Derived bisexualitytiny, the pharmaceutical composition

 

(57) Abstract:

Describes the new derived bisexualitytiny represented by the General formula /I/, or its pharmaceutically acceptable salt, which is suitable as increasing insulin sensitivity medicines and pharmaceutical composition. The values IN the1IN2L in the formula (I) specified in paragraph 1 of the claims. Also described pharmaceutical composition based on compounds of formula (I), showing hypoglycemic activity. 2 C. and 7 C.p. f-crystals, 1 table.

The invention relates to a new derivative of bisexuality and its pharmaceutically acceptable salts, are useful as pharmaceuticals, in particular as a hypoglycemic drugs (drugs that increase insulin sensitivity), and containing pharmaceutical compositions.

Sulfanilamide connection and biguanide compounds currently used clinically as a synthetic hypoglycemic drugs for the treatment of diabetes. Biguanide connection, however, is rarely used because they induce lactic acidosis and their glycemic effect and generate very little side effects, but care must be taken in their application, since they sometimes cause hypoglycemia.

In recent years, increasing insulin sensitivity medicines can be hypoglycemic effect by increasing insulin sensitivity in peripheral tissues, attract attention as successors of the above-mentioned synthetic hypoglycemic drugs.

Compounds with increasing insulin sensitivity effect, were synthesized as described for example in International patent publication N publication 92/03425 (1992).

In such circumstances, the authors of the present invention previously found that the derived Bicocca or thiazolidine have an excellent boost insulin susceptibility action, and filed a patent application for the invention [cf International patent publication N publication 93/03021 (1993)].

The authors of the present invention carried out intensive studies on the substances with increasing insulin sensitivity effect, and found that the derived bisexuality represented by the following General formula (I) has excellent polysoude the ü in accordance with the present invention proposed a derivative of bisexuality, represented by the General formula (I)

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the symbols in the formula have the following meanings:

the same or different from each other and each represents fenelonov group which may be substituted,

L - (1) an oxygen atom, (2) a group represented by the formula (3) a group represented by the formula-S(O)n-, (4) a group represented by the formula-CO-, (5) a group represented by the formula

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(6) alkylenes group or alkenylamine group, which may respectively be interrupted (to contain in the chain), an oxygen atom and/or sulfur atom and which may respectively be substituted, or (7) a group represented by the formula

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R1is a hydrogen atom or a lower alkyl group, n is 0,1 or 2, R2is a hydrogen atom or a lower alkyl group, L1and L2the same or different from each other and each represents: (1) an oxygen atom, (2) a group represented by the formula (R1has the above values), (3) a group represented by the formula-S(O)n- (n has the above values), (4) a group represented by the formula-CO-, (5) a group represented by the formula

(R2has the above values), or (6) alkylenes group, alkenylamine group or pyridinylamino be substituted, and

- cycloalkenyl group, Allenova group or peridiniella group, which may respectively be substituted, or a pharmaceutically acceptable salt.

The compound of the present invention is a new compound, which structure is completely different from any known compounds which may enhance insulin sensitivity effect, because it has an unusual chemical structure as a bis-form, which (1,3,4-oxadiazolidine-3,5-Dion-2-yl) methyl group attached to both ends of the connecting group

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Further, the compound of the present invention is described in detail.

Unless otherwise noted, the term "lower" used in the definition of the General formula represents a normal or branched carbon chain having 1-6 carbon atoms.

Consequently, illustrative examples of the "lower alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-propyl and the like alkyl.

The term "Allenova group or alkenylamine group, which may respectively be interrupted by oxygen atom and/or sulfur atom and which may respectively be substituted," refers to all of unsubstituted alkilinity groups, unsubstituted alkenylamine groups, substituted alkilinity groups, substituted alkenylamine groups, unsubstituted alkilinity groups, interrupted (in the chain), an oxygen atom and/or sulfur atom, unsubstituted alkenylamine groups, interrupted (in the chain), an oxygen atom and/or sulfur atom, substituted alkilinity groups, interrupted (in the chain), an oxygen atom and/or sulfur atom, and substituted alkenylamine groups, interrupted (in the chain), an oxygen atom and/or sulfur atom, and the term "interrupted by an oxygen atom and/or sulfur atom" denotes not only the group in which the oxygen atom and/or sulfur atom is present between alkionovymi or alkenylamine chains, e.g.- L3-X1-L4-, -L3-X1-L4-L5and similar (in these formulas, X1and X2may be the same or may differ from each other and each represents an oxygen atom or a sulfur atom, and L3L4and L5may be the same or may differ from each other and each of them is sulfur directly connected to the core formula such as X1-L3-, -L3-X1-, -X1-L3-X2-L4-, -L3-X1-L4-X2-, -X1-L3-X2-L2-X3and similar groups (in these formulas, X1X2L3and L4have the above meanings and X3may be the same or different from the X1and X2value and denotes an oxygen atom or a sulfur atom).

These alkylene and alkenylamine groups are preferably groups with normal chain having from 1 (2 if alkenylamine groups) to 12 carbon atoms, or groups, branched-chain, substituted lower alkyl group. Illustrative examples of such alkilinity groups include methylene, ethylene, METROTILE, trimethylene, 1-mutilation, tetramethylene, 1-metallisation, 2 - metallisation, 3-metallisation, 1-ethylethylene, 2-ethylethylene, propylethylene, isopropylethylene, pentamethylene, 1-, 2-, 3 - or 4-methyltyramine, 1-, 2 - or 3 - ethyltryptamine, 1,1-, 1,2, 1,3-, 2,2-, 2,3- or 3.3-dimethyltrimethylene, hexamethylene, 1-, 2-, 3-, 4- or 5-methylpentylamino, 1-, 2-, 3 - or 4-ethylacrolein, 1,1-, 1,2, 1,3-, 1,4-, 2,2-, 2,3-, 2,4-, 3,3-, 4,4-dimethyltrimethylene, heptameron, 1-, 2-, 3-, 4-, 5- or 6-methylhexanamine, octamethylene, 1-, 2-, 3-, 4-, 5-, 6- or 7-methylheptane, undeletion, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-metallicameron, dodecamethyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10- or 11-methylundecanal and the like. Illustrative examples alkenylamine groups include vinile, propylen, 2-propanole, 1-methylvinyl, 2-methylvinyl, butylen, 2-butylen, 3-butylen, 1,3-butadienyl, 1-methylpropenyl, 1-methyl-2-propanole, penttinen, 1-methylbutanol, 1-methyl-2-butylen, 1-methyl-3-butylen, 1,1-dimethyl-2-propanole, hexarelin, 2-hexarelin, 3-hexarelin, 4-hexarelin, 5-hexarelin, 1,3-hexadienyl, 1,3,5-hexatriene, 1-methyl-2-penttinen, 1-methyl-3-penttinen, 1,1-dimethyl-2-butylen, 1,1-dimethyl-3-butylen, heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1,1-dimethyl-2-penttinen, 1,1-dimethyl-3-penttinen, 1,1-dimethyl-4-penttinen, 2-hoktanyan, 4-hoktanyan, 7-hoktanyan, 1,2,5,7-octatetraene, 1,1-dimethyl-2-hexarelin, 1,1-dimethyl-3-hexarelin, 1,1-dimethyl-5-hexarelin, 2-nonpenile, 4-nonpenile, 5-nonpenile, 8-nonpenile, 1,1-dimethyl-2-heptenyl, 1,1-dimethyl-3-heptenyl, 1,1-dimethyl-4-heptenyl, 1,1-dimethyl-6-heptenyl, 2-decoiler, 5-decoiler, 9-decoiler, 1,1-dimethyl-2-hoktanyan, 1,1-dimethyl-4-hoktanyan, 1,1-dimethyl-7-hoktanyan, 2-undecenyl, 5-undecenyl, 6-undecenyl, 10-underenumeration, 11-dodecenyl, 1,1-dimethyl-2-decoiler, 1,1-dimethyl-5-decoiler, 1,1-dimethyl-9-decoiler and the like.

Preferred substituents that can be these alkilinity and alkenylamine groups are halogen atoms, illustrative examples of halogen atoms include fluorine, bromine, iodine and the like atoms. Such groups can contain one or two Deputy.

The term "cycloalkenyl group, Allenova group or peridiniella group, which may respectively be substituted" represented by the formula represents all unsubstituted cycloalkenyl group, unsubstituted allenbyi group, unsubstituted pyridinediamine group, substituted cycloalkenyl group, substituted allenbyi group and substituted pyridinediamine group, and preferred examples cycloalkenyl groups include groups having from 3 to 7 carbon atoms, for example cyclobutanediyl, cyclopentanediol, cyclohexanediol, cycloheptenyl and the like, and each of these cycloalkenyl groups may have 1 or 2 lower alkyl groups as their preferred substituents and these lower groups include, described in the above illustrative example, the valence group, for example phenylene, naphthalenediol, intracardial, finalrender and the like.

