Derivatives of acridine synthesis method, pharmaceutical composition and method of treatment of malignant tumors


C07D219/04 - with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system

 

(57) Abstract:

The invention can be used in medicine to increase the sensitivity multilatina-resistant cancer cells to chemotherapeutic agents. Declared acridine derivatives of the formula I

< / BR>
where R0is hydrogen, halogen, C1- C4-alkyl, C1- C4-alkoxy, C1- C4-alkylthio, amino-, nitro-group; p is 1 or, when R0- C1- C4-alkoxy, p is 2 or 3; R1is hydrogen, C1- C4-alkyl, C1- C4-alkoxy, C1- C4-alkylthio; R2is hydrogen, C1- C4-alkyl; A is oxygen, sulfur, communication, group -(CH2)lNR9, where l is 0 or 1 and R9is hydrogen or methyl; B - C1- C4-alkylene, optionally substituted hydroxyl group, except that a hydroxyl group and A part cannot be linked to the same carbon atom when a is oxygen atom or sulfur, or a group - (CH2)lNR9or when A denotes a bond, then B means C2- C4-alkenylamine chain; R3is hydrogen, C1- C4-alkyl; m = 1 or 2; R4is hydrogen or halogen, C1- C4-alkyl, C1- C4-alkoxy, C1- C4- C4-alkoxy; R7is hydrogen, or R3and R7together form a group -(CH2)n- where n = 1 or 2; R8is hydrogen, C1- C4-alkoxy, and a group of the formula a

(a)

linked with the benzene ring in the 3 or 4 position relative to carboxamides Deputy, provided that when the group attached to the benzene ring at position 3, then R6should be in the position 6 of the benzene ring, or its physiologically compatible salts. Declared acridine derivatives of the formula Ia

< / BR>
where R0is hydrogen, halogen, C1- C4-alkyl, C1- C4-alkoxy; R1is hydrogen, C1- C4-alkoxy; R2is hydrogen; A is oxygen, sulfur, communication; B - unsubstituted C1- C4-Allenova chain; R4and R5the same and mean C1- C4-alkoxy, or their physiologically compatible salts. Derivatives of acridine General formula I is produced by interaction of the compound (II)

< / BR>
where the values of R0, R1p above, with a compound III

< / BR>
where the values of A, B, R3- R8above, in the presence of the agent of combination reaction. Further can be obtained physiologically compatible salts of the compounds I. Derivatives and the>, R1, R2, R6, A, B, p above, Q is a halogen atom, with a compound of formula V

< / BR>
or its salt, where the values of R3- R5, R7, R8above, in the presence of an acid acceptor. Can be obtained physiologically compatible salts of the compounds I. the Way of the destruction of the cells of the cancer exercise effects on tumor compound of formula I or Ia or their salts. The pharmaceutical composition includes the compound. It can be in the form for oral, buccal, parenteral or rectal administration. 6 C. and 6 C.p. f-crystals.

The present invention relates to the derivatives of acridine, methods for their preparation, to contain their pharmaceutical compositions and to their use in medicine. In particular, it relates to compounds and compositions that can improve the sensitivity multilatina-resistant (resistant to many drugs) of cancer cells to chemotherapeutic agents.

In many patients, the efficacy of chemotherapy in the treatment of cancer is low or decreases after the initial treatment leads to the development of resistance to anticancer drugs, known as multilocation kachestvennye cells become resistant to structurally different chemotherapeutic agents subsequent treatment with a single anticancer drugs. This acquired resistance to the drug can be a major clinical problem in the treatment of cancer. Some tumors characterized multilatina resistance and, therefore, no response to chemotherapy.

It turned out that this type of resistance may be cancelled due to some blocking calcium source tools such as Nicardipine and Verapamil: antiarrhythmic agents such as Amiodarone and Quinidine as well as due to the natural products, such as Cepharanthine. However, these compounds exhibit their increasing sensitivity multilatina-resistant cell activity only at very high doses, much higher inherent toxic level, and it is strictly within their clinical use in cancer chemotherapy.

Found a new group of compounds, which can improve sensitivity multilatina-resistant cancer cells to chemotherapeutic agents at the dose levels at which these new compounds are non-toxic.

Thus, the present invention relates to a compound of the formula I

< / BR>
where

R denotes a hydrogen atom or a nitro-group;

p - 1 or when R0represents C1-C4-alkoxyl, also can mean 2 or 3;

R1denotes a hydrogen atom or halogen or C1-C4-alkyl, C1-C4-CNS or C1-C4-allylthiourea;

R2denotes a hydrogen atom or a C1-C4is an alkyl group;

A denotes an oxygen atom or sulfur, a relationship or a group (CH2)lNH9(where l denotes 0 or 1 and R9denotes a hydrogen atom or methyl group);

B represents C1-C4-alkylenes chain, optionally substituted hydroxyl group, except that a hydroxyl group and A part cannot be linked to the same carbon atom when A represents an oxygen atom or sulfur or a group (CH2)lNR9or when A represents a bond, then B can also denote C2-C4-alkenylamine chain;

R3denotes a hydrogen atom or a C1-C4is an alkyl group;

m is 1 or 2;

R4denotes a hydrogen atom or halogen, or C1-C4-alkyl, C1-C4-CNS or C1-C4-allylthiourea;

R5denotes a hydrogen atom or a C1-C4-ALCO -CNS group;

R7denotes a hydrogen atom or R3and R7together form a group -(CH2)n- where n = 1 or 2;

R8denotes a hydrogen atom or a C1-C4-CNS group; and the group a

< / BR>
linked with the benzene ring in the 3-or 4-position relative to carboxamides Deputy, provided that when the group is linked to the benzene ring at position 3, then R6should be linked to the benzene ring at position 6;

and their salts and solvate, including their physiologically compatible salts and solvate.

As used herein, an alkyl group, as such or as part of the CNS or ancilliary may be an alkyl group with a linear or branched chain such as methyl, ethyl or prop-2-ilen group.

Halide Deputy can be an atom of fluorine, chlorine, bromine or iodine.

Group (group) R0when it is other than a hydrogen atom may be in position 5, 6, 7 or 8 molecules acridone, and R1when it is other than a hydrogen atom can be in position 1, 2 or 3 molecules of acridone.

Examples of the chain-A-B-CH2- include: -(CH2)2-; -(CH2)3-; -(CHB>2)3-; -OCH2CH(OH)CH2-; -NH(CH2)2-; -S(CH2)2- , and-S(CH2)3-.

A preferred class of compounds of formula I is one in which R0denotes a hydrogen atom or fluorine, or C1-C4-CNS (e.g. methoxy) group, a C1-C4-alkyl (e.g. methyl) group or a C1-C4-alkylthio (e.g., methylthio-) group, and R1denotes a hydrogen atom. When R0denotes another Deputy than a hydrogen atom, R0group preferably is in position 5 Greenaway molecules.

Another preferred class of compounds of formula I is one in which R2denotes a hydrogen atom.

When R3denotes a hydrogen atom or a C1-C4is an alkyl group, preferably R3represents C1-C4-alkyl (e.g. methyl) group.

Still another preferred class of compounds of formula (I) is one in which R4denotes a hydrogen atom or a C1-C4-CNS group (e.g. a methoxy group); R5denotes a hydrogen atom or a C1-C4-CNS (for example, methoxy-)group, and R8is ina least one of R4, R5and R8represents C1-C4-CNS (e.g. methoxy) group. Especially preferred class of compounds of formula (I) is one in which R4and R5each represents C1-C4-CNS (e.g. methoxy) group, and R8denotes a hydrogen atom.

As a preferred class of compounds of formula I is one in which R6denotes a hydrogen atom or a methyl, ethyl, methoxy or ethoxypropan.

A preferred group of compounds of formula (I) are those in which m is 1 and R3and R7together form a group -(CH2)2and their physiologically compatible salts and solvate.

A special group of compounds of formula I is any formula Ia

< / BR>
where

R0denotes a hydrogen atom or halogen, or C1- C4-alkyl, C1- C4-CNS, C1- C4-alkylthio - or nitro-group;

R1denotes a hydrogen atom or halogen, or C1- C4-alkyl, C1- C4-CNS or C1- C4-allylthiourea;

R2denotes a hydrogen atom or a C1- C4is an alkyl group;

EPI;

R4and R5each independently of one another denote C1- C4-CNS group;

and their physiologically compatible salts and solvate.

Especially preferred group of compounds of formula I is any formula Ia, in which R0denotes a hydrogen atom or fluorine, or C1- C4-CNS (for example, methoxy -, or C1- C4-alkyl (e.g. methyl) group;

R1and R2each represent a hydrogen atom and R4and R5each represent C1- C4-CNS (e.g. methoxy) group. Especially preferred are also compounds in which R0the group is at the 5 Greenaway molecules.

It goes without saying that the present invention includes all combinations of the abovementioned particular and preferred groups.

A particularly preferred compound according to the invention is 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-[1,2,3,4-tetrahydro - 6,7-dimethoxy-2-ethenolysis] ethyl] phenyl]-4-greencarbon and its physiological compatible salts and solvate.

Other preferred compounds according to the invention are:

9,10-dihydro-5-methoxy-9-oxo-N-[4--oxo-N-[4-[[3-[1,2,3,4-tetrahydro - 6,7-dimethoxy-2-ethenolysis]propyl]thio]phenyl]-4-greencarbon;

9,10-dihydro-5-methoxy-9-oxo-N-[4-[3-[1,2,3,4-tetrahydro - 6,7-dimethoxy-2-ethenolysis]propoxy]phenyl]-4-greencarbon;

9,10-dihydro-5-methyl-9-oxo-N-[4-[[3-[1,2,3,4-tetrahydro - 6,7-dimethoxy-2-ethenolysis]propyl]thio]phenyl]-4-greencarbon;

9,10-dihydro-5-methoxy-N-[2-methoxy-4-[3-[1,2,3,4-tetrahydro - 6,7-dimethoxy-2-ethenolysis]propyl]phenyl]-9-oxo-4-greencarbon;

9,10-dihydro-N-[2-methoxy-4-[3-[1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis]propyl]phenyl]-5-methyl-9-oxo-4 - greencarbon;

and their physiologically compatible salts and solvate.

Other preferred compounds according to the invention are:

N-[4-[4-[[[3,4-acid] methyl] methylamino] butyl]phenyl]- 9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[2-[[[3,4-acid] methyl] methylamino] ethyl] phenyl]- 9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[4-[[[3,4-acid] methyl] methylamino] butyl]phenyl]- 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[2-[[[3,4-acid] methyl] methylamino] ethyl] phenyl]- 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon;

and their physiologically compatible salts and solvate.

Still other preferred compounds according to the invention are:

N-[4-[3-[[[3,4-d is ethoxyphenyl] methyl] methylamino] ethyl] phenyl]- 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[[3-[[[3,4-acid] methyl] methylamino] propyl] thio] phenyl] - 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon;

and their physiologically compatible salts and solvate.

The following preferred compounds according to the invention are:

N-[4-[[3-[[[3,4-acid] methyl] methylamino] propyl] thio] phenyl] - 9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[4-[[[3,4-acid] methyl] methylamino] butyl]phenyl]- 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon;

N-[4-[3-[[2-[3,4-acid] ethyl]methylamino]propyl]phenyl]- 9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[2-[[2-[3,4-acid] ethyl]methylamino]ethoxy]phenyl]- 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon;

N-[4-[3-[[[3,4-acid]methyl]methylamino]propoxy]phenyl]- 9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[3-[[[3,4-acid] methyl] methylamino] propoxy] phenyl] - 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[2-[[2-[3,4-acid] ethyl] methylamino] ethyl]phenyl]- 9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[5-[[[3,4-acid] methyl] methylamino]pentyl]phenyl]- 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[3-[[[3,4-acid] methyl] methylamino]propoxy]phenyl]- 9,10-dihydro-9-oxo-4-accidentinsurance;

N-[4-[[3-[[[3,4-acid] methyl] methylamino] propyl] thio] phenyl] - 9,10-dihydro-5-fluoro-9-oxo-4-greencarbon;

N-[4-[2-[[[3,4-acid] methyl] methylamino] ethyl] phenyl]- 9,10-dihydro-5-methylthio-9-oxo-4-greencarbon;

N-[4-[2-[[[3,4-acid] methyl] methylamino] ethyl] phenyl]- 9,10-dihydro-5-methyl-9-oxo-4-greencarbon;

N-[4-[3-[[[3,4-acid] methyl] methylamino] propoxy]phenyl]-9,10-dihydro-5-methyl-9-oxo-4-greencarbon;

and their physiologically compatible salts and solvate.

Still other preferred compounds according to the invention are:

N-[4-[2-[[2-[3,4-acid] ethyl] methylamino] ethyl]phenyl]-9,10 - dihydro-9-oxo-4-greencarbon;

N-[4-[4-[[2-[3,4-acid] ethyl] methylamino]butyl]phenyl]-9,10 - dihydro-9-oxo-4-greencarbon;

N-[4-[2-[[2-[4-methoxyphenyl] ethyl]methylamino]ethyl]phenyl]-9,10 - dihydro-9-oxo-4-greencarbon:

N-[4-[2-[[2-[3,4-acid] ethyl]methylamino]ethoxy]phenyl]-9,10 - dihydro-2-(methylthio)9-oxo-4-greencarbon:

N-[4-[3-[[2-[3,4-acid] ethyl] methylamino] propoxy]phenyl]-9,10 - dihydro-9-oxo-4-greencarbon;

N-[4-[2-[[2-[4-methoxyphenyl] ethyl] methylamino]ethoxy]phenyl]-9,10 - dihydro-9-oxo-4-greencarbon;

4-acid]methyl]methylamino]propoxy]phenyl]-9,10 - dihydro-5-methoxy-9-oxo-4-greencarbon;

N-[4-[[2-[[[3,4-acid] methyl] methylamino] ethyl]thio]phenyl]-9,10 - dihydro-9-oxo-4-greencarbon:

and their physiologically compatible salts and solvate.

Suitable physiologically compatible salts of the compounds of formula I include salts of joining acids formed with organic or inorganic acids, such as hydrochloride, hydrobromide, sulphates, alkyl - or arylsulfonate (for example, methanesulfonate or p-toluensulfonate), phosphates, acetates, citrates, succinate, lactates, tartratami, fumarate and maleate. The solvate may be, for example, hydrates.

Other salts that are physiologically compatible, may be suitable for producing compounds of formula I and they are another part of the invention.

The ability of the compounds of formula I increase the sensitivity multilatina-resistant cells was demonstrated in vitro on multilatina-resistant cell line of Chinese hamster ovary (described Bech-Hansen and others , J. Cell.Physiol., 1976, 88, 23-32) and multilatina-resistant cell line breast cancer man (described Batist and other J. Biol.Chem., 1986, 261, 1544-1549), using a test similar to that described by Carmichael and D. the but-resistant cells was also demonstrated in vivo in the line of tumor cells P388P (described by Johnson and others, Cancer Treat. Rep., 1978, 62, 1535-1547). The methodology used is similar to that described Boesch and others, Cancer Research, 1991, 51, 4226-4233. However, in our study, compounds were administered orally, intravenously or administered intraperitoneally as a single dose.

The present invention therefore relates to the compound of formula I or its physiologically compatible salt or MES for use in therapy, more particularly for use in the treatment of mammals, including humans, suffering from cancer, for

(a) improve or increase the effectiveness of anticancer drugs, or

(b) increase or restore sensitivity of tumors to anticancer drug, or

(C) cancellation or reduction of acquired resistance induced or other kinds of tumors to anticancer drug.

Also, the present invention relates to a method of treatment of a mammal, including man, suffering from cancer, and this method includes the introduction of the above to the mammal an effective amount of the compounds of formula I or its physiologically compatible salt or MES, for

(a) improve or increase the efficiency of the antitumoral lekarzy

(C) cancellation or reduction of acquired resistance induced or other kinds of tumors to anticancer drug.

In one aspect the present invention relates to the use of compounds of formula I or its physiologically compatible salt or MES for the preparation of drugs for the treatment of a mammal, including man, suffering from cancer, for

(a) improve or restore sensitivity of tumors to anticancer drug, or

(b) increase or restore sensitivity of tumors to anticancer drug, or

(C) cancellation or reduction of acquired resistance induced or other kinds of tumors to anticancer drug.

You need to take into account that the compounds according to the present invention are introduced together with the anticancer drug. Thus, in another aspect, the present invention relates to a product containing a compound of formula I or its physiologically compatible salt or MES and anticancer drug, in the form of a combined preparation or simultaneous, separate or sequential use in the treatment of cancer, especially on the Sabbath. (b) increase or restore sensitivity of tumors to anticancer drug, or

(C) cancellation or reduction of acquired resistance induced or other kinds of tumors to anticancer drug.

Examples of suitable anti-tumor drugs used together with the compounds of the present invention are Vinca alkaloids (e.g. vincristine, vinblastine and vinorelbine), anthracyclines (e.g. daunorubicin, doxorubicin and aclarubicin), Taxol and its derivatives (e.g., Taxotere), podophyllotoxin (for example, etoposide and VP 16), mitoxantrone, actinomycin, colchicine, gramicidin D, amsacrine or any medication with cross resistantanti with the above drugs, characterized by the so-called MDR - phenotype (phenotype reaction of elimination of macrophages).

You need to take into account that, if the introduction of two drugs non-simultaneous, then the delay for the introduction of the second of the active ingredients should not be such that lost the healing effect of the combination.

Thus, in another aspect, the present invention relates to a compound of formula I or its physiologically compatible salt or MES and anticancer drug in the presence of any other in the human body or the stomach is shown anticancer drugs or

(b) increase or restore sensitivity of tumors to anticancer drug, or

(C) cancellation or reduction of acquired resistance induced or other kinds of tumors to anticancer drug.

Some tumors are often inherent multilatina resistance, especially carcinomas of the colon, carcinoma of the renal cells, hepatoma and the adrenal cortical carcinoma.

Other types of tumors, except initially sensitive, can often become multilatina-resistant, especially leukemia, limfoma, myeloma, pediatric tumors (e.g., neuroblastoma, sarcoma and cancer of the breast, ovary and lung.

Therefore, the compounds of the invention are particularly suitable in the treatment of mammals, including people receiving chemotherapy against one of the above types of cancer.

When using the compounds of formula I or its physiologically compatible salt or MES and anticancer drugs may be preferred application of the active ingredients in the form of separate pharmaceutical formulations, although it may be used one combined formini to be stable and mutually compatible in some of the applied formulation.

Pharmaceutical formulations suitable anticancer drugs and appropriate dosages and dosing standards generally match, if exercised introduction one anticancer drugs for the treatment of tumors.

Suitable pharmaceutical formulations and appropriate dosages and dosing norms compounds of formula I and their physiologically compatible salts and solvate are described below.

Thus, hereinafter, the invention relates to a pharmaceutical composition that includes a compound of formula I or its physiologically compatible salt or MES together with one or more physiologically compatible bases or excipients.

On the other hand, the present invention relates to a pharmaceutical composition that includes an effective amount of the compounds of formula I or its physiologically compatible salt or MES used in the treatment of mammals suffering from cancer, for

(a) improve or increase the effectiveness of anticancer drugs, or

(b) increase or restore sensitivity of tumors to anticancer drug, or

(C) cancellation or S="ptx2">

Compounds according to the invention can be formulated for oral, buccal, parenteral or rectal administration, of which the preferred oral and parenteral administration.

For oral administration the pharmaceutical compositions can prepare, for example, in the form of tablets or capsules, which are usually obtained with pharmaceutically compatible excipients such as binding agents (e.g., pre-gelatinizing corn starch, polyvinylpyrrolidone or oksipropilmetiltselljuloza); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); dispersing agents (e.g. sodium lauryl sulfate or sodium starch glycolate). Tablets can be coated with the coating itself by known methods. Liquid compositions for oral administration can be prepared, for example, in the form of solutions, syrups or suspensions, or they may be in the form of a dry product before use, dilute with water or other suitable solvent. Such liquid compositions can be obtained in the usual way with pharmaceutically compatible (acceptable) d is s, suitable for food fats); emulsifying agents (e.g. lecithin or ASAS (acacia)); non-aqueous solvents (for example, almond oil, ester oils, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-oxybenzoates or sorbic acid). The composition may also contain appropriate buffer salts, flavouring agents, colouring and sweetening agents.

Preparations for oral administration may be suitable manner formulated with obtaining a controlled release of active compounds.

For buccal injection composition can be prepared in the form of tablets or pellets formulated in the usual way.

Compounds of the invention can be formulated for parenteral administration by injection of a large dose or a continuous infusion. Formulations for injection may be in the form of a unit dose, for example in ampoules or in mnogochasovykh containers, with an added preservative. The composition can be in such forms as suspensions, solutions or emulsions in oil, water or alcohol solvent, and may contain agents for formulation, such as suspendresume agents, stabilisatoren diluted with a suitable solvent, for example sterile, not containing pyrogenic substances water.

Compounds of the invention can also be formulated in rectal (intestinal) compositions, such as suppositories, or held enemas, e.g. containing conventional spark basics, such as oil, cocoa butter or other glycerides.

The proposed daily dose of the compounds of the invention for administration to man (weighing about 70 kg) is about 10-1000 mg, more preferably about 25-500 mg Need to take into account that it may be necessary to implement certain changes doses, depending on age and condition of the patient and the route of administration. For example, a daily dose of about 1 mg/kg may be appropriate for administration through injection. The daily dose can be administered as a single unit or as two or more parts of a single unit, enter the appropriate time intervals.

Compounds of General formula I and their physiologically compatible salts and solvate can be obtained following conventional methods. In the following description, the groups R0- R8, m, p, A and B are specified for compounds of formula I values, unless nothing else.

So obanya formula II

< / BR>
with the compound of the formula (III):

< / BR>
The reaction can be carried out using reagent combinations commonly used in peptide synthesis, such as dicyclohexylcarbodiimide (not necessarily in the presence of 1-oxybenzoates), diphenylphosphonate or N, N'-carbodiimide. The reaction is usually carried out in an inert solvent, such as a simple ether(e.g. tetrahydrofuran), halogenougljovodonika (e.g. dichloromethane), an amide (e.g. dimethylformamide) or a ketone (for example acetone) and at a temperature of, for example, from -10 to +100oC, more preferably at about room temperature.

According to another General method B, the compound of the formula I can be obtained by reacting the compounds of formula IV

< / BR>
where

Q denotes a halogen (e.g. bromine),

with the compound of the formula V

< / BR>
or its salt. The reaction can be carried out in the presence of an acid acceptor, such as a carbonate of an alkali metal (e.g. potassium carbonate) in the presence or in the absence of solvent and at elevated temperature (e.g., 50-120oC). Suitable solvents are ketones (e.g. acetone, methyl ethyl ketone or methylisobutylketone) and alcohols (Narimanovo be obtained by recovering the compounds of formula VI

< / BR>
in which A denotes an oxygen atom or a bond,

using a suitable reducing agent, such as sociallyengaged, in an inert solvent, such as a simple ether (for example tetrahydrofuran), at elevated temperature.

The compounds of formula VI can be obtained by recovering the compounds of formula VII

< / BR>
by catalytic hydrogenation, for example using hydrogen in the presence of a catalyst based on a noble metal (e.g. palladium). Catalysis can be facilitated by use of, for example, coal. The hydrogenation can be carried out in a solvent such as alcohol (e.g. ethanol), and preferably at a temperature of about 20-100oC (for example, when 20-50oC) and at atmospheric pressure. Alternatively, you can restore when using iron and conc. hydrochloric acid at elevated temperature (for example, at the boiling point under reflux). This alternative recovery process leaves untouched any double bond present in the compound of formula VII.

The compounds of formula VII can be obtained by reacting the compounds of formula VIII.

< / BR>
or it is the journey of the base, such as an organic base (e.g. triethylamine or N,N-diisopropylethylamine), or inorganic bases such as carbonate of an alkali metal (e.g. potassium carbonate or bicarbonate of an alkali metal (e.g. sodium bicarbonate).

If the free acid VIII enter into interaction with the amine V, you can use a combination of reagents and conditions described in method A for the reaction of compounds of formula II with the compound of the formula III.

If using an activated derivative of a compound of formula VIII can be, for example, galoyanized acid (e.g. the acid chloride acid), produced by the interaction of the free acid VIII with a halogenation agent (e.g. thionyl chloride). It is activated derivative compounds of formula VIII can be administered during the interaction with the compound of the formula V in a solvent such as acetone, in the presence of a base such as sodium bicarbonate.

The compounds of formula VIII, where A denotes a bond, can be obtained by nitriding the compounds of formula IX.

< / BR>
with the help of nitric acid.

The compounds of formula VIII, where A denotes a bond, and B represents a group-CH=CH-, you can usually get p the foam. The hydrolysis can be performed using conventional methods, for example by using sodium hydroxide in aqueous ethanol.

The compounds of formula X can be obtained by reacting the compounds of formula XI

< / BR>
where

R11denotes a hydrogen atom or a C1-C4-alkyl, C1-C4-CNS or hydroxyl group,

with the compound of the formula XII

(C6H5)3R = CHCO2R10XII

where

R10has the above value,

in an inert solvent such as a hydrocarbon (e.g. toluene), and at elevated temperatures. To obtain the compounds of formula X, where R6represents C1-C4-CNS group from the compounds of formula XI, where R11denotes a hydroxyl group, the above reaction is carried out by alkylation of the hydroxyl group using, for example, alkylhalogenide.

The compounds of formula VIII, where A denotes an oxygen atom, can be obtained by hydrolysis of compounds of formula XIII

< / BR>
where

R10have the above meaning.

The hydrolysis can be performed using conventional methods, for example by applying hydroxy formula XIV

L - B - CO2R10,

where

L denotes a halogen atom (e.g. bromine),

with the derived NITROPHENOL in the presence of a carbonate of an alkali metal (e.g. potassium carbonate) in a solvent such as acetone.

The compounds of formula III, where A denotes an oxygen atom or sulfur, or a bond, can be obtained by restoring the compounds of formula XV

< / BR>
where

A denotes an oxygen atom or sulfur or a bond,

using the conditions described above for the recovery of the compounds of formula VII.

The compounds of formula XV can be obtained by heating the compounds of formula XVI

< / BR>
where

Q denotes a halogen atom (e.g. bromine),

A represents an oxygen atom or sulfur, or connection,

with the compound of the formula V, above, under the conditions described above in method B.

