (m, 6H, 2 CH3).

8-Etoxycarbonyl-3-methyl-4-oxo-2-(4-phenoxyphenyl)-4H-1-benzopyran (intermediate compound LXXVI).

The connection specified in the title was obtained as compound LXXI, only as the source instead of intermediate compound LXXV used connection LXX. Purification was performed column chromatography on silica gel, elwira a mixture of petroleum ether : ethyl acetate 6 : 4. Evaporation in vacuum gave the pure product as specified in the title, with a melting point of 98 - 100oC.

8-Carboxy-3-methyl-4-oxo-2-(4-phenoxyphenyl)-4H-1-benzopyran (intermediate compound LXXVII).

This compound was obtained in the same manner as the intermediate compound LXXII, but as the source instead of intermediate compound LXXVI used compound LXXI. Melting point 216 - 218oC.

8-Carboxy-2-(t-butyl)-3-methyl-4-oxo-4H-1-benzopyran (intermediate compound LXXVIII).

6 ml of pualeilani was added dropwise to stirred up a solution of 8.9 g of ethyl 2-hydroxy-3-pdli to room temperature and was poured into a mixture of 200 g of crushed ice and 30 ml of 10 N. of hydrochloric acid. After extraction with diethyl ether, the organic phase was washed with brine, dried on anhydrous sodium sulfate and was evaporated to dryness in vacuum. The result was 11.4 g of crude ethyl 2-pivaloyloxy-3-propionyl benzoate.

2.4 g of this compound was dissolved in 4 ml of anhydrous pyridine and added to 1 g of anhydrous t-butoxide potassium. The resulting mixture was heated for 15 min at 100oC, cooled to room temperature and poured into 50 g of a mixture of ice water containing 8 ml of 10 N. hydrochloric acid. After extraction with diethyl ether, the organic phase was washed with brine, dried on anhydrous sodium sulfate and was evaporated to dryness in vacuum. The result was obtained 2.1 g of crude ethyl 2-hydroxy-3-(2-pivaloylpyruvic)-benzoate, which was used in the next stage without further purification. 2 g of this compound was heated at 100oC for 15 min after dissolution in a mixture containing 15 ml of acetic acid and 1.5 ml of 37% hydrochloric acid. After cooling to room temperature the mixture was poured into 100 ml of water and was extracted with diethyl ether. The organic phase is washed with 5% aqueous acidic sodium carbonate and then with water, dried on anhydrous sulfate Nathan.

1.5 g of the above ester was dissolved in 20 ml of ethanol. Then slowly, keeping the temperature 25 - 35oC, was added 3 ml of 10 n sodium hydroxide. After holding at room temperature for 1.5 h, the reaction mixture was diluted with 100 ml of water and was extracted with ethyl acetate. The aqueous layer was acidified 3 N. hydrochloric acid. The precipitate was collected with suction, washed with water and was led from ethanol. There was obtained 0.8 g of compound indicated in the title, melting at 225 - 228oC.

8-Carboxy-2-cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran (intermediate compound LXXIX).

This compound was obtained according to the sequence of reactions and the methods described for intermediate connection LXXVIII, only as a starting compound used chloride cyclohexylcarbamate acid, not pivaloyloxy; there were also other minor differences. Ethyl 2-cyclohexylcarbonyl-3-propionyl benzoate was obtained after 8 h of shaking at room temperature and rearranged into ethyl 2-hydroxy-3-(2-cyclohexylcarbonyl)benzoate by heating with t-piperonyl potassium for 2.5 h at 100oC. When heated in a mixture of acetic and hydrochloric acid at 100oC for 1.5 h was proven title, was carried out at room temperature for 20 minutes After crystallization from 40% ethanol the compound indicated in the title, melted at 224oC.

8-Etoxycarbonyl-2-(2-furyl)-3-methyl-4-oxo-4H-1-benzopyran (intermediate compound LXXX).

A mixture of 3.2 g of intermediate compound XC and 1.3 g of anhydrous t-butoxide of potassium in 8 ml of anhydrous pyridine was shaken for 15 min at 60oC, cooled to room temperature and poured into 60 ml of a mixture of ice water containing 15 ml of 10 N. hydrochloric acid. After extraction with ethyl acetate the organic phase is washed with 5% aqueous sodium bicarbonate and water and dried on anhydrous sodium sulfate. Upon evaporation in vacuum was obtained 2.5 g of crude ethyl 3-(2-furoyl-propionyl)-2-hydroxy benzoate.

2.5 g of the thus obtained compounds were shaken for 30 min at 100oC with 10 ml of acetic acid and 0.7 ml of 37% hydrochloric acid. After cooling to room temperature the mixture was poured into 180 ml of water. The connection specified in the title, besieged, collected during the filtration with suction and washed with water: crystallization was performed from isopropanol. Output 1.5 g, melting point 137 - 139oC.

8-Carboxy-2-(2-furyl)-3-methyl-4-oxitocina of sodium in 40 ml of methanol was shaken at room temperature for 1 h and was poured into 500 ml of water. After extraction with ethyl acetate, the aqueous layer was acidified 3 N. hydrochloric acid. The connection specified in the title, besieged, collected during the filtration with suction and washed with water; the crystallization is carried out from a mixture of methanol : chloroform 7: 3. Yield 2.55 g, melting point 272 - 277oC.

8-Etoxycarbonyl-3-methyl-4-oxo-2-(2-thienyl)-4H-1-benzopyran (intermediate compound LXXXII).

This compound was obtained in two stages, according to the methods described for intermediate compound LXXX, but instead of intermediate compound XC used connection XCI. The connection specified in the title, after crystallization from isopropanol melted at 116 - 118oC.

8-Carboxy-3-methyl-4-oxo-3-(2-thienyl)-4H-1-benzopyran (intermediate compound LXXXIII).

This compound was obtained according to the method described for intermediate compound LXXXI, only intermediate compound LXXXII was used instead of compound LXXX. After crystallization from a mixture of methanol and chloroform 7 : 3 melting point of this compound was 287 - 294oC.

8-Carboxy-4-oxo-2-phenyl-4H-1-benzothiophen (intermediate connection LXXXIV).

A mixture of 1 g of 8-methoxycarbonyl-4-oxo-2-phenyl-4H-1-beaten for 2.5 h at room temperature. After evaporation in vacuo was added until complete dissolution of water and this solution was extracted with chloroform. Selected aqueous phase was acidified with diluted hydrochloric acid until complete precipitation of the crude product, which was filtered and purified by crystallization from acetic acid. Yield 0.62 g, melting point 302oC.

(E)-8-Etoxycarbonyl-3-methyl-4-oxo-2-(2-styryl)-4H-1 - benzopyran (intermediate compound LXXXV).

This compound was obtained in three stages according to the methods described for intermediate XC (the first stage) and intermediate compound LXXX (the second and third stages). In the first stage used (E)-cinnamoroll instead of 2-frailcare; obtained (E)-ethyl 2-hydroxy-3-(2-styryl-propionyl)-benzoate was used for the second stage without purification. The connection specified in the title, after crystallization from isopropanol melted at 129 - 130oC.

(E)-8-Carboxy-3-methyl-4-oxo-2-styryl-4H-1-benzopyran (intermediate compound LXXXVI).

This compound was obtained according to the method described for intermediate compound LXXXI, only as the source used intermediate compound LXXXV, not compound LXXX, and the reaction was held Pelosi at 284 - 286oC.

8-Carboxy-3-methyl-2-(4-were)-4-oxo-4H-1-benzopyran (intermediate compound LXXXVII).

A mixture of 1.9 g of 2-hydroxy-3-propionyl benzoic acid (obtained according to Brit, up 1.343, 119, 1974), 5.2 g of anhydrous 4-methylbenzoate sodium and 3.9 ml of 4-methylbenzylamine shook for 8.5 h at 185 - 195oC. After cooling to room temperature hardening mass was left overnight in 100 ml of chloroform. Then the mixture was shaken with 5% aqueous solution of sodium carbonate until then, until the pH of the aqueous phase does not become 8.9. The organic phase was again extracted with diethyl ether, and the aqueous phase was decanted together again was extracted with diethyl ether and acidified 10 N. hydrochloric acid. The residue was purified by thin-layer chromatography on silica gel, elwira a mixture of chloroform : methanol 100 : 2 to 100 : 20. The connection specified in the title, was obtained by evaporation in vacuo of the combined fractions that contain it. The melting point of this compound after crystallization from ethanol was 249 - 251oC.

8-Etoxycarbonyl-2-(4-forfinal)-3-methyl-4-oxo-4H-1-benzopyran (intermediate connection LXXXVIII)

This compound was obtained in three stages according to the methods described for intermediate slowly instead of 2-frailcare, and the reaction continued for 20 h at room temperature, yielding ethyl 2-(4-perbenzoate)-3-propionyl benzoate. This compound without further purification was used for the second stage. After washing with diethyl ether and crystallization from ethanol the compound indicated in the title, melted at 128 - 130oC.

8-Carboxy-2-(4-forfinal)-3-methyl-4-oxo-4H-1-benzopyran (intermediate compound LXXXIX).

A solution of 3.3 g of intermediate compound LXXXVIII and 0.6 g of the hydrate of lithium hydroxide in 50 ml of tetrahydrofuran, 10 ml of methanol and 10 ml of water kept at room temperature for 5 h, and then poured into 300 ml of 1 N. hydrochloric acid. The precipitate was collected with suction, washed with water and dried. The result was obtained 2.3 g of compound indicated in the title, which after recrystallization from 95% ethanol melted at 249 - 250oC.

Ethyl 2-(2-pyrolox)-3-propionyl benzoate (intermediate compound XC)

4.35 ml of 2-frailcare was added dropwise at 10 to 15oC to shake a mixture of 8.9 g of ethyl-hydroxy-3-propionyl benzoate and 5.4 g of 4-dimethylaminopyridine in 25 ml dichlormethane. After exposure for 2 h at room temperature the reaction gasil 200 Mali in vacuum. The residue was purified column chromatography on silica gel, elwira a mixture of petroleum ether : ethyl acetate 4 : 1. The result was obtained 9.4 g of compound indicated in the title, in the form of solid viscoplasticity substance, which without further purification was used in the next stage.

The NMR spectra at 60 MHz (CDCl3, ):

8.2 (1H, dd, CH at position 4 of the benzene ring);

8.0 (1H, dd, CH at 6 position of benzene ring);

7.7 - 7.8 (1H, dd, CH at position 5 of the furan ring);

7.43 (1H, t, CH at position 5 of the benzene ring);

7.45 (1H, s, CH at position 3 of furan ring);

6.6 - 6.8 (1H, m, CH at position 4 of furan ring);

4.3 (2H, q, COOCH2CH3);

2.9 (2H, q, COCH2CH3);

0.95 - 1.35 (6H, m, 2 of CH3).

Ethyl 3-propionyl 2-(2-thienylboronic)-benzoate (intermediate compound XCI).

This compound was obtained according to the method described for intermediate XC, but using chloride 2-taylorbow acid instead of 2-frailcare.

The NMR spectra at 60 MHz (CDCl3, ):

7.1 - 8.35 (6H, m, aromatic CHs).

4.25 (2H, q, COOCH2CH3);

2.9 (2H, q, COCH2CH3);

0.95 - 1.3 (6H, m, 2 of CH3).

8 Methoxycarbonyl the ml ethylbenzylamine and 360 g of polyphosphoric acid was shaken for 3 h at 90oC. After cooling to room temperature the mixture was poured into crushed ice, collected crude product during filtration, washed with water and purified by crystallization from ethanol. The melting point of 170 - 171oC.

Elemental analysis for C17H12O3S:

Calculated (%): C, 68.90; H, 4.08; S At 10.82.

Found (%): C At 68.59; H, 4.13; S 10.69.

The NMR spectra at 200 MHz (CDCl3, ):

8.83 - 8.95 (dd, 1H, CH benzothiophene in position 5);

8.45 - 8.53 (dd, 1H, CH benzothiophene in position 7);

7.68 - 7.80 (m, 2H, 2-phenyl CHs in position 2 and 6);

7.55 - 7.65 (t, 1H, CH benzothiophene at position 6);

7.45 - 7.55 (m, 3, 2-phenyl CHs in position 3, 4 and 5);

7.24 (s, 1H, CH benzothiophene at position 3);

4.00 (s, 3H, COOH3).

8-Etoxycarbonyl-3-methyl bromide-4-oxo-2-phenyl-4H-1-benzopyran (intermediate connection XCIII).

A mixture of 9.2 g of 8-etoxycarbonyl-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran (obtained according to the Da Re, P et al., J. Med. Pharm. Chem., 2, 263, 1960), 6,4 g N-bromosuccinimide and 0.04 g of benzoyl peroxide in 80 ml of anhydrous carbon tetrachloride was dissolved at reflux distilled within 1.5 hours After cooling to room temperature the formed succinimide was collected with suction and washed with cold tetrachloride , filtering with suction. The result was obtained 9.2 g of compound indicated in the title, which after crystallization from a mixture of acetone : n-hexane, melted at 133 - 134oC.

8-Etoxycarbonyl-3-acetoxymethyl-4-oxo-2-phenyl-4H-1 - benzopyran (intermediate connection XCIV).

A solution of 10.2 g of three-hydrate of sodium acetate in 30 ml of water at room temperature was added dropwise to a solution of 29 g of the intermediate XCIII in 300 ml of dimethylformamide. After shaking for 1.5 h at 50oC the reaction mixture was poured into 2 l of water. The connection specified in the title, precipitated, was collected during the filtration with suction; after crystallization from acetone there was obtained 20 g of compound with a melting point of 151 - 152oC.

8-Carboxy-3-hydroxymethyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate connection XCV).

116 ml of 1 n sodium hydroxide was added over 10 min to shake a suspension of 14.8 g of the intermediate XCIV in 300 ml of 95% ethanol. Then the reaction mixture was heated for 15 min at 60 - 65oC, the resulting clear solution was kept at room temperature for 1 h After evaporation in vacuo the residue was dissolved in 200 ml of water, and the solution in which the temperature of the connection, specified in the title, were collected during the filtration with suction, washed with water and crystallized from isopropanol. The result was obtained 9.3 g of compound with a melting point 237 - 240oC.

Ethyl 2-(4-Nitrobenzyloxy)-3-propionyl benzoate (intermediate compound XCVI).

The connection specified in the title, was obtained according to the procedure described for intermediate XC, only instead of 2-frailcare used 4-nitrobenzoate. Received the product in the form of solid viscoplasticity substance (melting point 78 - 80oC)

The NMR spectra at 60 MHz (CDCl3, ):

7.85 - 8.50 (m, 6H, aromatic CHs);

7.50 (t, 1H, CHs in position 5 phenolic ring);

4.25 (g, 2H, CH2O);

3.95 (g, 2H, CH2);

0.95-1.30 (m, 6H, CH3).

8-Etoxycarbonyl-3-methyl-2-(4-nitrophenyl)-4-oxo-4H-1-benzopyran (intermediate compound XXI).

The mixture was 29.7 g of intermediate compound XCVI and 10.18 g of anhydrous t-butoxide potassium in 89 ml of anhydrous pyridine was dissolved for 13 h at 100oC. the Reaction mixture was cooled to room temperature, poured into 400 ml of 4 Nude hydrochloric acid and was extracted with dichloromethane. The organic layer is repeatedly washed with water, AOI product was purified column chromatography on silica gel, elwira a mixture of hexane : ethyl acetate 7:3. Evaporation in vacuo of the collected fractions gave 7 g of compound indicated in the title, which melted at 145 - 148oC.

8-Carboxy-3-methyl-2-(4-nitrophenyl)-4-oxo-4H-1-benzopyran (intermediate compound XCVIII).

A suspension of 0.38 g of intermediate compound XCVII in 4.75 ml of dioxane and 4.75 ml of methanol was shaken under 50oC. Was added 1.29 ml of 1 n sodium hydroxide, and at the same temperature for 3 h continued shaking. The reaction mixture was cooled to room temperature and added 3 N. hydrochloric acid up until the pH was not equal to 1. When filtering the resulting suspension with suction was obtained 0.13 g of compound indicated in the title; after crystallization from dioxane it melted at 320 - 321oC.

8-Etoxycarbonyl-3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran (intermediate connection XCXIX).

3.16 ml of 1,8-diazabicyclo [5.4.0]undec-7-ene was added dropwise via syringe at 0oC to shake a mixture of 3 g of ethyl 2-hydroxy-3-propionyl benzoate and 5.53 ml triperoxonane anhydride. The reaction mixture was shaken at 60oC for 4 h, then cooled to room temperature and diluted etilazette and evaporated to dryness in vacuum. The residue was purified column chromatography on silica gel, elwira a mixture of petroleum ether : ethyl acetate 95:5; as a result, there was obtained 0.8 g of compound indicated in the title.

The NMR spectra at 200 MHz (CDCl3, ):

8.41; 8.37 (2dd; 2H, CHs in position 5 and 7 benzopyrrole ring);

7.51 (t, 1H, CH at 6 position benzopyrrole ring);

4.46 (q, 2H, COOCH2);

2.22 - 2.27 (m, 3H, JH-F= 2.16 Hz, CH3in position 3 benzopyrrole ring);

1.39 (t, 3H, CH2CH3).

8-Carboxy-3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran (intermediate compound C).

The connection specified in the title, was obtained in the same manner as the intermediate compound LXII, only instead of connecting LXI used intermediate compound XCIX and after dilution with water instead of filtering carried out the extraction with ethyl acetate. After drying on anhydrous sodium sulfate and evaporation to dryness in vacuo of the organic layer was obtained the compound indicated in the title, in the form of a solid residue, which melted at 175 - 178oC.

3-[4-(2-Methoxyphenyl)-1-piperazinil] -N-methyl-Propylamine (intermediate compound CI).

42 ml of 35% aqueous methylamine was added to a solution of 8.2 g of 3-[4-(oC for 5 h, then was cooled to 30oC. the Solvent is evaporated in vacuo, and the residue was shaken for 30 min with 100 ml of diethyl ether. Solids collected by filtration with suction, dissolved in 200 ml of a mixture of chloroform : 5 N. methanolic ammonia 100 : 5 to 100 : 15. The fractions containing the compound indicated in the title, were collected together and evaporated in vacuum. The result was obtained 3 g of intermediate compound CI in the form of a thick oil.

The NMR spectra at 60 MHz (DMCO-d6, ):

6.80 (s, 4H, aromatic CHs);

3.75 (s, 3H, OCH3);

3.20 - 2.75 (m, 4H, CH3s piperazine in position 3, 5);

2.75 - 2.10 (m, 8H, CH2s piperazine in position 2, 6, and CH2CH2CH2);

2.40 (s, 1H, NH);

2.30 (s, 3H, NCH3);

1.80 - 1.40 (m, 2H, CH2CH2CH2).