The substituents that may be on arenovich groups, peridiniella groups or Allenova group in particular is not limited, provided that they are used in this field of chemistry as Vice-aromatic carbon rings and pyridine rings, preferred examples include a halogen atom, a lower alkyl group, lower halogenating group, a lower alkoxygroup, a cyano, a nitro-group, and the like, as well as the amino group or karbamoilnuyu group which may be substituted by a lower alkyl group.

Illustrative examples of the "halogen atom" and the "lower alkyl group" are those referred to above, and the term "lower halogenation group" means a group that possible atom or hydrogen atoms of the above lower alkyl group substituted by one or more halogen atoms. As examples of the halogen atom used a fluorine atom, illustrative examples of the lower halogenoalkanes group include vermeil, deformity, trifluoromethyl, 2,2,2-triptorelin, pentafluoroethyl, 3,3,3-cryptochromes and the like.

Illusi-, Deut-butoxy-, tert-butoxy-, pentyloxy (amyloxy), isopentylamine-, tert-pentyloxy, neopentylene-, 2-methylbutoxy-, 1,2-DIMETHYLPROPANE-, 1 ethylpropoxy, hexyloxy and the like.

The term "amino group", which may be substituted by lower alkyl group " means an unsubstituted amino group and amino group, mono - and disubstituted by the above illustrative of the lower alkyl groups, and illustrative examples of the lower alkyl substituted amino group include mono (lower alkyl) amino groups, for example methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino-, second -, butylamino-, tert-butylaminoethyl (amyl) amino-, isopentylamine, neopentylene-, tert-pentylamine, hexylamine and the like group, and symmetric or asymmetric di(lower alkyl)amino, such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamine, ethylmethylamino, methylpropylamine and similar groups.

The term "carnemolla group which may be substituted by lower alkyl group" refers to unsubstituted karbamoilnuyu group and carbamoyl group, mono - or disubstituted by the above illustration is include mono (lower alkyl) carbamoyl group, for example, N-methylcarbamoyl, N-ethylcarbazole, N-propellerblades, N-isopropylcarbamate, N-second-butylcarbamoyl, N-isobutylamino, N-second-butylcarbamoyl, N-tert. -butylcarbamoyl, N-intercalator, N-exaltabitur and the like, and symmetric or asymmetric di(lower alkyl) carbamoyl group, for example N, N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylamino, N, N-dibutylamino, N-ethyl-N-methylcarbamoyl, N-methyl-N-propellerblades and the like.

Since the compound (I) of the present invention has an acidic proton on his oxazolidinone nuclei, it can form salts with bases. Pharmaceutically acceptable salts of compounds (I) are included in the present invention. Examples of such salts include salts with inorganic bases, such as alkali metals (e.g. sodium and potassium), alkaline earth metals (e.g. magnesium and calcium) and trivalent metals (e.g. aluminum), and with organic bases such as methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine, lysine, ornithine and the like base.

Since the connection of the connection. In addition, because some deputies have double bond or asymmetric carbon atoms on the basis of their presence, there are geometric isomers and optical isomers. All of these isomers in separated form and mixtures thereof are included in the present invention.

In addition, since the compound (I) of the present invention and its salts selected in some cases in the form of a hydrate or solvate, or polymorph substances, the present invention also includes these hydrates, various pharmaceutically acceptable solvate, for example with ethanol, and the like solvents, and polymorphic substances.

Specifically preferred examples of the compounds of the present invention are compounds in which the substituents that can be and are one or more substituents selected from the group consisting of halogen atom, lower alkyl group, lower halogenoalkanes group, lower alkoxygroup, ceanography, nitro, amino, lower alkyl substituted amino groups, carbamoyl group and lower alkyl substituted carbamoyl group, and the substituents that may be on alkalinous group or alkenylamine group L1and L2
1) alkalinous group or alkynylamino group, which may respectively be interrupted by oxygen atom and/or sulfur atom and which may respectively be substituted by one or more halogen atoms, or

2) a group represented by the formula where L1and L2respectively are alkalinous group or alkynylamino group, which may respectively be interrupted by oxygen atom and/or sulfur atom and which may respectively be substituted by one or more halogen atoms, and represents cycloalkenyl group, Allenova group or peritendinous group, which may respectively be substituted by one or more substituents selected from the group consisting of halogen atom, lower alkyl group, lower halogenoalkanes group, lower alkoxygroup, ceanography, nitro, amino, lower alkyl substituted amino groups, carbamoyl group and lower alkyl substituted carbamoyl group.

Below is Nabataean-2-yl)methyl]phenoxy]benzene, or its pharmaceutically acceptable salt.

(2) 1,4-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy]-2-butene or its pharmaceutically acceptable salt (specifically its (Z)-form).

(3) 1,9-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy]nonan or its pharmaceutically acceptable salt.

The compound of the present invention can be obtained by using different synthesis methods based on the characteristics of its underlying structure or his deputies. The following are typical examples of the method of obtaining.

The first method of obtaining

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(in the above formulas and L have the abovementioned meanings and Y1and Y2may be the same or different from each other and each represents a halogen atom, alkoxygroup, aralkylated or alloctype).

The compound (I) of the present invention is produced by reaction of bis-(N-carbarnoyl-N-hydroxyquinolyl) derivative represented by the General formula (II) with a carbonyl compound represented by the General formula (III).

In this case, examples of the halogen atom represented by Y1and Y2have the above values, and as alkoxygroup you can usually use the lowest alkoxygroup (for example, labels the gruppy not specifically limited, provided that they are (aromatic carbon core) oxypropane or aromatic carbon core) alkoxygroup. Usually apply phenoxy-, benzyloxy -, and a similar group.

Favorably perform the reaction of compound (II) with 2 mol or more. equivalents of the compounds (III), predpochtitelno in the presence of a base, for example sodium hydroxide, potassium hydroxide and the like of the base, at a temperature of from 0oC to 150oC in an inert organic solvent, for example tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, dimethoxyethane (monoglyme), bis-(2-methoxyethanol) ether (diglyme), methanol, ethanol, cellosolve (trade name 2-ethoxyethanol), methylcellosolve (trade name 2-methoxyethanol), dimethyl sulfoxide, sulfolane or similar solvent, or a mixture thereof.

In this regard, as shown in the following reaction scheme, the source compound (II) can be easily obtained

1) recovery of the corresponding bis-(formyl) of the compound (IV) to obtain bis-(hydroxymethyl) compounds, halogenoalkanes product to obtain bis-(halogenmethyl) compounds by reaction halogenoalkane (protected hydroxy)urea dust or

2) by reductive amination of the corresponding formulaicity (IV) hydroxylamine using a reducing agent to obtain bis-(hydroxyquinolyl) of the compound (VII) and reaction of the thus obtained compound with an alkali metal cyanate in the presence of water.

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(In the above formulas and L have the above values, Y3represents a halogen atom, R3represents an easily removable protective group for the hydroxy-group and M represents an alkali metal).

In this case, the halogen atom and alkali metal have the above values and examples of protective groups for the hydroxy-group include those groups which can be easily removed, for example kalkilya group (for example, benzyl and p-methoxybenzyl), lower alkyl groups (for example tert-butyl) and acyl groups (for example acetyl, TRIFLUOROACETYL and benzyloxycarbonyl).

The response of each stage can be done using commonly used technique. For example the reaction to obtain bis-(halogenmethyl) of the compound (V) of bis-(formyl) compound (IV) is preferably carried out in an inert organic solvent, for example alcohols (e.g. methanol), ethers (naprimer sodium or a similar reducing agent, which is usually used to obtain-CH2OH-CHO, and restored reaction product with a halogenation agent, such as halogenation. The reaction for obtaining bis-[N-(protected hydroxy)-N-carbamoylmethyl] the compound of the compound (V) can be carried out by reaction of the compound (V) with (protected hydroxy) - urea in an inert organic solvent, for example dimethylformamide or similar solvent that is commonly used in reactions of N-alkylation, preferably in the presence of a base such as sodium hydride, potassium carbonate or the like of the base, which is usually used in the reaction of N-alkylation. The removal of the protective group, although it varies depending on the type of the protective group can be carried out by treating compound triperoxonane acid or a similar acid, which is usually used to remove hydroxyamine groups, or in the event of such protective groups as benzyl group, recovery, for example, by catalytic regeneration in the presence of a catalyst, such as Pd-C or similar catalyst.

The reaction to obtain bis-(hydroxymethyl) compound (VII) from compound (IV) can be carried out by reaction of the compound (IV) with hydroxylamine illmer, complex, borane-pyridine and sodium borohydride), which is usually used for reductive amination, in an inert solvent, for example in an organic solvent such as alcohols (e.g. methanol and ethanol) or aromatic hydrocarbons (e.g. benzene, toluene and xylene), or in water or mix it with a solvent, if necessary in the presence of a catalyst, for example sodium acetate, p-toluenesulfonic acid or the like catalyst and using the device for azeotropic dehydration or dehydrating agent, if necessary. The Schiff base can be used in the recovery stage without highlighting.