The compounds of formula XVI, where A denotes an oxygen atom or sulfur, can be obtained by reacting the compounds of formula XVII

< / BR>
where

A denotes an oxygen atom or sulfur,

with dihalogenoalkane Q - B - CH2- Q, in the presence of a suitable base such as a carbonate of an alkali metal (e.g. potassium carbonate).

The compounds of formula XVI, where the Agent, such as tribromide phosphorus.

The compounds of formula XVIII can be obtained by restoring the compounds of formula XIX

< / BR>
using a suitable reducing agent such as DIBORANE.

The compounds of formula XIX can be obtained by subjecting the compound of formula XX

< / BR>
where

Q denotes a halogen atom (e.g. chlorine),

one or more successive syntheses Arndt-Eistert, i.e. reaction with diazomethane, followed by processing, for example, silver oxide and water).

You need to take into account also that the compounds of formula XIX, in which B denotes unsubstituted C2-C4-alkylenes chain, can also be obtained by subjecting the compound of formula XXI

< / BR>
the Wittig reaction with a suitable phosphoramidon (for example, as (C6H5)3P = CH(CH2)OH), followed by reduction of the double bond using a suitable reducing agent such as DIBORANE, and oxidation of the primary alcohol to the carboxylic acid using a suitable oxidizing agent such as chromium oxide(VI).

The compounds of formula III, where A denotes the group (CH2)lNR9you can get by restoring the compounds of formula XXII

< / BR>
in which B' represents a bond and the underwater reductant, such as sociallyengaged, in an inert solvent such as a simple ether (for example tetrahydrofuran), at elevated temperature.

The compounds of formula XXII can be obtained by recovery of formula XXIII

< / BR>
by catalytic hydrogenation, for example, as described above to obtain compounds of formula VI.

The compounds of formula XXIV can be obtained by reacting the compounds of formula XXIV

< / BR>
where

Q denotes a halogen atom (e.g. chlorine),

with the compound of the formula V, above, under the conditions described above in method B.

The compounds of formula IV can be obtained by reacting the compounds of formula II, above, with a compound of formula XXV

< / BR>
where

Q denotes a halogen atom (e.g. bromine),

in the conditions described above in the manner And for the reaction of compounds of formula (II) with the compound of the formula III.

The compounds of formula V, where R3represents C1-C4is an alkyl group, can be obtained by reacting the compounds of formula XXVI

< / BR>
with benzaldehyde in the presence of C1-C4-alkylhalogenide. Subsequent hydrolysis of the resulting Quaternary salt by treatment razbavlennye is the RUPE.

Needless to say that the above General methods can be used to obtain the compounds of formula I in which B contains a hydroxyl substituent. However, it may be preferable to restore the intermediate compound, which contains oxoprop, to obtain the desired intermediate compound, which contains hydroxyl Deputy, at an appropriate stage of the common way.

Intermediate compounds of formulas III, IV, VI, VII, VIII, X, XIII, XV, XVI, XVIII, XIX, XXII and XXIII are novel compounds and constitute a further object of the present invention.

The compounds of formula II by itself is known or can be obtained by conventional means, such as the methods described by G. W. Rewcastle and W. A. Denny in Synth. Commun, 1985, 217-222.

Compounds of formula V, IX, XI, XII, XIV, XVII, XX, XXI, XXIV and XXVI themselves known or can be obtained in the usual way.

The compounds of formula XXV in itself known or can be obtained in the usual way. For example, the compounds of formula XXV, where A denotes an oxygen atom, can be obtained by reaction of a derivative of 4-acetamidophenol with dihalogenoalkane Q-BCH2-Q followed by acid hydrolysis using, de salt, for example, a physiologically compatible salt, this can be accomplished by reacting the compounds of formula I in free base form with an appropriate acid, preferably with an equivalent amount, in a suitable solvent, such as alcohol (e.g. ethanol or methanol), an aqueous alcohol (e.g. aqueous ethanol), halogenougljovodonika (for example, dichloromethane), esters (e.g. ethyl acetate) or an ether (e.g. tetrahydrofuran) or a mixture of two or more such solvents.

Physically compatible salts can also be obtained from other salts, including other physiologically compatible salts of the compounds of formula I in the application of conventional methods.

You also need to take into account that in the above multistage processes, the different methods described for the introduction of the desired target product desired groups can be performed in various sequences of the described sequences. The sequence of reactions in multistage processes should be selected in such manner that the applied reaction conditions are not affected groups in the molecule, which is desirable in the target product.

The invention is further illustrated the wounds of the invention. All temperatures are given in degrees Celsius (oC).1H-NMR Spectra get in dilute solutions in CDCl3if not specified anything else. The solvents indicated, dried over sodium sulfate. Used for column chromatography silica gel brand Merck 60, 230-400 mesh mesh. The following abbreviations are used: THF = tetrahydrofuran: DMF = dimethylformamide.

Intermediate compound I.

(a) 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-(3-(4-nitrophenoxy) propyl)isoquinoline

A mixture of 1-(3-bromopropane)-4-nitrobenzene (10 g), 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline-hydrochloride (8.8 g) and potassium carbonate (10.6 g) in DMF (100 ml) is heated at 100oC for 16 hours. The mixture was then filtered and the filtrate is evaporated. The residue is treated with water and extracted with dichloromethane. The organic layer was washed with water, dried and evaporated to obtain an oil, which crystallizes from ether, giving the title compound (11.3 g), so pl. 100oC.

The following compounds have the same intermediate compounds 1A follows:

(b) 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-(3)(4-nitrophenyl(thio)- propyl)isoquinoline

The title compound (5.3 g) obtained as oil (which then kristaller CLASS="ptx2">

NMR includes: = of 4.05 (6H, s, 2xOCH3).

(C) 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-(2-(4-nitrophenyl(ethyl)- isoquinoline

The title compound (16 g) obtained as solid from 1-(2-bromacil)-4-nitrobenzene (10 g) and 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (10,9 g). So pl. 118oC NMR spectrum includes = 3,9 (6H, s, 2xOCH3).

(d) 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-(4-(4-nitrophenyl) butyl)-isoquinoline

The target connection (12,6 g) are obtained in the form of oil from 1-(4-bromobutyl)-4-nitrobenzene (12.5 g) and 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline-hydrochloride (11.1 g). The product was then purified column chromatography, elwira mixture with dichloromethane-methanol (99:1).

The NMR spectrum consists of 3.85 (6H, s, 2xOCH3)

Intermediate compound 2

(a) 4-(3-(1,2,3,4-Tetrahydro-5,6-dimethoxy-2-ethenolysis) propoxy)-aminobenzoyl

A solution of intermediate compound 1(a) (16 g) in ethanol (200 ml) hydronaut at room temperature and at atmospheric pressure in the presence of 10% palladium-on-coal (1.6 g). After complete absorption of hydrogen, the catalyst is filtered off and the solution concentrated to obtain the title compound (14,7 g) in the form of an oil which crystallized from hexane. So pl. 100oC.

2: 3350 cm-1.

(b) 4-(2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-ethenolysis)- ethyl)-aminobenzoyl

Intermediate compound 1 () (14 g) restore according to the method for intermediate 2(b), receiving the title compound (12 g) as a solid. So pl. 120oC.

(g) 4-(4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-ethenolysis)- butyl)-aminobenzoyl

Intermediate compound 1(g) (8.5 g) restore according to the method for intermediate compound (2A). The product was then purified by column chromatography, elwira mixture with dichloromethane-methanol (99:1), and receive the title compound (4.3 g) in the form of oil, which solidified. IR-spectrum: frequency NH2: 3350 cm-1.

Intermediate compound 3

(a) 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-((4-nitrophenoxy) acetyl)-isoquinoline

A mixture of (4-nitrophenoxy)-acetic acid (50 g) and thionyl chloride benzene, getting 4-nitrophenoxyacetic in the form of solids. The solution of this solid (9.4 g) in acetone (100 ml) is added dropwise to a stirred mixture of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline-hydrochloride (10 g) and sodium hydrogen carbonate (9 g) in acetone (100 ml) at 0oC. Stirring is continued at room temperature for 16 hours, the mixture was then filtered and the filtrate concentrated. The residue is treated with water and extracted with dichloromethane. The organic layer is washed with water, dried and concentrated, obtaining the title compound (6.6 g) as oil. IR-spectrum: frequency CO: 1650 cm-1.

A manner similar to the method for producing the intermediate compound 3(a) receive the following connection:

(b) 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-[3-(4-nitrophenyl)-1 - oxopropyl] -isoquinoline

The target compound (12.3 g) are obtained in the form of a solid substance, so pl. 134oC 4-nitrobenzophenone acid (9.75 g) and 1,2,3-tetrahydro-6,7-dimethoxyisoquinoline (11.6 g).

Intermediate compound 4.

(a) 2-((4-Aminophenoxy)acetyl)-1,2,3,4-tetrahydro-6,7 - dimethoxyisoquinoline

Intermediate compound 3(a) (6.6 g) was dissolved in a mixture of methanol (100 ml) with concentrated hydrochloric acid (50 ml) is reflux for 3 hours. The mixture was then cooled, poured on ice, alkalinized with sodium hydroxide and extracted with ethyl acetate. Organic layer washed with water, dried and evaporated, obtaining the title compound (4 g) as oil. IR-spectrum: frequency NH2: 3360 cm-1.

(b) 2-(3-(4-AMINOPHENYL)-1-oxopropyl)-1,2,3,4-tetrahydro-6,7 - dimethoxy-isoquinoline

A solution of intermediate 3(b) (12 g) in ethanol-dioxane (18 ml, 5:1) hydronaut at room temperature and at atmospheric pressure in the presence of 10% palladium-on-coal (1.2 g). After complete absorption of hydrogen the catalyst is filtered off and the solution concentrated, obtaining the title compound (11 g) as a solid. IR-spectrum: frequency NH2: 3360 cm-1frequency CO: 1650 cm-1.

The intermediate compound 5

(a) 4-(2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-ethenolysis)-ethoxy)-aminobenzoyl

A solution of intermediate 4(a) (4 g) in THF (50 ml) was added dropwise to a stirred suspension of sociallyengaged (1.8 g) in THF (20 ml) at room temperature, and the mixture is refluxed for 3 hours. To the cooled mixture gently add water, then filtered off, washed with THF, evaporated and extragroup: frequency NH2: 3350 cm-1.

Such intermediate compounds 5(a) provides the following connections:

(b) 4-(3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-ethenolysis)propyl-aminobenzoyl

The target compound (8.6 g) are obtained in the form of a solid substance with so pl. 138oC by restoring the intermediate compound 4(b) (11 g).

The intermediate compound 6

(a) 1-(3-Bromopropane)-3-methoxy-4-nitrobenzene

A mixture of intermediate 18 (2.4 g), 1,3-dibromopropane (7.5 ml) and potassium carbonate (2.2 g) in DMF (30 ml) was stirred at room temperature for 24 hours. The mixture is filtered and the filtrate is evaporated to dryness. The residue is treated with water and extracted with dichloromethane. The organic extract is then washed with 5% sodium hydroxide solution and brine, dried and concentrated in vacuo, obtaining the title compound (3.5 g) in the form of oil

NMR spectrum: = 2,3 (2H, m, CH2); 3,6 (2H,T., CH2Br); and 3.8 (3H, s, OCH3); to 4.1 (2H, T., CH2O).

The following compounds have the same intermediate compound 6(a) follows:

(b) 1-(3-Bromopropane)-3-methyl-4-nitrobenzene

The title compound (33 g) are obtained in the form of an oil from 3-methyl-4-nitro-phenol (25 g) and 1,3-di is x2">

(C) 1-(3-Bromopropane)-3-ethyl-4-nitrobenzene

The title compound is obtained from 3-ethyl-4-NITROPHENOL and 1,3-dibromopropane. NMR spectrum: = 1,23 (t, 3H, CH3-CH2-); 2,2 (m, 2H, CH2-CH2-CH2); 2,8 (K.,2H, CH2-CH3); 3,5 (t, 2H, CH2Br); to 4.1 (t,2H, O-CH2-); and 6.6 (m, 2H, Ar); 7,8 (D., 2H, Ar)

Intermediate compound 7.

(a) 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-(3-(3-methoxy-4-nitrophenoxy)- propyl)-isoquinoline

A mixture of intermediate compound 6(a) (0.7 g), 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (0.4 g) and potassium carbonate (0.36 g) in DMF (25 ml) is heated at 60oC for 16 hours. The mixture is filtered and the filtrate is evaporated. The residue is treated with water and extracted with dichloromethane. The organic layer is dried, concentrated and the resulting residue purified by column chromatography, elwira mixture with dichloromethane-methanol (99:1) obtain the title compound (0.64 g) as oil. NMR spectrum: = 3,8 (9H, 2c., 3xOCH2).

Such intermediate compounds 7(a) provides the following connection:

(b) 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-(3-(3-methyl-4-nitrophenoxy)-propyl) -isoquinoline

The title compound (5.3g) will get oil from intermediate 6(b) (5.7 g) and 1,2,3,4-is Intermediate compound 8

(a) 2-Methoxy-4-(3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinoline) -propoxy)-aminobenzoyl)

A solution of intermediate compound 7(a) (0.64 g) in ethanol (25 ml) hydronaut at room temperature and at atmospheric pressure in the presence of 10% palladium-on-coal (60 mg). After completion of hydrogen absorption, the catalyst is filtered off and the solution concentrated in vacuo, obtaining the title compound (0.4 g) as a solid, NMR-spectrum: = 3,8 (9H, c., 3xOCH3); 3,0 (2H, sh.S., NH2).

Such intermediate compounds 8(a) provides the following connection:

(b) 2-Methyl-4-(3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-ethenolysis)-propoxy)- aminobenzoyl

The title compound (4.8 g) obtained as oil (which then crystallizes) of intermediate compound 7(b) (5.3g). NMR spectrum: = 2,1 (3H, s, CH3), and 3.8 (6H, s, 2xOCH3).

Intermediate compound 9.

(a) 3-Methyl-4-nitrobenzyloxy acid

3-Methyl-4-nitrobenzoate (10 g) in ether (100 ml) was added dropwise to a solution of diazomethane (obtained from 30 g of N-methyl-N-nitroso n-toluene-sulfonamida) at 0oC. the Reaction mixture was stirred at room temperature for 3 hours and then concentrated in wetware silver oxide in water (obtained from silver nitrate (20 g) and diluted with sodium hydroxide (100 ml)). The mixture is stirred for 3.5 hours at 75-80oC and filtered. The filtrate is diluted with water, acidified with a solution of nitric acid and the product extracted with hot diisopropyl ether, treated with brine and concentrated in vacuo, obtaining the title compound (6 g) as a solid substance, so pl. 95oC.

In the same way get the following connection:

(b) 3-Methoxy-4-nitrobenzyloxy acid, so pl. 130-131oC.

From 3-methoxy-4-nitrobenzonitrile.

Intermediate compound 10. Ethyl-3-(3-hydroxy-4-nitrophenyl)-2-propenoate

To a solution of 3-hydroxy-4-nitrobenzaldehyde (5 g) in toluene (50 ml) added carbethoxymethylthio in (8.9 g) and the mixture refluxed for 2 hours. The mixture was then concentrated and the residue purified by column chromatography, elwira with a mixture of cyclohexane with ethyl acetate (6: 4), upon receipt of the title compound (6.2 g) as a solid. So pl. 95oC.

Intermediate compound 11. Ethyl-3-(3-methoxy-4-nitrophenyl)-2-propenoate

To a solution of intermediate compound 10 (5,88 g) in DMF (50 ml) is added potassium carbonate (4.4 g) and methyliodide (4 ml). The mixture is stirred at room temperature for 2 nd extract is dried and concentrated, receiving the title compound (6.2 g) as a solid. So pl. 130oC.

Intermediate compound 12. 3-(3-Methoxy-4-nitrophenyl)-2-Papanova acid

To a suspension of intermediate compound 11( 6.2 g) in ethanol (50 ml) is added 1N. the sodium hydroxide solution (50 ml). The mixture is refluxed for 1 hour and then poured on cracked ice. Add 1 n hydrochloric acid (60 ml) and the precipitate is filtered off, receiving the title compound (4 g) as a solid. NMR-spectrum (DMCO-d6): = 8,95 (3H. S., OCH3).

The intermediate connection 13. 3-(3-Ethoxy-4-nitrophenyl)-2-Papanova acid

Using reactions similar to those described for intermediates 11 and 12 receive the title compound (3.1 g) in wine solids, so pl. 272oC, of intermediate compound 10 (4.0 g), ethyliodide (4 ml) and potassium carbonate (2.6 g), followed by saponification of the ester function.

Intermediate compound 14

(a) 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-(3-methoxy-4-nitrophenyl) -1-oxo-2-propenyl)-isoquinoline

A mixture of intermediate compound 12 (4.9 g) and 1-oxybisethanol (2,95 g) in DMF (100 ml) was stirred at room temperature for 10 minutes. Add 1,2,atoi temperature for 16 hours and then filtered.

The filtrate was concentrated in vacuo, treated with diluted hydrochloric acid, then with dilute sodium hydroxide solution and extracted with dichloromethane. The organic extract is dried, concentrated in vacuo and the residue purified by column chromatography, elwira first mixture with ethyl acetate-cyclohexane (4:6), then with ethyl acetate, thus obtaining the title compound, which crystallized from a mixture of ethyl acetate and ether and obtained in the form of crystals (6.5 g). NMR spectrum: = of 3.85 (6H, s, 2xOCH3); of 3.95 (3H, s , OCH3).

These compounds have a similar intermediate compound 14(a) follows:

(b) 2-(3-(3-Ethoxy-4-nitrophenyl)-1-oxo-2-propenyl)1,2,3,4 - tetrahydro-6,7-dimethoxyisoquinoline

The title compound (5.3 g) are obtained in the form of a solid substance, so pl. 152oC, from intermediate 13 (3.0 g) and 1,2, 3,4-tetrahydro-6,7-dimethoxyisoquinoline (2.5 g).

(C) 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-((3-methyl-4-nitrophenyl)- acetyl)-isoquinoline

The target compound (2.8 g) obtained as oil from the intermediate compound (9) (a) (1.8 g) and 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (1.9 grams).

IR-spectrum: frequency CO: 1650 cm-1.

Intermediate compound 153
).

These compounds have a similar intermediate compound 15 (a) follows:

(b) 2-(3-(4-Amino-3-ethoxyphenyl)-1-oxopropyl)-1,2,3,4-tetrahydro-6,7 - dimethoxyisoquinoline.

The target compound (4.5 g) obtained as oil from intermediate 14 (b) (5.3g). IR-spectrum: frequency CO: 1640 cm-1the frequency of NH2: 3450 cm-1.

(a) 2-((4-Amino-3-were-acetyl)-1,2,3,4-tetrahydro-6,7 - dimethoxyisoquinoline

The title compound (2.4 g) obtained as oil from intermediate 14(b) (2.8 g), IR range: frequency CO: 1650 cm-1the frequency of NH2: 3340 - 3440 cm-1.

The intermediate connection 16

(a) 2-Methoxy-4-(3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-ethenolysis] -propyl]-aminobenzoyl

A solution of intermediate 15(a) in THF (30 ml) was added dropwise to a stirred suspension socialwise hydride (1.84 g) in THF (50 ml) at room temperature and the mixture is refluxed for 2 hours. Carefully add water to the cooled mixture, which was then fioi dried and concentrated in vacuo, receiving the title compound (4,2 g) as oil. IR-spectrum: frequency NH23340 - 3440 cm-1.

Similar intermediate compound 16(a) provides the following connections:

(b) 2-Ethoxy-4-(3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-ethenolysis) -propyl)-aminobenzoyl

The title compound (2.5 g) obtained as oil from intermediate 15(b) (4.5 g). The IR-spectrum, frequency of NH2: 3340 - 3440 cm-1.

(a) 2-Methyl-4-(2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-ethenolysis/ethyl) -aminobenzoyl

The title compound (1.7 g) obtained as a solid substance, so pl. 105oC, from intermediate 15 (C) (2.4 g).

Intermediate compound 17. 3-Chloro-4-NITROPHENOL

Concentrated nitric acid (10 ml) in acetic acid (30 ml) was added dropwise to a chilled solution of 3-chlorophenol (10 g) in acetic acid (10 ml). After 1 hour at -5oC, the mixture was poured on ice, extracted with ether, dried over sodium sulfate and evaporated. The residue is then purified by column chromatography, elwira with a mixture of hexane with ethyl acetate (85-15), to obtain the title compound (9 g). So pl. 120oC.

The intermediate connection 18. 3-Methoxy-4-NITROPHENOL

A solution of intermediate autoclave for 16 hours at 100oC. the Mixture is cooled and poured on ice and acidified with concentrated hydrochloric acid. The methanol is then evaporated in a vacuum, causing the crystallization of the title compound (3.5 g). So pl. 142oC.

Intermediate compound 19. 1-(2-Chloroethoxy)-3-methyl-4-nitrobenzene

A mixture of 3-methyl-4-NITROPHENOL (10 g) 1-bromo-2-chlorethane (16 ml) and sodium hydroxide (2.9 g) in water (50 ml) stirred at the boiling temperature under reflux for 16 hours. The mixture is diluted with water and the product extracted with methylene chloride. The organic extract was dried over sodium sulfate and concentrated in vacuo, obtaining the title compound in the form of oil (10,81 g). NMR spectrum: = 2,5 (C., 3H, -CH3); a 3.9 (t, 2H, CH2-O) and 4.3 (t, 2H, -CH2-Cl).

Intermediate compound 20

(a) 3,4-Dimethoxy-N-methylbenzeneethanamine

3,4-Dimethoxybenzonitrile (100 g) is mixed with benzaldehyde (59 g), and evaporated on a rotary evaporator, getting oil. Then add methyliodide (69 ml) and the mixture is heated for 48 hours at 40oC and then for 3 hours then boiled with 80% ethanol (500 ml). After half of the ethanol evaporates, the solution is treated with ether ( 1 liter) to give a solid, which is filtered off, Promyshlennye (80 g) in the form of oil, which is distilled under reduced pressure. So Kip. 92 - 95oC at 0.1 mm RT. Art.

(b) 3,4-Dimethoxy-N-methylbenzeneethanamine

3,4-Dimethoxybenzaldehyde (100 g) is mixed with benzaldehyde (64 g) and evaporated on a rotary evaporator to obtain oil. Then add methyliodide and the mixture is heated for 48 hours at 40oC and then boiled with 80% ethanol (800 ml) for 3 hours. After half of the ethanol evaporates, the solution is treated with ether (1 liter) to give a solid, which is filtered off, washed with ether, treated with dilute sodium hydroxide solution and extracted with ether, receiving the title compound (69 g) in the form of oil, which is distilled under reduced pressure. So Kip. 91oC at 0.03 mm RT. Art.

The following amines receive such intermediate compounds 20(a) and 20(b) follows:

(b) 4-fluoro-N-methylbenzeneethanamine in the form of oil. IR-spectrum: includes peak at 3300 cm-1(NH). Their 4-forbindelsesanalyse and under the conditions.

(d) 4-Methoxy-N-methylbenzeneethanamine in the form of oil. The infrared spectrum includes a peak at 3310 cm-1(NH). 4-methoxybenzylamine and under the conditions.

(d) 4-Methoxy-N-methylbenzeneethanamine in the form of oil. The IR spectrum of Ventilatoren in the form of oil. The infrared spectrum includes a peak at 3310 cm-1(NH). From 4-(methylthio)benzoylmethylene and under the conditions.

(g) 4-Methyl-N-methylbenzeneethanamine in the form of oil. The infrared spectrum includes a peak at 3310 cm-1(NH). 4-methylbenzeneethanamine and under the conditions.

The intermediate connection 21

(a) 3,4-Dimethoxy-N-methyl-N-(3-(3-methyl-4-nitrophenoxy)propyl)- benzoylmethylene

A mixture of intermediate compound 6(b) (6 g), intermediate 20(b) (4 g) and potassium carbonate (3.3 g) in DMF (80 ml) is heated at 60oC for 36 hours. The mixture is filtered and the filtrate is evaporated. The rest bring in water and extracted with dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and evaporated. Then the remaining oil chromatographic, elwira mixture with dichloromethane-methanol (99:1) to give the title compound as an oil (4.6 g).

NMR spectrum: = 2,2 (C., 3H,-CH3); 2,4 (C., 3H, N-CH3); and 3.8 (SD, 6H, 2-OCH3).

In the same way receive the following connections:

(b) 3,4-Dimethoxy-N-(3-(3-methoxy-4-nitrophenoxy)-propyl)-N - methyl-benzoylmethylene

In the form of oil. From intermediate 6(a) and intermediate 20(b). NMR spectrum: = 2,2 (C., 3H, N-CH3); 3,85-3,9 (2 S., 3H-6H, 3 O-CH3the exact connection 6(b) and intermediate 20(b). NMR spectrum: = 2,2 (C., 3H, N-CH3); 3,85-3,9 (2 S., 6H, 20-CH3).

(g) 3,4-Dimethoxy-N-methyl-N-(2-(3-methyl-4-nitrophenoxy)-ethyl/- benzoylmethylene in the form of oil. From intermediate 19 and 20(b). NMR spectrum: = 2,3 (C., 3H, N-CH3); 2,5 (2 S., 3H, N-CH3); 3,8 (C., 6H, 2-OCH3).

Intermediate compound 22

(a) N-(3-(4-Amino-3-methylphenoxy)propyl)-3,4-dimethoxy-N - methylbenzol-methanamine

A solution of intermediate 21(a) (4.6 g) in ethanol (100 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (450 mg). Upon completion of hydrogen absorption, the catalyst is filtered off and the solution concentrated to obtain the title compound (3.7 g) as oil. NMR spectrum: = 2,0 (C., 3H, CH3); 2,1 (2 S., 3H, N-CH3); 3,7 (C., 6H, 2 OCH3).

In the same way receive the following connections:

(b) N-(3-(4-Amino-3-methoxyphenoxy)propyl)-3,4-dimethoxy-N - methyl-benzoylmethylene in the form of oil. From the intermediate compound (21 b). NMR: = 2,2 (C., 3H, N-CH3); 3,85-3,9 (C., 3H, OCH3); 3,9 (C., 6H, 2 OCH3).

(C) N-(3-(4-Amino-3-ethyleneoxy)propyl)-3,4-dimethoxy-N - methylbenzeneethanamine in the form of oil. From intermediate 21 (b).

NMR spectrum: = 2,1 (C., 3H, N-CH3); 3,7 (C., 6H, 2 OCH3).

(d) 21 (d).