Ethyl 2-benzoyl-3-ethylbenzo[b] furan-7-carboxylate (intermediate compound CII).

A mixture of 11.1 g of ethyl 2-hydroxy-3-propionyl benzoate, 9.9 g of pencilvania, 6.9 g of anhydrous potassium carbonate and 200 ml of acetone was dissolved at the temperature of reflux distilled within 7 hours After cooling to room temperature, the inorganic salt was separated by filtration and the solution evaporated in vacuo. The residue was purified thin layer of HRO is the Aquum collected fractions, containing it was then crystallized from 90% ethanol. Yield 9.8 g, melting point 64 - 66oC.

7-Carboxy-2-benzoyl-3-ethyl-benzo[b]furan (intermediate compound III).

A mixture of 7 g of intermediate compound CII, 275 ml 0.95 N. sodium hydroxide and 400 ml of dioxane was shaken for 4 h at the temperature of reflux distilled. After cooling to room temperature dioxin evaporated in vacuum and replaced by the same volume of water. After filtration using charcoal, the solution was acidified with diluted hydrochloric acid, the precipitate was filtered and purified by crystallization from acetone. Output 4.94 g, melting point 193 - 195oC.

8-Methoxycarbonyl-3-methyl-2-(4-were)-4-oxo-4H-1-benzopyran (intermediate compound CIV).

This compound was obtained in three stages according to the methods described for intermediate XC (the first stage) and intermediate compound LXXX (the second and third stages). In the first stage 4-methylbenzoate was used instead of 2-frailcare, and methyl 2-hydroxy-3-propionyl benzoate was used instead of ethyl 2 - hydroxy-3-propionyl benzoate. The reaction proceeded at room temperature for 4 hours the result was obtained 2-(4-mative is UP>C without further purification. In the third stage, instead of 37% hydrochloric acid was using 96% sulfuric acid. The connection specified in the title, melted at 174 - 175oC after crystallization from ethanol.

8 Ethoxy-carbonyl-2-(4-biphenylyl)-3-methyl-4-oxo-4H-1-benzopyran (intermediate CV connection).

This compound was obtained in three stages according to the methods described for intermediate XC (the first stage) and the intermediate CIV (the second and third stages). At the first stage 4-phenylbenzophenone used instead of 2-frailcare, and the reaction continued for 20 h at room temperature and 13 h at reflux distilled. Purification was performed column chromatography on silica gel, elwira a mixture of petroleum ether : ethyl acetate 100 : 5 to 100 : 10, the result was obtained 2-(4-biphenylyl)-3-propionyl benzoate. The connection specified in the title, melted at 165 - 167oC after washing with 95% ethanol.

8-Carboxy-2-(4-biphenylyl)-3-methyl-4-oxo-4H-1-benzopyran (intermediate compound CVI).

A mixture of 4.3 g of intermediate compound CV and 35 ml of 35% hydrochloric acid in 50 ml of 1,4-dioxane and 15 ml of water was dissolved at reflux distilled within 16 hours After cooling, the mixture was poured into 200 ml of water and was extracted with what I'm after acidification of the aqueous layer diluted hydrochloric acid, collected with suction, washed with water and dried. The result was obtained 2.5 g of compound indicated in the title, which melted at 242.5 - 244oC.

8-Carboxy-2-(4-hydroxyphenyl)-3-methyl-4-oxo-4H-1-benzopyran (intermediate compound CVII).

A mixture of 3 g of 8-etoxycarbonyl-2-(4-methoxyphenyl)-3-methyl-4-oxo-4H-1-benzopyran (obtained according to JP 58-225083) and 60 ml of 48% Hydrobromic acid and 80 ml of acetic acid was dissolved at reflux distilled within 8 hours After cooling, the mixture was poured into 500 ml of water, and the precipitate was collected with suction and washed with water. The crude product was purified by thin-layer chromatography, elwira first with a mixture of chloroform : isopropanol 9 : 1 to 7 : 3 and then with methanol. The result was obtained 1 g of compound indicated in the title, which melted at 300oC.

4-[4-(2-Methoxyphenyl)-1-piperazinil] -N-methyl-butylamine (intermediate compound VIII).

A solution of 3.8 ml triperoxonane anhydride in 25 ml of anhydrous dichloromethane was added dropwise with shaking at 0oC to a solution of 2.53 g of 4-[4-(2-methoxyphenyl)-1-piperazinil] -butylamine in 25 ml of anhydrous dichloromethane. After shaking for 2 h at room temperature the reaction mixture is diluted dhakwani; the result of 3.3 g of pure 4-[4-(2-methoxyphenyl)-1-piperazinil]-N-TRIFLUOROACETYL-butylamine.

The NMR spectra at 60 MHz (CDCl3, ):

7.70 - 8.00 (bs, 1H, NH);

6.80 - 7.20 (m, 4H, aromatic CHs);

3.85 (s, 3H, CH3O);

2.90 - 3.80 (m, 12H, CH2s piperazine, CH2N and CH2NHCO);

1.50 -2.05 (m, 4H, C-CH2CH2-C).

To a solution containing 3.3 g of the above intermediate compound in 46 ml of anhydrous dimethylformamide with shaking at 0oC portions was added 0.88 g of 50% sodium hydride. After shaking for 1 h at the same temperature was added 0,57 ml under the conditions. The reaction mixture was shaken for another 1.5 h at 0oC, and then poured into water and was extracted with ethyl acetate. The organic layer was washed with water, dried on anhydrous sodium sulfate and was evaporated to dryness in vacuum. The result was obtained 1.13 g of crude 4-[4-(2-methoxyphenyl)-1-piperazinil] -N-TRIFLUOROACETYL-N-methyl-butylamine, which is used in the following stage without further purification. 0.18 g of sodium borohydride was added to a solution of 1.13 g of the above intermediate compound in 30 ml of ethanol, and the resulting mixture was shaken at 60oC for 1 h After cooling to room temperature is stirred for anhydrous sodium sulfate and evaporated in vacuum to dryness. The result was obtained 0.82 g of pure compound indicated in the title.

The NMR spectra at 60 MHz (CDCl3, ):

6.80 - 7.20 (m, 4H, aromatic CHs);

3.85 (s, 3H, CH3O);

2.90 - 3.20 (m, 4H, CH2s piperazine position 3 and 5);

2.30 - 2.80 (m, 8H, CH2s piperazine position 2 and 6; 2 CH2N);

2.50 (s, 3H, CH3N);

1.80 (s, 1H, NH);

1.40 - 1.80 (m, 4H, C-CH2-CH2-C).

1-(3-Amino-2,2-dimethylpropyl)-4-(2-methoxyphenyl)-piperazine.

The connection specified in the title, can be obtained by treating 1-(2-methoxyphenyl)-piperazine-Isobutyraldehyde, 37% formaldehyde in water and acetic acid at 90 - 150oC or the same reagents in ethanolic hydrogen chloride (reaction manniche). The compound obtained is 1-(2-formyl-2-methylpropyl)-4-(2-methoxyphenyl)-piperazine miniroot treatment with excess ammonia in terms of recovery. The latter may give hydrogen or a catalyst (such as PD/C, Raney Nickel or platinum dioxide) in a solvent (e.g. ethanol, methanol, isopropanol, dichloromethane, chloroform or dimethylformamide) at a temperature of from room temperature up to 80oC or a metal hydride (for example, borohydride sodium, cyanoborohydride sodium or potassium or triacetoxy and acid (for example, gaseous hydrogen chloride or acetic).

This compound can react with 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyrano as described below in example 12, giving 8-(2,2-dimethyl-3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades)- 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

8-Triftoratsetata-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

This compound was obtained according to the procedure described for intermediate XXIII, but only when used intermediate compound XXIV instead of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. It can be used as the source instead of intermediate compound XXIII in the reaction described in example 32 to obtain 8-(2-[4-(2-methoxyphenyl)-1-piperazinil]-ethylaminomethyl)-3-methyl-4 - oxo-2-phenyl-4H-1-benzopyran.

8-(2-Chloroethylthiomethyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

This intermediate compound can be obtained by the method described for intermediate compounds XLIV, only when using the intermediate XXIV instead of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. It can interact with the compound having the formula H-B, according to the reaction path (a), to which Iran.

This compound can be obtained by the interaction of the intermediate compound XXIV with 2 chloroethylsulphonic in halogenated solvent type dichloromethane in presence of triethylamine at 0 - 40oC, according to A. A. Goldberg, J. Chem.Soc., 464, 1945. This connection can communicate with a suitable connection H-B, according to the reaction path (m), in order to receive the corresponding end of the connection.

In doing so, as described above, but using as the original 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, you can get end connection F1'-Y36-(CH2)2-B.

8-Chlorosulfonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

This intermediate compound can be obtained by the interaction of 8-amylinomimetic-3-methyl-4-2-phenyl-4H-1-benzopyran (the synthesis of which is described in obtaining the intermediate XXI) with chlorine in water at a temperature of from -10 to +10oC according to the work. T. B. Johnson et al., J. Chem.Soc., 61, 2548, 1939. The interaction of this intermediate with the appropriate compounds of formula A-NH-Z-B, following the path of the reaction n can be obtained target products.

Example 1. 8-{ 2-[4-(2-Methoxyphenyl)-1-piperazinil] -1-oxoethyl}- 3-IU the La was added dropwise at 20 25oC to shake a mixture containing 21.4 g of the intermediate compound VI and 4.1 g of potassium carbonate in 120 ml of methanol. After shaking at the same temperature for 4 h, the reaction mixture was evaporated in vacuum. The residue was extracted with chloroform, and the organic solution washed with water, dried on anhydrous sodium sulfate/potassium, filtered and evaporated in vacuum. The resulting crude product was dissolved in acetone and added a slight excess of ethanolic hydrogen chloride. After filtration with suction and recrystallization from 95% ethanol was obtained 16.3 g of compound indicated in the title, with a melting point 195 - 199oC.

Example 2. 8-{2-[4-(2-Were)-1-piperazinil]-1-oxoethyl}-3 - methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

This compound was obtained according to example 1, except using 1-(2-were)-piperazine instead of 1-(2-methoxyphenyl)-piperazine and the reaction was carried out for 1 h in dimethylformamide, and not within 4 h in methanol. Melting point 203 - 206oC (isopropanol)

Example 3. 8-{2-[4-(2-Ethoxyphenyl)-1-piperazinil]-1-oxoethyl}- 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

This compound was obtained according to example 1, but welterfolge, not for 4 h in methanol. Melting point 208 - 210oC (isopropanol).

Example 4. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-1-oxopropyl}- 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

A solution of 10 ml of 37% formaldehyde in 15 ml of methanol was added dropwise at 0oC for 3 min to a solution of 5.75 g of 1-(2-methoxyphenyl)-piperazine in 10 ml of methanol. After soaking for 12 h at 0oC the mixture was evaporated in vacuo and re-dissolved in 15 ml of methanol. 20 ml 3.6 N. hydrogen chloride and diethyl ether was added at 0oC. After shaking in a vacuum the residue is suspended in 15 ml of 1,4-dioxane. In the conditions of shaking at 20 - 25oC was added a solution of 8.3 g of intermediate compound V in 100 ml of 1,4-dioxane. After shaking for 8 h at reflux distilled, the reaction mixture was cooled to 30 - 40oC. Then was added to a mixture of 50 ml of methanol and the mixture was subjected to reflux distilled even 2 hours After cooling to 20 to 25oC the resulting solution was diluted with 300 ml diethyl ether. When the specified temperature, the shaking was continued for another 3 hours the Connection specified in the title, was obtained after filtration with suction and recrystallization from ethanol. Output 4 g, melting point 209 - 210

A mixture of 4.24 g of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 6.3 g of anhydrous potassium carbonate in 60 ml of dimethylformamide was shaken for 30 min at 80oC. Then was added 5.23 g of 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine and shaking was continued at 80oC for 3.5 hours the Reaction mixture was cooled to room temperature, poured into a mixture of ice water and was extracted with ethyl acetate. The organic extracts were washed with an aqueous solution of sodium chloride, dried on anhydrous sodium sulfate and evaporated in vacuum to dryness. The residue was transferred to ethanol and to the solution was added an excess of ethanolic hydrogen chloride. The output of the connection specified in the title, was 8.16 g, melting point 198 - 203oC.

Example 6. 8-{2-[4-(2-Methoxyphenyl)-1-piperazinil]-etoxycarbonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran the dihydrochloride.

The connection specified in the title, was obtained by the method described in example 5, but instead of 1-(3-chloropropyl)-4-(2 - methoxyphenyl)-piperazine used 1-(2-chloroethyl)-4-(2 - methoxyphenyl)-piperazine. The melting temperature was 200 - 203oC (ethanol).

Example 7. 8-{3-[4-(2-Chlorophenyl-1-piperazinil]-propoxycarbonyl}- 3-methyl-4-oxo-2-phenyl-4H-1-benzole in 25 ml of dimethylformamide was shaken at room temperature for 15 minutes Was added 4.81 g of intermediate compound 1 and the shaking continued for 2 days. Then the reaction mixture was poured into 200 ml of cold water and was extracted with diethyl ether and ethyl acetate. The organic extracts were washed in turn with an aqueous solution of sodium chloride, 0.1 N. acetic acid, aqueous solution of sodium chloride, aqueous 4% solution of sodium carbonate and water and then dried on anhydrous sodium sulfate. After evaporation to dryness in vacuo the residue was dissolved in 160 ml of acetonitrile and added an excess of hydrogen chloride in diethyl ether. Insoluble compound indicated in the title, was recrystallized from acetonitrile. Output 3.6 g, melting point 138 - 143oC

Example 8. 8-[3-(4-Phenyl-1-piperazinil)-propoxycarbonyl] -3 - methyl-4-oxo-2-phenyl-4H-1-benzopyran the dihydrochloride.

The connection specified in the title, was obtained by the method described in example 7, but instead of 1-(2-chlorophenyl)-piperazine hydrochloride used 1-phenyl-piperazine. The recrystallization was carried out from methanol, melting point 229 - 231oC.

Example 9. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propoxycarbonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran the dihydrochloride.

Connection, given hydrochloride used 1-(2-methoxyphenyl)-piperazine hydrochloride. This is an alternative way for the product from example 5.

Example 10. 8-{ 3-[4-(2-Methoxyphenyl)-1-piperazinil]-2-methyl-2 - propoxycarbonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran the dihydrochloride.

5.29 g of intermediate compound XXVIII in 25 ml 1,2-dichloroethane at 60oC dropwise added to a solution of 6 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 22 ml of 1,2-dichloroethane. The reaction mixture was subjected to reflux distilled for 16 h, then cooled to room temperature and poured into cold 0.5 n sodium hydroxide solution. Then added water and dichloromethane. The organic phase was separated, washed with an aqueous solution of sodium chloride and dried on anhydrous sodium sulfate. The solvents are evaporated and the oily residue was purified by thin-layer chromatography on silica gel, elwira a mixture of petroleum ether : ethyl acetate 85 : 15. The collected fraction was evaporated in vacuum to dryness, the residue dissolved in ethanol. To obtain the connection specified in the title, was added an excess of ethanolic hydrogen chloride. The result was 6.71 g of compound indicated in the title, with a melting point of 203 204oC.

Example 11. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propellerblades}-3-myelocele connection XXXVII was heated at 180oC for 5 hours and After cooling the mass of dark color was purified by thin-layer chromatography on silica gel, elwira a mixture of dichloromethane : methanol 100 : 3. The fractions containing the compound indicated in the title, were gathered together, the solvent was boiled away in vacuum and the residue is dissolved in boiling ethanol. The solution was filtered, acidified ethanolic hydrogen chloride and left overnight at 20 - 25oC. the Crude product was collected with filtration and crystallized from ethanol was obtained from 5 g of compound indicated in the title, having a melting point 182 - 186oC.

Example 12. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propellerblades}-3-methyl-4 - oxo-2-phenyl-4H-1-benzopyran the dihydrochloride hemihydrate.

A solution of 4.48 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran in 40 ml of chloroform was added in drops within 10 min at room temperature to a solution of 3.74 g of 3-[4-(2-methoxyphenyl)-1-piperazinil]-Propylamine obtained according to GB 2161807, and 1.97 g of triethylamine in 50 ml of chloroform. After shaking for 2 h, the solution was washed first with 0.5 G. hydrochloric acid, then saturated aqueous sodium bicarbonate and finally with water. Chloroformyl the solution was dried on besod is 11; the result is 6.67 g of compound indicated in the title, with a melting point 182 - 186oC. the path is an alternative way of obtaining the product from example 11.

Received also the following salts: hydrate monochloride, melting point 151 - 154oC, nanomeasurement, melting point 162 - 164oC and ()-hydrate of premalatha, melting point 110 - 112oC.

This example describes the condensation of the amine, 3-[4-(2-methoxyphenyl)-1-piperazinil] -Propylamine with carbonylchloride and 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonylchloride. It should be noted that Amin is possible to condense with the corresponding free acid or the corresponding ethyl ester by heating them equimolar amounts of solvent or without him. When using a solvent suitable hydrophilic or hydrophobic solvent with a high boiling point. The amine can be synthesized also at room temperature with an equimolar amount of the corresponding free acid in the presence of N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine in solvent type dichloromethane, chloroform, tetrahydrofuran or dimethylformamide.

Example 13. 8-{2-[4-( CLASS="ptx2">

The connection specified in the title, was obtained by the method described in example 16, only used intermediate compound XIV instead of intermediate compounds XV and were heated at 55 - 60oC for 32 h in Addition, there were the following changes. After collecting the base filtering carried out the cleaning of thin-layer chromatography on silica gel, first elwira a mixture of chloroform:methanol 100:0.5, and then 100:1. The fractions containing the compound indicated in the title, were gathered together, and the solvents removed in vacuo. The residue was led their ethanol. After filtration of the solid residue was transferred into a pot of boiling water and to dissolve it, add a sufficient quantity of dilute hydrochloric acid. The crystalline salt was separated upon cooling and was collected during the filtration with suction. Melting point 119 - 123oC.

Example 14. 8-{3-[2-(2-Methoxyphenoxy)-ethylamino]-propellerblades}-3-methyl-4 - oxo-2-phenyl-4H-1-benzopyran hydrochloride.

The connection specified in the title was obtained as described in example 1, but instead of 1-(2-methoxyphenyl)-piperazine was used 2-(2-methoxyphenoxy)-ethylamine (obtained according Augstein, J. et. al., J. Med. Chem. , 8,356, 1965), and about 100 : 5. Melting point 200 - 202oC (ethanol).

Example 15. 8-[3-(4-Phenyl-1-piperazinil)-propellerblades]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran monochloride hemihydrate.