The reaction for obtaining the compound (II) from compound (VII) may be carried out by reaction of the compound (VII) with an alkali metal cyanate in an inert organic solvent such as alcohols (e.g. methanol and ethanol), a simple ether (e.g. tetrahydrofuran) or a mixture, if necessary, in the presence of an acid catalyst, for example hydrochloric acid or similar catalyst.

Depending on the type, etc. of a group of the formula bis(formyl) compound (IV) can be obtained in various ways, for example, by reaction of a simple ester or ti is warping, or by restoring the corresponding bis-(nitrilo) of the compound (VIII) with a reducing agent, such as diisobutylaluminium or similar connection. When the starting compound used bis(tolyl), the compound (IX), bis-(halogenmethyl) compound (V) can also be obtained by reaction of the starting compound with a halogenation agent.

The second way of obtaining

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(In the above formulas and L have the above values, Y4represents a halogen atom or alkoxygroup and Y5and Y6may be the same or different from each other and each represents a halogen atom, alkoxygroup, aralkylated or alloctype).

The compound (I) of the present invention can also be obtained using the corresponding bis-(hydroxyquinolyl) of the compound (VII) as a starting compound and reaction with isocyanates (X) represented by the General formula (X) or N-acylamide acid (XI).

Illustrative examples of the halogen atom, alkoxygroup, aralkylated and alloctype above.

Although the reaction varies depending on the type of the source connection, a positive wire is, created when cooled to room temperature, in an inert solvent, for example in an organic solvent, such as tetrahydrofuran, dioxane, ethers (e.g. diethyl ether, dimethylformamide, dimethyl sulfoxide or the like solvent or solvent mixture, if necessary, in the presence of a base, for example sodium hydroxide, potassium hydroxide, trimethylamine, triethylamine or similar grounds.

The third way to obtain

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(In the above formulas , L and Y5have the above values).

The compound (I) of the present invention can also be obtained by cyclization of the corresponding bis-(N-hydroxy-N - acylaminorhodanines) of the compound (XII) by treatment with base.

The base used in the second method of obtaining, also used in this reaction, the compound (XII) is an intermediate product of the third mode of production, because it is produced in the second production method of the reaction of the compound (VII) with compound (X) in the absence of a base.

As a consequence, the reaction with the processing base in the second method carried out in the same manner as described in the third method of obtaining.

Even the>represents-SO - or-SO2- can also be obtained by oxidation of the corresponding compounds having the-S - or-SO-.

The oxidation can be performed using commonly used techniques, applying a positive oxidant such as organic percolate (for example, permorming acid, peracetic acid, perventing acid, m-chloroperbenzoic acid, porftolio acid or hydrogen peroxide.

Another way to get

Because the connection of the present invention has a simple ester (thioester), amide group, aminogroup and similar groups, it can be obtained by conventional methods, for example the above methods produce a single ether, simple tiefer, amidation, N-alkylation, reductive amination, and similar techniques.

The compound of the present invention, thus obtained, is isolated and purified as a free compound or its salt, hydrate or different types of MES.

Pharmaceutically acceptable salts of compound (I) of the present invention can be obtained in the usual reaction of salt.

The selection and cleaning is performed using commonly used histography and similar methods.

The tautomers and geometric isomers can be divided on the basis of the selection of the appropriate starting material or use of the differences in physico-chemical properties of the isomers.

Optical isomers can also be obtained in the form of pure stereochemical isomers by selecting the appropriate starting material or the separation of racemic compounds (for example, a method in which the compound is transformed into diastereomer salt with conventional optically active base and then spend the decomposition of salts on the optical antipodes).

Industrial applicability

Since the compound (I) of the present invention and salts thereof and similar derivatives have excellent hypoglycemic action, based on its increase insulin susceptibility of action, low toxicity, and almost do not cause side effects, they are suitable as pharmaceuticals for the prevention and treatment of diabetes, especially ainsliezubaida diabetes (type II), and various types of diabetic complications and as a drug for use in combination with insulin.

Excellent hypoglycemic effect of the compounds of the present invention, based on its Hypoglycemic effect

Male mice QC age 4 - 5 weeks were purchased from CLEA Japan Inc. These animals are individually cultivated with the use of high-energy feeds (CMF produced by Oriental Yeast). Animals, body weight which was more than 40 g were used in the test.

Measurement of blood glucose was performed by taking 10 μl blood samples from the tail vein, removal of protein from samples processed its 100 μl of 0.33 N perchloro acid, and after centrifugation glucose measurements obtained in the supernatant by the method using glucoseoxidase. Six animals with blood sugar levels more than 200 mg/DL were used as one group in the test.

Each drug suspended in 0.5% methylcellulose and oral was administered daily for 4 days. Blood samples were collected from the tail vein before injection and on the fifth day of injection drugs. The sugar level in the blood was determined by the above method.

Hypoglycemic activity was expressed as the degree of reduction in blood sugar levels compared to the level prior to the introduction and statistically evaluated, considering that a significant threshold p = 0.05.

* = p below 0.05

** = p below 0.01

*** = p below 0,001

As a result, the connection is Alo the degree of reduction of the blood sugar level 53%***at the dose of 30 mg/day. In addition, the low toxicity of the compounds of the present invention confirmed test for toxicity.

Pharmaceutical composition that contains one or more compounds represented by the General formula (I), and pharmaceutically acceptable salts as the active component are in the form of various dosage forms such as tablets, powders, fine granules, granules, capsules, pills, solutions, injectable solutions, suppositories and the like forms using commonly used pharmaceutical carriers, fillers and other additives. It is administered orally or parenterally.

Clinical dose of the compound of the present invention applied to humans, sometimes chosen by taking into consideration symptoms, body weight, age, gender, and the like of each patient, it usually ranges from 1 to 2000 mg per day for adult humans by oral administration and this daily dose is selected above, you can apply once a day or divided into multiple doses for one day. As the dose varies depending on various conditions, in some cases, the dose is less than the above limit, can have full force and effect.

Examples of liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, which contain a generally used inert diluent such as purified water, ethanol and podobnosti agent, auxiliary agents (for example, moisturizer), suspendisse agent, sweetening agent, corrigent, flavouring agent, antiseptic agent and the like.

Examples of the injections for parenteral administration include aseptic aqueous and non-aqueous solutions, suspensions and emulsions. The diluents, aqueous solutions and suspensions include, for example, distilled water for injection use, and physiological saline. Examples of diluents for use in non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil), alcohols (e.g. ethanol) and Polysorbate 80 (trade name). Such compositions can also contain additional agents, such as tonic, antiseptic agent, a moisturizing agent, emulsifying agent, dispersing agent, a stabilizer (e.g., lactose), solubilizers or facilitate solubilization agent and the like. These agents are sterilized, for example by filtration through removing bacteria filter, the addition of a bactericide or irradiation. Alternative you can get a sterile solid composition and dissolve it in sterilized is subramania

To describe the present invention further detail by the following examples.

Since the new compounds included in the source materials, examples of their receipt below as reference examples.

Reference example 1

1,3-Bis-(4-formylphenoxy)benzene (6,36 g) was dissolved in a mixed solvent of 30 ml of methanol and 60 ml of tetrahydrofuran, to the solution under cooling with ice and then added 0.75 g of sodium borohydride. After stirring the solution for 30 minutes under ice cooling, it was mixed with 80 ml of 1 N hydrochloric acid and was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated. Thus obtained residue was dissolved in a 4 N solution of hydrogen chloride in 1,4-dioxane and the solution was stirred 2 hours at room temperature. The solvent is evaporated under reduced pressure and the residue was chromatographically on a column of silica gel (used a mixture of hexane and ethyl acetate, 9 : 1) to give 6.0 g of 1,3-bis-[(4-chloromethyl)phenoxy]benzene.

Melting point: 37 - 39oC.

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

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Reference example 2

2,7-Bis-(4-formalin in the solution when cooled then added borohydride sodium (0,576 g 15.2 mmole). After stirring 1 hour at room temperature the solution was mixed with 1 N hydrochloric acid (60 ml) and was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then the solvent evaporated.

Thus obtained residue (1.7 g) was added a 4 N solution of hydrogen chloride in 1,4-dioxane (20 ml) and the mixture was stirred 3 hours at room temperature. After the reaction, the solvent evaporated and the resulting powder was washed with water and diethyl ether and then dried, obtaining 2,7-bis-(4-chloromethylene)naphthalene (1,41 g 57%)

Melting point: 95 - 97oC.

The data of mass spectrometry (m/z) : 409 (M+)

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

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In the same manner as described in referential examples 1 and 2, were obtained the following compounds.

Bis-[(4-chloromethyl)phenyl] ether;

Bis-[(4-chloromethyl)phenyl]methane;

1,4-Bis-[(4-chloromethyl)phenoxy]benzene;

1,5-Bis-[(4-chloromethyl)phenoxy]pentane;

TRANS-1,4-Bis-[[(4-chloromethyl)phenoxy]methyl]cyclohexane;

CIS-1,3-Bis-[(4-chloromethyl)phenoxy]cyclohexane;

1,2-Bis-[(4-chloromethyl)phenoxy]benzene;

Reference example 3

Dimethylformamide (150 ml) was added at 21.3 begins 1.5 hours. The reaction mixture was cooled to room temperature and poured into water, the thus obtained precipitate was washed with water and then dried under reduced pressure, getting to 26.9 g of 1,9-bis-(4-formylphenoxy)nonane.