NMR spectrum: = 2,0 (C., 3H, N-CH3); 2,2 (C., 3H, N-CH3); 3,8 (C., 6H, 2OCH3).

The intermediate connection 23. Diethyl-(3-methyl-4-nitrobenzyl)- malonate

To a solution of sodium ethylene (obtained from 1.35 g of sodium in ethanol (30 ml)) add diethylmalonate (9,2 ml) and then added dropwise 3-methyl-4-nitrobenzylamine (13,4 g). The mixture is stirred for 30 minutes at room temperature, then 30 minutes, refluxed and then concentrated. The residue is treated with water and hexane, and the precipitate is filtered off and the filtrate is extracted with diethyl ether. The organic extract is dried over sodium sulfate and concentrated, obtaining the title compound as an oil (4 g). NMR spectrum: = 1,15 (t, 6H, 2xCH3-CH2); 2,5 (C., 3H, CH3-Ar); and 3.16 (SD, 2H, CH2-Ar); 4,0 (K., 4H, 2xCH2CH3); 7,0 (m, 2H, Ar), and 7.7 (D., 1H, Ar).

The intermediate connection 24. 3-(3-Methyl-4-nitrophenyl)- propionic acid

Intermediate compound 23 (4 g) was added dropwise to a solution of potassium hydroxide (3.1 g) in water and the mixture is stirred at the boiling point under reflux for 2 hours, diluted with water, washed with diethyl ether and then acidified with dilute hydrochloric acid. After extraction with diethyl is unity in the form of a solid yellow (2.3 g).

The NMR spectrum (CDCl3): = 2,5 (C., 3H, CH3); to 2.9 (m, 4H, 2 CH2).

Intermediate compound 25

(a) N-(3,4-Acid/-methyl)-N-methyl-3-methyl-4 - nitrobenzonitrile.

A mixture of intermediate compound 9(a) (2 g) and 1-oxibendazole (1.6 g) in DMF (35 ml) was stirred at room temperature for 5 minutes. Add intermediate compound 20(b) (1,9 g) in DMF (20 ml), then dicyclohexylcarbodiimide (2.1 g) and the mixture is stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with dichloromethane. The combined, dried organic extracts evaporated and the residue purified by column chromatography, elwira mixture with dichloromethane-methanol (97:3), and receive the title compound (1.7 g) as oil. The infrared spectrum includes the signal at 1640 cm-1(CO).

In the same way receive the following connections:

(b) N-[[3,4-Acid]methyl]-N-methyl-3-methoxy-4 - nitrobenzonitrile

From intermediate 9(b) and intermediate 20(b) IR spectrum includes the signal at 1645 cm-1(CO).

(C) N-[[3,4-Acid]-methyl]-N-methyl-3-methyl-4SUB>3); 2,9 (C., 3H, N-CH3); 3,8 (C., 6H, 2 OCH3).

The intermediate connection 26.

(a) 4-Amino-3-methyl-N-[[3,4-acid]methyl]-N-methyl - benzonatate

A solution of intermediate 25(a) (1.7 g) in ethanol (60 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (0.25 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the solution concentrated, obtaining the title compound (1.4 g) as oil. The infrared spectrum includes signals at 3450-3350 cm-1(NH2and 1630 cm-1(CO).

In the same way receive the following connections:

(b) 4-Amino-3-methoxy-N-[[3,4-acid] methyl]-N - methylbenzeneethanamine. From intermediate 25(b). The infrared spectrum includes signals at 3450-3350 cm-1(NH2) and 1625 cm-1(CO).

(b) 4-Amino-3-methyl-N-[[3,4-acid] methyl]-N - methylbenzophenone. From intermediate 25(b). NMR spectrum: = 2,1 (3H, s, CH3): 2,75 (3H, s, N-CH3): of 3.8 (6H, s, 2 OCH3).

The intermediate connection 27.

(a) 4-Amino-3-methyl-N-[[3,4-acid]methyl]-N - methylbenzeneethanamine

A solution of intermediate 26(a) (1.4 g) in THF (50 ml) was added dropwise to a stirred suspension of sociallyengaged (0,7 Noah mixture gently add water the mixture is then filtered through zletovo pad, washed with THF, evaporated and extracted with ether. The ether extracts are dried and evaporated to obtain the title compound (1 g) as oil. The infrared spectrum includes signal when 3450-3350 cm-1(NH2).

In the same way receive the following connections:

(b) 4-Amino-3-methoxy-N-[[3,4-acid]methyl]-N - methylbenzeneethanamine. From intermediate 26(b). The infrared spectrum includes signal when 3455-3345 cm-1(NH2).

(b) 4-Amino-3-methyl-N-[[3,4-acid] methyl]-N - methylbenzeneethanamine in the form of oil. From intermediate 26(b). NMR spectrum: = 2,0 (3H, s, -CH3): 2,1 (3H, s, N-CH3); and 3.8 (6H, s, 2 OCH3).

The intermediate connection 28.

N-[[3,4-Acid] methyl] -N-methyl-3-methoxy-4 - nitrobenzene-2-propenamide

A mixture of intermediate compound 12 (3 g) and 1-oxybisethanol (1,95 g) in DMF (100 ml) was stirred at room temperature for 10 minutes. Add intermediate compound 20(b) (2.5 g) then dicyclohexylcarbodiimide (2,95 g) and the mixture is stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated in vacuo, treated with a dilute solution of hydrochloric keys dried over sodium sulfate and concentrated. The residue is purified by column chromatography, elwira with ethyl acetate, to obtain the title compound (4.4 g) NMR spectrum: = 2,9 (3H, s, N-CH3): of 3.85 (3H, s, OCH3): of 3.9 (6H, s, 2 OCH3).

The intermediate connection 29. 4-Amino-3-methoxy-N-(3,4-acid) methyl)-N-methyl - benzoylpropionic.

A solution of intermediate 28 (8,4 g) in a mixture of methanol with ethyl acetate (1 : 1, 100 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (0.3 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the solution concentrated to obtain the title compound (7,3 g in the form of oil. The infrared spectrum includes signals at 3450-3350 cm-1(NH2and 1635 cm-1(CO).

The intermediate connection 30. 4-Amino-3-methoxy-N-[[3,4-acid] methyl]-N-methylbenzeneethanamine.

A solution of intermediate 29 (to 7.32 g) in tetrahydrofuran (100 ml) was added dropwise to a stirred suspension of sociallyengaged (2.3 g) in tetrahydrofuran (100 ml) at room temperature and the mixture is refluxed for 1 hour. Carefully add water (20 ml) to the cooled mixture, which is filtered through calinou pad, washed with diethyl alcohol, concentrate, and akutem column chromatography on silica gel, elwira mixture with dichloromethane-methanol (95: 5) to give the title compound as an oil (2.5 g), IR range includes signal when 3440-3340 cm-1(NH2).

The intermediate connection 31.

(a) N-[[3,4-acid]methyl]-N-methyl-4-nitrobenzophenone

A mixture of 4-nitrobenzeneboronic acid (31 g) with thionyl chloride (200 ml) is refluxed for 1 hour. The solution is then concentrated and evaporated with benzene to obtain oil. This oil is dissolved in acetone (100 ml) and added dropwise to a stirred mixture of intermediate 20(b) (28, 6 g) with sodium bicarbonate (35 g) in acetone (150 ml) at room temperature. Stirring is continued for 4 hours, the mixture was then filtered and the filtrate concentrated. The residue is poured into water and then extracted with dichloromethane. The organic phase is evaporated to obtain the title compound (41.5 g) in the form of oil. Recrystallization from ethanol gives the title compound in the form of solids. So pl. 90oC.

(b) N-[[3,4-Acid]methyl]-N-methyl-4-nitrobenzonitrile.

A mixture of 4-nitrobenzyloxy acid (22 g) with thionyl chloride (200 ml) is refluxed for 3 hours. RA is ml) and added dropwise to a stirred mixture of intermediate 20(b) (22 g) and sodium hydrogen carbonate (15.3 g) in acetone (100 ml) at room temperature. Stirring is continued for 6 hours, the mixture was then filtered and the filtrate concentrated. The residue is poured into water and extracted with ethyl acetate. The organic phase is washed first with dilute sodium hydroxide solution, then with water, dried and concentrated to obtain the title compound (22,3 g) as oil. The infrared spectrum includes a peak at 1650 cm-1(CO).

Similar intermediate compound 31(a) and intermediate 31(b) given the following amides:

(C) N-(2-(3,4-Acid)ethyl)-N-methyl-4-nitrobenzophenone in the form of oil. The infrared spectrum includes a peak at 1640 cm-1(CO). 4-nitrobenzeneboronic acid and intermediate 20(a).

(g) N-(2-(3,4-Acid)ethyl)-N-methyl-4 - nitrobenzophenone in the form of oil. The infrared spectrum includes a peak at 1640 cm-1(CO). 4-nitrobenzophenone acid and intermediate 20(a).

(d) N-[2-[3,4-Acid]ethyl]-N-methyl-4 - nitrobenzonitrile in the form of oil. The infrared spectrum includes a peak at 1650 cm-1(CO). 4-nitrobenzyloxy acid and intermediate compound (20A).

(e) N-[[3,4-Acid]methyl]-N-methyl-4-nitrobenzophenone in the form of oil. The infrared spectrum includes a peak at 1640 cm-1(CO). 4-nitrobenzophenone acid and intermediate 20(g).

(C) N-(2-(4-Methoxyphenyl)ethyl)-N-methyl-4-nitrobenzophenone in the form of an oil: IR spectrum includes a peak at 1650 cm-1(CO). 4-nitrobenzeneboronic acid and intermediate 20(d).

(and) N-[[4-Forfinal]methyl]-N-methyl-4-nitrobenzophenone in the form of an oil: IR spectrum includes a peak at 1640 cm-1(CO). 4-nitrobenzeneboronic acid and intermediate 20(b).

(K) N-[[4-[Methylthio] phenyl]methyl]-N-methyl-4-nitrobenzophenone in the form of oil. The infrared spectrum includes a peak at 1640 cm-1(CO). 4-nitrobenzeneboronic acid and intermediate 20(e).

(l) N-[2-[4-Methoxyphenyl]ethyl]-N-methyl-nitrobenzonitrile in the form of oil. The infrared spectrum includes a peak at 1650 cm-1(CO).

4-nitrobenzyloxy acid and intermediate 29(d).

(m) N-[[3,4-Acid] methyl] -N-methyl-4 - nitrobenzophenone in the form of an oil; IR includes a peak at 1650 cm-1(CO). 4-nitrobenzophenone acid and intermediate 20(b).

The intermediate connection 32

(a) 4-Amino-N-[[3,4-acid]methyl]-N-methylbenzenesulfonamide
-1(CO) and peak at 3350 - 3430 cm-1(NH2).

(b) 4-Amino-N-[[3,4-acid]methyl]-N-methylbenzeneethanamine

Intermediate compound 31(b) (22 g) was dissolved in a mixture of methanol (300 ml) and concentrated hydrochloric acid (150 ml) at room temperature and under stirring. Slowly add then iron powder (18 g) and the reaction mixture is refluxed for 3 hours. The mixture was then evaporated, alkalinized with sodium hydroxide solution and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated to obtain the title compound (14 g) as oil. The infrared spectrum includes peaks at 1620 cm-1(CO) and 3350 - 3450 cm-1(NH2).

Such intermediate compounds 32(a) and 32(b) provides the following connections:

(b) 4-Amino-N-(2-(3,4-SUP>-1(NH2). From intermediate 31(b).

(g) 4-Amino-N-(2-(3,4-acid)ethyl)-N - methylbenzylamine in the form of oil. The infrared spectrum includes peaks at 1630 cm-1(CO) and 3340 - 3420 cm-1(NH2). From intermediate 31(g).

(d) 4-Amino-N-[2-[3,4-dimethoxy] ethyl] -N-methylbenzeneethanamine in the form of oil, IR spectrum includes peaks at 1640 cm-1(CO) and 3330 - 3420 cm-1(NH2). From intermediate 31(d).

(e) 4-Amino-N-[[3,4-acid] methyl] -N - methylbenzophenone in the form of an oil; IR includes peaks at 1640 cm-1(CO) and 3350 - 3440 cm-1(NH2). From intermediate 31(e).

(W) 4-Amino-N-[[4-acid] methyl]-N-methylbenzophenone in the form of oil, IR spectrum includes peaks at 1650 cm-1and 3330 - 3420 cm-1(NH2). From intermediate 31(W).

(C) 4-Amino-N-(2-(4-acid)ethyl)-N - methylbenzylamine in the form of oil, IR spectrum includes peaks at 1640 cm-1(CO) and 3340 - 3430 cm-1(NH2). From intermediate 31(C).

(I) 4-Amino-N-[[4-forfinal]methyl]-N-methylbenzenesulfonamide in the form of oil. The infrared spectrum includes peaks at 1640 cm-1(CO) and 3340 - 3430 cm-1(NH2). From intermediate 31 (and at 1640 cm-1(CO) and 3340 - 3430 cm-1(NH2). From intermediate 31(K).

(l) 4-Amino-N-(2-(4-methoxyphenyl)ethyl)-N - methylbenzeneethanamine in the form of oil. The infrared spectrum includes peaks at 1635 cm-1(CO) and 3340 - 3440 cm-1(NH2). From intermediate 31(l).

(m) 4-Amino-N-[[3,4-acid] methyl] -N - methylbenzophenone in the form of oil. The infrared spectrum includes peaks at 1630 cm-1(CO) and 3340 - 3420 cm-1(NH2). From intermediate 31(m).

The intermediate connection 33

(a) 4-Amino-N-[[3,4-acid]methyl]-N-methylbenzeneethanamine

A solution of intermediate 32(a) (30 g) in THF (150 ml) was added dropwise to a stirred suspension of sociallyengaged (10 g) in THF (150 ml) at room temperature and the mixture is refluxed for 3 hours. To the cooled mixture gently add water, then the mixture is filtered, washed with THF, evaporated, and extracted with ether. The combined ether extracts are dried and evaporated to obtain the title compound (21 g) as oil. The infrared spectrum includes a peak at 3370 - 3440 cm-1(NH2).

(b) 4-Amino-N-[[3,4-acid]methyl]-N-methylbenzeneethanamine

A solution of intermediate 32(b) (14 g) nature and the mixture is refluxed for 3 hours. To the cooled mixture gently add water, then the mixture is filtered, washed with THF, evaporated and extracted with ether. The combined ether extracts are dried and evaporated to obtain the title compound (9.5 g) in the form of butter.

The infrared spectrum includes a peak at 3360 - 3430 cm-1(NH2).

Similar intermediate compounds 33(a) and 33(b) provides the following connections:

(a) 4-Amino-N-(2-(3,4-acid)ethyl)-N - methylbenzeneethanamine in the form of oil-in IR spectrum includes a peak at 3360 - 3430 cm-1(NH2).

From intermediate 32 ().

(g) 4-Amino-N-(2-(3,4-acid)ethyl)-N - methylbenzylamine in the form of oil. The infrared spectrum includes a peak at 3360 - 3460 cm-1(NH2).

From intermediate 32 (g).

(d) 4-Amino-N-(2-(3,4-acid)ethyl)-N - methylbenzeneethanamine in the form of oil. The infrared spectrum includes a peak at 3360 - 3430 cm-1(NH2).

From intermediate 32 ().

(e) 4-Amino-N-((3,4-acid)methyl)-N - methylbenzylamine in the form of oil. The infrared spectrum includes a peak at 3360 - 3440 cm-1(NH2).

From intermediate 32 (e).

(W) 4-Amino-N-((4-methoxyphenyl)methyl)-N - mative the aqueous compound 32 (W).

(C) 4-Amino-N-(2-(4-methoxyphenyl)ethyl)-N - methylbenzeneethanamine in the form of oil. The infrared spectrum includes a peak at 3330 - 3460 cm-1(NH2).

From intermediate 32(C).

(I) 4-Amino-N-((4-forfinal)methyl)-N-methylbenzeneethanamine in the form of oil. The infrared spectrum includes a peak at 3350 - 3430 cm-1(NH2).

From intermediate 32(and).

(K) 4-Amino-N-((4-methylthio)phenyl)-methyl-N-methylbenzeneethanamine in the form of oil. The infrared spectrum includes a peak at 3350 - 3430 cm-1(NH2).

From intermediate 32(K).

(l) 4-Amino-N-(2-(4-methoxyphenyl)ethyl)-N-methylbenzeneethanamine in the form of oil. The infrared spectrum includes a peak at 3360 - 3440 cm-1(NH2).

From intermediate 32(l).

(m) 4-Amino-N-((3,4-acid)methyl)-N - methylbenzeneethanamine in the form of oil. The infrared spectrum includes a peak at 3360 - 3440 cm-1(NH2).

From intermediate 32(m).

The intermediate connection 34

(a) N-(2-(3,4-Acid)ethyl)-N-methyl-2- (4-nitrophenoxy)ndimethylacetamide

A mixture of (4-nitrophenoxy)-acetic acid (31 g) and thionyl chloride is refluxed for 2 hours. The solution is concentrated and evaporated with benzene obtained with itocnode compounds 20(a) (50 g) and sodium hydrogen carbonate (22 g) in acetone (250 ml) at room temperature. Stirring is continued for 4 hours, the mixture is filtered and the filtrate concentrated. The residue is treated with water and extracted with ethyl acetate. The organic phase is washed first with dilute sodium hydroxide solution, then with water, dried and concentrated. Recrystallization from ethanol gives the title compound (82 g). So pl. 121oC.

Similar intermediate compound 34(a) provides the following connections:

(b) N-((3,4-Acid)methyl)-N-methyl-2- (4-nitrophenoxy)ndimethylacetamide so pl. 130oC. From (4 nitrophenoxy-acetic acid and intermediate 20(b).

(C) N-methyl-2-(4-nitrophenoxy)-N-(phenylmethyl-ndimethylacetamide). So pl. 98oC. From (4 nitrophenoxy)acetic acid and N-methylbenzeneethanamine.

(g) N-((3,4-Acid)methyl)-N-methyl-2-(4-nitrophenylthio)- ndimethylacetamide in the form of oil. NMR spectrum: = 3,0 (3H, s, N-CH3), and 3.8 (6H, s, OCH3). From (4 nitrophenylthio)-acetic acid and intermediate 20(b).

(d) N-(2-(4-Methoxyphenyl)ethyl)-N-methyl-2-(4-nitrophenoxy)- ndimethylacetamide, so pl. 107oC. From (4 nitrophenoxy)acetic acid and intermediate 20(d).

(e) N-((4-Methoxyphenyl)methyl)-N-methyl-2-(4-nitrophenoxy)- ndimethylacetamide, so pl. 120oC. yl)-2-(4-nitrophenoxy)-ndimethylacetamide. So pl. 126oC. From (4 nitrophenoxy)acetic acid and intermediate 20(W)

(C) N-Methyl-N-[[4-methylthio]phenyl]methyl]-2-(4-nitrophenoxy)-ndimethylacetamide. So pl. 122oC. From (4 nitrophenoxy)acetic acid and intermediate 20(e).

(and) N-Ethyl-2-(4-nitrophenoxy)-N-(phenylmethyl)-ndimethylacetamide in the form of oil. The infrared spectrum includes a peak at 1655 cm-1(CO). From (4 nitrophenoxy)-acetic acid and N-ethylbenzylamine.

The intermediate connection 35.

(a) 2-(4-Aminophenoxy)-N-(2-(3,4-acid)ethyl)-N-methylacetamide

A solution of intermediate 34(a) (37.5 g) in ethanol (350 ml) hydronaut at room temperature in the presence of 10% palladium-on - coal (3.5 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the solution concentrated to obtain the title compound (34 g) as oil. The infrared spectrum includes peaks at 1650 cm-1(CO) and 3340-3400 cm-1(NH2).

Similar intermediate compound 35(a) provides the following connections:

(b) 2-(4-Aminophenoxy)-N-((3,4-acid)methyl)-N-methylacetamide in the form of oil. The infrared spectrum includes peaks at 1650 cm-1(CO) and 3340-3400 cm-1(NH2). From intermediate 34(b).

00-3420 cm-1(NH2).

From intermediate 34 (b).

(g) 2-(4-Aminophenylthio)-N-((3,4-acid)methyl)-N-methyl-ndimethylacetamide in the form of oil. The infrared spectrum includes peaks at 1645 cm-1(CO) and 3350 cm-1(NH2). From intermediate 34 (g).

(d) 2-(4-Aminophenoxy)-N-(2-(4-methoxyphenyl)ethyl)-N-methyl-ndimethylacetamide in the form of oil. The infrared spectrum includes peaks at 1630 cm-1(CO) and 3350-3420 cm-1(NH2). From intermediate 34 (d).

(e) 2-(4-Aminophenoxy)-N-((4-methoxyphenyl)methyl)-N-methylacetamide in the form of oil. The infrared spectrum includes peaks at 1650 cm-1(CO) and 3340-3430 cm-1(NH2). From intermediate 34 (e).

(W) 2-(4-Aminophenoxy)-N-methyl-N-((4-(were)methyl)-ndimethylacetamide in the form of oil. The infrared spectrum includes peaks at 1650 cm-1(CO) and 3350-3420 cm-1(NH2). From intermediate 34 (W).

(C) 2-(4-Aminophenoxy)-N-methyl-N-((4-(methylthio)phenyl)methyl)-ndimethylacetamide in the form of oil. The infrared spectrum includes peaks at 1660 cm-1(CO) and 3340-3420 cm-1(NH2). From intermediate 34 (C).

(and) 2-(4-Aminophenoxy)-N-ethyl-N-(phenylmethyl)-ndimethylacetamide in the form of oil. The infrared spectrum includes peaks at 1650 cm-1(CO) and 3350-3430 cm-1(NH2). From intermediate soedinenii

A solution of intermediate 35 (a) (20 g) in THF (200 ml) was added dropwise to a stirred suspension socialwise hydride in THF (100 ml) at room temperature and the mixture is refluxed for 3 hours. To the cooled mixture gently add water, then the mixture is filtered, washed with THF, evaporated and extracted with ether. The combined ether extracts are dried and evaporated to obtain the title compound (11 g) in the form of oil, IR spectrum includes a peak 3350-3430 cm-1(NH2).

Such intermediate compounds 36 (a) provides the following connections:

(b) N-(2-(4-Aminophenoxy)ethyl)-3,4-dimethoxy-N-methylbenzol-methanamine in the form of oil. The infrared spectrum includes a peak at 3360-3420 cm-1(NH2).

From intermediate 35 (b)

(C) N-(2-(4-Aminophenoxy)ethyl)-N-methylbenzeneethanamine in the form of oil. The infrared spectrum includes a peak at 3330-3420 cm-1(NH2).

From intermediate 35 (b).

(g) N-(2-(4-Aminophenylthio)ethyl)-3,4-dimethoxy-N-methylbenzeneethanamine in the form of oil. NMR spectrum: = 2,30 (3H, s, N-CH3); of 3.85 (6H, s, OCH3).

From intermediate 35 (g).

(d) N-(2-(4-Aminophenoxy)ethyl)-4-methoxy-N-mative the th connection 35 (d).

(e) N-(2-(4-Aminophenoxy)ethyl)-4-methoxy-N-methylbenzeneethanamine in the form of oil. The infrared spectrum includes a peak at 3350 - 3430 cm-1(NH2). From intermediate 35 (e).

(W) N-(2-(4-Aminophenoxy)ethyl)-4-methyl-N-methylbenzeneethanamine in the form of oil. The infrared spectrum includes a peak at 3350-3430 cm-1(NH2). From intermediate 35 (W).

(C) N-[2-(4-Aminophenoxy)ethyl] -N-methyl-4-(methylthio)benzoylmethylene in the form of oil. The infrared spectrum includes a peak at 3350-3420 cm-1(NH2). From intermediate 35 (C).

(and) N-[2-(4-Aminophenoxy)ethyl] -N-ethylbenzylamine in the form of oil. The infrared spectrum includes a peak at 3360-3430 cm-1(NH2). From intermediate 35 (and).

The intermediate connection 37

(a) 3,4-Dimethoxy-N-methyl-N-(3-(4-nitrophenoxy)propyl)-benzenediamine.

A mixture of 1-(3-bromopropane)-4-nitrobenzene (18.7 g) with an intermediate compound 20(a) (14.1 g) is heated for 30 minutes at 140oC and then diluted with water. The mixture is extracted with dichloromethane and the organic phase is washed with water, dried and concentrated. The residue is purified by column chromatography, elwira a mixture of dichloromethane in methanol (95:5) to give the title compound (18 g) in the form of an oil, the NMR spectrum on the of 37 (a), receive the following connections:

(b) 4-Methoxy-N-methyl-N-(3-(4-nitrophenoxy)propyl)-benzenediamine in the form of oil. NMR spectrum includes signal when = is 2.40 (3H, s, N - CH3). From 1-(3-bromopropane)-4-nitrobenzene and intermediate 20 (d).

(C) 3,4-Dimethoxy-N-methyl-N-(3-(4-nitrophenoxy)propyl)-benzoylmethylene in the form of oil. NMR spectrum includes signal when = is 2.40 (3H, s, N-CH3). From 1-(3-bromopropane)-4-nitrobenzene and intermediate 20(b).

(g) 3,4-Dimethoxy-N-methyl-N-(3-(4-nitrophenyl)thio)-propyl)- benzoylmethylene in the form of oil. NMR spectrum includes signal when = is 2.40 (3H, s, N-CH3). From 1-((3-bromopropyl)thio)-4-nitrobenzene and intermediate 20(b).

Intermediate compound 38

(a) N-[3-(4-Aminophenoxy]-3,4-dimethoxy-N-methylbenzeneethanamine

A solution of intermediate 37(a) (18 g) in ethanol (200 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (1 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the solution concentrated to obtain the title compound (15 g) as oil. The infrared spectrum includes a peak at 3300-3370 cm-1(NH2).

Such intermediate compounds 38(a) given the following link is 0-3430 cm-1(NH2). From intermediate 37 (b).

(C) N-[3-(4-Aminophenoxy]propyl]-3,4-dimethoxy-N-methylbenzeneethanamine in the form of oil. The infrared spectrum includes a peak at 3360-3430 cm-1(NH2). From intermediate 37(b).

(g) N-/3-(4-AMINOPHENYL)thio)propyl)-3,4-dimethoxy-N-methylbenzeneethanamine in the form of oil. The infrared spectrum includes a peak at 3370-3450 cm-1(NH2). From intermediate 37(g).