The method described in example 11, there was obtained the compound indicated in the title; only instead of 1-(2-methoxyphenyl)-piperazine used 1-phenylpiperazin; and instead of heating for 5 h heating for 2 hours as of the eluate was used a mixture of dichloromethane : methanol 100 : 4. Melting point (decomposition) 255 - 258oC (87% ethanol).

Example 16. 8-{N-Methyl-2-[4-(2-methoxyphenyl)-1-piperazinil]-ethylcarbamate}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran monohydrochloride.

A mixture of 3.56 g of intermediate compound XV, of 2.35 g of 1-(2-methoxyphenyl)-piperazine, 2.76 g of anhydrous potassium carbonate and 1.66 g of potassium iodide in 25 ml of dimethylformamide was shaken for 6 h at 100oC. After cooling, the solvent was removed in vacuo and the residue was transferred into 50 ml of water was shaken at room temperature for 1 h and collected during the filtration process. Then washed with water and was led from 95% ethanol in the presence of small amounts of activated carbon (for discoloration). The base was dissolved in 105 ml of boiling 0.086 N. hydrochloric acid. After shown in the title (melting point 201 - 203oC).

Example 17. 8-{1-Hydroxy-2-[4-(2-methoxyphenyl)-1-piperazinil]-ethyl}-3-methyl-4 - oxo-2-phenyl-4H-1-benzopyran hydrochloride.

1.36 g of sodium borohydride was added in portions to a solution of 15.5 g of compound obtained in example 1 in 1500 ml of methanol at 0 to 5oC. After shaking at a temperature of 0 to 5oC for 90 min for a slight acidification of the reaction mixture was added 3 N. hydrochloric acid; the mixture is then evaporated in vacuum. The residue was dissolved in 2 N. aqueous sodium hydroxide solution and was extracted with chloroform. The organic layer was dried on anhydrous sodium sulfate/calcium chloride, filtered, acidified ethanolic hydrogen chloride and evaporated in vacuum. After washing with diethyl ether, the crude product was led from ethanol was obtained 9.5 g of compound indicated in the title, with a melting point 248 - 249oC.

Example 18. 8-{1-Hydroxy-2-[4-(2-were)-1-piperazinil]-ethyl}-3-methyl-4-oxo-2 - phenyl-4H-1-benzopyran hydrochloride.

This compound was obtained according to example 17, only as a source it is better to use the compound obtained in example 2 than the compound obtained in example 1. Melting point 257 - 258o

This compound was obtained according to example 17, only better as the original use of the compound obtained in example 3 than the compound obtained in example 1. Melting point 241 - 242oC (methanol).

Example 20. 8-{1-Hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinil]-propyl}-3-methyl-4 - oxo-2-phenyl-4H-1-benzopyran hydrochloride.

This compound was obtained according to example 17, only better as the original use of the compound obtained in example 4 than the compound obtained in example 1. The crude base was purified by thin-layer chromatography (silica gel, eluate is a mixture of ethyl acetate : chloroform 4 : 1). The fractions containing the pure basis, were gathered together, acidified with ethanolic hydrogen chloride and evaporated in vacuum. The residue was led from ethanol. Melting point 156 - 160oC.

Example 21. 8-{1-Hydroxy-4-[4-(2-methoxyphenyl)-1-piperazinil]-butyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride monohydrate.

A solution of 3.04 g of intermediate compound XXXVIII and 2.45 g of 1-(2-methoxyphenyl)-piperazine in 21 ml of anhydrous dimethylformamide was shaken at room temperature for 5 hours Then added 1.22 g of 1-(2-methoxyphenyl)-piperazine and the mixture strival aqueous solution of sodium bicarbonate, then an aqueous solution of sodium chloride and evaporated to dryness in vacuum. The residue was purified by thin-layer chromatography on silica gel, elwira a mixture of ethyl acetate : methanol 95 : 5. The collected fractions were shaken in a rotary evaporator, and the residue was dissolved in 0.81 M ethanolic hydrogen chloride and again shook in a vacuum. The solid residue was led from a mixture of water : ethanol 9 : 1, in order to obtain 2.43 g of compound indicated in the title, with a melting point of 144 - 146oC.

Example 22. 8-{1-Ethoxy-2-[4-(2-methoxyphenyl)-1-piperazinil]-ethyl}-3-methyl-4-oxo-2 - phenyl-4H-1-benzopyran hydrochloride.

6 ml of anhydrous dimethyl sulfoxide was added to 6.55 g of sodium hydride (50% in mineral oil, repeatedly washed with hexane) under nitrogen. A solution of 3 g of the compound obtained in example 17, in 50 ml of anhydrous dimethyl sulfoxide at 20-25oC was added to this mixture. After shaking at 20oC for 1 h was added 0.66 g of ethylbromide. The reaction mixture was shaken at the above temperature for another 20 min and then poured into a mixture of ice water. The crude product obtained after filtration with suction, was purified by thin-layer chromatography (silica gel, eluate - a mixture of chloroform : ethyl acetate 8 : 2). gorodom and shook in a vacuum. The residue was led from a mixture of chloroform : diethyl ether, and dried in vacuum. The result was obtained 1.6 g of compound indicated in the title, with a melting point 209oC.

Example 23. 8-{N-Methyl-2-[4-(2-methoxyphenyl)-1-piperazinil]-ethylaminomethyl}-3 - methyl-4-oxo-2-phenyl-4H-1-benzopyran the dihydrochloride hemihydrate.

A mixture of 5.2 g of intermediate compound XXVII, 3.1 g of 1-(2-methoxyphenyl)-piperazine and 2.2 g of anhydrous potassium carbonate in 50 ml of dimethylformamide was shaken for 7 h at 70oC. After cooling to 20 to 25oC the reaction mixture was poured into 500 ml of water and was extracted with dichloromethane. The organic phase is washed with water and dried on anhydrous sodium sulfate. The solvent was removed in vacuum. The residue was purified by thin-layer chromatography on silica gel, elwira a mixture of ethyl acetate: petroleum ether 98:2. The connection specified in the title, was obtained by salt formation using ethanolic hydrogen chloride. Its melting point 217-219oC.

Example 24. 8-{N-Acetyl-2-[4-(2-methoxyphenyl)-1-piperazinil]-ethylaminomethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

A mixture of intermediate compound XXXIII and 5.3 g of 1-(2-methoxyphenyl)-piperazine in 75 ml of d is lively in water and dried on anhydrous sodium sulfate. The solvent was removed in vacuum. The residue was purified by thin-layer chromatography on silica gel, elwira a mixture of dichloromethane : methanol 100 : 0.2. After the formation of the salt with ethanolic hydrogen chloride and recrystallization from methanol there was obtained 4.4 g of compound indicated in the title. This compound melted at 227-228oC and contained 1 equivalent of methanol.

Example 25. 8-[4-2-Methoxyphenyl)-1-piperazinylmethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

A mixture of 3.42 g of intermediate compound XXXII, 2.74 g of 1-(2-methoxyphenyl)-piperazine and 0.71 g of anhydrous potassium carbonate in 34 ml of anhydrous dimethylformamide was shaken for 2 h at 0oC. the Reaction mixture was poured into water and filtered with suction. The obtained solid residue was purified by thin-layer chromatography on silica gel, elwira a mixture of ethyl acetate : petroleum ether 6 : 4. The collected fraction was evaporated in vacuum to dryness, and the residue was led from methyl ethyl ketone. The resulting base was treated in ethanol solution molar equivalent of water 2.25 N. hydrochloric acid to obtain the compound indicated in the title; melting point 168-170oC.

Example 26. 8-{N-Methyl-N-[4-(2-methox the ü 5 g of intermediate compound XXXI, 2.9 g of 1-(2-methoxyphenyl)-piperazine and 2 g of anhydrous potassium carbonate in 50 ml of dimethylformamide was shaken for 3 h at 20 - 25oC. Then the reaction mixture was poured into 500 ml of water and was extracted with dichloromethane. The organic phase is washed with water and dried on anhydrous sodium sulfate. The solvent was removed in vacuum. The residue was purified by thin-layer chromatography on silica gel, elwira a mixture of ethyl acetate : petroleum ether 6 : 4, and was led from acetone. There was obtained 3.6 g of the base of the connection specified in the title, which melted at 144 - 145oC. the Base was dissolved in ethanol, adding 8 N. hydrochloric acid and water, as a result, after drying in vacuum at 100oC was obtained the compound indicated in the title, with a melting point of 218 to 220oC.

Example 27. 8-{2-[4-(2-Methoxyphenyl)-1-piperazinil]-ethoxymethyl}- 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran the dihydrochloride.

A mixture of 4 g of intermediate compound XVIII, 2.4 g of 1-(2-methoxyphenyl)-piperazine, 1.96 g of potassium iodide and 1.65 g of anhydrous potassium carbonate in 40 ml of anhydrous dimethylformamide was dissolved in 7 h at 90oC. After cooling to room temperature the mixture is poured into water and was extracted with dichloromethane. United extract. The residue was led from ethyl acetate, and the collected crystals were dissolved in ethanol and treated with excess ethanolic hydrogen chloride. The resulting 5.21 g of compound indicated in the title, with a melting point 199 - 201oC.

Example 28. 8-{2-[2-(2-Ethoxyphenoxy)-ethylamino]-ethoxymethyl}- 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

The connection specified in the title, was obtained according to the procedure described in example 27, but instead of 1-(2-methoxyphenyl)-piperazine was used 2-(2-ethoxyphenoxy)-ethylamine and spent stage purification by thin layer chromatography on silica gel, elwira a mixture of ethyl acetate : methanol 97 : 3. The result was obtained 4.25 g of compound indicated in the title. Melting point 191 - 193oC.

Example 29. 8-{2-[4-(2-Methoxyphenyl)-1-piperazinil]-ethylthiomethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

2.5 g of potassium carbonate, 2.13 g of potassium iodide and 3.15 g of 1-(2-methoxyphenyl)-piperazine was added to a solution of 5 g of intermediate compound XXI in 50 ml of dimethylformamide, the mixture was shaken at 90oC for 4.5 h, After cooling to room temperature the reaction mixture was poured into 450 ml of water and was extracted with whom and in vacuum. The residue was dissolved in acetone and the resulting solution was treated with a molar equivalent of 3.8 N. hydrogen chloride in diethyl ether. Then filtered and recrystallization from ethanol; the resulting 6.15 g of compound indicated in the title, with a melting point 223 - 224oC.

Example 30. 8-{2-[4-(2-Methoxyphenyl)-1-piperazinil]- ethylsulfanyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran the dihydrochloride hemihydrate.

The connection specified in the title, was obtained by the method described in example 29, but instead of intermediate compound XXI was used intermediate compound XXVI, and the shaking was not conducted for 4.5 h, and 2.5 h After the usual procedure, the residue was purified by thin-layer chromatography on silica gel, elwira a mixture of ethyl acetate:methanol 97:3. The collected fractions were acidified with excess ethanolic hydrogen chloride and evaporated to dryness in vacuum. The residue was led from ethanol, the result was obtained 5.2 g of compound indicated in the title, with a melting point of 170 172oC. the Specified connection contains 1 equivalent of ethanol.

Example 31. 8-{2-[4-(2-Methoxyphenyl)-1-piperazinil]- ethylsulfanyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

oC. the resulting material was dissolved in 1,2-dichloroethane and was acidified ethanolic hydrogen chloride. After recrystallization from a mixture of methanol:water 1:3.5 was obtained 4.4 g of compound indicated in the title, melting point 229 - 233oC.

Example 32. 8-{ 2-[4-(2-Methoxyphenyl)-1-piperazinil] -ethylamino}- 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran the dihydrochloride.

A solution of 3.7 g of intermediate compound XXIII in 10 ml of dimethylformamide was added in drops at 0oC to a suspension of 0.9 g of sodium hydride (50% in mineral oil) in 9 ml of dimethylformamide. The cooling bath was removed, and after 30 min at 20 - 25oC was added a solution of 4.1 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine in 10 ml of dimethylformamide. The mixture was shaken for 5 h at 90oC, and then cooled to 20 to 25oC. was Added 0.25 g of sodium hydride (50% in mineral oil) and then 1.36 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine in 5 ml of formamide. The mixture was shaken for 8 h at 90oC, and then cooled to 20 to 25oC. Carefully added 200 ml of water, and then spent the extraction with ethyl acetate. the STATCOM was purified by thin-layer chromatography on silica gel, elwira a mixture of n-hexane : ethyl acetate 3 : 2. The result was the mixture of the base of the connection specified in the title, with the corresponding N-triperoxonane connection.

3.8 g of this mixture was dissolved in 35 ml of ethanol and 35 ml of dimethylsulfoxide. To this solution in portions at 20 - 25oC, was added 0.55 g of sodium borohydride. At the same temperature and the mixture was shaken for 3 h, then poured into 200 ml of water and was extracted with ethyl acetate. The organic layers were washed with water, dried on anhydrous sodium sulfate and evaporated to dryness in a vacuum. The residue was dissolved in dichloromethane. To obtain the connection specified in the title, was added 2 equivalent of ethanolic hydrogen chloride. The compound obtained was recrystallization from ethanol; yield 3.8 g, melting point 231 - 234oC.

Example 33. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propylamino}- 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride 2.75-hydrate.

Using 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine instead of 1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine, and the rest doing so, as described in example 32, was received on the connection specified in the title. The melting point of 206 to 208oC (10% ethanol).

A mixture of 4.5 g of intermediate compound XXXIX, 3.9 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyrane, 8.3 g of triacetoxyborohydride sodium and 3.4 ml of acetic acid in 40 ml of 1,2-dichloroethane was shaken for 6 h at 20 - 25oC. Then added 15 ml of 5% aqueous sodium bicarbonate solution and shake the mixture for another 10 minutes Then the mixture was podslushivaet the addition of 0.5 n sodium hydroxide solution and was extracted with chloroform. The organic extracts were washed with water and dried on anhydrous sodium sulfate. The solvent is evaporated in vacuo, and the residue was purified by thin-layer chromatography on silica gel, elwira a mixture of ethyl acetate : petroleum ether 9 : 1. The resulting base was dissolved in dichloromethane and added 1 equivalent of ethanolic hydrogen chloride. After removal under vacuum of the solvent the residue was led from 50% ethanol; as a result, there was obtained 1.6 g of compound indicated in the title, with a melting point of 151 - 153oC.

Example 35. 8-[N-Methyl-3-[4-(2-methoxyphenyl)-1-piperazinil]-propylamino} -3 - methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride hemihydrate.

A mixture of 4 g of the compound obtained in example 33, a base, 4.35 ml of 37% aqueous formaldehyde and 1.15 g of cyanoborohydride of sodium in 25 ml ACE is islote. After 4 h the solvent evaporated in vacuum. To the residue was added 80 ml of ethyl acetate and 200 ml of 1 n sodium hydroxide solution, cooled with ice, the organic phase is washed with water, dried on anhydrous sodium sulfate and evaporated in vacuum to dryness. The residue was purified by thin-layer chromatography on silica gel, elwira a mixture of ethyl acetate : petroleum ether 3 : 1. Thus obtained pure base was dissolved in diethyl ether. Then added 1 equivalent of ethanolic hydrogen chloride and the solvent was removed in vacuum. Crystallization of the residue from water gave 2 g of compound indicated in the title, with a melting point of 186 - 187oC.

Example 36. 8-{N-Acetyl-3-[4-(2-methoxyphenyl)-1-piperazinil]-propylamino)-3 - methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride hydrate.

A mixture of 4.8 g of the compound obtained in example 33, a base, 2.8 ml of acetic anhydride and 33 ml of pyridine was shaken for 3 h at 80oC. the Reaction mixture after cooling to 20 -25oC was poured into 200 ml of a mixture of ice-water, acidified using 10 N. hydrochloric acid and was extracted with dichloromethane. The organic extracts were washed with water, dried on anhydrous sodium sulfate and was evaporated to dryness in vacuum. The residue was purified of Tonkolili in dichloromethane. Then added 1 equivalent of ethanolic hydrogen chloride and the solvent was removed in vacuum. The residue was led from acetonitrile. Received 3 g of compound indicated in the title, which contained 0.33 equivalent of acetonitrile. Melting point 208.5 - 210.5oC.

Example 37. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propionamido}-3-methyl-4-oxo-2 - phenyl-4H-1-benzopyran hydrochloride.

A mixture of 3.97 g of intermediate compound X and 3.07 g of 1-(2-methoxyphenyl)-piperazine in 40 ml of dimethylformamide was shaken for 6 h at 60oC. Then the reaction mixture was cooled to room temperature and poured into water. The organic phase obtained in the subsequent extraction with dichloromethane, washed with water and dried on anhydrous sodium sulfate. The solvent was removed in vacuum. The crude residue was led from ethanol, the result is the basis of the connection specified in the title, which is then dissolved in hot ethanol. To the solution was added 1 molar equivalent of 0.81 M ethanolic hydrogen chloride, there was obtained 4 g of compound indicated in the title, having a melting point 255 - 257oC.

Example 38. 8-(2-[4-(2-Methoxyphenyl)-1-piperazinil] -ethylurea)-3-methoxyphenyl)-piperazine was shaken for 5 h at 100oC. Then added 1.8 g of 1-(2-methoxyphenyl)-piperazine and continued shaking for 2 h at the same temperature. The reaction mixture after cooling to room temperature, poured into water and was extracted with ethyl acetate. The organic phase is washed with an aqueous solution of sodium hydroxide, dried on anhydrous sodium sulfate and was evaporated to dryness in vacuum. The crude product was purified by thin-layer chromatography on silica gel, elwira a mixture of ethyl acetate : methanol 98 : 2. The collected fractions were evaporated to dryness in vacuum and was led from a mixture of water : ethanol 4 : 6. The crystals are re-dissolved in dichloromethane and treated with 1 molar equivalent methanesulfonic acid. The crude methanesulfonate, obtained by evaporation in a vacuum, was led from a mixture of ethyl acetate : ethanol 1 : 1. Was obtained 2.35 g of the product specified in the title, melting at 191 - 193oC.

Example 39. 8-(2-[4-(2-Methoxyphenyl)-1-piperazinil]-ethoxy)-3-methyl-4-oxo-2 - phenyl-4H-1-benzopyran hydrochloride hydrate.

A mixture of 6.61 g of intermediate compound XI, 8.34 g of 1-(2-methoxyphenyl)-piperazine and 1.26 g of sodium iodide in 70 ml of dimethylformamide was shaken for 17 h at 80oC. After cooling to 20 to 25oC reaction smeshinka extracts washed with an aqueous solution of sodium chloride, dried on anhydrous sodium sulfate and evaporated in vacuum to dryness. The residue was purified by thin-layer chromatography on silica gel, elwira a mixture of dichloromethane : methanol 99 : 1, then a mixture of dichloromethane : methanol 98 : 2. The fractions containing the base of the connection specified in the title, were gathered together, and the solvent was removed in vacuum. The residue was dissolved in ethanol and added ethanolic hydrogen chloride. The connection specified in the title, was crystallized and then collected when the filtration with suction. The recrystallization was performed from 95% ethanol. Yield 6.5 g, melting point 224 - 225oC.