The data of mass spectrometry (m/z) : 368 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,20 - 1,30 (10H, m) of 1.65 and 1.80 (4H, m), 4,07 (4H, t), 7,11 (4H, d), 7,86 (4H, d), 9,86 (2H, s).

In the same manner as described in reference example 3, were obtained the following compounds.

Reference example 4

(Z)-1,4-Bis-(4-formylphenoxy)-2-butene

The data of mass spectrometry (m/z): 296 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 4,78 (4H, d), 5,97 (2H, t), 7,02 (4H, d), to 7.84 (4H, d), 9,90 (2H, s).

Reference example 5

1,6-Bis-(4-formylphenoxy)hexane

The data of mass spectrometry (m/z): 326 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 1,75 - of 1.55 (4H, m), 1,75 - of 1.85 (4H, m), 4,10 (4H, t), for 7.12 (4H, d), 7,83 (4H, d), 9,89 (2H, s)

Reference example 6

1,4-Bis-(4-formylphenoxy)Bhutan

The data of mass spectrometry (m/z): 299 (M+).

Spectrum of nuclear magnetic resonance (CDCl3EXT is-1,4-Bis-(4-formylphenoxy)-2-butene

The data of mass spectrometry (m/z): 297([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: to 4.68 (4H, DD), 6,11 (2H, m), 7,03 (4H, d), 7,83 (4H, d), 9,89 (2H, s),

Reference example 8

1,7-Bis-(4-formylphenoxy)heptane

The data of mass spectrometry (m/z): 340(M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 1,10-2,10 (10H, m), of 4.05 (4H, t), 6,98 (4H, d), 7,82 (4H, d), 9,88 (2H, s).

Reference example 9

1,3-Bis-[(4-formylphenoxy)methyl]benzene

The data of mass spectrometry (m/z): 346 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: to 5.17 (4H, s), 7,07 (4H, d), 7,30 - of 7.70 (4H, m), 7,74 (4H, d), 9,89 (2H, s)

Reference example 10

1,5-Bis-(4-formylphenoxy)-3,3-dimethylpentan

The data of mass spectrometry (m/z): 340 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: of 1.09 (6H, s) to 1.87 (4H, t), of 4.16 (4H, t), 6,97 (4H, t), 7,87 (4H, t), 9,88 (2H, s)

Reference example 11

CIS-1,3-Bis-(4-formylphenoxy)cyclopentane

The data of mass spectrometry (m/z): 311 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 1,70 - to 7.50 (6H, m), 4,90 - 5,20 (2H, m), 6,98 (4H, d), the SS spectrometry (m/z): 311 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 2,10 - of 2.25 (5H, m), of 2.51 - of 2.58 (1H, m), 4,88 - of 4.95 (2H, m), 6,97 (4H, d), 8,82 (4H, d), 9,87 (2H, s).

In the same manner as described in referential example 4 were obtained the following compounds.

Reference example 13

1,8-Bis-(4-formylphenoxy) octane

The data of mass spectrometry (m/z): 354 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 0,90 is 2.00 (12H, m), Android 4.04 (4H, t), of 6.99 (4H, d), 7,83 (4H, d), 9,88 (2H, s).

Reference example 14

2,2'-Bis-(4-formylphenoxy)ethyl ester

The data of mass spectrometry (m/z): 314 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 3,80 - 4,10 (4H, m), 4,10 - of 4.25 (4H, m), 7,02 (4H, d), a 7.85 (4H, d), 9,87 (2H, s)

Reference example 15

1,2-Bis-(4-formylphenoxy)ethane

The data of mass spectrometry (m/z): 271 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: of 4.45 (4H, m), 7,06 (4H, d), 7,86 (4H, d), to 9.91 (2H, s)

Reference example 16

1,3-Bis-(4-formylphenoxy)propane

The data of mass spectrometry (m/z): 285 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal Scandicci)Dean

The data of mass spectrometry (m/z): 383 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 0,90 is 2.00 (16H, m), Android 4.04 (4H, t), 6,98 (4H, d), 7,82 (4H, d), 9,87 (2H, s)

Reference example 18

1,11-Bis-(4-formylphenoxy) undecane

The data of mass spectrometry (m/z): 397 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 0,90 - 2,00 (18H, m), Android 4.04 (4H, t) to 7.00 (4H, d), to 7.84 (4H, d), 9,88 (2H, s)

Reference example 19

1,12-Bis-(4-formylphenoxy)dodecan

The data of mass spectrometry (m/z): 411 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 0,90 - 2,00 (20H, m), Android 4.04 (4H, t), 6,98 (4H, d), 7,82 (4H, d), 9,87 (2H, s)

Reference example 20

1,5-Bis-(4-formylphenoxy)-2,2,3,3,4,4-hexafluoropentane

The data of mass spectrometry (m/z): 421 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 4,58 (4H, c), was 7.08 (4H, d), to $ 7.91 (4H, d), to 9.93 (2H, s).

Reference example 21

p-Forbindelse (7.7 g), 5,9, 5-chlororesorcinol and 12.3 g of anhydrous potassium carbonate were added to 50 ml of dimethylsulfoxide and the mixture was stirred 12 hours at 100oC. After the reaction was added 100 ml of water and 200 ml of ethyl the East sodium then it was dried over anhydrous magnesium sulfate and the solvent evaporated. Educated oily material was chromatographically on a column of silica gel (a mixture of hexane and ethyl acetate, 7:1) to give 3.5 g of 1,3-bis-(4-formylphenoxy)-5-chlorobenzene.

The data of mass spectrometry (m/z): 352 (M+) (GC-MS).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 6,69 (1H, t, phenyl), to 6.88 (1H, d, phenyl), 7,14 (4H, m, phenyl), of 7.90 (4H, m, phenyl), 9,95 (2H, s, - CHO).

Reference example 22

(a) 3,5-Dihydroxytoluene (and 3.72 g) and 7.62 g of 4-perbenzoate was dissolved in 50 ml of dimethylsulfoxide and the solution is then added 2,52 g of 60% sodium hydride. After stirring 4 hours at 60oC was added ice water and ethyl acetate to separate an organic layer. The organic layer is washed with 10% aqueous potassium carbonate solution and dried over anhydrous magnesium sulfate and then the solvent evaporated. The residue was recrystallize from isopropanol, getting 5.5 g of 1,3-bis-(4-cianfrocca)-5-methylbenzene.

The data of mass spectrometry (m/z): 326 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

< / BR>
(b) 1,3-Bis-(4-cianfrocca)-5-methylbenzo (7,06 g) was dissolved in 150 ml of methylene chloride and the solution cooled in ice, was added by the om to the mixture was added

100 ml of a saturated aqueous solution of ammonium chloride and 5% sulfuric acid and the formed organic layer was separated. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and then the solvent evaporated. To the obtained residue was added diisopropyl ether and the formed crystals thus separated by filtration, getting 6.5 g of 1,3-bis-(4-formylphenoxy)-5-methylbenzene.

The data of mass spectrometry (m/z): 332 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
Reference example 23

(a) 40% potassium Fluoride-alumina (3 g) and 0.4 g of 18-crown-6-ether were added to 50 ml of a solution in acetonitrile of 1.55 g of resorcinol and 5.34 g of 4-fluoro-3-triftormetilfosfinov. After heating the reaction mixture under reflux overnight, the insoluble portion was separated by filtration, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was recrystallize from a mixture of hexane and ethylacetate CLASS="ptx2">

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: to 6.88 (1H, t), 6,98 - 7,03 (4H, m), 7,51 (1H, t), to 7.77 (2H, d), to 7.99 (2H, d),

(b) 1,3-Bis-(4-formyl-2-triptoreline)benzene was obtained in the same manner as described in reference example 22 (b)

The data of mass spectrometry (m/z): 455 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: make 6.90 (1H, t), 6,99 - 7,02 (2H, m), 7,07 (2H, d), to 7.50 (1H, t), 8,01 (2H, d), by 8.22 (2H, d), 9,98 (2H, s).

Reference example 24

(a) Anhydrous triperoxonane acid (20 ml) was added to a 20 ml solution in dichloromethane, 1,53 g 3-(4-cianfrocca)aniline and the reaction mixture was stirred 30 min at room temperature. The solvent is evaporated under reduced pressure and the thus obtained residue was dissolved in 40 ml of 2-butanone. Then the solution was added 3,14 g iodotope bromide and of 2.09 g of potassium carbonate. The reaction mixture was heated under reflux for 3 hours, the insoluble portion was separated by filtration and the solvent evaporated under reduced pressure. In the thus obtained residue was added 30 ml of methanol, 20 ml of water and 1.10 g of potassium carbonate. The reaction mixture was heated under reflux for 2 hours, diluted with water and then Tim was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue from evaporation was purified by chromatography on a column of silica gel (eluent mixture of hexane and ethyl acetate, 2:1) to give 1.52 g of 3-(4-cianfrocca)-N-methylaniline.