The intermediate connection 39. 9,10-Dihydro-2-(methylthio)-9-oxo-4-greencarbon acid

(I) 2-((2-Carboxyphenyl)amino)-5-(methylthio)benzoic acid

A mixture of 2-chloro-5-(methylthio)benzoic acid (10 g), Anthranilic acid (7 g), potassium carbonate (14 g) and copper (1 g) in 2-(2-methoxyethoxy)ethanol (100 ml) is heated at 180oC for 24 hours. Then add water (400 ml), and the catalyst is filtered off. The filter is acidified with diluted hydrochloric acid. The precipitate is filtered off, washed with water, dried and crystallized from methanol to obtain the title compound (4.5 g) as crystals. The infrared spectrum includes peaks at 3300 cm-1(NH) and 1700 cm-1(CO2H).

(II) 9,10-Dihydro-2-(methylthio)-9-oxo-4-greencarbon acid

The product of the above paragraph (1) (2) - Rev. P>oC), and slowly add water (15 ml). The mixture was then heated at 100oC for 10 minutes and then poured on cracked ice. The formed precipitate is filtered off, washed with water and crystallized from methanol to obtain the title compound (1.6 g). The infrared spectrum includes a peak at 1690 cm-1(CO2H) and the peak at 1620 cm-1(CO).

The intermediate connection 40.

N-[4-(3-Bromopropane)phenyl]-9,10-dihydro-9-oxo-4-greencarbon

(I) N-[4-(3-Bromopropane/phenyl]ndimethylacetamide

A mixture of N-(4 oksifenil)ndimethylacetamide (10 g) and potassium carbonate (11 g) in DMF (200 ml) is stirred for 20 minutes at room temperature. Then add 1.3-dibromopropan (35 ml) and stirring is continued for 4 hours. The mixture is filtered and the filtrate concentrated in vacuo. The residue is treated with water and extracted with dichloromethane. The organic phase is washed first with dilute sodium hydroxide solution, then with water, dried and concentrated to obtain a solid substance, which is then proscout with hexane in obtaining the title compound (14 g).T.sq. 120oC.

(II) 4-(3-Bromopropane)-aminobenzoyl

A mixture of the product of the above part I (13 g) and 6 N. hydrochloric acid (200 ml) is boiled with Obratnaya dichloromethane. The organic phase is evaporated to obtain the title compound (7 g) as oil. The infrared spectrum includes a peak at 3360-3450 cm-1(NH).

(III) N-[4-(3-Bromopropane)phenyl] -9,10-dihydro-9-oxo-4 - greencarbon

A mixture of 9,10-dihydro-9-oxo-4-greencarbon acid (1.5 g) and 1-examensarbete (1.1 g) in DMF (50 ml) was stirred at room temperature for 10 minutes. The product of the above part (II) (1.5 g) were then added, after which add dicyclohexylcarbodiimide (1.3 g), and the mixture is stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated in vacuo, treated with water and extracted with dichloromethane. The combined, dried organic extracts concentrated to obtain to obtain the title compound (0.5 g), which is recrystallized from acetonitrile T. pl. 126oC.

The intermediate connection 41. N-[(3,4-Acid)methyl]-N - methyl-4-nitrophenylarsonic-methanamine

A mixture of intermediate 20(b) (2.8 g), intermediate 56 (3 g) and potassium carbonate (2.3 g) in DMF (50 ml) is heated at 60oC for 24 hours. Then the mixture is evaporated, extracted with dichloromethane, washed with water, dried and concentrated from the Poluy (3.7 g), pl. 120oC.

The intermediate connection 42. N-[(3,4-Acid) methyl]-N - methyl-4-AMINOPHENYL-aminocarbonyl-methanamine

A solution of intermediate 41 (3.6 g) in ethanol (100 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (500 mg). Upon completion of hydrogen absorption, the catalyst is filtered off and the filtrate concentrated to obtain the title compound (3.5 g), NMR spectrum includes signals at = 2,5/3H,s, N-CH3); and 3.8 (6H, s, OCH3).

The intermediate connection 43. N-[2-(4-Aminophenylamino)ethyl]-3,4-dimethoxy-N-methylbenzeneethanamine

A solution of intermediate 42 (3.5 g) in THF (50 ml) was added dropwise to a stirred suspension of sociallyengaged in THF (30 ml) at room temperature and the mixture is refluxed for 48 hours. To the cooled mixture gently add water, then the mixture is filtered through critovao gasket. The filtrate is evaporated to dryness and subjected to column chromatography (dichloromethane-methanol), the remaining residue gives the title compound (1.4 g). NMR spectrum includes signals at = 2,15 (3H, c., N-CH3; 2.5 and 3 (4H, 2 so, -CH2-CH2); 3,7 (6H., c. OCH3).

The intermediate connection 44. 9,10-Dihydro-5,7-dimethoxy-9-ox is di -(I) (1 g) in 2,3-butanediol (20 ml) in toluene (10 ml) is heated at 120oC. After the toluene is no longer Argonauts add P-ethylmorpholine (10 ml) and the mixture was stirred at 120oC for 1 hour. After cooling and dilution with 2 n potassium carbonate solution is filtered through celite. Filter is acidified using 2 N. hydrochloric acid and greenish precipitate was separated by filtration. The product (4 g) in polyphosphoric acid (50 g) is heated at 120oC for 1.5 hours to obtain the title compound, which is obtained as a solid (1.5 g) by precipitation with water and purified by dissolving in 1 N. the sodium hydroxide solution and re-precipitation with acetic acid (pH 4).

Analysis: C16H13NO50.5 H2O

found, %: C 62,1; H 4,6; N 4,3

calculated, %: From 62.3; H 4,6; N 4,5

Such intermediate compounds 44 get the following acid.

The intermediate connection 45. 9,10-Dihydro-6,7,8-trimetoksi-9-oxo-4-greencarbon acid (1.5 g). The infrared spectrum includes a peak at 1620 cm-1(CO). From 3,4,5-trimethoxyaniline (3.8 g) and 2-iodizatio acid (5 g).

The intermediate connection 46. 3-(2-Bromacil)-nitrobenzene

Tribromide phosphorus (0,94 ml) was added dropwise to a solution of 3-nitroacetanilide alcohol (5 aces and then treated with potassium carbonate solution and then with water. The organic layer is dried and concentrated in vacuo to obtain the title compound as oil (4,51 g). NMR spectrum: = of 3.25 (m, 2H, CH2-C6H5and 3,55 (m, 2H, CH2-B)

The intermediate connection 47.

(a) N-[(3,4-Acid)methyl]-N-methyl-3-nitrobenzonitrile

A mixture of intermediate 46 (2.2 g), intermediate 20 (b) (1,71 g) and potassium carbonate (1,58 g) in DMF (50 ml) is heated at 60oC for 36 hours. The mixture is filtered and the filtrate concentrated in vacuo. The residue is treated with water and extracted with methylene chloride. The organic extract is dried, concentrated and purified by column chromatography on silica gel, elwira mixture of methylene chloride with methanol (99:1) upon receipt of the title compound as an oil (1 g). NMR spectrum: = 2,2(C., 3H, N-CH3); 3,7 (c. 6H, 2xOCH3).

In the same way get the following connection:

(b) N-[(3,4-Acid)methyl]-N - methyl-3-(3-nitrophenoxy)-propanamine

From 3-(3-bfromproxy)nitrobenzene and intermediate 20 (b). NMR: = 2,2(C. 3H, N-CH3): 3,35 (c. 2H, N-CH2-C6H5); and 3.8 (c. 6H, 2xOCH3).

The intermediate connection 48.

(a) 3-Amino-N-[(3,4-acid)methyl]-N-methylbenzoselenazole 10% palladium-on-coal (0.15 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the solution concentrated to obtain the title compound (0.8 g) as oil. NMR spectrum: = 2,25 (C. , 3H, N-CH3); 3,4 (c. 2H, NH2) and 3.8 (SD, 6H, 2xOCH3).

In the same way get the following connection:

(b) N-(3-(3-Aminophenoxy)propyl)-3,4-dimethoxy-N-methylbenzeneethanamine

From intermediate 47(b) NMR spectrum: = 2,2 (C., 3H, N-CH3), and 2.7 (SD, 2H, NH2), 3,4 (S., 2H, N-CH2-C6H5), and 3.7 (SD, 6H, 2xOCH3).

The intermediate connection 49. N-[(3,4-Acid)methyl]-N-methyl - 3-(3-nitrophenyl)-2-propenamide

A mixture of 3-nitrocatechol acid (10 g) and 1-oxybisethanol (compared to 8.26 g) in DMF (100 ml) was stirred at room temperature for 10 minutes, add the intermediate compound 20(b) (9.2 grams), then dicyclohexylcarbodiimide (10,63 g). The mixture is stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated in vacuo, treated with diluted hydrochloric acid, then with dilute sodium hydroxide solution and extracted with methylene chloride. The organic extract is dried and concentrated to obtain the title compound (15,63 g). NMR spectrum: = 3,1 (C., 3H, N-CH3); 3,75 (C., 6H, 2 is panamin

A solution of intermediate 49 (10 g) in ethanol (100 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (1 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the filtrate was concentrated in vacuo. The residue is purified by column chromatography on silica gel, elwira mixture of methylene chloride with methanol (98:2) to give the title compound as oil (5,56 g). NMR spectrum: = 2,7 (S., 2H, N-CH3); 3,65 (C., 6H, hon3).

The intermediate connection 51. 3-Amino-N-[(3,4-acid)methyl]- N-methylbenzeneethanamine

A solution of intermediate 50 (5 g) in THF (100 ml) was added dropwise to a stirred suspension of sociallyengaged (2,31 g) in THF (80 ml) at room temperature and the mixture is refluxed for 2 hours. To the cooled mixture carefully add water (20 ml), the mixture is then filtered. The filtrate is concentrated, treated with water and extracted and the product purified by column chromatography on silica gel, elwira mixture of methylene chloride with methanol (97:3) to give the title compound as oil (2,46 g). NMR spectrum: = 2,1 (C., 3H, N-CH3); 3,35 (S., 2H, N-CH2-C2H5), and 3.7 (SD, 6H, hon3).

The intermediate connection what zaldehyde (1) (2 g) and 3-oksipropilmetiltselljuloza (2) (5.3g) in the presence of a solution of n-utility (1.6 M) in hexane (16,5 ml) gives the title compound (2.6 g) as oil. NMR spectrum: = 3,4 (2H, T., CH2OH), and 3.6 (3H, s, OCH3). (1): C. A. 113(19): 171567W; (2): A. R. Hands, and A. F. H. F. Mercer Chem. Soc. (c) (1968) 2448.

The intermediate connection 53. 4-(4-Bromo-1-butenyl)-2-methoxy-1-nitrobenzene

Tribromide phosphorus (0.33 ml) was added dropwise to a solution of intermediate 52 (2.6 g) in anhydrous diethyl ether (10 ml) at 0oC. the Mixture is stirred at room temperature for 1 hour, then washed with potassium carbonate solution (1 M) and water. The organic layer is dried and concentrated in vacuo to obtain the title compound (3.3 g) as a yellow oil. NMR spectrum: = 3,35 (2H, T., CH2-Br), and 3.8 (3H, s, O-CH3).

The intermediate connection 54. N-(4-(3-Methoxy-4-nitrophenyl)-3-butenyl - 3,4-dimethoxy-N-methylbenzeneethanamine

A mixture of intermediate 53 (3.3 grams), intermediate 20(b) (2.5 g) and potassium carbonate (1.9 g) in DMF (20 ml) was stirred at room temperature for 48 hours. The mixture is filtered and the filtrate is evaporated. The rest bring in water and extracted with dichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The oily residue is then purified by column chromatography on silica gel, elwira mixture with dichloromethane-methanol (95:5) to obtain titulek is., OCH3).

The intermediate connection 55. 4-Amino-N-[(3,4-acid)methyl]-3-methoxy-N-methylbenzeneethanamine

A solution of intermediate 54 (1.2 g) in ethanol (50 ml) with ethyl acetate (20 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (0.1 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the solution concentrated to obtain the title compound (1 g) in the form of an oil, the NMR spectrum includes signals: = 2,1 (3H, s, N-CH3); the 3.65 (3H, s, O-CH3); 3,7 (6H, s, hon3).

The intermediate connection 56. 2-Chloro-N-(4-nitrophenyl)-acetamin

Chlorocatechol (11 ml) was added dropwise to a stirred mixture of potassium carbonate (18,8 g) and 4-nitroaniline (15 g) in DMF (100 ml) maintained at 0oC). The mixture was then allowed to stand overnight at room temperature and poured on cracked ice. Get stuff yellow and crystallized from toluene containing isopropanol (10%) to give the title compound (10 g).

So pl. 180oC NMR-spectrum: / = 4,1 (2H, s, COCH2Cl); to 7.4 and 8.1 (4H, m, aromatic); or 10.3 (1H, sh.S., NH).

The intermediate connection 57. 3,4-Dihydro-6,7-dimethoxy - N-(4-nitrophenyl)-2-(1H)-ethanolamine

A mixture of intermediate with the increase night at 60oC. After cooling, the reaction mixture was poured on cracked ice and get insoluble matter is dried to obtain the title compound. So pl. 173-178oC. NMR spectrum: = 2,8 (4H, S., HSN2); 3,2 (2H, s , COCH2N); 3,7 (2H, s, N-CH2-C6H5); 3,7 (6H, m, hon3); 6,2-8,15 (6H, m, aromatic), and 9.3 (1H, sh.S., NHCO).

The intermediate connection 58. N-(4-AMINOPHENYL)-3,4-dihydro-6,7 - dimethoxy-2(1H)-ethanolamine

A suspension of intermediate 57 (15 g) and 10% palladium-on-coal (1 g) in ethanol (200 ml) was stirred at room temperature under slightly increased pressure of hydrogen. After 2 hours the catalyst is filtered off and washed with a mixture of dichloromethane with methanol (9:1). The filtrate and the washing solution is concentrated and the crystalline residue after washing with ethanol and drying represents the title compound (10.6 g). So pl. 185oC NMR spectrum includes signals: = 2,8 (4H, S., HSN2); 3,15 (2H, s, CO-CH2N); 3,6 (2H, SS., phenyl-CH2N); 3,7 (6H, s, hon3); 6,15-of 7.3 (6H, m, aromatic), 8,65 (1H, sh.S., CONH).

The intermediate connection 59. N-(2-(1,2,3,4-Tetrahydro-6,7-dimethoxy - 2-ethenolysis)ethyl)-1,4-diaminobenzene

A solution of borane in tetrahydrofuran (1 M, 35.4 ml) are added to lane for 4 hours the reaction mixture is cooled, treated with concentrated hydrochloric acid to obtain a solution concentration of about 3 N. in hydrochloric acid and again refluxed for 15 minutes. Add 10 n sodium hydroxide solution and the mixture extracted with dichloromethane. The organic layer is washed with water, dried and concentrated to obtain residue, which, after purification on silica gel by column chromatography with elution with a mixture of toluene with Isopropylamine (95: 5) gives the title compound in the form of oil (1.2 g). NMR spectrum includes signals at = 2,6 (4H, sh.S., phenyl-CH2-CH2N); of 3.45 (4H, s, CH2-NH-phenyl and phenyl-CH2N); 3,6 (6H, s, hon3), and 6.3 (6H, s, aromatic).

The intermediate connection 60. 4-[2-[2,3-Dihydro-5,6-dimethoxy-1H-isoindole-2-yl]ethyl]benzolamide

4,5-Bichromatically (2.35 g, S. H. Wood. M. A. Peny and C. C. Tung F. A. C. S. (1950), 72, 2989-2991) at room temperature is added to stirred suspension of 50% aqueous sodium hydroxide solution (5 ml), toluene (25 ml), 4-aminophenylalanine (1.5 g) and Aliguat (0.2 g). The heterogeneous mixture was stirred at room temperature for 16 hours, poured into water and extracted with methylene chloride. The organic layer is dried and the solvent is evaporated in vacuum. The residue is purified put the connection in the form of a solid (0.6 g). So pl. 150oC NMR spectrum includes signals at = 2,7 (4H, m, phenyl-CH2-CH2-N); and 4.6 (2H, sh.S., NH2); 3,7 (6H, s, hon3); and 3.8 (4H, s, 2 N-CH2-phenyl), a 6.2 to 7.0 (6H, m, aromatic).

The intermediate connection 61. 1-(4-Nitrophenyl)-2-(1,2,3,4 - tetrahydro-6,7-dimethoxy-2-isoquinoline)-alanon-hydrobromide.

A solution of 6,7-dimethoxy-1,2,3,4-tetrahydroquinoline (15,63 g) and 2-bromo-4'-nitroacetophenone (16,47 g) in a mixture of ethanol (150 ml) with methylene chloride (150 ml) is heated at 60oC for 24 hours. After cooling to room temperature, crystals appear yellow. Their is filtered off and dried in vacuum, obtaining the title compound (9.4 g). So pl. 216oC. the NMR spectrum (DMCO-d6includes signals at = 3,6 (6H, s, 2 OCH3) and 4.2 (2H, s, N-CH2-phenyl), of 4.95 (2H, s, CO-CH2-N), and 6.6 (2H, aromatic isoquinoline); 8 ( 4H, m, aromatic).

The intermediate connection 62. 3,4-Dihydro-6,7-dimethoxy - a -(4-nitrophenyl)-2-(1H)-izochinolina.

To a suspension of intermediate 61 (9.4 g) in methanol (600 ml) is added in portions a solution of sodium borohydride (2,44 g) and the mixture is stirred at room temperature for 16 hours. The reaction mixture was diluted with water (200 ml), filtered and evaporated in vacuum. OS is the group of the title compound (1,15 g), after crystallization from ethanol. So pl. 130oC. the NMR spectrum includes signals at = 2,4-3,1 (6H, m, HSN2), and 3.7 (6H, s , hon3) and 4.2 (1H, sh.S., OH); 4,8 (1H, m, H-C-OH); the 6.1 and 8.1 (6H, m, aromatic).

The intermediate connection 63. -(4-AMINOPHENYL)-3,4-dihydro-6,7-dimethoxy-2-(1H)-izochinolina.

A solution of intermediate 62 (2.4 g) in ethanol (200 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (0.3 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the solution concentrated, obtaining the title compound (1.9 g) as a solid white color. So pl. 168oC.

NMR spectrum includes signals at = 2,4-2,9 (6H, m, 3-CH2); 3,5 (2H, sh. S., NH2); 3,7 (6H, s, 2 OCH3);, 4,55 (1H, T., H-SON); 6,25 to 7.1 (6H, m, aromatic).

The intermediate connection 64. 2-Bromo-N-Methyl-N-[(4-nitrophenyl) methyl]ndimethylacetamide.

To a solution of bromoacetamide (30 g) in methylene chloride (20 ml) at 0oC add a solution of N-methyl-4-nitrobenzene-methanamine (8,3 g, G. I. Wilson, F. Chem. Soc. 1926, 2461) in methylene chloride (10 ml) and triethylamine (12 ml). The reaction mixture is stirred for 5 minutes at 0oC, then added to water (20 ml). Methylenchloride layer is dried and evaporated in vacuum. The residue is purified the organisations (15 g) as oil. NMR spectrum includes signals at = 3,1 (3H, s, N-CH3), 3,9 (2H, s, CH2Br), 4,55 (2H, s, phenyl-CH2-N-); to 7.0 to 8.3 (4H, m, aromatic).

The intermediate connection 65. 3,4-Dihydro-6,7-dimethoxy-N-methyl-N-[[4-nitrophenyl]methyl]-2(1H)- ethanolamine.

A mixture of intermediate compound 64 (1.8 g), 6,7-dimethoxy - 1,2,3,4-tetrahydroisoquinoline (1.4 g) and potassium carbonate (1.6 g) in DMF (150 ml) is stirred over night. After removing insoluble substances by filtration, the solvent is evaporated in vacuo and the residue partitioned between dichloromethane and water. The organic phase is dried, then concentrated under reduced pressure and the product, after purification by column chromatography with elution with a mixture of methylene chloride with methanol (96:4), represents the title compound (1.65 g). NMR spectrum includes signals at = at 2.8 (4H, m , HSN2); 3,0 (3H, s, N-CH3), to 3.33 (2H, s, CO-CH2N); 3,6 (2H, s, N-CH2-phenyl), and 3.7 (6H, s , hon3), 4,55 (2H, s, phenyl-CH2-NHCO), a 6.2 to 8.1 (6H, m, aromatic).

The intermediate connection 66. N-[[4-AMINOPHENYL]methyl]-3,4 - dihydro-6,7-dimethoxy-N-methyl-2(1H)-ethanolamine.

A solution of intermediate 65 (1.65 g) in ethyl acetate (100 ml) hydronaut at room temperaturemonitor filtered off and the solution concentrated to obtain the title compound (1,43 g) as a solid white color. So pl. 175-215oC. the NMR spectrum includes signals at = at 2.8 (7H, m, NCH3and 2xCH2); 3,2 (2H, s, CO-CH2N); 3,5 (2H, s, N-CH2-phenyl); 3,7 (6H, s, 2xCH3).

The intermediate connection 67. N-[[2-AMINOPHENYL]methyl]-3,4 - dihydro-6,7-dimethoxy-N-methyl-2(1H)-ethanolamine

A solution of intermediate 66 (1,49 g) in THF (150 ml) was added dropwise to a stirred suspension of sociallyengaged (0,47 g) in THF (100 ml) at room temperature for 4 hours. To the cooled mixture carefully add water (5 ml), the mixture is then filtered and the filtrate is concentrated and the residue is extracted with methylene chloride. The organic layer is dried and evaporated. The resulting product was then purified by column chromatography on silica gel, elwira mixture of methylene chloride with Isopropylamine (92:8). Get the title compound in the form of oil (0.7 g). NMR spectrum includes signals at = of 2.15 (3H, s , N-CH3); to 2.55 (7H, m, 4xCH2); 3,55 (2H, s, NH2); the 3.65 (6H, s, 2xCH3); and 6.3, and 7.1 (6H, m, aromatic)

The intermediate connection 68. 2-[[3,4-Acid)methyl]methylamino]-N-methyl-N-[(4-nitrophenyl)- methyl]-ndimethylacetamide

A mixture of intermediate compound 64 (4.3 g), intermediate 20(b) (3,26 g) and potassium carbonate (4,14 g) in DMF (100 ml, the which is extracted with methylene chloride. After washing with water and drying the organic layer is evaporated to obtain a syrup, which was purified by column chromatography on silica gel, elwira mixture with ethyl acetate-cyclohexane (1: 1). Get the title compound in the form of oil (5.7 g). NMR spectrum includes signals at = 2,3 (3H, s, N-CH3); 3,7 (6H, s, 2xOCH3); and 4.5 (2H, s, phenyl-CH2-NHCO).

The intermediate connection 69. N-[(4-AMINOPHENYL)methyl]-2-[(3,4 - acid)methyl]-methylamino)-N-methylacetamide

A solution of intermediate 68 (5.7 g) in a mixture of ethyl acetate with methanol 1:2 (100 ml) hydronaut at room temperature and at atmospheric pressure in the presence of 10% palladium-on-coal (0.8 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the filtrate is concentrated, obtaining the title compound (5.2 g) as oil. NMR spectrum includes signals at = 3,8 (6H, s, hon3); and 4.5 (2H, s, phenyl-CH2-NCO).

The intermediate connection 70. N-[(4-AMINOPHENYL)methyl] -N'-[(3,4 - acid)methyl]-N,N'-dimethyl-1,2-diaminoethane

A solution of intermediate 69 (5,2 g) in THF (150 ml) was added dropwise to a stirred suspension of sociallyengaged (1 g) in THF (50 ml) at room temperature the shape to dryness and the residue is diluted with methylene chloride and extracted with 1M hydrochloric acid. The aqueous layer was alkalinized with an aqueous solution of sodium hydroxide (1M) and extracted with methylene chloride. The organic layer is dried and then concentrated in vacuo. The residue is purified by column chromatography on silica gel, elwira using a mixture of cyclohexane with methylene chloride and Isopropylamine (5:4: 1). Get the title compound in the form of oil (2 g). NMR spectrum includes signals at = 2,1 (6H, s, 2xNCH3) and 2.4 (4H, s, 2xNCH2); 3,2 (4H, m, 2xN-CH2-phenyl); and 3.6 (6H, s, 2xOCH3); of 3.85 (2H, s, NH2); 6,1-a 7.5 (7H, m, aromatic).

The intermediate connection 71. 3,4-Dimethoxy-N-methyl-N-[4- (4-nitrophenyl)-2-butenyl]-benzoylmethylene

A mixture of intermediate 20(b) (9 g), potassium carbonate (8 g) and 1-chloro-4(4-nitrophenyl)-2-butene (10.6 g, Morgan and others , 7. Med. Chem. 8(1986), 1398-1405) in 4-methyl-2-pentanone (300 ml) is refluxed for 18 hours. After cooling, the mixture is filtered and evaporated in vacuum. The residue is purified by column chromatography, elwira mixture of methylene chloride with methanol (97,5:2,5). Get the title compound (2 g) as oil. NMR spectrum includes signals at = 2,2 (3H, s, N-CH3); a 3.9 (6H, s, 2xOCH3); 5,7 (2H, m, double bond) and 6.9 (3H, m, aromatic, phenyl(OCH3)

Intermediate compound 71 (1.7 g) is dissolved at room temperature and under stirring in a mixture of methanol (50 ml) and conc. hydrochloric acid (2 ml). Then slowly add iron powder (1.5 g) and the reaction mixture is refluxed for 1 hour. The mixture was then evaporated, alkalinized with sodium hydroxide and extracted with diethyl ether. The organic layer is dried and evaporated in vacuum, obtaining the title compound (0.21 g) as oil. NMR spectrum includes signals at = of 2.15 (3H, s, N-CH3), and 3.8 (6H, s, 2xOCH3), to 5.55 (2H, m, double bond), 6,3-7,2 (7H, m, aromatic).

The intermediate connection 73. 3,4-Dimethoxy-N-methyl-N-[3-[4 - nitrophenyl] -2-propenyl]-benzoylmethylene

A mixture of intermediate 20(b) (3.6 g), 1-chloro-3-/4-nitrophenyl/-2-propene (4.8 g, Cignalla etc., J. Med. Chem., 8 (1965), 326-329) and potassium carbonate (3.5 g) in 4-methyl-2-pentanone (60 ml) is refluxed for 3 hours. After cooling, the mixture is filtered and the filtrate is evaporated in vacuum. The residue is purified by column chromatography, elwira mixture of methylene chloride with methanol (95:5). Get the title compound (4.9 g) as oil. NMR spectrum: = of 2.25 (3H, s, NCH3); 3,2 (2H, d, N-CH2-CH= CH), 3,5 (2H, s, NCH2-phenyl), 3,85 (6H, I, phenyl - NO2).