Elemental analysis:

Found, %: C, 66.38, H 6,34, N 5.35, Cl 6.76, H2O 3.35,

Calculated, %: C, 66.34, H 6,14, N 5,33, Cl 6,75, H2O 3,43,

The NMR spectra at 60 MHz (CDCl3CD3OD):

7.8 - 7.1 (m, 8H, aromatic protons benzopyrrole ring);

7.1 - 6.6 (m, 4H, aromatic protons 2-metoksifenilny ring);

4.8 - 4.4 (m, 2H, OCH2);

3.9 - 3.0 (m, 10H, 5 CH2N);

3.8 (s, 3H, OCH3);

2.1 (s, 3H, CH3).

Example 40. 8-(3-[4-(2-Methoxyphenyl)-1-piperazinil]-propoxy)-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran the dihydrochloride.

This compound was obtained by the method described in example 39, but mushroomtherapy was considered unnecessary. Melting point 226 - 227oC.

Example 41. 8-(4-[4-(2-Methoxyphenyl)-1-piperazinil]-butoxy)-3-methyl-4-oxo-2-phenyl-4H - 1-benzopyran the dihydrochloride.

A mixture of 7.75 g of intermediate compound XVI, 4.7 g of 1-(2-methoxyphenyl)-piperazine, 3.3 g of potassium iodide and 2.8 g of anhydrous potassium carbonate in 78 ml of dimethylformamide was shaken for 2 h at 75oC. After cooling to 20 to 25oC the reaction mixture was poured into 600 ml of water and was extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate, and the solvent is then boiled away into the vacuum. The residue was purified column chromatography on silica gel, elwira with ethyl acetate. Thus obtained compound indicated in the title, as the base was then converted into the dihydrochloride by treatment of its ethanolic hydrogen chloride. After crystallization from ethanol there was obtained 6.5 g of compound indicated in the title. Melting point 217 - 219oC.

Example 42. 8-(5-[4-(2-Methoxyphenyl)-1-piperazinil] -pentyloxy)-3-methyl-4-oxo-2-phenyl - 4H-1-benzopyran hydrochloride.

This compound was obtained by the method described in example 41, but instead of intermediate compound XVI used intermediate C (ethanol).

Example 43. 8-(3-[4-(2-methoxyphenyl)-1-oxo-1-piperazinil]-propoxy)-3-methyl-4-oxo-2 - phenyl-4H-1-benzopyran 1.75 - hydrate.

2.93 g of monoperoxyphthalate of magnesium in 10 ml of water was added dropwise at -15oC to a solution of 4.34 g of the compound obtained in example 40, and 0.1 g of benzyl(triethyl)ammonium chloride in 20 ml dichloromethane and 20 ml of methanol. The mixture was shaken for 2 h at 0oC, and then warmed to room temperature. The mixture is poured into water and brought it to alkaline by adding aqueous sodium hydroxide solution. After extraction dikhloretana was obtained a solid residue, which was purified by thin-layer chromatography, elwira a mixture of dichloromethane : methanol 9 : 1. The collected fractions containing the pure substance was evaporated in vacuum to dryness, and the residue was led from acetonitrile. The result was obtained 0.5 g of compound indicated in the title, with a melting point 89 - 92oC.

Example 44. 8-2-(2-[2-(2.6-Dimethoxyphenoxy)-ethylamino] -ethoxy)-3-methyl-4-oxo-2-phenyl - 4H-1-benzopyran hydrochloride.

A mixture of 4.5 g of intermediate compound XII, 3.7 g of triphenylphosphine and 2.85 g of 2.6-dimethoxybenzaldehyde (obtained according to Nelson, W. L., et al. , J. Med. Chem, 22, 1125, 1979) in 45 ml of benzene was dissolved at 20 - 25oo
C added 0.61 g of sodium borohydride. The mixture was stirred for 1 h at 0oC and for 1 h at 20 - 25oC, then poured into a mixture of ice water and was extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified column chromatography on silica gel, elwira a mixture of dichloromethane : methanol 49 : 1. The resulting base was treated with ethanolic hydrogen chloride. The connection specified in the title, was obtained after crystallization from ethanol. Yield 40%, melting point 200 - 203oC.

Example 45. 8-(2-Hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinil]-propoxy)-3-methyl-4 - oxo-2-phenyl-4H-1-benzopyran hydrochloride.

A solution of 3.7 g of intermediate compound XL and 4.64 g of 1-(2-methoxyphenyl)-piperazine in 40 ml of dimethylformamide was shaken for 3 h at 80oC. After cooling to 20 to 25oC the reaction mixture was poured into 400 ml of water and was extracted with dichloromethane. The aqueous phase was podslushivaet 1 N. a solution of sodium hydroxide and was extracted with ethyl acetate. The combined organic extracts were washed with water and dried on anhydrous sodium sulfate. Rast is the fact. The fractions containing the product that is listed in the title, as its Foundation, were collected together and evaporated in vacuum. The residue was dissolved in dichloromethane and added 1 equivalent of ethanolic hydrogen chloride. The solvents were removed in vacuo and the residue was led from ethanol. Received 5 g of compound indicated in the title, which contained 1 equivalent of ethanol. Melting point with decomposition was 126 - 128oC.

Example 46. 8-{ 3-[4-(2-Methoxyphenyl)-1-piperazinil] -propylthio}- 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

A mixture of 4.4 g of intermediate compound XXXIV, 2.5 g of 1-(2-methoxyphenyl)-piperazine, 1 g of potassium iodide and 1.8 g of anhydrous potassium carbonate in 40 ml of dimethylformamide was shaken for 3 h at 100oC. After cooling to 20 to 25oC the reaction mixture was poured into 350 ml of water and was extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate and then the solvent evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira a mixture of ethyl acetate : petroleum ether 3 : 2. Crystallization from ethanol there was obtained 3.9 g of compound indicated in the title. The melting point of 96 - 99oC.

Note the ptx2">

A solution of 3.8 g of intermediate compound XXXV and 4 g of 1-(2-methoxyphenyl)-piperazine in 40 ml of dimethylformamide was heated at 60oC for 7 h, After cooling to 20 to 25oC the reaction mixture was poured into 500 ml of water and was extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate, and then in a vacuum boiled away the solvent. The residue was purified by thin-layer chromatography on silica gel, elwira a mixture of ethyl acetate : petroleum ether 1 : 1. Received the basis of the connection specified in the title. It was dissolved in ethanol and added 1 equivalent of ethanolic hydrogen chloride, the result was obtained 4.5 g of compound indicated in the title and having a melting point 226 - 228oC.

Example 48. 8-{2-[4-(2-Methoxyphenyl)-1-piperazinil]- ethylsulfanyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

A solution of 4.5 g of intermediate compound XLII and 3.8 g of 1-(2-methoxyphenyl)-piperazine in 40 ml of dimethylformamide was heated for 7 h at 70oC. After cooling to 20 to 25oC the reaction mixture was poured into 150 ml of water and was extracted with dichloromethane. The organic solution was washed with water and dried on anhydrous sodium sulfate, then the solvent wypalanie ether 3 : 7. The connection specified in the title, was obtained during the formation of the salt with ethanolic hydrogen chloride. Yield 2.9 g, melting point 236 - 238oC.

Example 49. 8-{N-Methyl-2-[4-(2-methoxyphenyl)-1-piperazinil]- ethylsulfanyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

The connection specified in the title, was obtained by the method described in example 48, but instead of intermediate compound XLII used intermediate compound XLI. Melting point 194 - 198oC (ethanol).

Example 50 8-{N-Carbarnoyl-3-[4-(2-methoxyphenyl)-1-piperazinil]- propylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate hemihydrate.

A mixture of 4.06 g of compound of example 33 and 1.5 g of potassium cyanate in 42 ml of glacial acetic acid was shaken for 4 h at 50oC. the Reaction mixture was poured into a mixture of ice water and was parselocale. The precipitate was collected with filtration with suction, dried and purified by thin-layer chromatography, using a column with silica gel and elwira a mixture of ethyl acetate : methanol 98 : 2. The fractions containing the product that is listed in the title, in the form of the base, was evaporated in vacuum to dryness. After dissolving in 30 ml of dichloromethane to the residue was added 1 equivalent of meanswhen is to be placed, specified in the title (melting point 157 - 160oC without decomposition). The compound obtained contained 1 molar equivalent of ethanol.

Example 51. 8-{4-[4-(2-Methoxyphenyl)-1-piperazinil]-1-oxobutyl}- 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

A solution of 1.33 ml of anhydrous dimethyl sulfoxide in 9 ml of dichloromethane was added at -70oC to a solution of 0.74 ml oxalyl chloride in 6 ml of dichloromethane. After shaking for 15 min at -70oC was added a solution of 2.8 g of compound from example 21 (a base) in 14 ml of dichloromethane. At the same temperature after 15 min was added 4.7 ml of anhydrous triethylamine, and within 30 minutes the temperature rose to -30oC. Stirring was continued at -30oC for another 30 minutes After the temperature rose to 0oC the mixture was diluted with 120 ml of water and was extracted with dichloromethane. The organic phase is washed with water, dried on anhydrous sodium sulfate and evaporated in vacuum to dryness. The residue was purified by thin-layer chromatography in a column of silica gel, elwira a mixture of ethyl acetate : dichloromethane 9 : 1. The fractions containing the product that is listed in the title, in the form of the base, was evaporated in vacuum to dryness, and the residue dissolved in 30 ml of dichloromethane was added the La. There was obtained 2.9 g of compound indicated in the title, with a melting point 194 - 195oC.

Example 52. 8-{3-[2-(1,4-Benzodioxane)-methylamino]- propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

A mixture of 5.56 g of intermediate compound XLIII as the base, 4.58 g of 2-(p-toluensulfonyl)-1,4-benzodioxane and 1.9 g of anhydrous potassium carbonate in 80 ml of anhydrous dimethylformamide was shaken for 5 h at 110oC. the Reaction mixture was cooled to room temperature, poured into water and was extracted with dichloromethane. The organic phase is washed with water, dried on anhydrous sodium sulfate, filtered, and evaporated in vacuum to dryness. The residue was purified by thin-layer chromatography, using a column of silica gel with elution with a mixture of ethyl acetate : methanol 95 : 5. The fractions containing the compound indicated in the title, in the form of the base, was evaporated to dryness in vacuum. The residue was dissolved in ethanol and added 1 equivalent methanesulfonic acid, dissolved in ethyl acetate. Mass of crystals this way the product was filtered and then recrystallization from ethanol. The result was obtained 2.4 g of compound indicated in the title, with a melting point of 172 - 174oC.

="ptx2">

A solution of 2.8 g of intermediate compound XLVI and 0.13 g of p-toluensulfonate acid in 150 ml of methanol was subjected to reflux distilled within 5 hours After cooling to 20 to 25oC was added 0.8 g of anhydrous potassium carbonate and within 3 h continued shaking. After filtration of the reaction mixture was evaporated to dryness in vacuum, the result was obtained 2.5 g of 8-(4,4-dimethoxymethyl)-3 - methyl-4-oxo-2-phenyl-4H-1-benzopyran.

NMR (CDCl3, ):

1.6 - 1.9 (4H, m, CHCH2CH2CH);

2.2 (3H, s, CH3flavone);

2.9 (2H, t, F1-CH2);

3.3 (6H, s, 2 OCH3);

4.4 (1H, t, CH(OCH3)2);

7.3 (1H, dd, CH flavone in position 6);

7.5 - 7.8 (6H, m, CH of flavone in position 7 and 5 phenyl CH);

8.1 (1H, dd, CH flavone in position 5).

A solution of 2.5 g of compound, thus obtained, 10 ml of water and 30 ml of acetic acid was heated for 2.5 h at 50oC. Then the reaction mixture was cooled to room temperature, diluted with a mixture of water with ice, podslushivaet aqueous sodium carbonate and was extracted with chloroform. The organic phase is dried on anhydrous sodium sulfate, filtered, and evaporated to dryness in vacuum. The residue was purified column chromatography on silica gel, elwira mixture petroianuiii was used in the next stage without further purification.

NMR (CDCl3, ) :

1.9 - 2.1 (2H, dd, CH2CH2CH2CHO);

2.2 (3H, s, CH3flavone);

2.5 (2H, t, CH2CHO);

2.9 (2H, t, F1-CH2);

7.3 (1H, dd, CH flavone in position 6);

7.5 - 7.7 (6H, m, CH of flavone in position 7 and phenyl CH);

8.1 (1H, dd, CH flavone in position 5);

9.7 (1H, s, CHO).

2.3 ml of 6 N. hydrochloric acid in ethanol, a solution of 2.1 g of the previously obtained compound in 40 ml of methanol and 0.45 g of cyanoborohydride sodium were sequentially added to a solution of 8 g of 1-(2-methoxyphenyl)-piperazine in 30 ml of methanol. After shaking the reaction mixture at room temperature for 24 h, it was poured into 500 ml of a mixture of ice water and was extracted with dichloromethane. The organic phase is washed with water, dried on anhydrous sodium sulfate and was evaporated to dryness in vacuum. The residue was purified by thin-layer chromatography, using a column with silica gel, was suirable a mixture of ethyl acetate : petroleum ether 9 : 1. The fractions containing the product that is listed in the title (as the base), was evaporated to dryness in vacuum. The residue was dissolved in 30 ml of dichloromethane and added 1 equivalent methanesulfonic acid. The solvent is evaporated in vacuo, and the residue was led from acetone. Was obtained 2.35 g of compound indicated the yl] -3 - methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

This compound was obtained by the method described in example 11, using instead of 1-(2-methoxyphenyl)-piperazine 4-phenylpiperidine and conducting the reaction for 1 h instead of 5 o'clock Purification was performed by thin-layer chromatography, using a column with silica gel and elwira a mixture of dichloromethane : methanol 100 : 5. Melting point 157 - 159oC (ethyl acetate). The corresponding base melted at 147 - 149oC (ethanol).

Example 55. 8-[3-(4.4-Diphenyl-1-piperidinyl)-propellerblades] -3-methyl - 4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

This compound was obtained by the method described in example 11, using 4,4-diphenylpiperazine instead of 1-(2-methoxyphenyl)-piperazine and carrying out the reaction for 2 hours instead of 5 hours melting point 221 - 223oC (ethyl acetate).

Example 56. 8-{3-[4-(4-Perbenzoic)-1-piperidinyl]- propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

This compound was obtained by the method described in example 11, using 4-(4-perbenzoic)-piperidine instead of 1-(2 - methoxyphenyl)-piperazine and carrying out the reaction for 30 min instead of 5 o'clock Purification was performed by thin-layer chromatography, using a column of silica gel with elution with a mixture of dichloromethane : 5 N. methanolic ammonia in cootes who yl)-1-piperidinyl] -propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

This compound was obtained by the method described in example 11, using 4-(2-oxo-1-benzimidazolinyl)-piperidine instead of 1-(2-methoxyphenyl)-piperazine. Purification was performed by thin-layer chromatography, using a column with silica gel, was suirable mixture of bromoform : 5 N. methanolic ammonia 100 : 3. Melting point 238 - 241oC (ethanol).

Example 58. 8-{3-[4-(2-Pyrimidinyl)-1-piperazinil]- propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

The connection specified in the title, was obtained by the method described in example 11, using 1-(2-pyrimidinyl)-piperazine instead of 1-(2-methoxyphenyl)-piperazine and carrying out the reaction for 2 hours the Product was purified by thin-layer chromatography, using a column with silica gel, was suirable a mixture of chloroform : methanol 100 : 3. The target fraction was dissolved in dichloromethane and to the solution was added 1 equivalent methanesulfonic acid. After evaporation in vacuo of the solvent the residue was boiled for 1 h with ethyl acetate, and then collected by filtration. Melting point 209 - 210oC. the resulting product contained 0.2 equivalent of ethyl acetate and 0.1 equivalent of water. The corresponding base melted at 178 - 180oC (ethanol).

Example 59. 8-{3-[asanee in the title, was obtained following the description in example 11, only instead of 1-(2-methoxyphenyl)-piperazine used 1-(2-hydroxyphenyl)-piperazine and heated instead of 5 h was carried out for 1.5 hours as of the eluate at column chromatography used a mixture of dichloromethane : methanol 100 : 3 to 100 : 10. The melting point of 118 - 120oC (95% ethanol).

Example 60. 8-{4-[4-(2-Methoxyphenyl)-1-piperazinil]- butylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

This compound was obtained by the method used in example 12, only instead of 3-[4-(2-methoxyphenyl)-1-piperazinil]-Propylamine was used 4-[4-(2-methoxyphenyl)-1-piperazinil] -butylamine. The reaction mixture was shaken at room temperature for 22 h, washed with water and filtered with suction, washing out any insoluble solids with water. The crude residue was dried and purified column chromatography on silica gel, elwira a mixture of ethyl acetate : methanol 9 : 1. The fractions containing pure product in the form of a Foundation, gathered together was evaporated in vacuum to dryness and dissolved in dichloromethane. To the solution was added methanesulfonyl acid, salt besieged by adding 2 volumes of ethyl acetate and filtered. After recrystallization from ethanol was the l 0.3 molar equivalent of ethanol.

Example 61. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propylsulfonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

This compound was obtained following the description in example 12, only instead of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound VIII and the shaking was carried out for 24 hours instead of 2.5 hours the Crude product was purified column chromatography on silica gel, elwira a mixture of ethyl acetate : methanol 98.5 : 1.5 to. The collected fractions containing pure product in the form of the base, was evaporated to dryness in vacuo, and then dissolved in dichloromethane. To the solution was added methanesulfonyl acid, and the solvent was removed by evaporation in a vacuum. To obtain the product specified in the title, crude salt was led from ethanol. Melting point 198 - 200oC.

Example 62. 8-{3-[N-Methyl-2-(2-methoxyphenoxy)-ethylamino]- propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

A solution of 10.5 ml of 40% formaldehyde in water was added to the suspension at 6.66 g of the compound obtained in example 14, in 55 ml of acetonitrile and 20 ml of water. After shaking for 15 min at room temperature to the solution was added 2.70 g of 95% cyanoborohydride sodium, and after another 15 min in those who, the residue was washed with 250 ml water and 250 ml of chloroform. After addition of 3 n sodium hydroxide organic phase was separated, and the aqueous phase was twice extracted with chloroform. The solvent was removed from the collected organic phases when their evaporation in vacuo, and the residue was purified by thin-layer chromatography on silica gel, elwira a mixture of chloroform : 5.2 N. methanolic ammonia 100 : 0.5 to 100 : 2. The collected fractions containing pure product that is listed in the title (as the base), was evaporated to dryness in vacuo, and the residue was dissolved in hot ethanol. The solution was acidified ethanolic hydrogen chloride, and the residue, after evaporation in vacuo of the solvent, washed with diethyl ether, and shaken at room temperature. The crude product was collected with filtration and led from acetonitrile. There was obtained 3.1 g of compound indicated in the title, with a melting point of 146 to 148oC.