The data of mass spectrometry (m/z): 224 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 2,82 (3H, c), 3,86 (1H, c), of 6.29 (1H, t), 6,36 (1H, d), 6,46 (1H, d), 7,02 (2H, d), 7,18 (1H, t), 7,58 (2H, d)

(b) in the same manner as described in reference example 22 (a), received the following connection.

3-(4-Cianfrocca)-N-(4-cyanophenyl)-N-methylaniline

Source connection: 3-(4-cianfrocca)-N-methylaniline.

The data of mass spectrometry (m/z): 325 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 3,37 (3H, s), 6,83 - 6,91 (4H, m),? 7.04 baby mortality - 7,06 (3H, m), 7,42 (1H, t), 7,47 (2H, d), 7,63 (2H, d)

(c) in the same manner as described in reference example 22 (b), received the following connection.

3-(4-Formylphenoxy)-N-(4-formylphenyl)-N-methylaniline

Source connection: 3-(4-cianfrocca)-N-(4-cyanophenyl)-N-methylaniline

The data of mass spectrometry (m/z): 331 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)
<) In the same way, as described in reference example 23 (a), received the following connection.

1,3-Bis-(4-cyano-2,6-divergence)benzene

The data of mass spectrometry (m/z): 385 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 6,78 - for 6.81 (2H, m), to 6.95 (1H, t), 7,35 (1H, t), 8,07 (4H, d)

(b) in the same manner as described in reference example 22 (b), received the following connection.

1,3-Bis-(4-formyl-2,6-divergence)benzene

The data of mass spectrometry (m/z): 391 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 6,64 - of 6.71 (3H, m), 7,24 (1H, t), EUR 7.57 (4H, d), to 9.93 (2H, s)

Reference example 26

(a) in the same manner as described in reference example 23 (a), received the following connection.

1,3-Bis-(4-cyano-3-triptoreline)benzene

The data of mass spectrometry (m/z): 449 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 7,16 - 7,20 (3H, m), 7,44 - 7,47 (2H, m), 7,60-to 7.64 (3H, m), 8,16 (2H, d)

(b) in the same manner as described in reference example 22 (b), received the following connection.

1,3-Bis-(4-formyl-3-tryptophanate)benzene

The data of mass spectrometry (m/z): 455 ([M+H]+).

SPECT is 37 (2H, d), 7,51 (1H, t) to 8.14 (2H, d), 10,30 (2H, s)

In the same manner as described in reference example 3, were obtained the following compounds.

Reference example 27

1,3-Bis-(4-formylphenoxy)-4-nitrobenzene

The data of mass spectrometry (m/z): 363 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: of 6.8 to 7.3 (6H, m), 7,8 - 8,0 (4H, m) to 8.14 (1H, d), for 9.95 (1H, s), 9,98 (1H, s).

Reference example 28

2,6-Bis-(4-formylphenoxy)benzonitrile

The data of mass spectrometry (m/z): 342 ([M-H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: for 6.81 (2H, d), 7,25 (4H, d), 7,52 (1H, t), of 7.96 (4H, d), 10,00 (2H, s).

Reference example 29

2,4-Bis-(4-formylphenoxy)benzonitrile

The data of mass spectrometry (m/z): 343 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 6,72 (1H, d), 6.89 in (2H, DD), 7,19 (2H, d), 7,21 (2H, d), 7,71 (1H, d), 7,94 (4H, d), 9,96 (2H, s).

Reference example 30

(a) in the same manner as described in reference example 22 (a), received the following connection.

1,3-Bis-(4-cianfrocca)-5-methoxybenzo

The data of mass spectrometry (m/z): 342 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, GNC is sulochna example 22 (b), received the following connection.

1,3-Bis-(4-formylphenoxy)-5-methoxybenzo

The data of mass spectrometry (m/z): 348 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: of 3.78 (3H, s), to 6.39 (1H, t), 6,48 (2H, d), 7,13 (4H, d), 7,87 (4H, d), 9,94 (2H, s)

Reference example 31

(a) in the same manner as described in reference example 22 (a), received the following connection.

1,3-Bis-(4-cianfrocca)-5-torbenson

The data of mass spectrometry (m/z): 330 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: is 6.54 (2H, m), of 6.65 (1H, d), 7,10 (4H, d), to 7.67 (4H, d)

(b) in the same manner as described in reference example 22 (b), received the following connection.

1,3-Bis-(4-formylphenoxy)-5-torbenson

The data of mass spectrometry (m/z): 337 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: to 6.57 (2H, m), 6,7 (1H, d), 7,16 (4H, d), to $ 7.91 (4H, d), 9,96 (2H, s)

Reference example 32

(a) in the same manner as described in reference example 22 (a), received the following connection.

1,3-Bis-(4-cianfrocca)-4-Brabanthal

The data of mass spectrometry (m/z): 392 ([M+H]+).

Spectrum of nuclear magnetic RES in the reference example 22 (b), received the following connection.

1,3-Bis-(4-formylphenoxy)-5-Brabanthal

The data of mass spectrometry (m/z): 396 ([M+H]-).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 6,8 - 7,0 (2H, m), 7,0 is 7.3 (4H, m), 7,68 (1H, d), 7,8 - 8,0 (4H, m), 9,94 (2H, s)

Reference example 33

(a) in the same manner as described in reference example 22 (a), received the following connection.

3,5-Bis-(4-cianfrocca)-N,N-dimethylaniline

The data of mass spectrometry (m/z): 355 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: to 2.94 (3H, s), equal to 6.05 (1H, t), 6,23 (2H, d),? 7.04 baby mortality (4H, d), 7,60 (4H, d)

(b) in the same manner as described in reference example 22 (b), received the following connection.

3,5-Bis-(4-formylphenoxy)-N,N-dimethylaniline

The data of mass spectrometry (m/z): 361 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 2,95 (3H, s), 6,11 (1H, t), 6,27 (2H, d), 7,10 (4H, d), to 7.84 (4H, d), 9,92 (2H, s)

Reference example 34

(a) in the same manner as described in reference example 22 (a), received the following connection.

1,3-Bis-(4-cianfrocca)-4-chlorobenzene

The data of mass spectrometry (m/z): 346 (M+).

Range of the poison is Kim the same way as described in reference example 22 (b), received the following connection.

1,3-Bis-(4-formylphenoxy)-4-chlorobenzene

The data of mass spectrometry (m/z): 352 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 6,9 - 7,2 (6H, m), 7,52 (1H, d), 7,8 - 8,0 (4H, m), 9,94 (2H, s).

Reference example 35

The following compound was obtained by the same processing as described in reference example 22 (a), followed by the same processing as in reference example 22 (b), without isolating the 1,3-bis-(4-cyano-2-pertenece)benzene.

1,3-Bis-(2-fluoro-4-formylphenoxy)benzene.

Data mass spectrometry (m/z): 354 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 6,8 - to 6.95 (3H, m), 7,10 (2H, d), 7,39 (1H, t), of 7.6 to 7.8 (4H, d), 9,92 (2H, d)

Reference example 36

(a) in the same manner as described in reference example 22 (a), received the following connection.

1,3-Bis-(2-chloro-4-cianfrocca)benzene

The data of mass spectrometry (m/z): 381 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 6,72 - 6,91 (3H, m), of 6.99 (2H, d), and 7.5 (1H, m), 7,52 (2H, DD), to 7.77 (2H, d).

b) in the same manner as described in reference example 22 (b), AI (m/z): 387 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: is 6.78 (1H, t), of 6.90 (2H, DD), 7,06 (2H, d), the 7.43 (1H, t), 7,74 (2H, DD), to 7.99 (2H, d), to 9.91 (2H, s)

Reference example 37

(a) in the same manner as described in reference example 22 (a), received the following connection.

1,3-Bis-(3-chloro-4-cianfrocca)benzene

The data of mass spectrometry (m/z): 381 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: for 6.81 (1H, t), 6,92 (2H, d), 6,97 (2H, DD), 7,10 (2H, d), was 7.45 (1H, t), 7,63 (2H, d)

(b) in the same manner as described in reference example 22 (b), received the following connection.

1,3-Bis-(3-chloro-4-formylphenoxy)benzene

The data of mass spectrometry (m/z): 387 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

/ : of 6.7 to 7.1 (7H, m), 7,47 (1H, t), 7,92 (2H, d), 10,35 (2H, s).

Reference example 38

(a) in the same manner as described in reference example 22 (a), received the following connection.

1,3-Bis-(4-cianfrocca)-4,6-dichlorobenzene

The data of mass spectrometry (m/z): 380 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
(b) in the same manner as described in Sylvie mass spectrometry (m/z): 386 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
Reference example 39

(a) in the same manner as described in reference example 22 (a), received the following connection.

1,3-Bis-(4-cianfrocca)-4-ethylbenzene

The data of mass spectrometry (m/z): 340 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: to 1.19 (3H, t, - CH2CH3), 2,58 (2H, K, - CH2CH3), 6,65 - of 7.70 (11H, m, phenyl)

(b) in the same manner as described in reference example (22) (b), received the following connection.