The intermediate connection 74. 4-[3-[[(3,4-Acid)methyl] methylamino]-1-propenyl]-aminobenzoyl

Intermediate compound 73 (4.8 g) was dissolved in a mixture of methanol (100 ml) and concentrated hydrochloric acid (10 ml) at room temperature and under stirring. Then slowly add iron powder (5 g) and the reaction mixture is refluxed for 0.5 hours. After cooling, the mixture is evaporated, diluted with water (20 ml), alkalinized with sodium hydroxide solution, concentrated and extracted with diethyl ether. The organic layer is dried and evaporated. Get the title compound (3.9 g) as oil. NMR spectrum: = 2,2 (3H, s, NCH3) and 3.15 (2H, d, N-CH2-CH=CH), 3,5 (2H, s, NCH2-phenyl), 3,6 (2H, s, NH2), and 3.8 (6H, s, 2xOCH3), the 5.7 and 7.6 (9H, m, aromatic double bond).

The intermediate connection 75. 1,2,3,4-Tetrahydro-6-methoxy-2- (2-(4-nitrophenyl)ethyl)-isoquinoline

A mixture of 1-(2-bromacil)-4-nitrobenzene (6.4 g), 1,2,3,4-tetrahydro-6-methoxyethylamine (4.6 g, Daniel J. Sall and Gary L. Grunewald, J. Med. Chem. 1987, 30, 2208-2216) and potassium carbonate (9.7 g) in DMF (150 ml) was stirred at 50oC for 15 hours. The mixture is evaporated to dryness and the residue extracted with dichloromethane. The organic layer protivodiareynah with methanol (98:2). Get the title compound (2 g) in the form of oil, which solidifies upon standing. NMR spectrum: = 3,6 (2H, m, N-CH2aryl), and 3.7 (3H, s, OCH3).

The intermediate connection 76. 4-(2-1,2,3,4-Tetrahydro-6-methoxy - 2-ethenolysis)ethyl)-aminobenzoyl

A solution of intermediate 75 (2 g) in ethanol (100 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (0.2 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the filtrate was concentrated in vacuo, obtaining the title compound (1.8 g) as orange oil, which upon standing hardens.

NMR spectrum: = 3,4 (2H, s, NH2), 3,55 (2H, s, N-CH2-Ar), the 3.65 (3H, s , OCH3).

The intermediate connection 77. 1,2,3,4-Tetrahydro-6,7-dimethoxy - 2-[3-[3-nitrophenyl]-1-oxo-2-propenyl]isoquinoline

A mixture of 3-nitrocatechol acid (10 g) and 1-oxybisethanol (8,2 g) in DMF (100 ml) was stirred at room temperature for 10 minutes. Then add 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (10 g), and then add bicyclogermacrene (10.6 g) and the mixture was stirred at 50oC for 48 hours and then filtered off, the filtrate was concentrated in vacuo, treated with dilute solution of sodium hydroxide Ographie, elwira mixture with dichloromethane-methanol (97: 3). Get the title compound (7.8 g). NMR spectrum: = of 3.85 (6H, s, OCH3).

The intermediate connection 78. 2-(3-(3-AMINOPHENYL)-oxopropyl)- 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline

A solution of intermediate 77 (7.8 g) in ethanol (100 ml) hydronaut at room temperature in the presence of 100% palladium-on-coal (1 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the filtrate was concentrated in vacuo, obtaining the title compound (6.8 g). IR-spectrum: frequency CO: 1640 cm-1; frequency NH2: 3450 cm-1.

The intermediate connection 79. 3-(3-(1,2,3,4-Tetrahydro-6,7 - dimethoxy-2-ethenolysis)propyl)-aminobenzoyl

A solution of intermediate 78 (6.8 g) in THF (100 ml) was added dropwise to a stirred suspension of sociallyengaged (3 g) in THF (100 ml) at room temperature and the mixture is refluxed for 3 hours. Then, the cooled mixture gently add water, the mixture is filtered, evaporated and extracted with ether. The extract is dried and evaporated down to obtain the title compound (5.4 g) in the form of oil, which solidified upon standing.

IR-spectrum: frequency NH2: 3360-3450 cm-1.

Propoxy-3-(4-nitrophenoxy)propane (6 g, Sigma) and intermediate 20(b) (5 g) in isopropanol (100 ml) is refluxed for 18 hours and evaporated. The oily residue is crystallized from ether, receiving the title compound (8,3 g) as a solid white color.

NMR spectrum: = 2,3 (3H, s, N-CH3), a 3.9 (6H, s, OCH3).

The intermediate connection 81. 1-[4-Aminophenoxy[-3-(3,4 - acid)methyl]methylamino]-2-propanol

A solution of intermediate 80 (8 g) in ethanol (100 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (0.8 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the filtrate was concentrated in vacuo. The oily product is then purified by column chromatography, elwira mixture with dichloromethane-methanol (95:5), and get the title compound (5.8 g) in the form of an oil, the NMR-spectrum: = of 2.25 (3H, s , N-CH3), and 3.8 (6H, s, OCH3).

The intermediate connection 82. 3,4,5-Trimetoksi-N-methyl-N-(3-(4 - nitrophenoxy)propyl)benzoylmethylene

A mixture of 1-(3-chloropropoxy)-4-nitrobenzene (4.6 g), 3,4,5-trimetoksi-N-methylbenzeneethanamine (4.1 g, Sigma) and potassium carbonate (2.9 g) in DMF (60 ml) is heated at 70oC for 24 hours. The mixture was then filtered and the filtrate is evaporated. Axis purified by column chromatography, elwira mixture with dichloromethane-methanol (99:1). Get the title compound (5.8 g) as a yellow oil. NMR spectrum: = 2,15 (3H, s, N-CH3), 3,3 (2H, s, CH2-Ar), 3,7 (9H, s, OCH3).

The intermediate connection 83. N-[3-[4-Aminophenoxy]propyl]-3,4,5 - trimetoksi-N-methylbenzeneethanamine

A solution of intermediate 82 (5.8 g) in ethanol (100 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (0.5 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the solution concentrated, obtaining the title compound (5.1 g) as oil. NMR spectrum: = of 2.25 (3H, s, N-CH3); 3,5 (2H, s, CH2-Ar), and 3.8 (9H, s, OCH3).

The intermediate connection 84. 1,2,3,4,-Tetrahydro-6,7-dimethoxy - 2-[(4-methoxy-3-nitrophenyl)-acetyl]isoquinoline

A mixture of 4-methoxy-3-nitrophenylarsonic acid (1.2 g) and 1-oxybisethanol (0.95 g) in DMF (30 ml) was stirred at room temperature for 10 minutes. Then add 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (1.1 g) in DMF (20 ml), after which dicyclohexylcarbodiimide (1.2 g) and the mixture is stirred at room temperature for 6 hours, then filtered off, the filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extragere is which crystallizes from ethanol in the form of a solid white color. So pl. 175oC. IR range: 1650 cm-1(CO).

The intermediate connection 85. 2-((3-Amino-4-methoxyphenyl)acetyl)- 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline

A solution of intermediate 84 (1.6 g) in ethanol (50 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (0.3 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the solution concentrated, obtaining the title compound (1.4 g) as oil. IR-spectrum: frequency CO: 1650 cm-1the frequency of NH2: 3340-3440 cm-1.

The intermediate connection 86. 5-(2-(1,2,3,4-Tetrahydro-6,7 - dimethoxy-2-ethenolysis)ethyl)-2-methoxyaminomethyl

A solution of intermediate 85 (1.4 g) in THF (30 ml) was added dropwise to a stirred suspension of sociallyengaged (0.9 g) in THF (50 ml) at room temperature and the mixture is refluxed for 3 hours. Then to the cooled mixture gently add water, the mixture was then filtered, evaporated and extracted with ether. The extract is dried and evaporated, obtaining the title compound (1.2 g) in the form of oil, which solidified upon standing. IR-spectrum: 3340-3440 cm-1(NH2).

The intermediate connection 87. 1,2,3,4-Tetrahydro-2-[3-(4 - nitrophenyl)propyl]isoquinoline

With stirred at 70oC for 24 hours. The mixture was then filtered and the filtrate is evaporated. The residue is treated with water and extracted with dichloromethane. The organic layer was washed with water, dried, evaporated and purified by column chromatography, elwira mixture with dichloromethane-methanol (96:4). Get the title compound (8.8 g) as a yellow oil. NMR spectrum: = 3,6 (2H, s, N-CH2Ar); to 4.1 (2H, T., O-CH2).

The intermediate connection 88. 4-[3-[1,2,3,4-Tetrahydro-2 - ethenolysis] propoxy]-aminobenzoyl

Intermediate compound 87 (8.8 g) was dissolved in a mixture of methanol (80 ml) with concentrated hydrochloric acid (50 ml) at room temperature and under stirring. Then portions add iron powder (7.9 g) and the mixture refluxed for 2 hours. The mixture was then cooled, poured on ice, alkalinized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated, obtaining the title compound (4.5 g) as a red oil. NMR spectrum: = 3,7 (2H, s, N-CH2-Ar), 3,9 (2H, T., O-CH2).

The intermediate connection 89. 1,2,3,4-Tetrahydro-7-methoxy-2- [2-[4-nitrophenyl]ethyl]isoquinoline

A mixture of 1-(2-bromacil)-4-nitrobenzene (3.7 g), 1,2,3,4-tetrahydro-7-methoxyethylamine (2,7 is the atur boiling under reflux for 48 hours. The mixture is evaporated to dryness and the residue extracted with dichloromethane. The organic layer is washed with water, filtered and evaporated. The residue is then purified by column chromatography, elwira mixture with dichloromethane-methanol (99: 1) obtain the title compound (1.6 g) as an orange solid (1.6 g). So pl. 92-94oC NMR spectrum: = 3,6 (2H, m, N - CH2Ar), and 3.7 (3H, s, OCH3).

The intermediate connection 90. 4-[2-[1,2,3,4-Tetrahydro-7-methoxy]-2-ethenolysis]-aminobenzoyl

A solution of intermediate 89 (1.6 g) in ethanol (100 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (0.16 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the filtrate was concentrated in vacuo, obtaining the title compound (1.4 g) as a white solid. So pl. 82-84oThe NMR-spectrum: = 3,4 (2H, s, NH2), of 3.45 (2H, s, N - CH2-aryl), 3,55 (3H, s, OCH3).

The intermediate connection 91. 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-[2-[3-nitrophenyl]ethyl]-isoquinoline

A mixture of 1-(2-bromacil)-3-nitrobenzene (2.3 g), 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline-hydrochloride (2.3 g) and potassium carbonate (3 g) in DMF (50 ml) is heated at 50oC for 12 hours. The mixture was then filtered and the filtrate is evaporated. is cromatografia, elwira mixture with dichloromethane-methanol (99:1). Get the title compound (1.4 g) as a yellow oil.

NMR spectrum: = 3,6 (2H, s, N - CH2Ar); of 3.75 (6H, s, OCH3).

The intermediate connection 92. 3-(2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-ethenolysis)ethyl)-aminobenzoyl

A solution of intermediate 91 (1.4 g) in ethanol (50 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (0.14 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the filtrate was concentrated in vacuo, obtaining the title compound (1,15 g) as a yellow oil, which solidified. NMR spectrum: = 3,6 (2H, s, N - CH2Ar in), 3.75 (6H, s, OCH3), and 4.5 (2H, s, NH2).

The intermediate connection 93. N-[[3,4-Acid]methyl]-4-methoxy-N-methyl-3-nitrobenzonitrile

A mixture of 4-methoxy-3-nitrobenzoate acid (1,2, S. A. 87. 8468h) and 1-oxybisethanol (0.95 g) in DMF (30 ml) is stirred for 10 minutes. Then add the intermediate compound 20(b) (1.1 g) in DMF (20 ml), after which dicyclohexylcarbodiimide (1.2 g) and the mixture is stirred at room temperature for 6 hours and then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted chromatography elwira mixture with dichloromethane-methanol(95: 5). Thus obtained the title compound (1.5 g) as oil. IR-spectrum: 1640 cm-1(CO).

The intermediate connection 94. 3-Amino-N-[[3,4-acid]methyl]-4-methoxy-N-methyl-benzoylacetone

A solution of intermediate 93 (1.45 g) in ethanol (40 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (0.25 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the solution concentrated, obtaining the title compound (1.2 g) as oil. IR-spectrum: 1630 cm-1(CO), 3350-3450 cm-1(NH2).

The intermediate connection 95. 3-Amino-N-[[3,4-acid]methyl]-4-methoxy-N-methyl-benzolate

A solution of intermediate 94 (1.2 g) in THF (30 ml) was added dropwise to a stirred suspension of sociallyengaged (0.9 g) in THF (50 ml) at room temperature and the mixture is refluxed for 3 hours. To the cooled mixture gently add water, the mixture was then filtered, washed with THF, evaporated and extracted with ether. The extract is dried and evaporated, obtaining the title compound (1 g) as oil. IR-spectrum: 3350-3450 cm-1(NH2).

The intermediate connection 96. 1,2,3,4-Tetrahit,6-dimethoxyisoquinoline (0.25 g; R. D. Haworth, J. Chem. Soc. 2281 (1987); Robin D. Clark, J. Med. Chem. 596-600, 33 (1990)) and potassium carbonate (0.5 g) in DMF (25 ml) is heated at 60oC for 3 hours.

The mixture was then filtered and the filtrate is evaporated. The residue is treated with water, extracted with dichloromethane, dried, evaporated and purified by column chromatography, elwira mixture with dichloromethane-methanol (99:1) obtain the title compound (0.3 g) as an orange solid. So pl. 97oC NMR spectrum: = 3,6 (2H, s, N - CH2-Ar); of 3.75 (6H, s, OCH3).

The intermediate connection 97. 4-(2-(1,2,3,4-Tetrahydro-5,6-dimethoxy-2-ethenolysis)ethyl)-aminobenzoyl

A solution of intermediate 96 (0.3 g) in ethanol (20 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (30 mg). Upon completion of hydrogen absorption, the catalyst is filtered off and the filtrate was concentrated in vacuo, obtaining the title compound (0,22 g) as a yellow oil. NMR spectrum: = 3,55 (2H, s, N - CH2Ar), 3,65-of 3.85 (8H, OCH3and NH2).

The intermediate connection 98. 1,2,3,4-Tetrahydro-6,7,8-trimetoksi-2-(2-(4-nitrophenyl)ethyl)-isoquinoline

A mixture of 1-(2-bromacil)-4-nitrobenzene (0.34 g), 1,2,3,4-tetrahydro-6,7,8-trimethoxyaniline (0.33 g) (J. Chem. Soc. D. (20), 1296-1297 (1970)) and potassium carbonate is to treat the water, extracted with dichloromethane, dried, evaporated and purified by column chromatography, elwira mixture with dichloromethane-methanol (99:1) obtain the title compound (0.34 g) as a solid red color. So pl. 110oC. NMR spectrum: = 3,55 (2H, s, N - CH2Ar); 3,70 (6H, s, OCH3in ), 3.75 (3H, s, OCH3).

The intermediate connection 99. 4-[2-[1,2,3,4-Tetrahydro-6,7,8-trimetoksi-2-ethenolysis]ethyl]aminobenzoyl

A solution of intermediate 98 (0.34 g) in ethanol (10 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (50 mg). Upon completion of hydrogen absorption, the catalyst is filtered off and the filtrate was concentrated in vacuo, obtaining the title compound (0.3 g) as a solid white color. So pl. 92oC NMR spectrum: = 3,55 (2H, s N - CH2Ar), 3,7-3,75 (11H, OCH3and NH2).

The intermediate connection 100. 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-[2-[4-nitrophenyl]ethyl]-isoquinoline

A mixture of 1-(2-bromacil)-4-nitrobenzene (for 9.64 g), 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline-hydrochloride (10,59 g) and potassium carbonate (17,38 g) in isopropanol (150 ml) is refluxed for 48 hours. The mixture was then filtered and the filtrate is evaporated to dryness. The resulting residue is treated with water and establisheda from a mixture of 2-propanol and diethyl ether, giving the title compound (10,27 g) So pl. 118-119oC.

Analysis: C19H22N2O4< / BR>
found, %: C 66,48; H 6,48; N 8,14

calculated, %: C 66,65; H 6,48; N 8,18

The intermediate connection 101. 4-[2-[1,2,3,4-Tetrahydro-6,7-dimethoxy-2-ethenolysis]ethyl]aminobenzoyl

Method a:

A solution of intermediate 100 (20 g) in ethanol (300 ml) hydronaut at room temperature and at atmospheric pressure in the presence of 10% palladium-on-coal (2 g). Upon completion of hydrogen absorption, the catalyst is filtered off and the solution concentrated, obtaining the title compound (17,2 g) in the form of oil, which solidifies when grinding in hexane.

Method b:

Iron powder (to 12.44 g) portions and at room temperature to a stirred solution of intermediate 100 (14 g) in a mixture of methanol (150 ml) with concentrated hydrochloric acid (150 ml). Then within 45 minutes of the boil under reflux, the mixture is cooled, poured on ice, alkalinized with sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated, obtaining the title compound. So pl. 128oC (ethanol).

Analysis: C19H24N2O2< / BR>
found, %: C 72,77; the toxi-2-ethenolysis]ethyl]phenyl]-4 - greencarbon

A mixture of 9,10-dihydro-5-methoxy-9-oxo-4-acryliccanvas acid (1.3 g) and 1-oxybisethanol (0,43 g) in DMF (30 ml) was stirred at room temperature for 10 minutes. Then add the intermediate product (2B) - (1G) in DMF (20 ml), then dicyclohexylcarbodiimide (0.66 g) and the mixture is stirred at room temperature for 16 hours, then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with water, dried and evaporated, receiving the remnant that purify by column chromatography, elwira mixture with dichloromethane-methanol (97:3), receive solid, which is recrystallized from isopropanol and filtered, obtaining the title compound (0.4 g), So pl. 215 - 225oC.

Analysis: C34H33N3O5< / BR>
found, %: C 72,3; H 5,9; N 7,4

calculated, %: C 72,5; H 5,9; N 7,4

Example 2. 9,10-Dihydro-5-methoxy-9-oxo-N-[4-[[3-[1,2,3,4- tetrahydro-6,7-dimethoxy-2-ethenolysis]propyl]thio]phenyl]-4 - greencarbon.

A mixture of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.7 g) and 1-oxybisethanol (0.35 g) in DMF (20 ml) was stirred at room temperature tecamid (0.5 g) and the mixture is stirred at room temperature for 16 hours, then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with dichloromethane. The combined, dried organic extracts are evaporated receiving oil which is purified by column chromatography, elwira mixture with dichloromethane-methanol (97: 3). The obtained solid material is recrystallized from acetonitrile, filtered off and get the title compound (0.26 g). So pl. 199oC.

Analysis: C35H35N3O5S (0.5 H2O)

found, %: C 67,7; H 5,9; N 6,6; S 5,2

calculated, %: C 67,9; H 5,9; N 6,8; S 5,2

Example 3. 9,10-Dihydro-5-methoxy-9-oxo-N-[4-[3-[1,2,3,4- tetrahydro-6,7-dimethoxy-2-ethenolysis]propoxy]phenyl]-4 - greencarbon

A mixture of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (1.5 g) and 1-oxybisethanol (0.5 g) in DMF (30 ml) was stirred at room temperature for 10 minutes. Then add the intermediate compound 2(a) (1.27 g) in DMF (20 ml), then dicyclohexylcarbodiimide (0,76 g) and the mixture is stirred at room temperature for 16 hours, then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with dichlor kolonochnoi chromatography elwira mixture with dichloromethane-methanol (97: 3). Solid precrystallizer of isopropanol and filtered, obtaining the title compound (0,89 g). So pl. 190oC.

Analysis of C35H35N3O6< / BR>
found, %: C 68,6; H 5,9; N 6,8

calculated, %: C 68,6; H 6,1; N 6,9

Example 4. 5-fluoro-9,10-dihydro-9-oxo-N-[4-[[3-(1,2,3,4- tetrahydro-6,7-dimethoxy-2-ethenolysis)propyl]thio]phenyl]-4 - greencarbon

A mixture of 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (1 g) and 1-oxybisethanol (0.5 g) in DMF (30 ml) was stirred at room temperature for 10 minutes. Then add the intermediate compound 2(b) (1.4 g) in DMF (20 ml), then dicyclohexylcarbodiimide (0.8 g) and the mixture is stirred at room temperature for 16 hours, then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with dichloromethane. The combined, dried organic extracts are evaporated receiving the remnant that purify by column chromatography, elwira mixture with dichloromethane-methanol (97: 3). Solid material is recrystallized from isopropanol and filtered, obtaining the title compound (0.28 g). So pl. 162oC.

; 6,8; S 5,2

Similar to the implementation of example 1 provides the following connections:

Example 5. 9,10-Dihydro-5-methyl-9-oxo-N-[4-[[3-[1,2,3,4- tetrahydro-6,7-dimethoxy-2-ethenolysis]propyl]thio]phenyl]-4 - acrylicbased

The combination of 9,10-dihydro-5-methyl-9-oxo-4-greencarbon acid (1 g) with intermediate compound 2 (b) (1.4 g) after crystallization from isopropanol, to give the title compound (0.45 g). So pl. 155oC.

Analysis for C35H35N3O4S (H2O)

found, %: C 68,8; H 5,9; N 6,8; S 5,0

calculated, %: C of 68.7; H 6,1; N 6,8; S 5,2

Example 6. 9,10-Dihydro-9-oxo-N-[4-[3-[1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis]propoxy]phenyl]-4-acrylicbased

The combination of 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate compound 2(a) (1.1 g) after crystallization from isopropanol gives the title compound (0.27 g). So pl. 220oC.

Analysis for C34H33N3O5(0.5 H2O)

found, %: C 71,4; H 5,9; N 7,3

calculated, %: C 71,3; H 6,0; N 7,3

Example 7. 9,10-Dihydro-9-oxo-N-[4-[2-[1,2,3,4-tetrahydro - 6,7-dimethoxy-2-ethenolysis]ethoxy]phenyl]-4-acrylicbased

The combination of 9,10-dihydro-9-oxo-4-greencarbon acid (0,37 g) with an intermediate compound 5 (a) (0,51 is C33H31N3O5(0.5 H2O)

found, %: C 70,4; H 5,7; N 7,5

calculated, %: C to 70.9; H 5,8; N 7,5

Example 8. 9,10-Dihydro-9-oxo-N-[4-[[3-[1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis]propyl]thio]phenyl]-4-greencarbon

The combination of 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate compound 2 (b) (1 g) after crystallization from isopropanol gives the title compound (0.04 g), So pl. 182oC

Analysis for C34H33N3O4S (1,5 H2O)

found, %: C 67,3; H 5,6; N 6,9; S 5,25

calculated, %:C 67,3; H 5,9; N 6,9; S 5,3

Example 9. 9,10-Dihydro-5-methyl-9-oxo-N-[4-[4-[1,2,3,4- tetrahydro-6,7-dimethoxy-2-ethenolysis]butyl]phenyl]-4 - greencarbon.

The combination of 9,10-dihydro-5-methyl-9-oxo-4-greencarbon acid (1 g) with intermediate compound 2 (g) (1,34 g) after crystallization from ethanol-acetone to give the title compound (0,86 g). So pl. 140oC.

Analysis for C36H37N3O4(H2O)

found, %: C 73,1; H 6,3; N 6,8

calculated, %: C 72,8; H 6,5; N 7,1

Example 10. 9,10-Dihydro-5-methoxy-9-oxo-N-[4-[3-[1,2,3,4- tetrahydro-6,7-dimethoxy-2-ethenolysis]propyl]phenyl]-4 - greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.3 g). So pl. 135oC.

Analysis for C35H35N3O5(H2O)

found, %: C to 70.9; H 6,0; N 6,7

calculated, %: C 70,6; H 6,3; N 7,05

Example 11. 9,10-Dihydro-5-methyl-9-oxo-N-[4-[3-(1,2,3,4- tetrahydro-6,7-dimethoxy-2-ethenolysis)propyl]phenyl]-4 - greencarbon

The combination of 9,10-dihydro-5-methyl-9-oxo-4-greencarbon acid (0,61 g) with an intermediate compound 5(b) (0,53 g) after crystallization from isopropanol gives the title compound (0.45 g). So pl. 120oC.

Analysis for C35H35N3O4(0.5 H2O)

found, %: C 73,2; H x 6.15; N 7,3

calculated, %: 73,7; 6.35mm; 7,4

Example 12. 5-fluoro-9,10-dihydro-9-oxo-N-[4-[2-(1,2,3,4- tetrahydro-6,7-dimethoxy-2-ethenolysis)thio]phenyl]-4-greencarbon

The combination of 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (1 g) with intermediate connection 2(in) (0.8 g) after crystallization from a mixture of acetonitrile with isopropanol gives the title compound (0.2 g). So pl. 212oC.

Analysis for C33H30FN3O4(H2O)

found, %: C 69,4; H 5,2; N 7,8

calculated, % 69,6; 5,6; 7,4

Example 13. 5-fluoro-9,10-dihydro-9-oxo-N-[4-[3-(1,2,3,4- tetrahydro-6,7-dimethoxy-2-ethenolysis)propyl]phenyl]-4 - greencarbon

The combination of 5-fluoro-9,10-isopropanol give the title compound (0.4 g).

So pl. 166oC.

Analysis for C34H32FN3O4(H2O)

found, %: C 70,3; H 5,4; N 7,2

calculated, %: 69,9; 5,8; 7,2

Example 14. 9,10-Dihydro-5-methyl-9-oxo-N-[4-[2-[1,2,3,4- tetrahydro-6,7-dimethoxy-2-ethenolysis]ethyl]phenyl]-4 - greencarbon

The combination of 9,10-dihydro-5-methyl-9-oxo-4-greencarbon acid (0,63 g) with intermediate connection 2(in) (0,62 g) after crystallization from ethanol gives the title compound (0.2 g).

So pl. 175oC.