Example 63. 8-{ N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinil]- propionamido}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

The connection specified in the title, was obtained in the form of crude base as described in example 37, but instead of intermediate compound X used intermediate compound L and Strahov and column chromatography on silica gel, elwira a mixture of ethyl acetate : methanol 95 : 5. The connection specified in the title, was obtained after crystallization from acetone. Melting point 200 - 202oC.

Example 64. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades]-3-phenyl-4-oxo-4H-1-benzopyran dimethanesulfonate.

The connection specified in the title, was obtained according to what described in example 12, only instead of 8-chlorocarbonyl-3-methyl-4 - oxo-2-phenyl-4H-1-benzopyran used intermediate compound LVI and shaking instead of 2.5 h was performed within 24 hours the Crude product was purified column chromatography, elwira a mixture of ethyl acetate : methanol 98 : 2; net basis, obtained by evaporation of the collected fractions in vacuo, dissolved in dichloromethane. Added 2 equivalent methanesulfonic acid; crude dimethanesulfonate obtained after evaporation of the solvent, recrystallization from acetone. Melting point 153 - 156oC.

Example 65. 8-{3-[(3,4-Dihydro-1-oxo-2H-naphthyl)-methylamino]-propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

A mixture of 6 g of intermediate compound XLIII, 2.4 g of 2-methylene-alpha-tetralone (obtained as described in Org.Synth., 60, 88, 1981) and 3.14 ml of triethylamine in 48 ml besod the Reaction mixture was diluted with water and was extracted with dichloromethane. The organic layers were washed with water, dried on anhydrous sodium sulfate and evaporated in vacuum to dryness. The crude residue was twice purified column chromatography, elwira first time with a mixture of dichloromethane : methanol 95 : 5, and then dichloromethane: methanol: 5.8 N. methanolic ammonia 98:2:0.2. Received 1.74 g of compound indicated in the title, in the form of a Foundation. This base was converted to the methanesulfonate by the method described in examples 61. To obtain the connection specified in the title, Sol recrystallization first from acetone and then from acetonitrile. Melting point 157 - 159oC.

Example 66. 8-{2-[4-(2-Methoxyphenyl)-1-piperazinil]-etoxycarbonyl-methyl} -3-methyl - 4-oxo-2-phenyl-4H-1-benzopyran the dihydrochloride.

The connection specified in the title, was obtained by the method described in example 5, but instead of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound XLVII, and instead of 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine used 1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine. The melting point of a mixture of ethanol : diethyl ether 193 - 196oC.

Example 67. 8-{4-[4-(2-Methoxyphenyl)-1-piperazinil]-butylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dimethanesulfonate.

oC.

Example 68. 8-{N-(2-tetrahydropyranyloxy)-3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate hemihydrate.

A solution of 3.6 g of 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine in 30 ml of anhydrous dimethylformamide was added dropwise with shaking at 0oC to a mixture of 3.92 g of O-(2-tetrahydropyranyl)-hydroxylamine (obtained as described R. N. Watrener et al. , Angewandte Chem. Int. Ed., 5, 511, 1966). Shaking was continued for 2 h at 0oC and then for 12 h at 110oC. the Reaction mixture was cooled to room temperature, the dimethylformamide was removed by distillation in vacuum. The residue was washed with water and was extracted with ethyl acetate. Together organic layers were washed with water and dried on anhydrous sodium sulfate. After evaporation of the solvent and vacuum was obtained 4.39 g of 1-[3-(2-tetrahydropyranyloxy)-propyl]-4-(2-methoxyphenyl)-piperazine.

1H-NMR (CDCl3, ):

6.50 - 6.75 (m, 4H, aromatic protons);

5.20 (bs, 1H, NH);

4.60 (m, 1H, O-CH-O);

3.30 - 4.00 (m, 5H, OCH3and CH2O tetrahydrofuran (THF);

2.80 - 2N);

1.30 - 2.00 (m, 6H, tetrahydrofuran 3 CH2, alkyl chain C-CH2-C).

A solution of 2.79 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 47 ml of chloroform was added dropwise at room temperature to a mixture of 3.26 g of the previously obtained compound and 1.42 g of potassium carbonate in 47 ml of chloroform. The reaction mixture was shaken for 3 h, and then diluted with 75 ml of chloroform and three times washed with 1 M sodium hydroxide. The organic layer was washed with water, dried on anhydrous sodium sulfate and evaporated in vacuum to dryness. The crude residue was purified column chromatography on silica gel, elwira a mixture of ethyl acetate : methanol 98 : 2. To obtain 2.99 g of pure compound indicated in the title, the collected fractions in base was evaporated to dryness in vacuum. The base was dissolved in dichloromethane and to the solution was added methanesulfonyl acid. The solvent was removed by evaporation in a vacuum, and for the connection specified in the title, crude salt was led from ethyl acetate. Melting point 159 - 160oC.

Example 69. 8-{ 4-[4-(2-Methoxyphenyl)-1-piperazinil]-butylamino}-3-methyl-4-oxo-2 - phenyl-4H-1-benzopyran methanesulfonate hemihydrate.

The connection specified in the title, was the Association XLVIII and instead of shaking for 7 h at 100oC shaking was performed 1 h at 70oC and 2 h at 130oC. After the usual processing crude residue was purified column chromatography on silica gel, elwira a mixture of ethyl acetate : methanol 95 : 5. The fractions containing pure product that is listed in the title (the Foundation) was collected and evaporated in vacuum to dryness. The residue was dissolved in dichloromethane and to the solution was added 1 equivalent methanesulfonic acid. After evaporation of the solvent in vacuo to dryness the crude salt was led from acetone, melting point 175-176oC.

Example 70. E-8-{2-[4-(2-Methoxyphenyl)-1-piperazinil-toksienosti}-3-methyl-4 - oxo-2-phenyl-4H-1-benzopyran.

A solution of 5.4 g 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 5.13 g of intermediate compound LII in 10 ml of chloroform containing 3 a molecular sieve, was dissolved at reflux distilled within 6 h of the Molecular sieve was removed by filtration, and the solution was evaporated to dryness in vacuum. The crude product was purified column chromatography on silica gel, elwira a mixture of ethyl acetate : petroleum ether 7 : 3. Were collected from two groups of fractions evaporated in vacuum to dryness. The first group of fractions (less polar) is almost entirely contained pure product specified in the title, and W the ASS="ptx2">

1H-NMR (CDCl3, ):

8.75 (dd, 0.5 H, CH benzopyran 7, Z);

8.65 (s, 0.5 H, CH imine, E);

8.30 (dd, 1H, CH benzopyran 5, E+Z);

8.15 (dd, 0.5 H, CH benzopyran 7, E);

8.00 (s, 0.5 H, CH imine, Z);

7.60 - 7.75 (m, 2H, CH of phenyl at the 2' and 6', E+Z);

7.50 - 7.60 (m, 3H, CH of phenyl 3', 4' and 5', E+Z);

7.45 (dd, 0.5 H, CH benzopyran 6, Z);

7.41 (dd, 0.5 H CH benzopyran 6, E);

6.70-7.10 (m, 4H, protons of phenyl, E+Z);

to 4.41 (t, 2H, CH2O, E+Z);

3.86 (s, 3H, CH3O, E+Z);

3.05 - 3.20 (m, 4H, 2 CH2piperazine, E+Z);

2.70 - 2.90 (m, 6H, 2 CH2piperazine and CH2N, E+Z);

2.20 (s, 1.5 H, CH3benzopyrano 3, Z);

2.18 (s, 1.5 H, CH3benzopyrano 3, E).

To obtain 2.5 g of pure product specified in the title, E-diastereoisomer was led from a mixture of ethanol : water 2 : 1, melting point 107 - 109oC.

Example 71. 8-{N-Hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinil]-propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate 0.25 H2O.

A solution of 2.04 g of compound from example 68 in the form of the base 104 ml 1.6 N. ethanolic hydrogen chloride was shaken at room temperature for 12 hours the Ethanol was removed by evaporation in vacuo, and the residue is washed 1 N. sodium hydroxide and dichloromethane. The organic layer was collected, washed Anya added 1 molar equivalent methanesulfonic acid. The solvent was removed and the crude methanesulfonate was led from acetone. Was obtained 1.02 g of compound indicated in the title and having a melting point of 211 - 213oC. the resulting product contained 0.25 mol of water.

Example 72. E-8-<2-{2-[4-(2-Methoxyphenyl)-1-piperazinil]-ethylcarbamate} -ethinyl>-3-methyl - 4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate 1.2 H2O.

The connection specified in the title, was obtained by the method described in example 61, but instead of intermediate compound VIII used the compound IV and 2-[4-(2-methoxyphenyl)-1-piperazinil]-ethylamin was used in place of the corresponding Propylamine; 1,1,2,2-tetrachloroethylene was used as solvent. In the end, the reaction mixture was diluted with water and chloroform and washed first with 1 N. aqueous sodium hydroxide and then with water. After drying on anhydrous sodium sulfate the organic layer was added methanesulfonyl acid, and the solvent was boiled away into the vacuum. The crude product was twice led from isopropanol, there was obtained the compound indicated in the title, containing 1.2 molar equivalent of water. Melting point 124 - 127oC.

Example 73. 8-(4-[4-(2-Methoxyphenyl)-1-piperazinil]-butylsulfonyl)-3-methyl-4 - ox is the example 38, only instead of intermediate compound XLIV used connection LIV; the shaking was carried out at 70oC for 3 h, and then after addition of catalytic amounts (0.01 equivalent) of potassium iodide - for another 3 h at 90oC. After purification column chromatography on silica gel, elwira a mixture of ethyl acetate : methanol 9 : 1, the connection specified in the title, was obtained in the form of the base. To the crude base is dissolved in dichloromethane, was added 1 molar equivalent methanesulfonic acid. After removal under vacuum of the solvent the obtained Sol was led from acetone; received the connection specified in the title, with a melting point of 183 - 184oC.

Example 74. 8-(3-[3-(2-Methoxyphenoxy)-propylamino]-propellerblades)-3-methyl-4-oxo - 2-phenyl-4H-1-benzopyran methanesulfonate hemihydrate.

The connection specified in the title, was obtained according to the method described in example 76, but instead of 2-(2,6-dimethoxyphenoxy)-ethylbromide used 3-(2-methoxyphenoxy)-propylchloride (obtained according to B. Willhalm, Tetrahedron, 20, 1185, 1964). The residue after extraction with dichloromethane was purified column chromatography on silica gel, elwira a mixture of dichloromethane : methanol : 5 N. methanol am and ethyl acetate : acetonitrile 9 : 1, received the connection specified in the title and melting at 87 - 90oC.

Example 75. 8-(3-[2-(2-Methylthiophene)-ethylamino]-propellerblades)-3-methyl-4-oxo - 2-phenyl-4H-1-benzopyran methanesulfonate.

1.85 g of 95% sodium borohydride was added to a solution of 7 g of intermediate compound LIX in 70 ml of methanol, shake at 0oC. After shaking at the same temperature for 1 h the solvent was removed by evaporation in a vacuum. The residue was diluted with water and 2 N. hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water, dried on anhydrous sodium sulfate and boiled away the dryness in vacuum, receiving 6.6 g of pure 2-(2-methylthiophene)-ethanol in the form of oil. To the solution thus obtained compound in 35 ml of pyridine was added by portions 8.57 g of p-toluensulfonate, shaking at 0oC. After shaking at room temperature for 14 h, the reaction mixture was poured into cold 2 N. hydrochloric acid and was extracted with dichloromethane. The organic layer was twice washed with water, dried on anhydrous sodium sulfate and was evaporated to dryness in vacuum. There was obtained 7.8 g of a mixture of 2-(2-methylthiophene)-ethyl-p-toluensulfonate and 2-(2-methylthiophene)-ethylchloride in sootnoshyeniya cleaning. A homogeneous mixture of 3.3 g of the above mixture and 8 g of intermediate compound XLIII was kept for 20 min at 140oC in the oil bath. Then the molten mass was cooled to room temperature and hardened. The solid residue was washed with dichloromethane and 4 N. sodium hydroxide. The organic layer was washed with water, dried on anhydrous sodium sulfate and evaporated to dryness in vacuum.

The crude product was purified column chromatography on silica gel, elwira mixture dihormati : methanol 9 : 1; received 2.07 g of compound indicated in the title, in the form of a Foundation. It turned an ordinary method methanesulfonate, which was led first from acetone and then from acetonitrile. Melting point 143 - 146oC.

Example 76. 8-{3-[2-(2,6-Dimethoxyphenoxy)-ethylamino]-propellerblades}-3-methyl-4 - oxo-2-phenyl-4H-1-benzopyran hydrochloride.

A homogeneous mixture of 3.3 g of 2-(2,6-dimethoxyphenoxy)-ethylbromide (obtained according to J. Augstein et al., J. Med. Chem., 8, 356, 1965) and 8.4 g of intermediate compound XLIII was heated for 10 minutes at 150oC in the oil bath. The molten mass was cooled to room temperature and hardened. The solid residue was washed with ethyl acetate and 2 N. sodium hydroxide. The PR is the residue was twice purified column chromatography on silica gel, elwira first with a mixture of ethyl acetate : methanol : 5 N. methanolic ammonia 97 : 3 : 0.3, and then a mixture of dichloromethane : methanol : triethylamine 90 : 10 : 0.3. Was obtained 3.3 g of compound indicated in the title, in the form of a Foundation. The crude hydrochloride is obtained in the usual way, was led first from acetone and then from acetonitrile. The melting point of 179 - 181oC.

Example 77. 8-{ 3-[4-(5-Chloro-2-methoxyphenyl)-1-piperazinil]- propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

This compound was obtained by the method described in example 11, but instead of 1-(2-methoxyphenyl)-piperazine used 1-(5-chloro-2-methoxyphenyl)-piperazine and the reaction instead of 5 h was carried out for 6 hours Purification was performed by thin-layer chromatography on silica gel, elwira a mixture of chloroform : 5 N. methanolic ammonia 100 : 1. The connection specified in the title, after crystallization from 95% ethanol melted at 163 - 166oC.

Example 78. (E)-8-{4-[4-(2-Methoxyphenyl)-1-piperazinil]-1 - butenyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

33.4 ml of a 1 M solution of lithium bis(trimethylsilyl)amide in anhydrous tetrahydrofuran was added dropwise within 15 min to a suspension of 6.4 g of bromide 3-hydroxypropyltrimethylammonium in 60 ml of anhydrous tetrahydrofur the Ana in 40 ml of tetrahydrofuran. The reaction mixture was shaken for 30 min at 0oC, and then for 1.5 h at room temperature. Treatment with methanol, followed by evaporation to dryness in vacuo gave a residue that was purified column chromatography on silica gel, elwira a mixture of ethyl acetate : petroleum ether 6 : 4. The collected fractions evaporated in a vacuum; it was obtained 4.17 g of 8-(4-hydroxy-1-butenyl)-3-methyl-oxo-2-phenyl-4H-1-benzopyran as a mixture of E-Z diastereoisomers in the ratio of 3.5 : 1 as defined in the NMR.

1H-NMR, 200 MHz (CDCl3, ):

8.10 - 8.20 (d. 1H, CH benzopyran 5, E + Z);

7.30 - 7.80 (m, 7H, other aromatics, E + Z);

6.80; 7.00 (2d, 1H, aryl-CH=, E + Z);

6.41 (dt, 0.78 H, CH-CH2E);

5.90 (dt, 0.22 H, CH-CH2, Z);

3.60 - 3.80 (m. 2H, CH2O, E + Z);

2.45 - 2.60 (m. 2H, CH-CH2E + Z);

2.18 (s, 3H, CH3benzopyrano 3, E + Z);

1.60 - 1.90 (sa, 1H, OH, E + Z).

1.65 g of p-toluensulfonate added to a solution of 2.2 g of the above mixture in 24 ml of anhydrous pyridine and shook at 0oC. Shaking at the same temperature was continued for 48 h and then the reaction mixture was poured into cold 1 N. hydrochloric acid and filtered with suction. Sticky solid residue was washed with water and dichloromethane. The solution was dried supernil}-3-butenyl p-toluensulfonate, have the same diastereoisomeric composition as specified above intermediate connection.

A solution of 2.85 g of the ester of p-toluensulfonate acid and 2.98 g of 1-(2-methoxyphenyl)-piperazine in anhydrous dimethylformamide was shaken for 48 h at room temperature. The mixture is then poured into 250 ml of water and was extracted with ethyl acetate. The organic layer was washed with water, dried on anhydrous sodium sulfate and evaporated to dryness in vacuum, obtaining a residue which was then purified column chromatography on silica gel, elwira a mixture of ethyl acetate : petroleum ether 6 : 4. The collected fraction was evaporated in vacuum to dryness, and the crude product was led from 70% ethanol. Was obtained 1.48 g of compound indicated in the title and melting at 119 - 121oC.

1H-NMR, 200 MHz (CDCl3, ):

8.14 (dd, 1H, CH benzopyran 5);

7.85 (dd, 1H, CH benzopyran 7);

7.41 - 7.70 (m, 5H, phenyl CHs);

7.34 (dd, 1H, CH benzopyran 6);

6.70 - 7.10 (m, 5H, aryl-CH= CHs methoxyphenyl);

6.30 - 6.50 (dt, 1H, Jtrans= 16.5, CH-CH2);

3.86 (s, 3H, CH3O);

3.00 - 3.15 (m, 4H, CH2piperazine);

2.50 - 2.80 (m, 8H, CH2, piperazine, CHCH2CH2N);

2.18 (s, 3H, CH3benzopyrano 3).

Example 79. (E)-8-[2-{ 2-{ 2-[4-(2-Methoxybenzene, specified in the title, was obtained according to example 6, but instead of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-benzopyran used intermediate compound III. After the usual processing, the residue was twice led from ethanol. The obtained solid was purified column chromatography on silica gel, elwira a mixture of chloroform : ethyl acetate 8 : 2. Received net basis, which is then dissolved in a mixture of chloroform : ethanol 1 : 1. To the solution was added methanesulfonyl acid, and the solvents evaporated in vacuo. The crude salt was led from isopropanol, thus obtaining the compound indicated in the title, which melted at 193 - 195oC. This compound is contained 0.33 equivalent of isopropanol and 0.25 equivalents of water.

Example 80. 8-{2-[4-(2-Methoxyphenyl)-1-piperazinil]-ethylcarbamate} -4 - oxo-2-phenyl-4H-1-benzopyran methanesulfonate hydrate.