1,3-Bis-(4-formylphenoxy)-4-ethylbenzene

The data of mass spectrometry (m/z): 346 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

/ : of 1.20 (3H, t, - H2CH3), 2,61 (2H, K, - CH2CH3), 6,70 - 8,00 (11H, m, phenyl), to 9.91 (2H, C. - CHO 2)

Reference example 40

(a) in the same manner as described in reference example 22 (a), received the following connection.

3,5-Bis-(4-cianfrocca)benzamide

The data of mass spectrometry (m/z): 355 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6- internal standard TMS)

< / BR>
(b) in the same manner as described in the e mass spectrometry (m/z): 362 ([M+H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6- internal standard TMS)

< / BR>
Reference example 41

At room temperature of 11.4 g of 4-methylaminoethanol dissolved in dimethyl sulfoxide, was added dropwise to a mixture of 11.6 g of tert-butoxide potassium and 100 ml of dimethylsulfoxide. After stirring for 20 min the reaction mixture was added to 10.5 g perbenzoate and stirring continued for 30 min at room temperature. The entire mixture was poured into water and the so formed precipitate was separated by filtration, washed successively with water and ethanol and dried, obtaining of 17.5 g of N,N-bis-(4-cyanophenyl)-methylamine.

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: of 3.42 (3H, s), 7,10 (4H, d), 7,58 (4H, d)

Reference example 42

Concentrated hydrochloric acid (45 ml) and ice was added 21.7 g of 4,4'-thiodianiline, the resulting mixture under ice cooling and then was added dropwise 50 ml of an aqueous solution of 15.2 g of sodium nitrite in 30 min After 5 min after the addition the reaction mixture was neutralized with sodium carbonate and was added dropwise into 250 ml ice solution in a mixture of water-benzene (3:2) of 22.4 g DANIDA copper (I) and 38.2 g of cyanide to the I-insoluble substances by filtration. The obtained organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was chromatographically on a column of silica gel, receiving of 11.7 g of bis-(4-cyanophenyl)sulfide fraction, buervenich chloroform.

The data of mass spectrometry (m/z): 236 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 7,39 (4H, d), 7,53 (4H, d)

Example 1.

(a) sodium Hydride (2,77 g, 60% oil dispersion) was washed with dry hexane and suspended in 200 ml of dimethylformamide and the suspension was then added 15.6 g of benzyloxycarbonyl in several portions at room temperature. The mixture was stirred for 20 min at an internal temperature of 100oC when heated in an oil bath. After cooling to room temperature, was added dropwise to 8.4 g of bis-[(4-chloromethyl)phenyl]ester, which was dissolved in 100 ml of dimethylformamide. The reaction mixture was again heated and stirred at an internal temperature of 100oC for 30 min, cooled with ice and then mixed with 100 ml of 1 N hydrochloric acid. The mixture was extracted with ethyl acetate and obtained the over anhydrous magnesium sulfate. After evaporation of the solvent was received of 15.4 g of crude crystals. Crystallization from 30 ml of ethanol was obtained 8.5 g of bis-[(4-(N-carbarnoyl-N-benzylamino)methyl]phenyl] ether.

The data of mass spectrometry (m/z): 527([M+H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
4,74 (4H, s, benzyl), 6,55 (4H, sh.with.,-NH2), 6,90 - 6,94 (4H, m, phenyl), 7,26 - 7,28 (4H, m, phenyl), 7,33 - 7,40 (10H, m, phenyl)

(b) Bis-[[4-(N-carbarnoyl-N-benzylamino)methyl] phenyl] ether (5 g) was dissolved in 200 ml of ethanol and the solution was then added 0.5 g of 10% palladium on coal. At room temperature in several portions were added 9,58 g of ammonium formate. After stirring for 2 hours the reaction mixture was filtered through celite, the residue was washed several times a small amount of dimethylformamide and then the filtrate and the washed solutions were combined and the solvent evaporated to education of the crude crystals, which were then washed with ethanol, receiving of 2.93 g of bis-[[4-(N-carbarnoyl-N-hydroxyamino)methyl]phenyl] ether.

The data of mass spectrometry (m/z): 347 ([M+H]+).

Spectrum of nuclear magnetic resonance (DMS-d6, internal standard TMS)

< / BR>
6.35mm (4H, s, -NH2O)methyl]phenyl] ether (2,93 g) suspended in 100 ml of tetrahydrofuran and the suspension under cooling with ice was slowly added to 25 ml of 2 N aqueous sodium hydroxide solution. After the reaction mixture became a homogeneous solution was added dropwise to 2.75 g ethylchloride and the mixture was stirred at room temperature for 13 hours. After adding 9 ml of 6 N hydrochloric acid under ice cooling, the reaction mixture was extracted with ethyl acetate (200 ml x 3) and the organic layer was washed successively with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting 2,77 g of crude crystals. Their recrystallized from a mixed solvent of 30 ml of ethanol and 5 ml of dioxane, getting 1.63 g of bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenyl] ether.

Melting point: 175 - 178oC.

Elemental analysis (for C18H14N4O7)

Calculated: C (%) 54,28; H (%) of 3.54; N (%) 14,07;

Found: C (%) 53,96; H (%) Of 3.69; N (%) 13,59.

The data of mass spectrometry (m/z): 397 ([M-H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
7,03 - 7,05 (4H, m, phenyl) 7.63 - 7.38 (4H, m, phenyl)

< / BR>
In the same manner as in example 1, was synthesized following compounds of examples 2-8.

Example 2

(a) Bis-[4-[[(N-benzyloxy-N-carbarnoyl)amino is AI (m/z): 345 ([M+H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
< / BR>
6,30 (4H, s, NH2x 2), 7,18 (8H, s, phenyl), 9,27 (2H, s, -OH x 2)

(c) Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenyl]methane

Melting point : 179-180oC.

Elemental analysis (for C19H16N4O6)

Calculated: C (%) 57,58; H (%) 4,07; N (%) 14,14;

Found: C (%) 57,11; H (%) 4.09 To; N (%) 13,08.

The data of mass spectrometry (m/z): 395 ([M-H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

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Example 3.

(a) 2,7-Bis-[4-[[(N-benzyloxy-N-carbarnoyl)amino]methyl]phenoxy]naphthalene

Melting point : 109 - 113oC.

The data of mass spectrometry (m/z): 669 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
(b) 2,7-Bis-[4-[[(N-carbarnoyl-N-hydroxy)amino]methyl]phenoxy]naphthalene

Melting point : 188 - 192oC.

The data of mass spectrometry (m/z) : 489 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
(c) 2,7-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] naphthalene

Melting point : 174 - 1766
, internal standard TMS)

< / BR>
Example 4

(a) 1,4-Bis-[4-[[(N-benzyloxy-N-carbarnoyl)amino]methyl]phenoxy]benzene

Melting point: 118 - 122oC.

The data of mass spectrometry (m/z), 619 ([M+H]+).

Spectrum of nuclear magnetic resonance (DMCO-d6, internal standard TMS)

< / BR>
(b) 2,7-bis-[4-[[(N-carbarnoyl-N-hydroxy)amino]methyl]phenoxy]benzene

The data of mass spectrometry (m/z) : 439 ([M + H]+) .

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
(C) 1,4-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] benzene

The data of mass spectrometry (m/z) : 489 ([M - H]-) .

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
< / BR>
7,05 (4H, s, phenyl)

< / BR>
Example 5

(a) 1,5-Bis-[4-[[(N-benzyloxy-N-carbarnoyl)amino]methyl]phenoxy]pentane

The data of mass spectrometry (m/z): 613 ([M + H]+) .

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
(b) 1,5-Bis-[4-[[(N-carbarnoyl-N-hydroxy)amino]methyl]phenoxy]pentane

The data of mass spectrometry (m/z): 433 ([M + H]+) .

Spectrum of nuclear magnetic resonance (DMSO-d6internal Stan

Source connection: 1,5-bis-[4-[(N-carbarnoyl-N-hydroxy)amino] methylphenoxy]pentane

Melting point: 156-157oC .

Elemental analysis (for C23H24N4O8)

Calculated: C (%) 57,02; H (%) 4,99; N (%) TO 11.56;

Found: C (%) 56,82 H (%) 4,69 N (%) Are 11.62.

The data of mass spectrometry (m/z): 483 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
< / BR>
< / BR>
< / BR>
6,93 (4H, m, phenyl), from 7.24 (4H, d, phenyl)

Example 6

(a) 1,3-Bis-[4-[[(N-benzyloxy-N-carbarnoyl)amino]methyl]phenoxy]benzene

The data of mass spectrometry (m/z) : 619 ([M + H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

< / BR>
< / BR>
6,60 - 7,42 (18H, m, phenyl)

(b) 1,3-Bis-[4-[[(N-carbarnoyl-N-hydroxy)amino]ethyl]phenoxy]benzene

(c) 1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] benzene

Parent compound : 1,3-bis-[4-[(N-carbarnoyl-N-hydroxy)aminomethyl] phenoxy]benzene

Melting point : 174-175oC.