Analysis for C34H33N3O4(H2O)

found, %: C 71,8; H 6,2; N 7,2

calculated, %: 72,2; 6,2; 7,4

Example 15. 9,10-Dihydro-N-[2-methoxy-4-[3-(1,2,3,4-tetrahydro - 6,7-dimethoxy - 2-ethenolysis)propyl]phenyl]-5-methyl-9-oxo-4 - greencarbon.

A mixture of 9,10-dihydro-5-methyl-9-oxo-4-greencarbon acid (1 g) and 1-oxybisethanol (0,53 g) in DMF (30 ml) was stirred at room temperature for 10 minutes. Then add the intermediate compound 16 (a) (1.28 g) in DMF (20 ml), then dicyclohexylcarbodiimide (0.74 g) and the mixture is stirred at room temperature for 16 hours, then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with is the column chromatography, elwira mixture with dichloromethane-methanol (95: 5). Get solid, which is recrystallized from ether. Thus obtained the title compound (0.54 g). So pl. 174oC

Analysis for C36H37N3O5< / BR>
found, %: C 72,9; H 6,3; N 7,4

calculated, %: 73,1; 6,3; 7,1

Example 16. 9,10-Dihydro-5-methoxy-N-[2-methoxy-4-[3-(1,2,3,4 - tetrahydro-6,7-dimethoxy-2-ethenolysis)propyl] phenyl] -9-oxo-4 - greencarbon

A solution of intermediate 16(a) (1.28 g) dicyclohexylcarbodiimide (0.74 g) in DMF (20 ml) is added, with stirring, to a solution of 9,10-dihydro-5-methoxy-9-oxo-4 - greencarbon acid (1 g) and 1-oxybisethanol (0.5 g) in DMF (20 ml). The resulting mixture is stirred over night at room temperature, filtered and concentrated in vacuo. The remainder of the processing dichloromethane and then washed successively with dilute sodium hydroxide solution and water. The organic layer is then dried and evaporated, receiving the remnant that purify by column chromatography, elwira mixture with dichloromethane-methanol (9:1). Get solid, which crystallized from ether, giving the title compound (0,43 g).

So pl. 188oC

Analysis for C3615 and example 16 given the following connections.

Example 17. 5-fluoro-9,10-dihydro-N-[2-methoxy-4-[3-(1,2,3,4-tetrahydro - 6,7-dimethoxy-2-ethenolysis)propoxy]phenyl]-9-hydroxy-4-greencarbon.

Combining 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (0.31 g) with an intermediate compound 8(a) (0.4 g), obtained after crystallization from ISO-propanol the title compound (0.2 g). So pl. 152oC

Analysis for C35H34FN3O6(1,5 H2O)

found,%: C, and 65.7; H, 5.6 and F 3,0; N 6,9

designed,%: 65,8; 5,8; 2,9; 6,6

Example 18. 9,10-Dihydro-5-methoxy-N-[2-methyl-4-[3-(1,2,3,4 - tetrahydro-6,7-dimethoxy-2-ethenolysis)propoxy]phenyl]-9-oxo-4 - greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (1.5 g) with an intermediate compound 8(b) (1.3 g) after crystallization from a mixture of isopropanol ethanol gives the title compound (0,53 g), so pl. 160oC.

Analysis for C36H37N3O60.5 H2O)

found,%: C 69,6; H 5,8; N 6,5

calculated,%: 70,1; 6,2; 6,8

Example 19. 9,10-Dihydro-5-methyl-N-[2-methyl-4-[2-(1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis)propoxy]phenyl]-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5-methyl-9-oxo-4-greencarbon acid (1 g) with intermediate compound 8(b) (1.4 g) after crystallization the UB>5(H2O)

found,%: C 71,0; H 6,1; N 6,5

calculated,%: 70,9; 6,4; 6,9

Example 20. 9,10-Dihydro-5-methoxy-N-[2-methyl-4-[2-(1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis)ethyl]phenyl]-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (1.7 g) with an intermediate compound 16(b) of 91.7 g) after crystallization from ethanol gives the title compound (0.21 g). So pl. 200-201oC.

Analysis for C35H35N3O5(0.5 H2O):

found,%: C to 71.9; H 5,9; N 6,9

calculated,%: 71,65; 6,2; 7,2

Example 21. 5-fluoro-9,10-dihydro-N-[2-methyl-4-[2-(1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis)ethyl)phenyl]-9-oxo-4-greencarbon

The combination of 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (1 g) with intermediate compound 16 (C) (1,25 g) after crystallization from ethanol gives the title compound (0.32 g). So pl. 210oC.

Analysis for C34H32FN3O4(0.5 H2O)

found,%: C 71,2; H 5,9; F 3,4; N 7,4

designed,%: 71,1; 5,8; 3,3; 7,3

Example 22. 9,10-Dihydro-N-[2-methoxy-4-[3-(1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis)propoxy]phenyl]-5-methyl-9-oxo-4-greencarbon.

The combination of 9,10-dihydro-5-methyl-9-oxo-4-greencarbon acid (0.7 g) split timing is.

Analysis for C36H37N3O6(0.5 H2O)

found,%: C to 70.2; H 6,1; N 6,8

calculated,%: 70,1; 6,2; 6,8

Example 23. N-(2-Ethoxy-4-[3-[1,2,3,-4-tetrahydro-6,7-dimethoxy-2 - izohinolinove]phenyl]-9,10-dihydro-5-methoxy-9-oxo-4 - greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.65 g) with an intermediate compound 16(b) (0.6 g) after crystallization from a mixture of isopropanol with acetonitrile (9:1) gives the title compound (0,22 g ). So pl. 198oC.

Analysis for C37H39N3O6< / BR>
found,%: C 71,1; H 6,4; N 6,9

calculated,%: 71,8; 6,3; 6,8

Example 24. N-[2-Methoxy-4-[3-[[3,4-acid]methyl]methylamino] propoxy]-phenyl]-5-fluoro-9,10-dihydro-9-oxo-4-greencarbon

A mixture of 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (1 g) and 1-oxybisethanol (0.5 g) in DMF (30 ml) was stirred at room temperature for 10 minutes. Intermediate compound 22(b) (1.2 g) in DMF is added to the mixture followed by the addition of dicyclohexylcarbodiimide (0.8 g) and the mixture is stirred at room temperature for 16 h and then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with dichloromethane. The volume of luira mixture with dichloromethane-methanol (97:3). Solid material is recrystallized from isopropanol and get the title compound (0.68 g). So pl. 108oC.

Analysis for C34H34FN3O6(H2O)

found,%: C to 66.4; H 5,5; F 3,0; N 7,0

designed,%: 66,11; 5,8; 3,1; 6,8

Example 25. N-[2-Methyl-4-[3-[[(3,4-acid)methyl]methylamino]propoxy] phenyl]-5-fluoro-9,10-dihydro-9-oxo-4-greencarbon

A mixture of 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (1 g) and 1-oxybisethanol (0,47 g) in DMF (30 ml) was stirred at room temperature for 10 minutes. Then add the intermediate compound 22(a) (1.2 g) in DMF (15 ml), after which dicyclohexylcarbodiimide (0.7 g) and the mixture is stirred at room temperature for 16 hours, then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with dichloromethane. The combined, dried organic extracts evaporated and the residue purified by column chromatography, elwira mixture with dichloromethane-methanol (98:2). Then the solid substance is recrystallized from isopropanol, receiving the title compound (0,86 g). So pl. 130oC.

Analysis for C34H34FN3O5< / BR>
found,%: C 69,93; H of 5.89; F and]-phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-greencarbon:

A mixture of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (1 g) and 1-oxybisethanol (0,62 g) in DMF (30 ml) move at room temperature for 10 minutes Then add the intermediate compound 22(b) (1 g) in DMF (20 ml), then dicyclohexylcarbodiimide (0,62 g), and the mixture is stirred at room temperature for 16 hours, then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with methylene chloride. The combined, dried organic extracts evaporated and the residue purified by column chromatography on silica gel, elwira mixture with dichloromethane-methanol (97: 3). After crystallization from isopropanol, the title compound obtained as a solid (0.4 g). So pl. 146oC.

Analysis for C35H37N3O7< / BR>
found,%: C 68,4; H 5,9; N 6,7

calculated,%: 68,7; 6,1; 6,9

In the same way obtain the following compounds.

Example 27. N-[2-Methyl-4-[3-[[[3,4-acid]-methyl]methylamino propoxy]phenyl-9,10-dihydro-5-methyl-9-oxo-4-greencarbon

The reaction mix (mix) 9,10-dihydro-5-methyl-9-oxo - 4-greencarbon acid (1 g) with intermediate compound 22(a) (1,23 g) is P CLASS="ptx2">

Analysis for C35H37N3O5< / BR>
found,%: C 72,5; H 6,5; N 7,1

calculated,%: 72,5; 6,4; 7,2

Example 28. N-[2-Methyl-4-[3-[[[3,4-acid]methyl]methylamino propoxy]phenyl-9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.9 g) with an intermediate compound 22 (a) (1.2 g) after crystallization from isopropanol gives the title compound as a solid (1.3 g). So pl. 145-150oC NMR spectrum: = 2,2 and 2.3 (2.with. 2x3H, N-CH3and CH3-Ar), and 3.4 (s, 2H, CH2Ar), and 3.7 (s, 6H, OCH3), 6,6-8,5-(m, 13H, aromatic).

Example 29. N-[2-Methyl-4-[2-[[[3,4-acid]methyl] methylamino]ethoxy]phenyl]-9,10-dihydro-5-methoxy-9-oxo-4 - greencarbon

The reaction mix 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (1.2 g with an intermediate compound 22 (g) (1.12 g) after crystallization from ethanol gives the title compound as a solid (0.6 g). So pl. 178-179oC.

Analysis for C34H35N3O6< / BR>
found,%: C 70,1; H 6,1; N 7,1

calculated,%: C 70,2 H 6,1 N 7,2

Example 30. N-[2-Ethyl-4-[3-[[[3,4-acid]methyl] methylamino]propoxy]phenyl]-5-fluoro-9,10-dihydro-9-oxo-4 - greencarbon

The reaction mix 5 fluoro-9,10-digidance gives the title compound as a solid (0.95 g). So pl. 146oC.

Analysis for C35H36FN3O5< / BR>
found,%: C 70,3; H 6,1; F 3,2; N 7,0

designed,%: 70,3; 6,1; 3,1; 7,0

Example 31. N-[2-Methoxy-4-[3-[[[3,4-acid] methyl] methylamino] propoxy]-phenyl]-9,10-dihydro-5-methyl-9-oxo-4 - greencarbon

The reaction mix 9,10-dihydro-5-methyl-9-oxo-4-greencarbon acid (0.8 g) with intermediate compound 22 (b) (1,14 g) after crystallization from isopropanol gives the title compound as a solid (0.4 g). So pl. 156-157oC.

Analysis for C35H37N3O6< / BR>
found,%: C 70,6; H 6,3; N 7,15

calculated,%: 70,6; 6,3; 7,05

Example 32. N-[2-Methyl-4-[2-[[[3,4-acid]methyl] methylamino]ethyl] phenyl]-5-fluoro-9,10-dihydro-9-oxo-4 - greencarbon

The reaction mix 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (0,82 g) with an intermediate compound 27 (a) (1.07 g) after crystallization from ethanol gives the title compound in the form of solid yellow (0.21 g). So pl. 125oC.

Analysis for C33H32FN3O4(1,5 H2O)

found,%: C 68,3; H 5,8; F 3,3; N 7,2

designed,%: 68,3; 6,1; 3,3; 7,2

Example 33. N-[2-Methyl-4-[2[[[3,4-acid]methyl] methylamino]ethyl] phenyl]-9,10-dihydro-5-methyl - intermediate compound 27 (a) (1 g) after crystallization from ethanol gives the title compound in the form of solid yellow (0.45 g). So pl. 160-161oC.

Analysis for C34H35N3O4(0.5 H2O)

found,%: C 73,4; H 6,3; N 7,5

Calculated,%; 73,1; 6,5; 7,5

Example 34. N-[2-Methoxy-4-[2-[[[3,4-acid] methyl] methylamino] ethyl]phenyl]-5-fluoro-9,10-dihydro-9-oxo-4 - greencarbon

The reaction mix 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (1 g) with intermediate compound 27 (b) (1.3 g) after crystallization from ethanol gives the title compound as a solid (0.55 g). So pl. 161-162oC.

Analysis for C33H32FN3O5< / BR>
found,%: C 69,3; H 5,8; N 7,5

calculated,%: 69,6; 5,6; 7,4

Example 35. N-[2-Methyl-4-[3-[[[3,4-acid]methyl] methylamino]propyl]phenyl]-9,10-dihydro-5-methoxy-9-oxo-4 - greencarbon.

The reaction mix 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0,69 g) with an intermediate compound 27 (C) (0.65 g) after crystallization from isopropanol gives the title compound in the form of solids (0,185 g). So pl. 154oC.

Analysis for C35H37N3O5< / BR>
found,%: C 72,65; H 6,4; N 7,0

calculated,%: 72,50; 6,4; 7,25

Example 36. N-[2-Methyl-4-[3-[[[3,4-acid]methyl]methylamino]propyl]- phenyl]-5-fluoro-9,10-dihydro-9-oxo-4-acridine the Union 27 (b) (0,59 g) after crystallization from isopropanol gives the title compound as a solid (0.26 g). So pl. 132oC.

Analysis for C34H34FN3O4< / BR>
found,%: C to 71.9; H 6,0; F 3,3; N 7,3

designed,%: 71,9; 6,0; 3,3; 7,45

Example 37. N-[2-Methoxy-4-[3-[[[3,4-acid]methyl]methylamino]propyl]- phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0,43 g) and intermediate 30 (0.5 g) after crystallization from isopropanol gives the title compound as a solid (0.16 g). So pl. 105oC.

Analysis for C35H37N3O6< / BR>
found,%: C 70,6; H 6,3; N 6,9

calculated,%: 70,6; 6,3; 7,0

Example 38. N-[2-Methoxy-4-[3-[[[3,4-acid]methyl]methylamino]propyl] phenyl]-5-fluoro-9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (0.4 g) with an intermediate compound 30 (0.5 g) after crystallization from ethanol-cyclohexane gives the title compound as a solid (0.26 g). So pl. 170-190oC.

Analysis for C34H34FN3O5H2O

found,%: C 67,7; H 5,7; N 6,6

calculated,%: 67,9; 6,0; 7,0

Example 39. N-[4-[4-[[[3,4-acid]methyl]methylamino] butyl]phenyl] -5-fluoro-9,10-dihydro-9-oxo-4-acre is 7 g) in DMF (30 ml) was stirred at room temperature for 10 minutes. Then add the intermediate compound 33 (a) (0.55 g) in DMF (30 ml), and then dicyclohexylcarbodiimide (0.34 g), and the mixture is stirred at room temperature for 16 hours, then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with dichloromethane. The combined, dried organic extracts evaporated until then, until there is oil, which is purified by column chromatography, elwira mixture with dichloromethane-methanol (95:5), and get the oil, which crystallized from ethanol and filtered, obtaining the title compound (0.32 g). So pl. 131oC.

Analysis for C34H34FN3O4< / BR>
found,%: C 71,4; H 5,9; N 7,3

calculated,%: 71,9; 6,0; 7,4

Example 40. N-[4-[2-[[[3,4-Acid]methyl]methylamino] ethyl]phenyl] -9,10-dihydro-5-methoxy-9-oxo-4-greencarbon

A mixture of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.8 g) and 1-oxybisethanol (0,41 g) in DMF (50 ml) was stirred at room temperature for 10 minutes. Then add the intermediate compound 33(b) (0.9 g) in DMF (30 ml), then dicyclohexylcarbodiimide (0,62 g), and the mixture is stirred at room temperature for 16 cha sodium and extracted with dichloromethane. The combined, dried organic extracts evaporated until then, until there is oil, which is purified by column chromatography, elwira mixture with dichloromethane-methanol (95:5) to give a solid. It is crystallized from isopropanol and filtered, obtaining the title compound (0.31 g). So pl. 172oC.

Analysis for C33H33N3O5< / BR>
found, %: C 71,3; H 6,0; N 7,35

calculated, %: 71,8; 6,0; 7,6

Example 41. N-[4-[4-[[[3,4-Acid]methyl]methylamino]butyl] phenyl] -9,10-dihydro-9-oxo-4-greencarbon

A mixture of 9,10-dihydro-9-oxo-4-greencarbon acid (4 g) and 1-oxybisethanol (2.83 g) in DMF (50 ml) was stirred at room temperature for 10 minutes. Then add the intermediate compound 33 (a) (5.5 g) in DMF (100 ml), then dicyclohexylcarbodiimide (3,45 g), and the mixture is stirred at room temperature for 16 hours, then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with dichloromethane. The combined, dried organic extracts evaporated until then, until there is oil, which is purified by column chromatography, elwira mixture dichlorotaurine compound (3.2 g). So pl. 140oC. Analysis for C34H35N3O4< / BR>
found, %: C of 74.3; H, 6.5; the N 7,7

calculated, % 74,3; 6,4; 7,6

Example 42. N-[4-[2-[[[3,4-Acid]methyl]methylamino]ethyl] phenyl] -9,10-dihydro-9-oxo-4-greencarbon

A mixture of 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with 1-oxibendazole (0.56 g) in DMF (50 ml) was stirred at room temperature for 10 minutes. Then add the intermediate compound 33(b) (1 g) in DMF (10 ml), then dicyclohexylcarbodiimide (0.7 g). The mixture is stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with dichloromethane. The combined, dried organic extracts evaporated until then, until there is oil, which is purified by column chromatography, elwira mixture with dichloromethane-methanol (9: 1) to give a solid. This solid is crystallized from acetonitrile and filtered, obtaining the title compound (0.35 g). So pl. 172oC.

Analysis for C32H31N3P4< / BR>
found, %: C 73,6; H 6,0; 8,0 N

calculated, %: 73,7; 6,0; 8,1

Such examples 39 to 42, receive trail-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate compound 38 (g) (1,16 g) after crystallization from ethanol gives the title compound (0.28 g). So pl. 140oC.

Analysis for C33H33N3O4< / BR>
found, %: C 69,7; H 5,7; N 7,5

calculated, %: 69,8; 5,9; 7,4

Example 44. N-[4-[2-[[Phenylmethyl] methylamino]ethoxy]phenyl]-9,10 - dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (1 g) with intermediate compound 36(C) (1 g) after crystallization from ethanol gives the title compound (0.8 g). So pl. 173oC.

Analysis for C30H27N3O3< / BR>
found, %: C and 75.5; H 5,6; N 8,8

calculated, %: 75,45; 5,7; 8,8

Example 45. N-[4-[3-[[2-]3,4-Acid]ethyl]methylamino] propoxy]phenyl]-9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (1 g) with intermediate compound 38(a) (1.44 g) after crystallization from ethanol gives the title compound (0,82 g). So pl. 140oC.

Analysis for C34H35N3O5< / BR>
found, %: C 71,7; H 6,3; N 7,4

calculated, %: 72,2; 6,2; 7,4

Example 46. N-[4-[3-[[[3,4-Acid]methyl]methylamino] propoxy]phenyl]-9,10-about acid (2 g) with an intermediate compound 38 (C) (2.4 g) after crystallization from isopropanol gives the title compound (1.2 g), so pl. 180oC.

Analysis for C34H35N3O6< / BR>
found, %: C 70,1; H 6,1; N 7,2

calculated, %: 70,2; 6,1; 7,2

Example 47. N-[4-[2-[[2-[4-Methoxyphenyl]ethyl]methylamino]ethoxy]- phenyl] -9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate compound 36(d) (0.9 g) after crystallization from ethanol gives the title compound (0.7 g), so pl. 165oC.

Analysis for C32H31N3O4< / BR>
found, %: C 73,6; H 6,0; 8,0 N

calculated, %: 73,7; 6,0; 8,1

Example 48. N-[4-[3-[[2-[4-Methoxyphenyl]ethyl]methylamino]propoxy] phenyl] -9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate compound 38(b) (0,94 g) after crystallization from ethanol gives the title compound (0.9 g). So pl. 160oC.

Analysis for C33H33N3O4< / BR>
found, %: C 73,9; H 6,2; N 7,8

calculated, %: 74,0; 6,2; 7,8

Example 49. N-[4-[2-[[4-[Methoxyphenyl]methyl]methylamino]ethoxy] phenyl]-9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.6 g) with an intermediate compound 36(e) (0,72 g) after crystallization WPI>4< / BR>
found, %: C 73,5; H 5,8; N, 8,1

calculated, %: 73,35; 5,8; 8,3

Example 50. N-[4-[2-[[[4-Were]methyl]methylamino]ethoxy]phenyl]-9,10 - dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.7 g) with an intermediate compound 36 (f) (0,78 g) after crystallization from isopropanol gives the title compound (0,23 g). So pl. 168oC.

Analysis for C31H29N3O3< / BR>
found, %: C 75,3; H 6,0; N, 8,1

calculated, %: 75,7; 5,95; 8,55

Example 51. N-[4-[2-[[[3,4-Acid]methyl]methylamino]ethoxy]phenyl] 9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (1 g) with intermediate compound 36 (b) (1,25 g) after crystallization from ethanol gives the title compound (1.39 g). So pl. 140oC

Analysis for C32H31N3O5< / BR>
found, %: C 71,7; H 6,2; N 7,7

calculated, %: 71,5; 5,8; 7,8

Example 52. N-[4-[2-[[[4-Methylthio] phenyl]methyl]methylamino]ethoxy]phenyl - 9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate compound 36 (C) (1 g) after crystallization from ethanol gives the title compound (0.75 g).

So pl. 150oC
Example 53. N-[4-[2-[[[3,4-Acid]methyl]methylamino]ethoxy]phenyl]- 9,10-dihydro-2-(methylthio)-9-oxo-4-acrylicbased

The reaction of a combination of intermediate 39 (0.7 g) with an intermediate compound 36 (b) (0,81 g) after crystallization from ethanol gives the title compound (0.45 g) So pl. 170oC.

Analysis for C33H33N3O5S

found, %: C 68,1; H 5,65; N 7,0; S 5,4

designed, %: 67,9; 5,7; 7,2; 5,5

Example 54. N-[4-[2-[[[3,4-Acid]methyl]methylamino]ethoxy]phenyl]- 9,10-dihydro-70(methylthio)-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-7-(methylthio)-9-oxo-4-greencarbon acid (0.7 g) with an intermediate compound 36 (b) (0,81 g) after crystallization from acetonitrile gives the title compound (0.14 g). So pl. 160oC.

Analysis for C33H33N3O5S

found, %: C 67,8; H 5,8; N 7,1; S 5,4

designed, %: 67,9; 5,7; 7,2; 5,5

Example 55. N-[4-[2-[[2-[3,4-Acid]ethyl]methylamino]ethoxy]phenyl] - 9,10-dihydro-2-(methylthio)-9-oxo-4-greencarbon

The reaction of a combination of intermediate 39 (0.8 g) with intermediate compound 36 (a) (0,93 g) after crystallization from ethanol gives the title compound (0,46 g). So pl. 150oC

Analysis for C34<-[2-[[2-[3,4-Acid]ethyl]methylamino]ethoxy]phenyl] - 9,10-dihydro-10-methyl-9-oxo-4-greencarbon

the reaction mix 9,10-dihydro-10-methyl-9-oxo-4-greencarbon acid (0,72 g) with an intermediate compound 36 (a) (0.9 g) after crystallization from isopropanol gives the title compound (0.8 g). So pl. 139oC.

Analysis for C34H35N3O5< / BR>
found, %: C 72,25; H 6,2; N 7,4

calculated: % 72,20; 6,2; 7,4

Example 57. N-[4-[2-[[[3,4-Acid]methyl]methylamino]ethoxy]phenyl]- 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-5-methoxy-9-oxo-greencarbon acid (0.8 g) with intermediate compound 36 (b) (0,94 g) after crystallization from ethanol gives the title compound (0.25 g). So pl. 184oC.

Analysis for C33H33N3O6< / BR>
found, %: C to 69.9; H 6,0; N 7,4

calculated, %: 69,8; 5,9; 7,4

Example 58. N-[4-[2-[[2-[3,4-Acid]ethyl]methylamino]ethoxy]phenyl - 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.8 g) with intermediate compound 36 (a) (0,98 g) after crystallization from ethanol gives the title compound (0.25 g). So pl. 190oC.

Analysis for C34H35N3O6< / BR>
found, %: C 70, 9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (1 g) with intermediate compound 38 (b) (1.4 g) after crystallization from ethanol gives the title compound (0.8 g). So pl. 130oC.

IR-spectrum : 1650 cm-1(CONH), 1620 cm-1(CO) and 3350 cm-1(NH).

Example 60. N-[4-[3-[[[3,4-Acid]methyl]methylamino]propoxy]phenyl]- 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (C) (1 g) after crystallization from ethanol gives the title compound (0.52 g). So pl. 150oC.

Analysis for C33H32FN3O5< / BR>
found, %: C 69,6; H 5,7; F 3,25; N 7,3

designed, %: 69,6; 5,7; 3,3; 7,4

Example 61. N-[4-[2-[[2-[3,4-Acid]ethyl]methylamino]ethyl]phenyl]- 9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0,76 g) with intermediate connection 33 (l) (1 g) after crystallization from acetonitrile obtain the title compound (0.7 g). So pl. 180oC.

Analysis for C33H33N3O4< / BR>
found, %: C 73,5; H 6,1; N 7,9

calculated, %: 74,0; 6,2; 7,8

Example 62. N-[4-[4-[[[4-Methylthio] phenyl]methyl]methylamino]butyl]phenyl](0.8 g) with intermediate connection 33 (K) (1 g) after crystallization from acetonitrile gives the title compound (0.64 g). So pl. 135oC.

Analysis for C33H33N3O2S

found, %: C 73,7; H 6,2; N 7,9; S 5,7

designed, %: 74,0; 6,2; 7,8; 6,0

Example 63. N-[4-[4-[[[4-forfinal] methyl]methylamino]butyl]phenyl]-9,10 - dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.7 g) with intermediate connection 33 (and) (0,86 g) after crystallization from acetonitrile gives the title compound (0,43 g). So pl. 151oC.

Analysis for C32H30FN3O2< / BR>
found, %: C 75,9; H 6,0; F 3,7; N 8,25

designed, %: 75,7; 5,9; 3,7; 8,3

Example 64. N-[4-[3-[[[4-Methoxyphenyl] methyl]methylamino]propyl]phenyl]-9,10 - dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0,72 g) with intermediate connection 33 (g) (0,85 g) after crystallization from isopropanol gives the title compound (0.64 g). So pl. 155o.