A mixture of 2.8 g of intermediate compound XLVII and 1.28 g of 1-hydroxybenzotriazole in 20 ml of anhydrous dimethylformamide was dissolved at 0 - 5oC for 15 minutes To this mixture for about 40 min was added dropwise a solution of 1.96 g of dicyclohexylcarbodiimide in 20 ml of anhydrous dimethylformamide. After shaking for 8 h at room those. the donkey shaking for 5 h and aging at the same temperature during the night nerastvorimaya substance was filtered, and the filtrate was poured into 300 ml of water and parselocale by adding 1 n sodium hydroxide. The mixture was extracted with dichloromethane, the organic layers separated, dried on anhydrous sodium sulfate and boiled away in a vacuum. The crude product was purified by thin-layer chromatography on silica gel, elwira a mixture of chloroform : methanol 95 : 5. To a solution of the resulting crude base in ethanol was added 1 molar equivalent methanesulfonic acid. Added diethyl ether until crystallization of salt. The obtained salt was then filtered and recrystallization from a mixture of ethanol : diethyl ether 1 : 2. Was obtained 1.15 g of compound indicated in the title, with a melting point of 160 - 162oC.

Example 81. 8-{N-Acetyl-3-[4-(2-methoxyphenyl)-1-piperazinil]-propellerblades}-3 - methyl-4-oxo-2-phenyl-4H-1-benzopyran.

A solution of 2.86 g of intermediate compound LVII, 5.04 g of 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine and 2.58 g of anhydrous potassium carbonate in 50 ml of dimethylformamide was shaken for 7 h at 90oC. After cooling to room temperature the reaction mixture was poured into 500 ml of water and extragere is in vacuum. The residue was purified column chromatography on silica gel, elwira a mixture of ethyl acetate : petroleum ether 7 : 3. Received 1.89 g of compound indicated in the title, melting at 62 - 63oC.

Example 82. 8-{2-[4-(2-Methoxyphenyl)-1-piperazinil]-ethylsulfanyl} -3 - methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

1.05 ml of 2-floridasurfer chloride was added dropwise to a solution of 5 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 1.4 ml of triethylamine, shaking at 0oC. for two days the reaction mixture was shaken at room temperature. After filtering off the solid precipitate, the solution was evaporated in vacuum to dryness; there was obtained a crude residue containing 8-(etenilsililidin)-3-methyl-4 - oxo-2-phenyl-4H-1-benzopyran, which was used without further purification. A mixture of 7.54 g of this residue and 5.8 g of 1-(2-methoxyphenyl)-piperazine and 4.15 g of potassium carbonate in 100 ml of dimethylformamide was shaken for 4 h at room temperature, poured into 600 ml of water and was extracted with ethyl acetate. The organic layer was evaporated in vacuum to dryness, and the residue was purified column chromatography on silica gel, elwira a mixture of petroleum ether : acetone, 8 : 2. The collected fraction was evaporated to dryness in vacuum and the crystal dichloromethane and added to the obtained solution of 1 equivalent methanesulfonic acid. The crude methanesulfonate, obtained by evaporation in a vacuum, was led from acetone. There was obtained 0.6 g of compound indicated in the title, melting at 202 - 203oC.

Example 83. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- proportionably} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

Shake a mixture of 0.8 g 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyrane, 0.75 g of 1-(3-aminopropyl)-4-(2-methoxyphenyl)-piperazine and 0.14 g of sulfur in 5 ml of pyridine was subjected to reflux distilled within 6 hours After evaporation in vacuo of the solvent the residue was purified by thin-layer chromatography on silica gel, elwira chloroform. Received the connection specified in the title (as base) was dissolved in dichloromethane and added 1 equivalent methanesulfonic acid. The connection specified in the title, was obtained by evaporation in vacuo and crystallization of the residue from acetonitrile. Yield 0.7 g, melting point 189 - 190oC.

Example 84. 8-{4-[4-(2-Methoxyphenyl)-1-piperazinil]- butylsulfonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate. 0.25 H2O.

The connection specified in the title, was obtained according to example 73, but instead of intermediate compound LIV used joint petroleum ether 7 : 3. To a solution of the crude base in dichloromethane was added 1 equivalent methanesulfonic acid. After removal of the solvent by evaporation in vacuo the resulting salt was led from acetone to obtain the compound indicated in the title. The melting point of 212 - 214oC.

Example 85. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-3-hydroxymethyl-4-oxo-2-phenyl-4H-1-benzopyran, 0.4 ethanol

A mixture of 3.6 g of the intermediate XCV and 1.65 g of 1-hydroxybenzotriazole in 35 ml of anhydrous dimethylformamide for 15 min at 0 to 5oC. a Solution of 2.5 g of dicyclohexylcarbodiimide in 35 ml of anhydrous dimethylformamide was added dropwise. After shaking for 1 h at the same temperature was added a solution of 1-(3-aminopropyl)-4-(2-methoxyphenyl)-piperazine. After shaking for 2 h at the same temperature and aging overnight at room temperature, the reaction mixture was evaporated in vacuum to dryness. The residue was purified by thin-layer chromatography, elwira a mixture of dichloromethane : methanol 100 : 3, followed by crystallization from ethanol. There was obtained 2.5 g of compound indicated in the title, with a melting point 152 - 154oC.

Example 86. 8-{3-[4-(2-Methoxyl diethylthiophosphate was added dropwise at 0 - 5oC in shake a solution of 4 g of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran (obtained as described Da Re et al., Ber., 99, 1962, 1966) and 3.75 g of 1-(3-aminopropyl)-4-(2-methoxyphenyl)-piperazine in 35 ml of anhydrous dimethylformamide. Immediately after this, at the same temperature was added dropwise 2.5 ml of triethylamine. After shaking for 30 min at 0 - 5oC and for 1 h at room temperature the reaction mixture is poured into 350 ml of 2.5% aqueous sodium carbonate. The precipitate was shaken for 1 h at room temperature, was filtered with suction, and was led from ethanol. Thus obtained base of the connection specified in the title, dissolved in dichloromethane and added 1 equivalent methanesulfonic acid. After evaporation in vacuo was obtained vitreous solid residue, which grind and subjected to reflux distilled for 1 h in acetone. Received 5 g of compound indicated in the title and melting at 191 - 194oC.

Example 87. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-2,3-dihydro-4-oxo-4H-1-benzopyran methanesulfonate.

A solution of 0.84 ml of thionyl chloride in 17 ml of anhydrous dichloromethane was added dropwise to a solution of 2.0 g of 8-carboxy-2,3-Digi smetana, shake at room temperature. Shaking was continued at the same temperature for another 1.5 h, then the solution was evaporated to dryness under vacuum, to obtain 8-chlorocarbonyl-2,3-dihydro-4-oxo-4H-1-benzopyran. Last used according to the method of example 10 instead of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran for receiving the base of the connection specified in the title. The base was purified column chromatography, elwira a mixture of ethyl acetate : methanol 85 : 15. The yield of pure reason was 1.91, After dissolution in dichloromethane, acidification methanesulfonic acid and evaporation in vacuo to dryness the resulting crude salt was led from acetonitrile. Received 1.57 g of compound indicated in the title and melting at 175 - 177oC.

Example 88. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-4-oxo-4H-1-benzopyran methanesulfonate. 1.25 H2O.

The connection specified in the title, was obtained by the method described in example 87, only instead of 8-carboxy-2,3-dihydro-4-oxo-4H-1-benzopyran used intermediate compound LXII. The crude methanesulfonate washed with diethyl ether, was filtered and was led from acetonitrile. Melting point 155 - 157oC.

This compound was obtained according to example 86, only instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran used 8-carboxy-6-bromo-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (obtained according to EP 107804). It was purified in the form of a base thin-layer chromatography on silica gel, elwira a mixture of dichloromethane : methanol 100 : 3, and was led from 95% ethanol. The melting point of 154 - 159oC.

Example 90. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propellerblades}-6-methoxy - 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

1.01 ml diethylthiophosphate and 0.85 ml of triethylamine was added to a solution of 1.7 g of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (obtained according to JP 61-15880) and 1.51 g of 1-(2-methoxyphenyl)-4-(3-aminopropyl)-piperazine in 20 ml of anhydrous dimethylformamide, stirred up at 0oC. After shaking for 1 h at a temperature of from 0oC to room, the reaction mixture was poured into a mixture of 100 ml of water and 10 ml of 1 n sodium hydroxide. The basis of the connection specified in the title, precipitate, it was filtered and washed with water. After drying it in the usual way turned into a methanesulfonate, which was led from acetonitrile. Yield 1.7 g, melting point 185 - 186oC.

is methanesulfonate.

0.8 g of the compound obtained in example 114, and 5.8 ml of 1 n sodium hydroxide in 10 ml of ethanol was shaken for 4 h at room temperature. After soaking in the night added 15 ml of 1 n sodium hydroxide and 15 ml of ethanol and the mixture was shaken for 1 h at room temperature. The methanol was boiled away in vacuum and to the residue was added water. The suspension was filtered with suction and obtained 0.48 g connecting the base specified in the title. Using conventional techniques, this connection was turned into methansulfonate salt of the compound indicated in the title, and recrystallization from acetonitrile. Melting point 200 - 202oC.

Example 92. 8-(3-[4-(2-Methoxyphenyl)-1-piperazinil] -propellerblades)-3,6-dimethyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

The connection specified in the title, was obtained according to example 90, but instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran used 8-carboxy-3,6-dimethyl-4-oxo-2-phenyl-4H-1-benzopyran (obtained as described Da RE et al., Arch. Pharm., 296, 714, 1963). The crude methanesulfonate was led from acetonitrile, he melted at 196 - 197oC.

Example 93. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propellerblades}-3 - methyl-6-nitro-4-oxo-2-phenyl-carbonyl-3-methyl-4-oxo-2-phenyl-4H-1 - benzopyran used intermediate compound LXVIII, instead of chloroform - 1,1,2-trichloroethane. After normal processing of the crude product was purified column chromatography, elwira a mixture of dichloromethane : methanol 98 : 2. The collected fractions were evaporated to dryness in vacuum and was led from ethanol; received the connection specified in the title, with a melting point 159.5 - 161oC.

Example 94. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propellerblades}-6 - amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

A mixture of 33 g of the compound obtained in example 93, 109 ml of 1 N. hydrochloric acid, 105 ml of water and 8.78 g of Raney Nickel in 950 ml of ethanol was first made in the Parr apparatus under hydrogen pressure of 2 ATM and 40oC, shaking the mixture for 12 hours and Then the catalyst was filtered and washed with 80% ethanol. The mother liquor was evaporated in vacuo to a volume of 80 ml and was filtered. The crude product was washed with water and suspended in water, then added 37% hydrochloric acid to pH 1. Nerastvorimaya substance was filtered with suction, and the filtrate was parselocale, adding 35% sodium hydroxide. The connection specified in the title, precipitate, it was filtered and washed with water. Drying gave 26 g of product, melting at 215 - 217oC used in example 95 without further purification. 4.7 g e specified in the title, with a melting point 218-219oC.

Example 95. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propellerblades}-6 - acetamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

The connection specified in the title, was obtained according to the procedure described in example 36, but instead of the compound obtained in example 33, used the compound obtained in example 94. The reaction mixture was diluted with water and filtered with suction, washing the precipitate with water. After drying at 80oC this solid residue was purified column chromatography on silica gel, elwira a mixture of chloroform : methanol 95 : 5. Evaporation in vacuo of the collected fractions and crystallization of the residue from 95% ethanol led to the product specified in the title. The melting point of 218 to 220oC.

Example 96. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propellerblades}-6 - ethylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

The mixture 8.42 g of the compound obtained in example 94, 0.45 ml of acetaldehyde, 0.59 g of 85% of cyanoborohydride sodium and 3.3 ml 4.85 N. ethanolic hydrogen chloride in 73 ml of methanol was shaken for 5 days at room temperature. Then the reaction mixture was poured in cold 1.5 n sodium hydroxide, the resulting suspension was diluted with water and outfilt choroform : methanol 100 : 3. After evaporation in vacuo of the collected fractions was obtained 6 g of compound from example 94 and 2.67 g of compound indicated in the title. Last melted at 198 - 201oC after recrystallization from ethanol.

Example 97. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propellerblades}-6 - dimethylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

The connection specified in the title, was obtained according to example 35, only instead of the compound obtained in example 33, used the compound obtained in example 94, and used 10 molar equivalents of a 40% formaldehyde instead of 7 molar equivalents, 3 mol lamborginid sodium instead of 2 mol and the shaking was carried out at room temperature for 18 hours instead of 4.5 hours After conventional treatment and purification of column chromatography on silica gel, elwira a mixture of chloroform : methanol 97 : 3, evaporation in vacuo of the collected fractions and crystallization of the residue from ethanol the product, specified in the title and melting at 183 - 186oC.

Example 98. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]propellerblades}-7-methoxy-3 - methyl-4-oxo-2-phenyl-4H-1-benzopyran.

The connection specified in the title, was obtained according to the procedure described in example 87, colorbody solid residue was purified column chromatography, elwira a mixture of ethyl acetate : methanol 8 : 2. The collected fraction was evaporated in vacuum to dryness, and the residue was led from acetonitrile. Received the connection specified in the title, which melted at 151 - 152oC.

Example 99. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propellerblades}-3-methyl - 4-oxo-2-(4-triptoreline)-4H-1-benzopyran methanesulfonate Politologija.

The connection specified in the title, was obtained in accordance with the procedure described in example 90, but instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran as the source used intermediate compound LXXII. After crystallization from acetonitrile methanesulfonate obtained melted at 90 - 120oC.

Example 100. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propellerblades}-2-(4 - benzoylphenyl)-3-methyl-4-oxo-4H-1-benzopyran methanesulfonate hemihydrate.

The connection specified in the title, was obtained according to the procedure described in example 90, only as a starting compound instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound LXXIV. The resulting crude methanesulfonate was led from acetonitrile, melting point 208 - 210oC.

2O.

The connection specified in the title, was obtained according to the procedure described in example 90, but starting compound instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound LXXVII. The resulting crude methanesulfonate was led from acetonitrile. Melting point 200 - 202oC.

Example 102. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-2,3-dimethyl-4-oxo-4H-1-benzopyran.

This compound was obtained according to example 86, but instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran used 8-carboxy-2,3-dimethyl-4-oxo-4H-1-benzopyran (obtained according to the Da Re, Farmaco Ed. Sci., 11, 678, 1956) and the reaction was carried out for 5 h at room temperature. The compound was purified by thin-layer chromatography on silica gel, elwira a mixture of chloroform : methanol 98 : 2, and then was led from acetone. Melting point 155 - 158.5oC.

Example 103. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-2-(t-butyl)-3-methyl-4-oxo-4H-1-benzopyran the dihydrochloride dehydrate.

The compound was obtained according to example 86, but instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound LXXVIII. The floor base was converted into the dihydrochloride in a mixture of methanol : diethyl ether. After recrystallization from methanol : diethyl ether 1 : 1 target product melted at 226 - 229oC.

Example 104. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-2-cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran.

This compound was obtained according to example 86, but instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound LXXIX and reaction was performed for 5 h at room temperature. Purification was performed by thin-layer chromatography on silica gel, elwira a mixture of chloroform : methanol 49 : 1; and then was led from acetonitrile. Melting point 155 - 157oC.

Example 105. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-2-(2-furyl)-3-methyl-4-oxo-4H-1-benzopyran.

This compound was obtained according to example 86, but instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound LXXXI and the reaction was carried out at room temperature for 5 hours After completion of a product specified in the title, was isolated by extraction with chloroform, and purified by thin-layer chromatography on silica gel, elwira a mixture of chloroform : methanol 49 : 1. Then conducted crystallization from acetonitrile. Melting point 151 - 153o

This compound was obtained according to example 86, only instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound LXXXIII. It was purified by shaking in water (to remove the dimethylformamide), followed by purification column chromatography on silica gel, elwira a mixture of chloroform : methanol, 49 : 1, and was led from acetonitrile. Melting point 174 - 175oC.

Example 107. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-4-oxo-2-phenyl-4H-1-benzothiophen.

A mixture of 2.8 g of intermediate compound LXXXIV and 3.4 g of 1,1'-carbonyldiimidazole in 60 ml of anhydrous dimethylformamide was dissolved under nitrogen for 1.5 h at room temperature. Then added 2.7 g of 1-(3-aminopropyl)-4-(2-methoxyphenyl)-piperazine. After 2 h shaking at room temperature the reaction mixture was poured into 300 ml of water and was extracted with chloroform. The organic layer was dried on anhydrous sodium sulfate and evaporated in vacuum. The residue was purified by thin-layer chromatography on silica gel, elwira a mixture of chloroform : methanol 49 : 1. Then washed with water and was led from acetonitrile. Received 2 g of compound indicated in the title and melting at 144 - 146oC.

Example 1 what about the compound was obtained according to example 86, only instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound LXXXVI. The compound was purified by crystallization from acetonitrile. Melting point 191 - 194oC.

Example 109. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-3-methyl-2-(4-were)-4-oxo-4H-1-benzopyran.

This compound was obtained according to example 86, only instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound LXXXVII and the reaction was conducted for 4 h at room temperature. After the connection specified in the title, was extracted by ethyl acetate, dried on anhydrous sodium sulfate and evaporated in vacuum. Then washed with diethyl ether and was led from acetonitrile. The melting point of 161 to 163oC.

Example 110. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-2-(4-methoxyphenyl)-3-methyl-4-oxo-4H-1-benzopyran.

This compound was obtained according to example 86, only instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran used 8-carboxy-2-(4-methoxyphenyl)-3-methyl-4-oxo-4H-1-benzopyran (obtained as described in EP 108986) and the reaction was carried out for 3.5 h at room temperature. The connection of ociali from acetonitrile. Melting point 158 - 161oC.

Example 111. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-2-(4-forfinal)-3-methyl-4-oxo-4H-1-benzopyran.

This compound was obtained according to example 86, only instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound LXXXIX. The compound was purified by thin-layer chromatography on silica gel, elwira a mixture of chloroform : methanol 100 : 2 to 100 : 6, and then were led out of 95% ethanol. The melting point of 166 to 168oC.

Example 112. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-6-methanesulfonamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

0.032 ml methanesulfonanilide in 1 ml of dimethylformamide was added dropwise over 10 min to a solution of 0.21 g of compound from example 94 and 0.062 ml of triethylamine in 4 ml of dimethylformamide, shaking at -20oC. Stirring was continued at the same temperature for 3.5 hours and Then the reaction mixture is poured into water, the resulting suspension was filtered with suction. After recrystallization from 80% ethanol was obtained 0.1 g of compound indicated in the title. Melting point 272 - 275oC.