Elemental analysis (for C24H18N4O8)

Calculated: C (%) 58,78; H (%) 3,70; N (%) 11,42;

Found: C (%) 58,69; H (%) Of 3.73; N (%) 11,13.

The data of mass spectrometry (m/z) : 489 ([M - H]-) .

7,37 (4H, d, phenyl)

Example 7.

(a) TRANS-1,4-Bis-[[4-[[(N-benzyloxy-N-carbarnoyl)amino] methyl]phenoxy] methyl]cyclohexane

The data of mass spectrometry (m/z) : 653 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

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< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
(b) TRANS-1,4-Bis-[[4-[[(N-carbarnoyl-N-hydroxy) amino] methyl] phenoxy] methyl]cyclohexane

The data of mass spectrometry (m/z) : 473 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
(c) TRANS-1,4-Bis-[[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy]methyl]cyclohexane

Source connection : TRANS-1,4-bis-[[4-[(N-carbarnoyl-N-hydroxy)aminomethyl]phenoxy]methyl] cyclohexane

Melting point : 175 - 176oC

Elemental analysis (for C26H28N4O8)

Calculated: C (%) 59,54; H (%) 5,38; N (%) FOR 10.68;

Found: C (%) 59,67; H (%) Of 5.48; N (%) 10,07.

The data of mass spectrometry (m/z): 523 ([M-H]) .

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
< / BR>
< / BR>
6,93 (4H, m, phenyl)

Example 8.

(a) CIS-1,3-Bis-[[(N-benzyloxy-N-carbarnoyl)amino] methyl]phenoxy]cyclohexane
Source connection : CIS-1,3-bis-[4-[(N-carbarnoyl-N-hydroxy)aminomethyl]phenoxy]cyclohexane

Amorphous

The data of mass spectrometry (m/z) : 495 ([M-H]).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,20 - 2,50 (8H, m, cyclohexyl)

< / BR>
< / BR>
6,98 (4H, m, phenyl)

Example 9.

(a) 1,2-Bis-[4-[[(N-benzyloxy-N-carbarnoyl)amino]methyl]phenoxy]benzene

(b) 1,2-Bis-[4-[[(N-carbarnoyl-N-hydroxy)amino]methyl]phenoxy]benzene

(c) 1,2-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] benzene

Melting point : 105-112oC .

Elemental analysis (for C24H18N4O81,4 H2O)

Calculated: C (%) 55,90; H (%) 4,07; N (%) 10,87;

Found: C (%) 56,14; H (%) Of 3.95% N (%) 10,53.

The data of mass spectrometry (m/z) : 487 ([M-H]).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
6,85 - to 6.88 (m, 4H: phenyl), 7,16 - 7,19 (m, 2H, phenyl),

7,24 - 7,29 (m, 6H, phenyl),

12,0 - 13,0 (sh.with. 2H),

< / BR>
Example 10.

(a) Aqueous methanol (12:88) (225 ml) was added to a mixture of (Z)-1,4-bis-(4-formylphenoxy)-2-butene (9,85 g), hydroxylamine hydrochloride (6,91 g) and sodium acetate (8,20 g) and the mixture was heated under reflux for 0.5 hours, the solvent is weatherization. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, obtaining crude crystals of (Z)-1,4-bis-[4-(N-gidroksimetil)phenoxy] -2-butene (10.4 g). Thus obtained crude crystals (1,74 g) was dissolved in a mixture of ethanol-tetrahydrofuran (1:2) (60 ml) and cooled with ice to this solution was added to the complex, borane-pyridine (1.1 ml) and the mixture was stirred for 1.25 hours. In the reaction mixture was added dropwise 10% hydrochloric acid (12 ml) and the mixture is then stirred for 0.5 hours under ice cooling and 4.5 hours at room temperature and then mixed with saturated aqueous potassium carbonate. The solvent is evaporated under reduced pressure and the resulting residue was diluted with water and was extracted with chloroform. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then evaporated under reduced pressure. The obtained residue was chromatographically on a column of silica gel and elution with a mixture of chloroform-methanol (50:1) to give (Z)-1,4-bis-[4-(N-hydroxyquinolyl)phenoxy)-2-butene (0,86 g)

Spectrum of nuclear magnetic is centered resin acid (1 ml) was added dropwise to a solution of (Z)-1,4-bis-[4-(N-hydroxyquinolyl)phenoxy]-2-butene (0,86 g) in a mixture of methanol-tetrahydrofuran (1:1), to the mixture was added 1 N aqueous solution of potassium cyanate (7.5 ml) and then stirred at room temperature for 1.25 hours. The solvent is evaporated under reduced pressure and the resulting residue was treated with 1 N aqueous solution of sodium hydroxide to pH 1 and extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, then the solvent is evaporated under reduced pressure, obtaining crude crystals of (Z)-1,9-bis-(4-[(1-hydroxyurea)methyl)phenoxy)-2-butene (1,02 g)

(c) a solution of (Z)-1,4-bis-[4-[(1-hydroxyurea)methyl)phenoxy)-2-butene (0.75 g) in tetrahydrofuran (20 ml) was added 2 N aqueous sodium hydroxide solution (6.9 ml) and then, with ice cooling, to the mixture was added dropwise ethylchloride (0,66 ml). After stirring the reaction mixture for 49 hours at room temperature the pH was set to 1 by addition of 6 N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The obtained residue was chromatographically on a column of silica gel with elution with a mixture of chlorofo the CSR-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy]-2-butene (0.31 g).

The product (b)

The data of mass spectrometry (m/z) : 417 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,43 (4H, s), 4,70 (4H, d), by 5.87 (2H, t), 6,52 (4H, s), 6.89 in (4H, d), 7,20 (4H, d), 9,24 (2H, s)

Product (s)

Melting point : 139 - 144oC.

Elemental analysis (for C22H20N4O8)

Calculated: C (%) 56,41; H (%) 4,30; N (%) 11,96;

Found: C (%) 56,25; H (%) 4,24; N (%) 11,85.

The data of mass spectrometry (m/z) : 467 ([M - H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: to 4.73 (4H, d), by 5.87 (2H, t), 6,98 (4H, d), 7,26 (4H, d), 12,42 (2H, sh. C.)

Example 11.

(a) in the same manner as described in example 10 (a), received the following connection.

1,9-Bis-[4-(hydroxyquinolyl)phenoxy]nonan

Source connection : 1,9-bis-(formylphenoxy)none

The data of mass spectrometry (m/z) : 403 ([M + H])+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,25 - 1,45 (10H, m) of 1.65 and 1.75 (4H, m) to 3.33 (2H, s), of 3.77 (4H, s) to 3.92 (4H, t), 6,85 (4H, d), 7,29 (4H, d)

(b) 1,9-Bis-[4-(hydroxyquinolyl)phenoxy] nonan (1.07 g) was dissolved in 75 ml of a mixture of tetrahydrofuran-dimethylformamide (4:1) and in argon atmosphere and cooled lies upon cooling, water was added dropwise 1 N aqueous sodium hydroxide solution and then the mixture was stirred 2 hours at room temperature. The solvent is evaporated under reduced pressure and the thus obtained residue was mixed with 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then evaporated under reduced pressure and the obtained residue was chromatographically on a column of silica gel. Thus obtained from fractions, buervenich a mixture of chloroform-methanol (40:1), the crude product (0,78 g) was recrystallized from methanol, getting 0,69 g of 1,9-bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy] nonane.

Melting point: 149 - 151oC.

Elemental analysis (for C27H32N4O8)

Calculated: C (%) 59,99; H (%) 5,97; N (%) 10,36;

Found: C (%) 60,00; H (%) 5,98; N (%) 10,36.

The data of mass spectrometry (m/z) : 541 ([M+H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,25 - 1,45 (14H, m), of 3.95 (4H, t), 4,70 (9H, s), 6,92 (4H, d), of 7.23 (4H, d), 12,42 (2H, sh.sec.)

Example 12.

(a) 1,4-Bis-(4-formylphenoxy)butane (3.98 g) was dissolved in 10.5 ml of a mixture of tetrahydrofuran-methanol (5: 1) solution, which was cooled with a mixture of ice and water to vsli 100 ml of 1 N hydrochloric acid and the mixture is again stirred at room temperature. Thus formed precipitate was separated by filtration. The crude product was washed successively with water and methanol and dried under reduced pressure, getting to 3.38 g of 1,4-bis-(4-hydroxymethylene)butane.

(b) 1,4-Bis-(hydroxymethylene)butane (1.78 g) was added to 25 ml of 4 N solution of hydrochloric acid-dioxane. The mixture was stirred 0.5 hour at 65oC, the solvent was evaporated under reduced pressure. Then the obtained residue was washed successively with water and methanol, dried under reduced pressure, obtaining of 1.95 g of 1,4-bis-(4-chloromethylene)butane.