Analysis for C32H31N3O3< / BR>
found, %: C 76,2; H 6,1; N 7,9

calculated, %: 76,0; 6,2; 8,3

Example 65. N-[4-[4-[[2-[4-Methoxyphenyl]ethyl]methylamino]butyl] phenyl]-9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (C) after CR is>35N3O3< / BR>
found, %: C to 76.4; H 6,6; N 7,8

calculated, %: 76,5; 6,6; 7,9

Example 66. N-[4-[3-[[2-[3,4-Acid]ethyl]methylamino] propyl]phenyl]-9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (g) (1 g) after powdering with ether gives the title compound (0.88 g).

So pl. 114oC.

Analysis for C34H35N3O4< / BR>
found,%: C 74,2; H 6,35; N 7,55

calculated,%: 74, 3mm; 6,4; 7,6

Example 67. N-[4-[4-[[2-[3,4-Acid]ethyl]methylamino] butyl]phenyl] -9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0,72 g) with intermediate connection 33 (C) (1 g) after crystallization from acetonitrile gives the title compound (0.12 g). So pl. 120oC.

Analysis for C35H37N3O4< / BR>
found, %: C 74,2; H 6,5; N 7,6

calculated, %: 74,6; 6,6; 7,45

Example 68. N-[4-[2-[[2-[4-Methoxyphenyl] ethyl]methylamino] ethyl]phenyl]-9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (l) (0.95 g) after crystallization from acetonitrile gives the title Conn; 8,1

calculated, %: 76,0; 6,2; 8,3

Example 69. N-[4-[3-[[[3,4-Acid]methyl]methylamino] propyl]phenyl] -9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (e) (1 g) after crystallization from acetonitrile gives the title compound (1 g). So pl. 112oC.

Analysis for C33H33N3O4< / BR>
found, %: C 74,1; H 6,2; N 7,7

calculated, %: 74,0; 6,2; 7,8

Example 70. N-[4-[5-[[[3,4-Acid]methyl]methylamino] pentyl]phenyl] -9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (m) (1,15 g) after powdering with ether gives the title compound (0,41 g). So pl. 110oC.

Analysis for C35H37N3O4< / BR>
found, %: C of 74.3; H 6,6; N 7,4

calculated, %: 74,6; 6,6; 7,45

Example 71. N-[4-[4-[[2-[3,4-Acid]ethyl]methylamino] butyl]phenyl] -9,10-dihydro-7-methoxy-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-7-methoxy-9-oxo-4-greencarbon acid (1 g) with intermediate connection 33 (b) (1.3 g) after crystallization from ethanol gives the title compound (0.85 grams).

So pl. 155oC.


Example 72. N-[4-[4-[[[3,4-Acid]methyl]methylamino]butyl]phenyl] -9,10 - dihydro-5-methoxy-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (a) (0,98 g) after crystallization from isopropanol gives the title compound (0.12 g). So pl. 157oC

Analysis for C35H37N3O5< / BR>
found, %: C to 71.9; H 6,4; N 7,2

calculated, %: 72,5; 6,4; 7,25

Example 73. N-[4-[3-[[[3,4-Acid]methyl]methylamino]propyl] phenyl] -5-fluoro-9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (0,72 g) with intermediate connection 33 (e) (0.9 g) after crystallization from ethanol gives the title compound (0,89 g). So pl. 158oC.

Analysis for C33H32FN3O4< / BR>
found, %: C to 71.9; H 6,1; F 3,25; N 7,7

designed, %: 71,65; 5,8; 3,4; 7,6

Example 74. N-[4-[2-[[[3,4-Acid]methyl]methylamino]ethyl] phenyl] -5-fluoro-9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (1 g) with intermediate connection 33 (b) (1.2 g) after crystallization from ethanol gives the title compound (0,78 g). So pl. 175oC.

Anal Sample 75. N-[4-[4-[[[3,4-Acid]methyl]methylamino]butyl]phenyl] -9,10 - dihydro-5-nitro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-5-nitro-9-oxo-4-greencarbon acid (0.6 g) with intermediate connection 33 (a) (0.7 g) after crystallization from acetonitrile gives the title compound (0.35 g). So pl. 174oC.

Analysis for C34H34N4O6< / BR>
found, %: C 68,6; H 5,7; N 9,5

calculated, %: 68,7; 5,8; 9,4

Example 76. N-[4-[2-[[[3,4-Acid]methyl]methylamino]ethyl] phenyl] -9,10-dihydroxy-5-nitro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-5-nitro-9-oxo-4-greencarbon acid (0.6 g) with intermediate connection 33 (b) (0,63 g) after crystallization from isopropanol gives the title compound (0.45 g). So pl. 197oC.

Analysis for C32H30N4O6< / BR>
found,%: C of 67.4; H 5,3; N 9,7

calculated,%: 67,8; 5,3; 9,9

Example 77. N-[4-[5-[[[3,4-Acid]methyl]methylamino] pentyl]phenyl] -5-fluoro-9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (m) (1 g) after crystallization from acetonitrile gives the title compound (0.29 grams). So pl. 130oC. Analysis for C35H
The reaction mix 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (C) (0,93 g) after powdering with ether gives the title compound (0.3 g). So pl. 182oC.

Analysis for C35H37N3O4< / BR>
found,%: C 74,2; H 6,6; N 7,8

calculated,%: 74,6; 6,6; 7,5

Example 79. N-[4[2-[[2-[3,4-Acid]ethyl]methylamino] ethyl]phenyl] -9,10-dihydro-5-methoxy-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (d) (0,94 g) after crystallization from isopropanol, to give the title compound (0.17 g). So pl. 179oC.

Analysis for C34H35N3O5< / BR>
found,%: C 72,3; H 6,0; N 7,8

calculated,%: 72,2; 6,2; 7,4

Example 80. N-[4-[4-[[2-[3,4-acid]ethyl]methylamino] butyl]pentyl]-9,10-dihydro-5-methoxy-9-oxo-4-greencarbon.

The reaction mix 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (C) (1 g) after crystallization from isopropanol gives the title compound (0.12 g). So pl. 170oC, IR range: 1645 cm-2(CONH), 1620 cm-1(CO) and 3300 cm-1(NH).

Example 81. N-[4-[3-[[[3,4-Acid]methyl]the method of 9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (e) (0.88 g) after crystallization from isopropanol gives the title compound (0.29 grams) So pl. 192oC. Analysis for C33H32N4O6< / BR>
found, %: C 67,8; H 5,6; N 9,4

calculated, %: 68,3; 5,6; 9,65

Example 82. N-[4-[3-[[[3,4-Acid]methyl]methylamino]propyl]phenyl] -9,10 - dihydro-5-methoxy-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (e) (0,93 g) after crystallization from ethanol gives the title compound (0.27 g). So pl. 180oC.

Analysis for C34H35N3O5< / BR>
found, %: C 72,0; H 6,1; N 7,6

calculated, %: 72,2; 6,2; 7,4

Example 83. N-[4-[2-[[Phenylmethyl]ethylamino]ethoxy]phenyl]-9,10 - dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate compound 36 (and) (0.9 g) after crystallization from ethanol gives the title compound (0.34 g). So pl. 157oC.

Analysis for C31H29N3O3< / BR>
found, %: C 75,3; H 5,9; N 8,4

calculated, %: 75,7; 5,9; 8,5

Example 84. N-[4-[4-[[[3,4-Acid]methyl]methylamino] butyl]phenyl] -9,10-dihydro-10-methyl-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-10-methyl-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (a) (1.04 g) after Christ) and 3250 cm-1(NH).

Example 85. N-[4-[2-[[[3,4-Acid]methyl]methylamino]ethyl] phenyl] -9,10-dihydro-10-methyl-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-10-methyl-9-oxo-4-greencarbon acid (0.87 g) with intermediate connection 33 (b) (1 g) after crystallization from isopropanol gives the title compound (0,42 g). So pl. 182oC.

Analysis for C33H33N3O4< / BR>
found, %: C 73,5; H 6,1; N 7,8

calculated, %: 74,0; 6,2; 7,8

Example 86. N-[4-[4-[[[3,4-Acid]methyl]methylamino]butyl] phenyl] -9,10-dihydro-7-methoxy-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-7-methoxy-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33 (a) (0.97 g) after crystallization from isopropanol gives the title compound (0.17 g). So pl.: 172oC.

Analysis for C35H37N3O5< / BR>
found,%: C 71,5; H 6,4; N 6,9

calculated,%: 71,4; 6,5; 7,1

Example 87. N-[4-[[2[[[3,4-Acid] methyl] methylamino] ethyl]thio] phenyl/-9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-9-oxo-4-greencarbon acid (0.7 g) with an intermediate compound 36 (g) (1 g) after crystallization from isopropanol gives the title compound (0.26 g). So pl. 113o; ,6; 5,8

Example 88. N-[4-[[3-[[[3,4-Acid]methyl]methylamino] propyl]thio] -phenyl]-9,10-dihydro-5-methyl-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-5-methyl-9-oxo-greencarbon acid (0.8 g) with intermediate connection 58(g) (1,09 g) after crystallization from ethanol gives the title compound (50 mg). So pl. 158oC

Analysis for C34H35N3O4S 0,5 H2O

found, %: C 69,4; H 5,9; N 6,9; S 5,6

designed, %: 69,1; 6,1; 7,1; 5,4

Example 89. N-[4-[[3-[[[3,4-Acid]methyl]methylamino] propyl]thio] phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-5-methoxy-9-oxo - greencarbon acid (1 g) with intermediate compound 38(g) (1.28 g) after crystallization from acetonitrile give the title compound (0,37 g). So pl. 184-186oC.

Analysis for C34H35N3O5S

found, %: C 68,1; H 5,9; N 6,8; S 5,2

designed, %: 68,3; 5,9; 7,0; 5,4

Example 90. N-[4-[[3-[[[3,4-Acid]methyl]methylamino] propyl]thio] phenyl]9,10-dihydro-5-fluoro-9-oxo-4-greencarbon

The reaction mix 9,10-dihydro-5-fluoro-9-oxo-greencarbon acid (0.9 g) with an intermediate compound 38 (g) (1.1 g) after crystallization from isopropanol gives the title Conn is: C 66,6; H 5,6; F 3,1; N 6,9; S 5,3

designed, %: 66,6; 5,6; 3,2; 7,1; 5,4

Example 91. N-[4-[2-[[[3,4-Acid] -methyl] methylamino] ethyl]phenyl-9,10-dihydro-5-methylthio-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5-methylthio-9-oxo-4-greencarbon acid (0.7 g) with intermediate connection 33(b) (0.74 g) after crystallization from ethanol gives the title compound (0.3 g). So pl. 190oC.

Analysis for C33H33N3O4S 0,5 H2O

found, %: C 68,5; H 6,1; N 7,2

calculated, %: 68,7; 5,9; 7,3

Example 92. N-[4-[2-[[[3,4-Acid]methyl]methylamino] ethyl]phenyl]- 9,10-dihydro-5-methyl-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5-methyl-9-oxo-4-greencarbon acid (1.27 g) with intermediate connection 33(b) (1.5 g) after crystallization from a mixture of isoprene with diisopropyl ether gives the title compound (0.3 g). So pl. 119oC.

Analysis for C33H33N3O4< / BR>
found, %: C 73,5; H 6,2; N 7,6

calculated, %: 74,0; 6,2; 7,8

Example 93. N-[4-[3-[[[3,4-Acid]methyl]methylamino] propoxy]phenyl]-9,10-dihydro-5-methyl-9-oxo-4-greencarbon

The combination of (reaction mix) 9,10-dihydro-5-methyl-9-oxo-4-greencarbon acid (1 g) with intermediate compound 38(b) (1.3 g) after cu is H35N3O5< / BR>
found, %: C 72,3; H 6,3; N 7,5

calculated, %: 72,2; 6,3; 7,5

Example 94. N-[4-[2-[[[3,4-Acid]-methyl]methylamino] ethylamino] phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (1.4 g) with intermediate connection 43 (1.4 g), after crystallization from isopropanol has the title compound (0.2 g). So pl. 196oC

Analysis for C33H34N4O5< / BR>
found, %: C 69,8; H 6,3; N 10,0

calculated, %: 69,9; 6,1; 9,9

Example 95. N-[4-[2-[[[3,4-Acid]methyl]methylamino] ethyl]phenyl] -9,10-dihydro-5,8-dimethoxy-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5,8-dimethoxy-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 33(b) (0,67 g) after crystallization from ethanol gives the title compound (0.15 g). So pl. 196oC.

Analysis for C34H35N3O60.5 H2O

found, %: C 68,99; H 5,76; N 7,18

calculated, %: 69,13; 6,14; 7,11

Example 96. N-[4-[2-[[[3,4-Acid]-methyl]methylamino] ethyl]phenyl] -9,10-dihydro-5,7-dimethoxy-9-oxo-4-greencarbon

The reaction mix (mix) intermediate 44 (1.4 g) with intermediate connection 33(b) (1.2 g) after crystalliza the SUB>3
O6< / BR>
found, %: C 70,09; H 6,35; N 7,01

calculated, %: 70,20; 6,06; 7,22

Example 97. N-[4-[2-[[[3,4-Acid]methyl]methylamino]ethyl] phenyl] -9,10-dihydro-6,7,8-trimetoksi-9-oxo-4-greencarbon

The combination of (reaction mix) intermediate 45 (0.6 g) with intermediate connection 33(b) (0.6 g) after crystallization from isopropanol gives the title compound (0.4 g). So pl. 158oC.

Analysis for C35H37N3O7< / BR>
found, %: C 68,69; H 6,32; N 6,40

calculated, %: 68,72; 6,10; 6,87

Example 98. N-[4-[3-[[[3,4-Acid]methyl]amino]propoxy] phenyl]-9,10-dihydro-9-oxo-4-greencarbon

A mixture of intermediate 40 (0.5 g) and 3,4-dimethoxybenzaldehyde (0.5 g) is heated at 140oC for 1 hour. Then water is added and the mixture extracted with dichloromethane. The dried organic phase is concentrated to obtain a solid substance, which was purified by column chromatography, elwira mixture with dichloromethane-methanol (9:1). The resulting solid is crystallized from benzene, get the title compound (50 mg). So pl. 138-139oC.

Analysis for C32H31N3O50.5 H2O

found, %: C 70,1; H 5,9; N 7,5

designed, %: 70,3; 5,9; 7,´┐Żoksamida

The solution of the substance of example 41 (0.55 g) and digidratirovannogo oxalic acid (0.126 g) in ethanol (10 ml), boiled for 2 minutes. After cooling and scratching with a stick on the walls of the glass crystallization occurs. The crystals are filtered and dried, and get the title compound (0.55 g).

So pl. 155-160oC.

Analysis for C36H37N3O8(0.5 H2O)

found, %: C to 66.3; H 5,9; N 6,3

calculated, %: 66,6; 5,9; 6,4

Example 100. Maleate N-[4-[4-[[[3,4-dimethoxyphenyl]methyl]methylamino]butyl] -phenyl]-9,10-dihydro - 9-oxo-4-greencarbon

A solution of the compound of example 41 (0.55 g) and maleic acid (0,130 g) in ethanol (50 ml), boiled for 2 minutes. After cooling and scratching stick on the wall of the Cup, crystallization occurs. The crystals are filtered and dried, obtaining the title compound (0.5 g). So pl. 205oC.

Analysis for C38H39N3O8< / BR>
found, %: C 68,2; H 5,9; N 6,2

calculated, %: 68,5; 5,9; 6,3

Example 101. Hydrochloride N-[4-[4-[[[3,4-acid]methyl]methylamino] butyl]-phenyl]-9,10-dihydro-9 - oxo-4-greencarbon

A hot solution of the compound of example 41 (0.55 g) in ethanol (50 ml) is treated with a slight excess of ethereal is m, receiving the title compound (0.4 g) as crystals. So pl. 165oC.

Analysis for C34H36ClN3O4H2O

found, %: C of 67.6; H 6,3; N 7,0

calculated, %: 67,5; 6,4; 7,0

Example 102. L(+)Lactate N-[4-[4-[[[3,4-acid]methyl]methylamino] -butyl]phenyl]-9,10-dihydro - 9-oxo-4-greencarbon.

A solution of the compound of example 41 (0.55 g) and L(+)-lactic acid (0.95 g) in isopropanol (30 ml), boiled for 2 minutes. After cooling and scratching stick on the wall of the Cup, crystallization occurs. The crystals are filtered and dried, obtaining the title compound (0.45 g). So pl. 120oC.

Analysis for C37H41N3O7< / BR>
found, %: C 69,5; H 6,5; N 6,6

calculated, %: 69,4; 6,6 N; 6,5

Example 103. Oxalate N-[3-[3-[[[3,4-acid] methyl] methylamino] propyl]-phenyl]-5-fluoro - 9,10-dihydro-9-oxo-4-greencarbon

A mixture of 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (1 g) and 1-examensarbete (0,63 g) in DMF (30 ml) was stirred at room temperature for 10 minutes. Then add the intermediate compound 51 (1.23 g) in DMF (3.9 ml), after which dicyclohexylcarbodiimide (0.8 g), and the mixture is stirred at room temperature for 16 hours and outfilter the comfort with methylene chloride. The combined, dried organic extracts evaporated until then, until there is oil, which, after purification using column chromatography on silica gel with elution with a mixture of methylene chloride with methanol (99:1), leads to the title compound (1.1 g). so pl. 126oC.

Analysis for C33H32FN3O4C2H2O4(H2O)

found, %: C and 63.9; H 5,4; F 2,8; N 6,2

designed, %: 63,5; 5,5; 2,9; 6,3

Similar to example 103 provides the following connections.

Example 104. N-[3-[3-[[[3,4-Acid]methyl]methylamino]propoxy]phenyl]-9,10-dihydro - 5-methoxy-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (1.5 g) with intermediate connection 48(b) (1.22 g) after crystallization from isopropanol gives the title compound (0,47 g) as a solid. So pl. 124oC.

Analysis for C34H35N3O6< / BR>
found, %: C 70,1; H 6,1; N 7,05

calculated, %: 7,92; 6,1; 7,2

Example 105. Oxalate N-[3-[3-[[[3,4-Acid]methyl]methylamino]propyl]-phenyl]-9,10-dihydro - 5-methoxy-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (1.26 g) with intermediate soedinenii>5C2H2O4(0.5 H2O)

found, %: C 65,2; H 6,2; N 6,2

calculated, %: 65,0; 5,8; 6,3

Example 106. Fumarate N-[3-[2-[[[3,4-acid]methyl]methylamino]ethyl] phenyl]-5-fluoro - 9,10-dihydro-9-oxo-4-greencarbon

The reaction mix 5 fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (0.34 g) with intermediate connection 48(a) (0.4 g) gives the title compound (0.3 g). So pl. 155oC.

Example 107. Fumarate N-[3-[2-[[[3,4-acid]methyl]methylamino]ethyl] phenyl]-9,10-dihydro-5 - methoxy-9-oxo-4-greencarbon.

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.36 g) with intermediate connection 48 (a) (0.4 g) gives the title compound (0,13 g) So pl. 140oC.

In examples 106 and 107 corresponding free base receive according to the method similar to example 103, and then converted into salts fumarate method similar to example 100.

Example 108. N-[4-[4[[[3,4-Acid]methyl]methylamino]butyl]-2-methoxyphenyl]-9,10-dihydro-5-methoxy-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0,38 g) with intermediate connection 55 (0.5 g) gives, after crystallization from isopropanol title compound (0.36 g) in the form of a solid BR>
calculated, %: 70,92; 6,45; 6,89

Example 109. 9,10-Dihydro-5-methoxy-9-oxo-N-[4-[[2-[1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis]ethyl]amino]phenyl]-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0,99 g) with intermediate connection 59 (1.2 g) after crystallization from acetonitrile gives the title compound (1.3 g).

So pl. 228 - 234oC.

Analysis for C34H34N4O50.5 H2O

found, %: C 69,37; H by 5.87; N 9,37

calculated, %: 69,48; 6,00; 9,50

Example 110. N-[4-[2-[2,3-Dihydro-5,6-dimethoxy-1H-isoindole-2-yl]-ethyl] phenyl] 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.54 g) with intermediate connection 60 (0.6 g) after crystallization from ethanol gives the title compound (0.3 g).

So pl. 215 - 225oC.

NMR spctr: = 2,85 (4H, c, N-(CH2)2-phenyl); 3,7 (6H, c, 2xOCH3), and 3.8 (3H, s, OCH3), 3,9 (4H, c, 1 x N-CH2-phenyl).

Example 111. 9,10-Dihydro-5,8-dimethoxy-N-[2-methoxy-4-[3-[1,2,3,4-tetrahydro - 6,7-dimethoxy-2-ethenolysis] propyl] phenyl] -9-oxo-4-greencarbon

The combination of 9,10-dihydro-5,8-dimethoxy-9-oxo-4-greencarbon acid (0.7 g) with an intermediate compound 16(a) (the C37H39N3O7H2O

found, %: C 67,44; H 5,94; N 6,80

calculated, %: 67,77; 6,30; 6,40

Example 112. 9,10-dihydro-5-methoxy-N-[4-[2-[1,2,3,4-tetrahydro-6,7-dimethoxy - 2-ethenolysis]-1-oxyethyl]phenyl]9-oxo-4-ukrainecarlisle

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0,49 g) with an intermediate compound 63 (0.5 g) after crystallization from acetonitrile gives the title compound (0.8 g)

So pl. 160 - 165oC

Analysis for C34H33N3O6H2O

found, %: C 68,51; H 5,74; N 7,25

calculated, %: 68,33; 5,90; 7,09

Example 113. 9,10-Dihydro-5-methoxy-9-oxo-N-[4-[[[2-[1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis]ethyl]methylamino]methyl]phenyl]-4 - acrylicbased

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0,53 g) with intermediate connection 67 (0.7 g) by precipitation with a mixture of methylene chloride with diethyl ether gives the title compound (0.5 g). So pl. 202oC.

Analysis for C36H38N4O51,25 H2O

found, %: C 68,68; H 6,27; N CHARGED 8.52

calculated, %: 68,71; 6,48; 8,90

Example 114. N-[4-[[[2-[[[3,4-Acid]methyl]methylamino]-ethyl]-methylamino]- methyl]phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-greencarbon

The combination of 9,10-d the tion from methanol gives the title compound (0.75 g) as a solid yellow color. So pl. 170oC.

Analysis for C35H38N4O50.5 H2O

found, %: C 69,69; H 6,30; N 9,10

calculated, %: 69,63; 6,51; 9.28 are

Example 115. 5-fluoro-9,10-dihydro-N-[2-methoxy-4-[3-[1,2,3,4-tetrahydro-6,7-dimethoxy - 2-ethenolysis]propyl]phenyl]-9-oxo-4-greencarbon

The combination of 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (0.5 g) with an intermediate compound 16(a) (0,63 g) after crystallization from ethanol gives the title compound (0.3 g).

So pl. 128oC

NMR spectrum: = 3,6 (3H, c., OCH3), and 3.8 (6H, c, 2 x OCH3), to 9.15 (1H, s, NHCO), 11,35 (1H, s, NH-acridan).

Example 116. N-[4-[[3-[[[3,4-Acid]methyl]methylamino]propylthio] -phenyl]- 9,10-dihydro-5-]methylthio]-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5-methylthio-9-oxo-4-greencarbon acid (0.3 g) with an intermediate compound 38 (g) (0.36 g) gives, after crystallization from methanol, the title compound (0,13 g). So pl. 142oC

NMR spectrum: = 2,2 (3H, c, SCH3), a 2.45 (3H, s, N-CH3, and 3.7 (6H, c, 2xOCH3)

Example 117. N-[4-[3-[[[3,4-Acid] methyl]methylamino]propyl]-2 - methoxyphenyl]-9,10-dihydro-5-methyl-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5-methyl-9-oxo-4-greencarbon acid (0.75 g) with an intermediate compound 30 ( 1 g) 3H, c, NCH3), to 2.55 (3H, c, CH3acridine), 3,42 (2H, c, N-CH2-phenyl), a 3.9 (9H, 3c, hon3)

Example 118. N-[2-Ethoxy-4-[3-[1,2,3,4-tetrahydro-6,7-dimethoxy-2-ethenolysis]- propyl]-phenyl]-5-fluoro-9,10-dihydro-9-oxo-4-greencarbon

The combination of 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (1 g) with intermediate compound 16 (b) (0,86 g) after crystallization from acetonitrile gives the title compound (0.4 g). So pl. 200oC

NMR spectrum: = 1,4 (2H, t, CH3-CH2); 3,7 (6H, c, 2xOCH3).

Example 119. N-[4-[4-[[[3,4-Acid]methyl]methylamino]-2-butenyl] phenyl]- 9,10-dihydro-9-oxo-4-greencarbon

The combination of 9,10-dihydro-9-oxo-4-greencarbon acid (154 mg) with an intermediate compound of 72 (210 mg) after crystallization from ethanol gives the title compound (80 mg). So pl. 140oC

Analysis for C34H33N3O4< / BR>
found, %: C 74,17; H between 6.08; N TO 7.61

calculated, %: 74,55; 6,07; to 7.67

Example 120. N-[4-[3-[[[3,4-Acid]methyl]methylamino]-1-propenyl] phenyl]- 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.95 g) with intermediate connection 74 (1.1 g) after crystallization from ethanol gives the title compound (0.7 g). So pl. 200o
Example 121. 5-Methoxy-9-oxo-N-[4-[2-[1,2,3,4-tetrahydro-6-methoxy-2 - ethenolysis]ethyl]phenyl]-9,10-dihydro-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.5 g) with intermediate connection 76 (0,48 g) after crystallization from a mixture of pyridine with water gives the title compound (0.4 g). So pl. 260oC.

Analysis for C33H31N3O4< / BR>
found, %: C 74,29; H the 6.06; N 8,02

calculated, %: 74,28; 5,86; 7,87

Example 122. 5-fluoro-9,10-Dihydro-9-oxo-N-[3-[3-[1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis]propyl]phenyl]-4-greencarbon

The combination of 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (1 g) with intermediate connection 79 (1.3 g) after crystallization from isopropanol gives the title compound (0.25 g). So PL 128oC.