Example 113. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-3-methyl-2-(4 - described in example 90, but as a starting compound instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound XCVIII. After shaking for 1 h at room temperature the reaction mixture was poured into cold 2% solution of sodium carbonate, precipitated solid precipitate was collected with filtration with suction. After drying and crystallization from ethanol was obtained is listed in the title compound, melting at 185 - 187oC.

Example 114. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-6-diethoxyphosphoryloxy-3-methyl-4-oxo-2-phenyl-4H - 1-benzopyran.

The connection specified in the title, was obtained according to the procedure described in example 90, but starting compound instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran used intermediate compound LXIII and instead of 1.1 equivalent of diethylthiophosphate used 2 equivalent of the substance. After filtration of the water was obtained the compound indicated in the title, which melted at 48 - 50oC. the Connection specified in the title, can be considered as prodrugs 8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-6-hydroxy - 3-methyl-4-oxo-2-phenyl-4H-1-benzopyrane methanesulfonate.

The crude basis of the connection specified in the title, was obtained according to the method described in example 90, but starting compound instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran used intermediate connection C. After the usual treatments of extraction with ethyl acetate the residue was purified column chromatography on silica gel, elwira a mixture of ethyl acetate : methanol 9 : 1. The compound obtained by using conventional methods has been converted to a methanesulfonate and recrystallized from ethyl acetate. Melting point 145 - 148oC.

Example 116. 8-{ N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinil] - propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

This compound was obtained according to example 12, but instead of 3-[4-(2-methoxyphenyl)-1-piperazinil] -Propylamine used intermediate connection CI. The crude base was purified by thin-layer chromatography on silica gel, elwira a mixture of chloroform: 5 N. methanolic ammonia 100 : 1, and then the usual way was transformed into the hydrochloride. After crystallization from acetone melting point 195 - 198oC.

Example 117. 7-{3-[4-(2-Methoxyphenyl)-1-piperazinil]- propellerblades}-2-benzoyl-3-ethyl-benzo[b]furan.

Example 118. 8-{3-[4-(2-methoxyphenyl)-1-piperazinil]- propellerblades}-2-(4-biphenylyl)-3-methyl-4-oxo-4H-1-benzopyran.

The connection specified in the title, was obtained according to example 86, but instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran used intermediate connection CVI. The reaction was continued for 20 h at room temperature. The base was purified by crystallization from ethanol (melting point 164 - 166oC).

Example 119. 8-{3-[4-(2-methoxyphenyl)-1-piperazinil]- propellerblades}-3-methyl-4-oxo-2-(3-pyridyl)-4H-1-benzopyran.

A mixture of 6.2 g of methyl 3-propionyl salicylate and 5.8 g of the hydrochloride of nicotinanilide in 18 ml of anhydrous pyridine was dissolved and heated for 2 h at 100oC under nitrogen. Then added 16 ml of triethylamine and continued heating at the same temperature for 1 h, the Reaction mixture was cooled to room temperature and poured into 600 ml of water. The residue was collected with suction and washed with water, the result was obtained 5.4 g of methyl 2-hydroxy-3-(2 - nicotineamide)-benzoate, which was used in the next stage without further purification. 3.4 g of thus obtained is connected is olaney acid. After cooling to room temperature the mixture was poured into 150 ml of water and was extracted with ethyl acetate. The organic phase is washed with 5% aqueous acidic sodium carbonate and then with water, dried on anhydrous sodium sulfate and boiled away in the vacuum, resulting in 1.3 g of crude 8-methoxycarbonyl-3 - methyl-4-oxo-2-(3-pyridyl)-4H-1-benzopyran.

1 g of this ester was dissolved in 9 ml of methanol and 15 ml of 1,4-dioxane and slowly added 1.7 ml of 10 n sodium hydroxide while maintaining the temperature at 20 - 25oC. After aging for 1 h at 50oC the reaction mixture was poured into 100 ml of water and was extracted with ethyl acetate. The aqueous layer was acidified using 1 N. hydrochloric acid. The precipitate was collected with suction; there was obtained 0.6 g of 8-carboxy-3-methyl-4 - oxo-2-(3-pyridyl)-4H-1-benzopyrane, which was used in the next stage without further purification.

The connection specified in the title, was obtained according to example 86, only been used thus obtained acid, 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran, and the reaction was carried out for 2 h at room temperature. The base was purified by thin-layer chromatography on silica gel, elwira a mixture of chloroform : methanol 98 : 2, and then was led from acetone. The output is rebamol} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

1 g of compound from example 59 and 0.32 g of 4-dimethylaminopyridine dissolved in 10 ml of dichloromethane. Then slowly added 0.15 ml of acetylchloride, while maintaining a temperature of 8 to 10oC. After exposure for 2 h at room temperature the reaction mixture is poured into 70 ml of water and was extracted with dichloromethane. The organic layer was washed with 5% aqueous acidic sodium carbonate and then with water and evaporated in vacuum to dryness. The crude base was purified by thin-layer chromatography on silica gel, elwira a mixture of ethyl acetate : methanol 9 : 1 followed by crystallization from ethanol. Yield 0.74 g of compound indicated in the title, melting point 120 - 123oC.

Example 121. 8-{3-[4-(2-Methylenedioxybenzyl)-1 - piperazinil]-propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

3 g of compound from example 59 and 1.8 ml of methyl isocyanate were dissolved in 30 ml of dry dimethylformamide and shaken at room temperature for 24 h the Mixture was diluted with water and shaken for 2 h, then filtered with suction. The crude base was purified by thin-layer chromatography on silica gel, elwira a mixture of chloroform : 5 N. methanolic ammonia 100 : 3. After crystallization from ethanol the connection specified in the zag is-acetoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

0.17 ml of acetylchloride was added dropwise over 5 min with shaking at 0oC to a solution of 1 g of compound of example 91 and 0.32 ml of triethylamine in 36 ml of chloroform. After shaking for 2 h at the same temperature, the reaction mixture was diluted with dichloromethane and water. The organic layer was separated, washed with water, dried on anhydrous sodium sulfate and evaporated in vacuum to dryness. After crystallization of the residue from acetonitrile, there was obtained 0.8 g of compound indicated in the title, melting at 148 - 149oC.

Example 123. (R, S)-8-{3-[4-(2-methoxyphenyl)-1-piperazinil]- propellerblades}-2,3-dihydro-4-hydroxy-4H-1-benzopyran methanesulfonate.

The connection specified in the title, was obtained by the method described in example 17, but starting compound instead of the compound of example 1 used the compound from example 87. The reaction mixture was diluted with water and shaken for 15 min, and then were extracted with ethyl acetate. Conventional treatment was obtained the crude product, which was purified by thin-layer chromatography on silica gel, elwira a mixture of dichloromethane:methanol 95:5. After evaporation in vacuo of the collected fractions was obtained pure base, which was transferred to metasolv xifei)-1-piperazinil]-propellerblades}-2- (4-AMINOPHENYL)-3-methyl-4-oxo-4H-1-benzopyran.

2,22 g of compound from example 113 and 0.56 g of Raney Nickel in 96 ml of ethanol and 4.8 ml of acetic acid was first made in the apparatus Parra (hydrogen pressure of 1 ATM) at room temperature. After shaking for 6 h the catalyst was filtered. The filtrate was parselocale 3 N. sodium hydroxide and diluted with water. After soaking for 2 days the precipitate of the compound indicated in the title, collected during the filtration with suction, washed with water and dried. Product recrystallization first from ethyl acetate and then from ethanol. Output 1.5 g, melting point 192 - 194oC.

Example 125. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propellerblades}-2-(4 - acetylaminophenol)-3-methyl-4H-1-benzopyran.

The connection specified in the title, was obtained by the method described in example 36, but instead of the compound obtained in example 33, used the compound obtained in example 134. The target product was purified by crystallization from 95% ethanol, melting point 207 - 209oC.

Example 126. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propellerblades}-2-(4-hydroxyphenyl)-3-methyl-4H-1 - benzopyran the dihydrochloride monohydrate.

The connection specified in the title, was obtained by the method described in example 86, but instead of 8-carboxy-4-the Oh temperature for 14 h, and hexamethylphosphoramide used as co-solvent. Selected diethylphosphonate ether compound indicated in the title, hydrolyzed in the alkaline treatment followed by neutralization with diluted hydrochloric acid. The resulting crude base was extracted with chloroform. The organic layer was washed with water and evaporated in vacuum. Sol obtained by adding ethanolic hydrogen chloride to acetonate solution of the base, was evaporated to dryness and washed with acetone. Melting point 193 - 205oC.

Example 127. 8-{3-[4-(2-Methoxyphenyl)-1-piperazinil]-propellerblades}-2-phenyl - 4,N, N'-trioxo-4H-1-benzothiophen monohydrate,

To 0.8 g of the compound from example 107 in 15 ml of acetic acid was added 0.32 ml of 30% hydrogen peroxide. The mixture was shaken for 3 h at 50oC. To this mixture was added in three equal portions at intervals of 2 h 0.48 ml of 30% hydrogen peroxide. After cooling, the mixture was poured into 240 ml of water, neutralized (pH 7) 5% aqueous acidic potassium carbonate and was extracted with chloroform. The organic layer was washed with water, dried on anhydrous sodium sulfate and boiled away in a vacuum. The result was obtained 0.18 g of compound indicated in the title and consumable after crystallize the l}-2-phenyl-benzo [b]furan.

The connection specified in the title, was obtained by the method described in example 86, but instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran used 7-carboxy-2-phenyl-benzo[b]furan (obtained according to EP 0306226) and the reaction was carried out for 1.5 h at room temperature. Purification was performed by crystallization from carbon tetrachloride. Melting point 132 - 136oC.

Example 129. 8-{N-Methyl-3-[4-(2-methoxyphenyl)-1-piperazinil]-propylsulfonyl}-3 - methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

2.29 g of intermediate compound (VIII) was added in portions with shaking at 0oC to a solution of intermediate compounds C1 and 0.95 g of triethylamine in 30 ml of chloroform. After shaking for 2 h at room temperature the reaction mixture was diluted with dichloromethane, water, and 0.5 N. sodium hydroxide. The organic layer was washed with water, dried on anhydrous sodium sulfate and was evaporated to dryness in vacuum. The residue was purified by thin-layer chromatography on silica gel, elwira a mixture of ethyl acetate:methanol 96:4. Upon evaporation in vacuo of the collected fractions was obtained the compound indicated in the title, in the form of a Foundation. In the usual way, he was transferred to salt methanesulfonate, which was led ሺ-(2-methoxyphenyl)-1-piperazinil]-butylcarbamoyl}- 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.

The connection specified in the title, was obtained by the method described in example 129, but instead of intermediate compound C1 was used connection VIII. The target product was led from acetonitrile. Melting point 173 - 175oC.

Pharmacological data.

Methodology.

Male rats weighing 200 - 300 g, female mice-albino weighing 20 to 30 grams and males hound dogs weighing 10 to 12 kg were obtained from Charles River, Italy and Nossan (Correzzana, Milan, Italy), respectively. The animals were kept with free access to food and water and forced cycle light-dark at 22 - 24oC until the day of the experiment, inclusive.

Short-term toxicity.

Short-term toxicity of the synthesized compounds were evaluated after intraperitoneal and oral administration of these compounds to female mice-albinos. Four (on a logarithmic scale) dose of compound was dissolved or suspended in 0.5% Methocel and injected in a volume of 10 ml/kg to groups of four mice. Mortality was recorded after 7 days of drug administration. Data analysis: the values LD50and the confidence limits of these values were calculated according to the method of Weil (Biometrics, 8, 249, 1952).

The study was rezeptservice 50 mM ice buffer Tris-HCl pH 7.4 in the volume 50 times the initial weight of the buffer. The homogenates were centrifuged for 10 min at 48000 g, and precipitation obtained in vitro, re-suspended in the same volume of ice buffer, and centrifuged; re-suspension was repeated 2 more times. Then, the resulting precipitation is again suspended in the same volume of buffer and incubation was performed under the conditions shown below in table. A.

The above-mentioned radiation receptor relationships, as well as experimental data obtained on dogs and set out below, provide an opportunity to establish that the compounds of the present invention are alpha1-blockers, i.e. that they are included in the class of substances, which are widely used as antihypertensive and anti-national Department of standardization agents (see for example, W. H. Frishman et al., Medical Clinics of N. America, 72, 427, 1988 and references, it is placed).

Communication [3H]8-OH-DPAT (5HT1A-receptors). The hippocampus of rats was homogenized in 50 mM ice Tris-HCl buffer pH 7.4 in the amount of 50 times the initial weight of the buffer. The homogenates were centrifuged for 10 min at 48000 g, obtained in vitro precipitation is again suspended in the same volume of ice buffer, incubated in was techipedia in the same volume of buffer and incubated under conditions below in the table. A.

According to studies conducted receptor relationships help to establish that the compounds of the present invention are ligands NT1A-receptor. Earlier it was reported that compounds that are 5HT1A-ligands have axiological and antidepressant effects on animals and humans (Hamon M, et al., Ann. N. Y. Acad. Sci., 600, 114,1990: Traber J. et al., T. I. P. S., 8, 437, 1987),

The study of receptor communications

The incubation was completed after the appropriate time (see table. A) rapid filtration through filters Whatman GF/B using a Brandel cell. Then the filters were twice washed in 15 ml ice buffer (see tab. A). The residual radioactivity of the filters was determined by liquid scintillation counters. Nonspecific relationship (which is usually 10 to 30%) was assessed by adding specific highly concentrated substituents (see table. A). First of all compounds were tested at a concentration of 1 to 10-6M, and full comparative curve (below a concentration of 10-11M) was built in conditions of considerable activity deputies. All these samples were repeated three times.

Comparative curves always analyzed using nonlinear the ri using the program ALLFIT, written for the IBM PC and famous from the National Institutes of Health, Bethesda, Maryland, USA.

K'-induced reduction sections of the urinary bladder of rats.

The bladder of rats was completely removed and immediately placed in Krebs solution warmed to 37oC. strips of muscle (20-30 mm long, 1 - 2 mm wide) were cut from the upper part of the bubble. Each strip was placed in a bath of 10 ml and added at a constant load of 1 g to isometric to a voltage meter (DY-1 Basile, Comerio, Varest, Italy). Contractions were recorded using a polygraph Basile 7070. After a 60-minute period balance strips were treated with 80 mM KCl (final concentration). This caused a phase reduction with subsequent slowdown and prolonged tonic component. When the tonic contraction was stable, the strips were washed, and after 30 min was induced contraction. After you have recorded two or more reproducible reactions in the bath added one of investigational medicinal substances in certain concentrations and after 30 min was induced contraction. The experimental group contained at least 2 specimens taken from different animals at each concentration of the investigated drug on regression analysis.

Effect on urethral contraction and blood pressure in dogs.

The experiments described were carried out according to the method Imagawa et al (J. Pharmacol. Methods, 22, 103-111, 1989), but with the following significant modifications: adult male hound dogs weighing 8 to 10 kg, were anestesiologi pentobarbital sodium, was intubated and was carried out by spontaneous ventilation air from the room. To control blood pressure in the arch of the aorta via the right carotid artery was injected polyethylene catheter.

Side left femoral vein was kemuliaan for infusion of anesthetic, and the right femoral vein was kemuliaan for administration of medicinal substances. For intra-arterial infusion of norepinephrine () polyethylene catheter was attached to the lower section of the stomach aorta through the right external iliac artery. Due to this procedure was distributed in a selective manner in the lower part of the urinary tract. Through a midline laparotomy were extracted bladder and proximal urethra. To prevent filling of the bladder both ureters were Coulibaly and urine is output to the outside. To record the pressure in the prostatic part of the urethra is Alenia strengthened in the prostate part of the channel. Was imposed ligature between the bladder neck and urethra to isolate the reaction of the latter and to prevent any interaction with the bladder. Another ligature was applied around Mekro-tip catheter and the external urethral orifice to secure the catheter. After the stabilization period and the subsequent surgical procedure (30 min), during which time carried out continuous monitoring of arterial pressure and the pressure in the prostatic part of the urethra, with an interval of 10 min was produced introduction. The dose was chosen such that it creates at least 100% increase in pressure in the prostate part. The compounds were administered in a cumulative manner with an interval of 15 - 20 min between injections and the injection was repeated after about 5 min after each injection of the compounds.

Curves showing the response to dose, were constructed by calculating the percentage inhibition of the increase in urethral pressure (induced) and the percentage drops in blood pressure, caused by the studied compounds. The magnitude of the ED25(dose inducing a 25% decrease) for diastolic crown corks) were calculated using linear regression analysis.

The compounds obtained in the examples were tested according to the methods described above. The results of these tests together with the comparative results for the standards are on the table. I and II. Compounds having affinity for the receptor (size IC50) less than ~ 500 nM, are considered to have good affinity. Usually preference is given to compounds having the value of the IC50less than 100 nM.

Below is effective daily dose (expressed in mg/kg body weight) for oral, parenteral or intravenous with:

a) obstructive disorders of the lower part of the urinary tract:

The total dose of 0.001 - 20

The preferred dose of 0.05 - 1

The most preferred ** - 0.3

b) as antihypertensive agents

The total dose of 0.01 - 20

The preferred dose is 0.1 - 5

The most preferred ** - 1

C) as anxiolytic-antidepressant drugs:

The total dose of 0.01 - 20

The preferred dose of 0.05 - 5

The most preferred ** - 0.5

g) as antispasmodics urinary bladder

The total dose of 0.01 - 20

The preferred dose of 0.02 - 10

The most preferred ** - 2

The most preferred values ** refer to OSISA in the treatment of these compounds and compositions also includes people who have one or more symptoms of depression (according to the definition Harrisson''s Principles of Internal Medicine, XII Ed., McGraw-Hill, Inc. p. 2124), or people who are experiencing symptoms of anxiety.

Selective use of dosages, namely those dosages that are active in the lower part of the urinary tract and do not have any significant effect on blood pressure, depends on the used compound, but can be generally applied dose of the selected connection, up to 4 times the ED50and not having a significant effect on blood pressure. Further improvement and optimization of dosage possible not more than the usual experiments.

Active compounds of the present invention can be used orally, for example with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules or compressed into tablets. Active compounds of the present invention together with fillers can be used for oral therapeutic injection in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, chewing gum, etc., These preparations should contain at least 0.5% of active compounds, but calices 70% by weight of the preparation. The number of active compound in these compositions is such that an acceptable dosage, and the required dosage can be obtained by taking a certain number of dosages. According to the present invention, the preferred compositions and preparations are prepared so that the unit forms oral dose contains 1.00 - 300 mg of active compound.