Analysis for C34H32FN3O4(1,5 H2O)

found, %: C 68,84; H 5,67; F 3,01; N 6,88

designed, %: 68,90; 5,95; 3,20; 7,09

Example 123. 9,10-Dihydro-5-methoxy-9-oxo-N-[3-[3-[1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis]propyl]phenyl]-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (1.2 g) with intermediate connection 79 (1.2 g) after crystallization from isopropanol gives the title compounds is prohibited, %: C 70,55; H 6,25; N 7,06

calculated, %: 70,56; 6,26; 7,05

Example 124. N-[4-[3-[[[3,4-Acid]methyl]methylamino]-2-oxopropoxy]-phenyl]- 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (1 g) with intermediate connection 81 (1.3 g) after crystallization from isopropanol gives the title compound (0.7 g), pl. 175oC

Analysis for C34H35N3O7< / BR>
found, %: C 68,38; H of 5.82; N 6,86

calculated, %: 68,33; 5,90; 7,03

Example 125. 9,10-Dihydro-5-methoxy-9-oxo-N-[4-[3-[[[3,4,5-trimethoxyphenyl] methyl]-methylamino]propoxy]phenyl]-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (1.5 g) with intermediate connection 83 (1.3 g) after crystallization from isopropanol gives the title compound (1.3 g). So pl. 186oC.

analysis for C35H37N3O7< / BR>
found, %: C 68,82; H between 6.08; N 6,83

calculated, %: 68,72; 6,10; 6,87

Example 126. Fumarate 5-fluoro-9,10-dihydro-N-[2-methoxy-5-[2-[1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis] ethyl] phenyl]-9-oxo-4-greencarbon

The combination of 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (1 g) with intermediate connection 86 (1.2 g) gives the title compound (0.5 g)

So the
calculated, %: 63,76; 5,35; by 5.87

Example 127. 9,10-Dihydro-9-oxo-N-[4-[3-[1,2,3,4-tetrahydro-2-ethenolysis] propoxy]phenyl]-4-greencarbon

The combination of 9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate connection 88 (0.9 g) after crystallization from ethanol gives the title compound (0.3 g). So pl. 182oC.

Analysis for C32H29N3O3(0.5 H2O)

found, %: C 74,88; H of 5.81; N 8,16

calculated, %: 74,98; 5,90; 8,20

Example 128 9,10-Dihydro-5-methoxy-9-oxo-N-[4-[2-[1,2,3,4-tetrahydro-7 - methoxy-2-ethenolysis]ethyl]phenyl]-4-greencarbon

The combination of 9,10-dihydro-5-Metacity-9-oxo-4-greencarbon acid (0.7 g) with an intermediate compound 90 (0.7 g) after crystallization from isopropanol gives the title compound (0.65 g). So pl. 213-216oC

Analysis for C33H31N3O4(0.5 H2O)

found, %: C 73,27; H 5,94; N 7,82

calculated,%: 73,04; 5,94; 7,74

Example 129. 9,10-Dihydro-5-methoxy-9-oxo-N-[3-[2-[1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis]ethyl]phenyl]-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.5 g) with an intermediate compound 92 (0,57 g) after crystallization from isopropanol gives the title compound (0.15 g). So pl. 152o
Example 130. 5-fluoro-9,10-dihydro-9-oxo-N-[3-[2-[1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis]ethyl]phenyl]-4-greencarbon

The combination of 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (0.5 g) with an intermediate compound 92 (0,57 g) after crystallization from isopropanol gives the title compound (0.35 g), pl. 178oC.

Analysis for C33H30FN3O4(0.5 H2O)

found, %: C 70,80; H are 5.36; F 3,34; N 7,34

designed, %: 70,70; 5,57; 3,38; 7,49

Example 131. Fumarate of N-[5-2-[[[3,4-acid]methyl]methylamino]ethyl] -2 - methoxyphenyl]-5-fluoro-9,10-dihydro-9-oxo-4-greencarbon

The combination of 5-fluoro-9,10-dihydro-9-oxo-4-greencarbon acid (0.8 g) with intermediate compound 95 (1 g) gives the title compound (0.5 g). So pl. 140-142oC.

Analysis for C37H36FN3O9(1,5 H2O)

found, %: C of 62.4; H 5,1; N 5,8

calculated, %: 62,35; 5,5; 5,9

Example 132. 9,10-Dihydro-5-methoxy-9-oxo-N-[4-[2-[1,2,3,4-tetrahydro-5,6 - dimethoxy-2-ethenolysis]ethyl]phenyl]-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0,19 g) with an intermediate compound 97 (0,22 g) after crystallization from a mixture of pyridine with water gives the title compound (0.32 g). So pl. 233) 6,5-8,5 (12H, m, aromatic).

Analysis for C34H33N3O5< / BR>
found, %: C 72,38; H 5,80; N 7,41

calculated, %: 72,45; 5,90; 7,45

Example 133. 9,10-Dihydro-5-methoxy-9-oxo-N-[4-[2-[1,2,3,4-tetrahydro-6,7,8 - trimetoksi-2-ethenolysis]ethyl]phenyl]-4-greencarbon

The combination of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (0.26 g) with intermediate connection 99 (0.3 g) after crystallization from isopropanol gives the title compound (0.3 g). So pl. 222-226oC.

NMR spectrum: = 2,4-2,9 (8H, m, 2xN-(CH2)2-aryl): to 3.45 (2H, s, N-CH2-aryl), 3,7 (9H, sh.S., OCH3), a 3.9 (3H, s, OCH3), 6,2-8,4 (11H, m, aromatic).

Analysis for C35H35N3O6(0.5 H2O)

found, %: C 69,46; H 6,14; N 6,84

calculated, %: 69,75; 6,02; 6,97

Example 134. 5-Amino-N-[4-[4-[[[3,4-acid]methyl]methylamino]butyl] phenyl]-9,10-dihydro-9-oxo-4-greencarbon

A suspension of compound of example 75 (0.15 g) in ethanol (40 ml) hydronaut at room temperature in the presence of 10% palladium-on-coal (70 mg). After absorption of hydrogen, the mixture is diluted with methylene chloride (50 ml). The catalyst is filtered off and the solution concentrated in vacuo, obtaining the title compound (85 mg) in the form of solids H 6,69; N 9,06

calculated, %: 71,31; 6.42 per; 9,92

Example 135. 9,10-Dihydro-5-methoxy-9-oxo-N-[4-[2-[1,2,3,4-tetrahydro-6,7 - dimethoxy-2-ethenolysis]ethyl]phenyl]-4-greencarbon

To stir a mixture of 9,10-dihydro-5-methoxy-9-oxo-4-greencarbon acid (28,9 g) and hydrate 1-oxybisethanol (15,66 g) in DMF (300 ml) maintained at 0oC, was added dropwise dodecacarbonyl (22,76 g) in DMF (50 ml), then the intermediate compound 101 (33,5 g) in DMF (150 ml). After 4 hours at 0oC and two days at room temperature, the mixture is filtered, the filtrate was concentrated in vacuo and the residue is treated with 1N solution of sodium hydroxide and extracted with dichloromethane. The organic layer is then washed with water, dried and evaporated to obtain a solid residue. It is dissolved in 500 ml of boiling pyridine and the solution is lighten by filtration. A clear solution is diluted with 10 ml of water and cooled distilled product. Get the title compound (52,82 g). So pl. 215-225oC.

NMR spectrum: = 2,60-2,95 (m, 8H, CH2); to 3.58 (s, 2H, N-CH2-phenyl); and 3.72 (s, 6H, OCH3), of 4.05 (s, 3H, OCH3acridone), 6,78 (2 s, 2H, Ar isoquinoline), 7,20-7,88 (m, 8H, Ar), 8,48 (t, 2H, H1and H8acridone), or 10.60 (s, 1H, CONH), 12,32 (s, 1H, NH of acridone).


Example 136. Maleate 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-[1,2,3,4-tetrahydro-6,7-dimethoxy-2-ethenolysis]ethyl]phenyl]-4-greencarbon

The compound of example 135 (100 mg) is dissolved in 50 ml of a mixture of dichloromethane and methanol (1: 1) and added maleic acid (22 mg). The mixture is boiled to obtain a clear solution and the solution is evaporated in vacuum. The residue is treated with hot methanol and cooled to obtain the title compound as yellow needles (90 mg). So pl. 171-187oC.

In the same way get the following salts of the compound of example 135: fumarate - so pl. 170-203oC; succinate - so pl. 135-143oC, L (+)-tartrate, pl. 165-180oC.

Example 137. Hydrochloride 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-[1,2,3,4-tetrahydro-6,7-dimethyl-2 - ethenolysis]ethyl]phenyl]-4-greencarbon

Compound 135 (100 g) is dissolved in a mixture of methanol with dichloromethane (4:1) and add an excess of methanolic solution of hydrogen chloride. MES extract after adding diethyl ether and filtering off. Get the title compound (approximately 100 mg). So pl. 225oC (softened with the gradual disappearance of the solvent).

Example 138. Cytotoxicity in vitro inhibitors of MDR (reaction of elimination of macrophages) cells AIC is SUP>R
C5was received by Dr. V. Ling (Hospital Princess Margaret. Toronto, Canada) and preserved in the form of a dependent of the adhesion forces of monolayer cultures VA-minimal essential medium supplemented with thymidine, adenosine, 10% fetal bovine serum, 2 mmol L - glutamine (Flow) 100 IU/ml penicillin and 100 mg/ml streptomycin in a humid atmosphere with 95% air and 5% carbon dioxide. Cells are transferred into a flask for crops twice a week after dissociation using add.

Produce a crop CHRC5cells at a density of 104cells per well in plate microtitration. After 24 hours, the medium removed and replaced with 0.1 ml of fresh medium containing serial twofold dilution of MDR inhibitors. Each inhibitor feel two times when the twofold dilution from 1250 to 20 nmol. The last well of each column is used to confirm the absence of toxicity at the highest dose of the inhibitor in the absence of doxorubicin. Other control conditions have on each plate microtitration: some cells (1 hole), doxorubicin (7 holes), amiodarone (number of double dilutions ranging from 5 mm to each of 2 wells). Add 0.1 ml at a concentration of 10 mg/ml solution Gardemeister-2-yl)-2,5 - diphenyltetrazolium (MTT: Sigma) to temnosine formisano product. In particular, each well add 20 ml of MTT solution with a concentration of 5 mg/ml prepared in bateriafina phosphate salt solution. After incubation for 4 hours at 37oC medium is sucked off and replaced with 0.1 ml of dimethylsulfoxide. After vigorous shaking, the number of the formed formazan (formisano product) investigate on its optical density at 550 nm. The absorbance directly corresponds to the number of surviving cells in the wells.

Calculations of cytotoxicity carried out at an average of two wells for each condition. The concentration of each M. R. - inhibitor giving 50% reduction in optical density compared to cells treated with a single doxorubicin, determine to a value EC50.

Results.

In the above test the compounds of the above examples have EC50in the field 0,018 is 0.72 mmol. For example, the compound of example 1 has EC50= 0.02 mmol, which is at least 100 times more effective than MDR inhibitors shown in the prototype and including amiodarone (EC50= 3 mmol) and verapamil (3 mmol). Introduction mouse connection example 1 oral no significant toxic effects at single doses up downy ingredient", as used below, means a compound of the invention and may, for example, be a compound of example 1.

Example A - Tablet for taking orally - tablet (mg)

active ingredient - 50,0

microcrystalline cellulose - 110,0

lactose is 67.5

starchy glycolate, sodium - 20,0

magnesium stearate - 2,5 - overall: 250,0

Medicine proceviat through a 250 mm sieve and then 5 powders are thoroughly mixed in the mixer and squeeze on 3/8 inch (0.95 cm) standard concave punch in a machine for the manufacture of tablets.

Example B - Capsule for oral administration - the capsule (mg)

active ingredient - 50,0

microcrystalline cellulose - 66,5

lactose P/ - 66,5

starchy glycolate, sodium - 15,0

magnesium stearate - a 2.0 overall: 200,0

Medicine proceviat through a 250 mm sieve and then five powders are thoroughly mixed in the mixer, and this mixture fill the shell gelatin capsules No. 2 on the machine for filling capsules.

Example In - Injectable composition for intravenous administration (10 mg in 10 ml) - % (by weight)

the active ingredient is 0.1

chemotherapeutic anticancer agent as required water for injection - 100,0

rasb the same agent) is dissolved by mixing in water for injection, to which is added slowly to the acid at pH 3.0. The solution is rinsed with nitrogen and filtered through sterile sterile filter with a pore size of 0.22 micron. Under aseptic conditions, this sterile solution contribute in sterile vials and the vials sealed.

Example D - Syrup for oral administration - % weight/volume

active ingredient - 2,0

chemotherapeutic anti-cancer agent if necessary dilute hydrochloric acid to pH 3

solution of sorbitol - 60 bytes

fragrances on request

distilled water up to 100

Active ingredient (respectively, chemotherapeutic anticancer agent) is dissolved in a certain amount of water with stirring, where gradually add hydrochloric acid to pH 3.0. Add a solution of sorbitol, flavouring substances and remaining water and pH was adjusted to 3.0. Syrup lighten by filtration through a suitable filter.

1. Derivatives of acridine General formula I

< / BR>
where R0is hydrogen, halogen, C1- C4-alkyl, C1- C4-alkoxy, C1- C4-alkylthio, amino-, nitro-group;

p = 1 or when R0= C1- C4-alkoxy, p = 2 or 3;

R1- water is od WITH1- C4-alkyl;

A is oxygen, sulfur, communication, group -(CH2)lNR9where l = 0 or 1 and R9is hydrogen or methyl;

B - C1- C4-alkylene, optionally substituted hydroxyl group, except that a hydroxyl group and A part cannot be linked to the same carbon atom, when A denotes an oxygen atom or sulfur, or a group -(CH2)lNR9or when A denotes a bond, then B means a2- C4-alkenylamine chain;

R3is hydrogen, C1- C4-alkyl;

m = 1 or 2;

R4is hydrogen or halogen, WITH1- C4-alkyl, C1- C4-alkoxy, C1- C4-alkylthio;

R5is hydrogen, C1- C4-alkoxy;

R6is hydrogen, C1- C4-alkyl or C1- C4-alkoxy;

R7is hydrogen or R3and R7together form a group -(CH2)n- where n = 1 or 2;

R8is hydrogen, C1- C4-alkoxy, and a group of the formula and

< / BR>
linked with the benzene ring in the 3 or 4 position relative to carboxamides Deputy, provided that when the group attached to the benzene ring at position 3, then R6must be the in which R0means a hydrogen atom or fluorine, or WITH1- C4-CNS, WITH1- C4-alkyl or C1- C4-allylthiourea and R1denotes a hydrogen atom.

3. Connection under item 1 or 2, in which R0the group is at the 5 Greenaway molecules.

4. Connection PP.1 to 3, in which R2means a hydrogen atom.

5. Connection PP.1 to 4, in which R4and R5every means WITH1- C4-CNS group, and R8denotes a hydrogen atom.

6. Connection PP. 1 to 5, in which m = 1 and R3and R7together form a group

7. Derivatives of acridine of formula Ia

< / BR>
where R0is hydrogen, halogen, C1- C4-alkyl, C1- C4-alkoxy;

R1is hydrogen, C1- C4-alkyl, C1- C4-alkoxy;

R2is hydrogen;

A is oxygen, sulfur, communication;

B - unsubstituted WITH1- C4-Allenova chain;

R4and R5same WITH1- C4-alkoxy,

or its physiologically compatible salt.

8. Connection on p. 7, in which R0denotes a hydrogen atom or fluorine, or WITH1- C4-CNS or1oznachaet1- C4-CNS group.

9. Connection on p. 8, in which R0the group is at the 5 Greenaway molecules.

10. Connection on p. 1, which represents a 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-[1,2,3,4-tetrahydro-6,7-dimethoxy-2-ethenolysis] ethyl] phenyl]-4-greencarbon and its physiologically compatible salts.

11. Connection on p. 1, selected from the group including:

9,10-dihydro-5-methoxy-9-oxo-N-[4-[[3-[1,2,3,4-tetrahydro-6,7-dimethoxy-2-ethenolysis]propyl]thio]phenyl]-4-greencarbon;

5-fluoro-9,10-dihydro-9-oxo-N-[4-[[3-[1,2,3,4-tetrahydro-6,7-dimethoxy-2-ethenolysis]propyl]thio]phenyl]-4-greencarbon;

9,10-dihydro-5-methoxy-9-oxo-N-[4-[3-[1,2,3,4-tetrahydro-6,7-dimethoxy-2-ethenolysis]propoxy]phenyl]-4-greencarbon;

9,10-dihydro-5-methyl-9-oxo-N-[4-[[3-[1,2,3,4-tetrahydro-6,7-dimethoxy-2-ethenolysis]propyl]thio]phenyl]-4-greencarbon;

9,10-dihydro-5-methoxy-N-[2-methoxy-4-[3-[1,2,3,4-tetrahydro-6,7-dimethoxy-2-ethenolysis]propyl]phenyl]-9-oxo-4-greencarbon;

9,10-dihydro-N-[2-methoxy-4-[3-[1,2,3,4-tetrahydro-6,7-dimethoxy-2-ethenolysis]propyl]phenyl]-5-methyl-9-oxo-4-greencarbon

and its physiologically compatible salts.

12. Soedineniya-9-oxo-4-greencarbon;

N-[4-[2-[[[3,4-acid] methyl] methylamino]ethyl]phenyl]-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[4-[[[3,4-acid] methyl] methylamino] butyl] phenyl]-5-fluoro-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[2-[[[3,4-acid] methyl] methylamino]ethyl]phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-greencarbon;

N-[4-[3-[[[3,4-acid]methyl]methylamino]propyl]phenyl]-5-fluoro-9- , 10-dihydro-9-oxo-4-greencarbon;

N-[4-[2-[[[3,4-acid] methyl] methylamino]ethyl]phenyl]-5-fluoro-9- , 10-dihydro-9-oxo-4-greencarbon;

N-[4-[[3-[[[3,4-acid] methyl] methylamino]propyl]phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-greencarbon;

N-[4-[[3-[[[3,4-acid] methyl] methylamino] propyl] thio] phenyl]-9,10-di - hydro-9-oxo-4-greencarbon;

N-[4-[4-[[[3,4-acid] methyl] methylamino] butyl] phenyl]-9,10-di - hydro-5-methoxy-9-oxo-4-greencarbon;

N-[4-[3-[[2-[3,4-acid] ethyl] methylamino]propyl]phenyl]-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[2-[[2-[3,4-acid] ethyl] methylamino]ethoxy]phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-greencarbon;

N-[4-[3-[[[3,4-acid] methyl]methylamino]propoxy]phenyl]-9,10-di - hydro-9-oxo-4-greencarbon;

N-[4-[3-[[[3,4-acid]] ethyl]methylamino]ethyl]phenyl]-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[5-[[[3,4-acid]methyl]methylamino]pentyl]phenyl]-5-fluoro-9- , 10-dihydro-9-oxo-4-greencarbon;

N-[4-[3-[[[3,4-acid]methyl]methylamino]propyl]phenyl]-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[2-[[[3,4-acid]methyl]methylamino]ethylamino]phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-greencarbon;

N-[4-[[3-[[[3,4-acid] methyl] methylamino] propyl] thio] phenyl]-9,10-dihydro-5-fluoro-9-oxo-4-greencarbon;

N-[4-[2-[[[3,4-acid] methyl] methylamino]ethyl]phenyl]-9,10-dihydro-5-methylthio-9]oxo-4-greencarbon;

N-[4-[2-[[[3,4-acid] methyl] methylamino]ethyl]phenyl]-9,10-dihydro-5-methyl-9-oxo-4-greencarbon;

N-[4-[3-[[[3,4-acid] methyl]methylamino]propoxy]phenyl]-9,10-dihydro-5-methyl-9-oxo-4-greencarbon;

N-[4-[2-[[2-[3,4-acid] ethyl]methylamino]ethyl]phenyl]-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[4-[[2-[3,4-acid]ethyl]methylamino]butyl]phenyl]-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[2-[[2-[4-methoxyphenyl] ethyl] methylamino]ethyl]phenyl]-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[2-[[2-[3,4-acid] ethyl] methylamino]ethoxy]phenyl]-9,10-dihydro-2-(methylthio)-9-oxo-4-greencarbon;

N-[4-[3-[[2-[3,4-acid]ethyl]METI the hydroxy]phenyl]-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[2-[[[3,4-acid]methyl]methylamino]ethoxy]phenyl]-9,10-dihydro-9-oxo-4-greencarbon;

N-[4-[3-[[[3,4-acid] methyl] methylamino] propoxy]phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-greencarbon;

N-[4-[[2-[[[3,4-acid] ethyl] methylamino] ethyl]thio]phenyl]-9,10-dihydro-9-oxo-4-greencarbon,

and its physiologically compatible salts.

13. Method of destruction of cells of the cancer, improving sensitivity and reducing resistance to anticancer tools, including impact on tumor cytotoxic agent, characterized in that as a cytotoxic agent using an effective amount of a derivative of acridine of formula I on PP.1 - 12 or its pharmaceutically acceptable salt.

14. Pharmaceutical composition having antitumor action that increases the sensitivity of tumors and reduce its resistance to the antitumor agent, comprising the active principle and a pharmaceutically acceptable target additives, characterized in that the active agent it contains an effective amount of a derivative of acridine of formula I on PP.1 - 12 or its pharmaceutically acceptable salt.

15. Compozitiile under item 14 or 15, characterized in that it is made in a form suitable for oral, buccal (cheek), parenteral or rectal administration.

17. Composition according to any one of paragraphs.14 to 16, characterized in that it is made in the form of a single dose.

18. The method of obtaining the acridine derivatives of General formula I on p. 1, characterized in that the compound of formula II

< / BR>
where the values of R0, R1p given in paragraph 1,

subjected to interaction with the compound of the formula III

< / BR>
where the values of A, B, R3- R8listed in paragraph 1,

in the presence of the agent to the reaction mixture, followed, if necessary, obtaining physiologically compatible salts of the compounds I.

19. The method of obtaining the acridine derivatives of General formula I on p. 1, characterized in that the compound of formula IV

< / BR>
where the values of R0, R1, R2, R6, A, B, p are given in paragraph 1;

Q is a halogen atom,

subjected to interaction with the compound of the formula V:

< / BR>
or its salt,

where the values of R3- R5, R7, R8, m is shown in paragraph 1,

in the presence of an acid acceptor, followed, if necessary, obtaining physiologically compatible salts of the compounds I.

 

Same patents:

The invention relates to 9-amino-1,2,3,4-tetrahydropyridines and related compounds of the formula I

< / BR>
in which Y is C= O or CHOH; R1is hydrogen or lower alkyl; R2is hydrogen, lower alkyl or phenyl-lower alkyl; R3is hydrogen, OR4in which R4is hydrogen, COR5in which R5is lower alkyl, X is hydrogen, lower alkyl, halogen, lower alkoxy-, hydroxy-group or trifluoromethyl, their geometric or optical isomers, N-oxides, or their pharmaceutically acceptable salts and accessions acids (acid additive salts), which are useful in reducing dysfunction in memory and are thus indicative for the treatment of disease Allgamer

The invention relates to organic chemistry and relates to an improved method of producing esters of N-metrocable-9-acridone different structures that exhibit intense biological properties, for example, are low-molecular inducers of interferons
The invention relates to an improved method for producing N-metrocable-9-acridone and its salts, which are low-molecular inducers of interferons and have immunomodulatory effects

The invention relates to 9-amino-1,2,3,4-tetrahydropyridines and related compounds of the formula I

< / BR>
in which Y is C= O or CHOH; R1is hydrogen or lower alkyl; R2is hydrogen, lower alkyl or phenyl-lower alkyl; R3is hydrogen, OR4in which R4is hydrogen, COR5in which R5is lower alkyl, X is hydrogen, lower alkyl, halogen, lower alkoxy-, hydroxy-group or trifluoromethyl, their geometric or optical isomers, N-oxides, or their pharmaceutically acceptable salts and accessions acids (acid additive salts), which are useful in reducing dysfunction in memory and are thus indicative for the treatment of disease Allgamer

The invention relates to the field of medicine, to biologically active substances produced by chemical means, specifically derivatives acridone and monosaccharides, and is intended for use as anti-infective, anti-inflammatory and anti-cancer agents with a wide spectrum of biological action

The invention relates to derivatives of 3-genocidally esters of the formula I or their pharmaceutically acceptable acid additive salts, where X is phenyl, Y is the group - (CH2)A- CR1R2- (CH2)BS(O)Z-R3where A and B are independently 0, 1 or 2, Z is 0, 1 or 2, R1and R2independently a hydrogen atom, (C1-C4)-alkyl, R3- (C1-C4)-alkyl or phenyl

The invention relates to new pcoralcalciumonline derived nitrogen-containing heterocyclic compounds, in particular to compounds of the formula I mentioned in the description

The invention relates to medicine, namely to otolaryngology, and can be used for the treatment of patients with sensorineural hearing loss in acute and chronic periods

The invention relates to new derivatives of 1,8-benzonitriles, method of production thereof, to compositions based on them and to intermediate compounds for the synthesis of novel derivatives

The invention relates to new derivatives of hinoklidina, pharmaceutical compositions containing such compounds and to the use of such compounds for the treatment and prevention of inflammatory disorders and disorders of the Central nervous system, as well as some other disorders

The invention relates to medicine and veterinary medicine, specifically to immunomodulatory drugs on the basis of hydrophobic derivatives of interferon inductors used in antiviral therapy

FIELD: medicine, phthisiology.

SUBSTANCE: one should lymphotropically introduce the mixture of 5.0 ml 0.25%-novocaine solution and 2.0 ml 1%-dioxidine solution or the mixture of 5.0 ml 0.25%-novocaine solution and 0.5 g cefazoline subcutaneously into jugular cavity and deeply behind xiphoid process, successively 1 point once daily, 5-7 injections/course. After injection the site of injection should be treated either with heparin ointment or ultrasound (1-3 MHz, PPM 0.2 W/sq. cm, for 2 min, through Vaseline oil) followed by evaluating roentgenological dynamics of the process 10-14 d later.

EFFECT: higher efficiency of differential diagnostics.

3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes diazepane derivative of the general formula (I)

or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.

EFFECT: valuable medicinal properties of compound.

5 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

FIELD: organic chemistry, cardiology, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I)

wherein R1, R2, R3 and Ra-Rh have values given in the description. Proposed compounds are useful in prophylaxis and treatment of arrhythmia, in particular, atrial and ventricular arrhythmia, Also, the invention relates to methods for preparing compounds of the formula (I) and intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

41 cl, 1 tbl, 8 ex

Up!