Tablets, capsules, lozenges, etc. can also contain the following ingredients: a binder-type microcrystalline cellulose, tragacanth gum or gelatin; an excipient type of starch or lactose; disintegrating substance type of alginic acid, corn starch, etc.; lubricant type stearate; sweetening agent type saccharin or sucrose or flavouring type of peppermint, methyl salicylate or orange flavoring. If a unit dosage is a capsule, it may contain in addition to the above materials carrier liquid type of fatty oil. Other dosage forms can contain various other materials which modify the physical form of a unit dosage, such as, for example, coating. Thus, tablets or pills may be coated with sugar, shellac, or other coating, localmessage agent and certain preservatives, colors and flavors. The materials used in the preparation of these various compositions should be clean in the pharmaceutical respect and non-toxic in the quantities used.

Active compounds of the present invention can be used for parenteral therapeutic administration in the form of a solution or suspension. These preparations should contain at least 0.1% of active compound, but the number can vary from 0.5 to 30% by weight of the total composition. The number of active compounds in such compositions should be such that was received appropriate dosage. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage contains from 0.2 to 100 mg of active compound. The solutions or suspensions may also include the following components: a sterile diluent type of water for injection, saline solution, fixed oils, polyethylene glycol, glycerine, propylene glycol or other synthetic solvents; antibacterial agents type benzyl alcohol or methylparaben; type antioxidants ascorbic acid or sodium bisulfite; helatoobrazovatel type of ethylendiaminetetraacetic is the atrium or dextrose. The capacity for non-single parenteral dose may be made of glass or plastic materials.

1. Heterobicyclic compound of the formula I

< / BR>
where is the ordinary or double bond;

X is sulfur atom or oxygen;

W is a valence bond or a carbonyl, methylene or hydroxymethylene group;

R2is a hydrogen atom, a C1- C6-alkyl, unsubstituted or substituted phenyl C1- C6alkenyl, C3- C6-carbazolyl, pyridyl, furyl, thienyl, benzoyl, phenyl, unsubstituted or substituted by phenoxypropane, phenyl, trifluoromethyl, C1- C6-alkoxy-, hydroxy-, amino-, C1- C6-acylamino - or nitro-group;

R3is a hydrogen atom or halogen, C1- C6-alkyl or hydroxy-C1- C6-alkyl;

R6is a hydrogen atom or halogen, nitro-, amino-, C1- C6-alkylamino-, di(C1- C6-alkyl)amino, C1- C6-acylamino-, C1- C6-alkylsulfonyl-, hydroxy-, C1- C6-alkoxygroup or C1- C6-alkyl;

R7is a hydrogen atom or a C1- C6-alkoxygroup;

Y represents one of the following groups, each of which presents the Z:

Y1IS-CO-;

Y2- -COO-;

Y3IS-CONH-;

Y4- -CON(CH3)-;

Y5- -SON(OH)-;

Y6- -CH(OH)-;

Y7- -CH(OAlKyl)-;

Y8- -CH = CH-;

Y10- -CH = CH-CONH-;

Y12- -CH2-;

Y13- -CH2COO-;

Y14- -CH2CONH-;

Y15- -CH2NH-;

Y16- -CH2N(CH3)-;

Y17- -CH2N(COCH3)-;

Y18- -CH2N(CONH2)-;

Y19- -CH2NHCO-;

Y20- -CH2N(CH3)CO-;

Y21- -CH2NH-CONH-;

Y22- -CH2NHSO2-;

Y23- -CH2O-;

Y24- -CH2S-;

Y25- -CH2SO-;

Y26- -CH2SO2-;

Y27- -CH2SO2NH-;

Y28- -CH2SO2N(CH3)-;

Y29- -NH-CONH;

Y30IS-N(CH3)-;

Y32- -N(CONH2)-;

Y33- -NHCO-;

Y34IS-N(CH3)CO-;

Y35- -NHSO2-;

Y37IS-O-;

Y38IS-S-;

Y39- -SO-;

Y40- -SO2-;

Y41- -SO2NH-;

Y42- -SO2N(CH3)-;

Y45- -CSNH-;

Y47-

Z is a linear or branched C1- C6-Allenova group;

B p the following groups:

A1is phenyl, substituted by one or two halogen atoms and/or one or two C1- C6-alkyl, C1- C6-alkoxy - or hydroxy-group;

A2- 2-pyrimidinyl group or

< / BR>
in which each of the L1and L2independently of each other a hydrogen atom, phenyl, 4-torbenson or 2-oxo-1-benzimidazolinyl group, provided that both L1and L2are not hydrogen atoms;

< / BR>
in which each of R10and R11independently a hydrogen atom or a C1- C6-alkoxygroup;

R12is a hydrogen atom or a C1- C6-alkyl;

n = 2 or 3,

or

< / BR>
in which R12has the specified values, provided that if R6and R7- hydrogen atoms, then Y cannot be an atom of oxygen or sulfur,

or its enantiomer, diastereoisomer, N - oxide or pharmaceutically acceptable salt, or a compound of the formula I, in which amino-, imino - and hydroxy-group can be substituted.

2. The connection according to p. 1, in which represents a double bond, X is an oxygen atom, W is a carbonyl group, R2is a phenyl group, R3is a methyl group, R6is a hydrogen atom, R7- the hydrogen atom.

4. The compound according to any one of the above paragraphs, in which Z represents trimethylene or tetramethylene group.

5. The compound according to any one of the above paragraphs, in which B represents one of the groups B1or B3.

6. The compound according to any one of the above paragraphs, in which B represents a 4-(2-methoxyphenyl)-1-piperazinilnom group.

7. The compound according to any one of the above paragraphs, in which Y, Z and B together represent 3-[4-(2-methoxyphenyl)-1-piperazinil]-profilirovannuju group.

8. The compound of formula I, selected from the following compounds:

8-{ 2-[4-(2-methoxyphenyl)-1-piperazinil] -1-oxoethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-(2-were)-1-piperazinil] -1-oxoethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-(2-ethoxyphenyl)-1-piperazinil] -1-oxoethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -1-oxopropyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{3-[4-(2-methoxyphenyl)-1-piperazinil]-propoxycarbonyl)}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-methoxyphenyl)-1-piperazinil]-etoxycarbonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-chlorophenyl-1-piperazinil)-propoxycarbonyl} -3-methyl-4-n,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil]-propoxycarbonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -2 - methyl-2-propoxycarbonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-(2-methoxyphenyl)-1-piperazinil]-ethylcarbamate}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[2-(2-methoxyphenoxy)-ethylamino]-propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-[3-(4-phenyl-1-piperazinil)-propellerblades] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ N-methyl-2-[4-(2-methoxyphenyl)-1-piperazinil] -ethylcarbamate} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 1-hydroxy-2-[4-(2-methoxyphenyl)-1-piperazinil] -ethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 1-hydroxy-2-[4-(2-were)-1-piperazinil]-ethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 1-hydroxy-2-[4-(2-ethoxyphenyl)-1-piperazinil] -ethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{1-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinil]-propyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 1-hydroxy-4-[4-(2-methoxyphenyl)-1-piperazinil]-butyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 1-ethoxy-2-[4-(2-methoxyphenyl-1-piperazinil] -ethyl}-3-methyl-4-oxo-2-phenyl-4H-1-Ben is
8-{ N-acetyl-2-[4-methoxyphenyl)-1-piperazinil]-ethylaminomethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-[4-2-methoxyphenyl)-1-piperazinylmethyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ N-methyl-N-[4-(2-methoxyphenyl)-1-piperazinil] -atsetamidometil} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-(2-methoxyphenyl)-1-piperazinil]-ethoxymethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[2-(2-ethoxyphenoxy)-ethylamino] -ethoxymethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-(2-methoxyphenyl)-1-piperazinil] -ethylthiomethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-(2-methoxyphenyl)-1-piperazinil]-ethylsulfanyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-(2-methoxyphenyl)-1-piperazinil]-ethylsulfanyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-(2-methoxyphenyl)-1-piperazinil] -ethylamino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil]-propylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 4-[4-(2-methoxyphenyl)-1-piperazinil] -butylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinil] -propylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ N-acetyl-3-[4-(2-methoxyphenyl)-1-piperazinil]-propylamino}-3-methyl-4-oxo-2-phenyl-4H-1-Ben is 2-methoxyphenyl)-1-piperazinil] -amiloride}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-(2-methoxyphenyl)-1-piperazinil] -ethoxy} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propoxy}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 4-[4-(2-methoxyphenyl)-1-piperazinil] -butoxy} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 5-[4-(2-methoxyphenyl)-1-piperazinil] -pentyloxy}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-oxo-1-piperazinil] -propoxy}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-2-{ 2-[2-(2,6-dimethoxyphenoxy)-ethylamino] -ethoxy}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinil] -propoxy}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propylthio} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propylsulfonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-(2-methoxyphenyl)-1-piperazinil] -ethylsulfanyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ N-methyl-2-[4-(2-methoxyphenyl)-1-piperazinil] -ethylsulfanyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ N-carbarnoyl-3-[4-(2-methoxyphenyl)-1-piperazinil] -propylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 4-[4-(2-methoxyphenyl)-1-piperazinil]-1-oxobutyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[(2l)-1-piperazinil]-butyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-[3-(4-phenyl-1-piperidinyl)-propellerblades] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-[3-(4,4-diphenyl-1-piperidinyl)-propellerblades] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(4-perbenzoic)-1-piperidinyl] -propellerblades} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-oxo-1-benzimidazolinyl)-1-piperidinyl]-propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-pyrimidinyl)-1-piperazinil] -propellerblades} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-hydroxyphenyl)-1-piperazinil]-propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 4-[4-(2-methoxyphenyl)-1-piperazinil] -butylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil]-propylsulfonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[N-methyl-2-(2-methoxyphenoxy)-ethylamino] -propellerblades} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinil]-propionamido}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-3-phenyl-4-oxo-4H-1-benzopyran,

8-{ 3-[(3,4-dihydro-1-oxo-2H-naphthyl)-methylamino]-propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-(2-methoxyphenyl)-1-piperazinil] -ethoxycarbonylmethyl}-3-meth is-4H-1-benzopyran,

8-{ N-(2-tetrahydropyranyloxy)-3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 4-[4-(2-methoxyphenyl)-1-piperazinil] -butylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

E-8-{2-[4-(2-methoxyphenyl)-1-piperazinil-toksienosti}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ N-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinil]-propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

E-8-{ 2-[4-(2-methoxyphenyl)-1-piperazinyl] -ethylcarbamate}-ethinyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 4-[4-(2-methoxyphenyl)-1-piperazinil] -butylsulfonyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[3-(2-methoxyphenoxy)-propylamino] -propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[2-(2-methylthiophene)-ethylamino] -propellerblades} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{3-[2-(2,6-dimethoxyphenoxy)-ethylamino]-propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinil] -propellerblades} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

(E)-8-{ 4-[4-(2-methoxyphenyl)-1-piperazinil]-1-butenyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

(E)-8-<2-{ 2-[4-(2-methoxyphenyl)-1-piperazinil] -etoxycarbonyl} -ethinyl>-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-(2-�yl)-1-piperazinil]-propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 2-[4-(2-methoxyphenyl)-1-piperazinil]-ethylsulfanyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil]-proportionably}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 4-[4-(2-methoxyphenyl)-1-piperazinil] -butylsulfonyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-3-hydroxymethyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades} -4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-2,3-dihydro-4-oxo-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-4-oxo-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades} -6-bromo-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil]-propellerblades}-6-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-3,6-dimethyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades} -3-methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -pravil}-6-acetamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-6-ethylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-6-dimethylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-7-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-3-methyl-4-oxo-2-(4-triptoreline)-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-2-(4-benzoylphenyl)-3-methyl-4-oxo-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-3-methyl-4-oxo-2-(4-phenoxyphenyl)-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-2,3-dimethyl-4-oxo-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-2-(t-butyl)-3-methyl-4-oxo-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades} -2-cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-2-(2-furyl)-3-methyl-4-oxo-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-3-methyl-4-oxo-2-thienyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades} -4-oxo-2-phenyl-4H-1-benzothia is/BR> 8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil]-propellerblades}-3-methyl-2-(4-were)-4-oxo-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-2-(4-methoxyphenyl)-3-methyl-4-oxo-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades} -2-(4-forfinal)-3-methyl-4-oxo-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades} -6-methanesulfonamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil]-propellerblades}-3-methyl-2-(4-nitrophenyl)-4-oxo-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades} -6-diethoxyphosphoryloxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran,

8-{ N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

7-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-2-benzoyl-3-ethyl-benzo[b]furan,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades} -2-(4-biphenyl)-3-methyl-4-oxo-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-3-methyl-4-oxo-2-(3-pyridyl)-4H-1-benzopyran,

8-{ 3-[4-(2-acetoxyphenyl)-1-piperazinil]-propellerblades}-3-methyl-4-oxo is o-2-phenyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil]-propellerblades}-6-acetoxy-3-methoxy-4-oxo-2-phenyl-4H-1-benzopyran,

(R,S)-8-{3-[4-(2-methoxyphenyl)-1-piperazinil]-propellerblades}-2,3-dihydro-4-hydroxy-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-2-(4-AMINOPHENYL)-3-methyl-4-oxo-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-2-(4-acetylaminophenol)-3-methyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades} -2-(4-hydroxyphenyl)-3-methyl-4H-1-benzopyran,

8-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades}-2-phenyl-4,N1N4-trioxo-4H-1-benzothiophen,

7-{ 3-[4-(2-methoxyphenyl)-1-piperazinil] -propellerblades} -2-phenyl-benzo[b]furan,

8-{ N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinil]-propylsulfonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,

8-{ N-methyl-4-[4-(2-methoxyphenyl)-1-piperazinil] -butylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran;

or a prodrug, enantiomer, diastereoisomer, N-oxide or pharmaceutically acceptable salt of such compounds.

9. Pharmaceutical composition, blocking action on1-adrenergic receptors and 5HT1receptors exhibiting antagonistic activity against CCSID, or a pharmaceutically acceptable salt, or a compound of the formula I, in which amino-, imino - and hydroxy-group can be protected in an effective amount and a pharmaceutically acceptable diluent or carrier.

10. The method of obtaining the compounds of formula I on p. 1 consists in the fact that the compound of General formula II

F1- Y - Z - L,

where F1represents a General formula

< / BR>
in which X, W, R2, R3, R6and R7have the values listed in paragraph 1;

L is a halogen atom or tsepliaeva group,

is subjected to condensation with the compound of the formula III

H - B

where B has the values specified in paragraph 1.

11. The method of obtaining the compounds of formula I on p. 1 consists in the fact that the compound of formula IV

F1- Y - H,

where F1group of General formula

< / BR>
in which W, X, R2, R3, R6and R7have the values listed in paragraph 1,

is subjected to condensation with the compound of the formula V

L - Z - B

where L is a halogen atom or tsepliaeva group,

Z and B have the values listed in paragraph 1.

12. The method of obtaining compounds of formula I on p. 1, where Z and B have the values listed in paragraph 1, and Y represents one of the groups Y3, Y4, allcauses that the compound of General formula VI

F1- X1- Q - Cl,

where F1group of General formula

< / BR>
in which R2, R3, R6, R7, W and X have the meanings specified in paragraph 1;

X1is a valence bond, methylene or venelinova group;

Q is carbonyl or sulfonylurea group,

is subjected to condensation with a compound of General formula VII

A - NH - Z - B

where A is a halogen atom, a C1- C6-alkyl or the group OPr, where Pr - protective group.

13. The method according to PP.10 - 12, namely, that the condensation is carried out in the environment of the polar solvent in the presence of a base at 20 - 140oC.

14. The method according to p. 13, namely, that as a reason to use potassium carbonate or triethylamine.

15. The method according to p. 13 or 14, namely, that as the polar solvent used dimethylformamide, chloroform, dichloromethane or methanol.

16. The method of obtaining compounds of formula I on p. 1, characterized in that compounds of General formula

F1- X1- COOH,

where F1matter specified in paragraph 10;

X1has the meaning as defined in paragraph 12,

is subjected to condensation with soedinenie values, specified in paragraph 12 for A,

or with compounds HS - Z - B, HO - Z - B or H2NO - Z - B, where Z and B have the meanings given in paragraph 1.

 

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The invention relates to the field of chemistry and can be used in industry as vulcanizing agents and vulcanization accelerators

The invention relates to the field of organic chemistry, specifically to a method for producing 2-(furyl-2)-1,3-oxazolidine formula I

< / BR>
with astragalina activity

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< / BR>
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The invention relates to vasoconstrictor /(benzodioxan, benzofuran and benzopyran)-alkylamino/-alkyl-substituted guanidine formula I, their pharmaceutically acceptable salts, or their stereochemical isomers, where X = O, CH2or a direct bond; R1= H, C1-C4alkyl, R2= H, C1-C6alkyl, C3-C6alkenyl, C3-C6quinil, R3= H, C1-C4alkyl; or R2and R1taken together, may form a bivalent radical of the formula/CH2/m-, where m = 4 or 5; or R1and R2taken together may form a bivalent radical of formula-CH=CH -, or the formula/CH2/n-, where n = 2, 3 or 4; or R3may indicate a relationship when R1and R2taken together form a bivalent radical of formula-CH=CH-CH= -, -CH= CH-N= or-CH=N-CH=; where one or two hydrogen atom substituted by a halogen atom, a C1-C6alkoxygroup, C1-C6the alkyl, CN, NH, mono - or di(C1-C6alkyl) amino group, aminocarbonyl, C1-C6alkylaminocarbonyl, R4-H or C1-C6-alkyl; Alk1denotes a divalent C1-C3-ascandilwy radical, A denotes dwuhvalentny a radical of the formula /, lk2represents C2-C15-alcander or C5-C7-cycloalkenyl, and each "R" represents 0, 1, 2, R7and R8each independently is H, a halogen atom, a C1-C6by alkyl, hydroxyl, C1-C6allyloxycarbonyl, C1-C6alkoxygroup, cyano, amino, C1-C6the alkyl, carboxyla, nitro or amino group, aminocarbonyl, C1-C6alkylcarboxylic or mono - or di-(C1-C6)alkylamino, provided that excluded /2-/ (2,3-dihydro-1,4-benzodioxin-2-yl)-methyl/-amino/-ethyl-guanidine

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< / BR>
where A is hydrogen or lower alkoxy,

E is hydrogen, hydroxyl, phenyl or piperidyl,

G phenyl not substituted or substituted with halogen and/or trifluoromethyl, fenoxaprop substituted by trifluoromethyl, benzyl, substituted phenylcarbinol, aminocarbonyl,

provided that E does not mean hydrogen or hydroxide, when G is phenyl, and their salts with inorganic acids

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< / BR>
in which R1group of the formula OR3where R3- cycloalkyl, 6-membered saturated a heterocycle;

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V - Allenova chain;

W - tetrazolyl, the group COR6or CONR7R8where R6, R7and R8- alkyl, cycloalkyl, phenyl, hydrogen
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