Product (a)

The data of mass spectrometry (m/z) : 302 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 3,80 - 4,20 (4H, m), 4,39 (4H, d), free 5.01 (2H, t), 6.87 in (4H, t), 7,20 (4H, d)

The product (b)

The data of mass spectrometry (m/z): 338 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 1,85 - of 2.15 (4H, m), 3,97 - 4,10 (4H, m), 4,56 (4H, s), 6,85 (4H, d), 7,29 (4H, d)

(c) 60% sodium hydride (0,41 g) and 1.71 of benzyloxycarbonyl was added in 20 ml of dimethylformamide and the mixture was stirred for 7.5 hours at 80oC. the reaction mixture at room temperature was added 1,4-bis-(4-chloromethylene alibali in the icy water, was mixed with 1 N hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. Formed crude product was washed with ethyl acetate, receiving of 1.94 g of 1,4-bis-[4-[(1-benzyloxyaniline)methyl]phenoxy]Bhutan.

(d) 1,4-Bis-[4-[(1-benzyloxyaniline)methyl] phenoxy]butane (1,94 g) was dissolved in 45 ml of a mixture of dimethylformamide-ethanol (8:1), the solution was mixed with 0.29 grams of 10% palladium on coal and then the mixture was stirred 22 hours at room temperature in a hydrogen atmosphere. The catalyst was removed by filtration through celite and the solvent evaporated under reduced pressure, getting 0.84 g of 1,4-bis-[4-[(1-hydroxyurea)methyl]phenoxy]Bhutan.

The product (c)

The data of mass spectrometry (m/z): 599 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: of 1.78 - 1.90 (4H, m), 3,90 - 4,00 (4H, m), 4,43 (4H, s), 4.72 in (4H, s), of 6.49 (4H, s), of 6.68 (4H, d), 7,18 (4H, d), 7,33 - 7,39 (10H, m).

Product (d)

The data of mass spectrometry (m/z): 419 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6internal standard is as described in example 10 (c), received the following connection.

1,4-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy]Bhutan

Parent compound: 1,4-bis-[4-[(1-benzyloxyaniline)methyl] phenoxy] Bhutan

Melting point: 188 - 192oC.

The data of mass spectrometry (m/z): 469 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,80 - of 1.95 (4H, m), 3,90 - 4,10 (4H, m), 4,71 (4H, s) 6,94 (4H, d), from 7.24 (4H, d), 12,42 (2H, sh.sec.)

Example 13.

(a) in the same manner as described in example 10 (a), received the following connection.

1,6-Bis-[4-(hydroxyquinolyl)phenoxy]hexane

The data of mass spectrometry (m/z): 360 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,20 - 1,80 (8H, m), 3,65 - 4,10 (8H, m), of 5.85 (2H, t), 6,85 (4H, d), 7,22 (4H, d)

(b) in the same manner as described in example 10 (b), received the following connection.

1,6-Bis-[4-[(1-hydroxyurea)methyl]phenoxy]hexane

The data of mass spectrometry (m/z): 447 [M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,20 - 2,00 (8H, m), of 3.94 (4H, t), 4,43 (4H, s), 6,24 (4H, s), 6,85 (4H, d), 7,18 (4H, d), a 9.25 (2H, s)

(c) in the same manner as described in example 10 (c), received sleduya: 171 - 176oC.

Elemental analysis (for C24H26N4O8)

Calculated: C (%) 57,83; H (%) of 5.26; N (%) 11,24;

Found: C (%) 57,52; H (%) 5,23; N (%) 10,96

The data of mass spectrometry (m/z): 497 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: of 1.40 - 1.50 (4H, m) of 1.65 and 1.75 (4H, m), of 3.97 (4H, m), 4,71 (4H, s), 6,93 (4H, d), from 7.24 (4H, d), 12,42 (2H, sh.sec.)

Example 14.

(a) in the same manner as described in example 10 (a), received the following connection.

(E)-1,4-Bis-[4-(hydroxyquinolyl)phenoxy]-2-butene

The data of mass spectrometry (m/z): 331 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: with 3.79 (4H, m), of 4.57 (4H, s), to 5.85 (2H, sh.with.) 6,03 - 6,05 (2H, m), 6.87 in (4H, d), of 7.23 (4H, d).

(b) in the same manner as described in example 10 (b), received the following connection.

(E)-1,4-Bis-[4-[(1-hydrochioride)methyl]phenoxy]-2-butene

The data of mass spectrometry (m/z): 417 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: of 4.44 (4H, m), 4,58 (4H, s), equal to 6.05 (2H, s), of 6.31 (4H, s, to 6.88 (4H, d), 7,19 (4H, d), 9,68 (2H, sh.sec.)

(c) in the same manner as described in example 10 (c), received the following connection.

(E)-1,4-Bis-[4-[(3,5-d the analyses (for C22H20N4O8)

Calculated: C (%) 56,41; H (%) 4,30; N (%) 11,96;

Found: C (%) 56,18; H (%) Of 4.46; N (%) 11,74.

The data of mass spectrometry (m/z): 467 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,60 (4H, t), 4,71 (4H, s), the 6.06 (2H, s), of 6.96 (4H, d), 7,26 (4H, d), 12,42 (2H, sh.sec.)

Example 15.

(a) in the same manner as described in example 10 (a), received the following connection.

1,7-Bis-[4-(hydroxyquinolyl)phenoxy]heptane

The data of mass spectrometry (m/z): 374 ([M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,30 - 1,50 (6H, m), 1,65 - of 1.85 (4H, m), 3,92 - 3,98 (8H, m), 6.89 in (4H, d), 7,30 (4H, d), 9,10 (2H. W.sec.)

(b) in the same manner as described in example 10 (b), received the following connection.

1,7-Bis-[4-[(1-hydroxyurea)methyl]phenoxy]heptane

The data of mass spectrometry (m/z): 461 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,30 - 1,50 (6H, m), 1,65 - of 1.85 (4H, m), of 3.95 (4H, t), 4,42 (4H, s) of 6.29 (2H, s) 6,86 (4H, d), 7,17 (4H, d), a 9.25 (2H, s).

(c) in the same manner as described in example 10 (c), received the following connection.

1,7-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy]HepB )

Calculated: C (%) 58,59; H (%) 5,51; N (%) OF 10.93;

Found: C (%) 58,34; H (%) Of 5.53; N (%) 10,79.

The data of mass spectrometry (m/z): 511 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,30 - 1,50 (6H, m), 1.60 - to of 1.85 (4H, m), of 3.97 (4H, s), 4,71 (4H, s), 6,92 (4H, d), from 7.24 (4H, d), 12,40 (2H, sh.sec.)

Example 16.

(a) in the same manner as described in example 10 (a),

received the following connection.

1,3-Bis-[4-[(hydroxyquinolyl)phenoxy]methyl]benzene

The data of mass spectrometry (m/z): 381 ([M + H]+)

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: of 3.78 (4H, s), 5,10 (4H, s), 5,86 (2H, s), to 6.95 (4H, d), of 7.23 (4H, d), 7,40 (3H, s), 7,52 (1H, s)

(b) in the same manner as described in example 10 (b), received the following connection.

1,3-Bis[[4-[(1-hydroxyurea)methyl]phenoxy]methyl]benzene

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: of 4.44 (4H, s), 5,12 (4H, s), 6,30 (4H, s), to 6.95 (4H, d), 7,20 (4H, d), 7,40 (3H, s), 7,53 (1H, s), 9,51 (2H, sh.sec.)

(c) in the same manner as described in example 10 (c), received the following connection.

1,3-Bis-[[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy]methyl] heptane

Melting point: 189 - 193oC.

Elemental analysis 6; H (%) 4,29; N (%) 10,47.

The data of mass spectrometry (m/z 517 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,69 (4H, s), 5,12 (4H, s), 7,01 (4H, d), 7,26 (4H, d), 7,41 (3H, s), 7,54 (1H, s).

Example 17.

(a) in the same manner as described in example 10 (a), received the following connection.

1,5-Bis-[4-(hydroxyquinolyl)phenoxy]-3,3-dimethylpentan

The data of mass spectrometry (m/z): 375 ([M + H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: was 1.04 (6H, s) to 1.79 (4H, t) to 3.92 (4H, s), was 4.02 (4H, t), 6,83 (4H, d), 7,21 (4H, d), 7,26 (2H, s)

(b) in the same manner as described in example 11 (b), received the following connection.

1,5-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] -3,3-dimethylpentan

The data of mass spectrometry (m/z): 511 ([M - H]-).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

with 1.07 (6H, s), is 1.81 (4H, t) 4,06 (4H, t), to 4.73 (4H, s), for 6.81 (4H, d), from 7.24 (4H, d).

Example 18.

(a) in the same manner as described in example 10 (a), received the following connection.

CIS-1,3-Bis-[4-(hydroxyquinolyl)phenoxy]cyclopentane

The data of mass spectrometry (m/z): 345 ([M + H]+).

The(4H, m), of 3.77 (4H, s), of 4.95 (2H, s), of 5.84 (2H, sh.C.), at 6.84 (4H, d), 7,22 (4H, d).

(b) in the same manner as described in example 10 (b), received the following connection.

CIS-1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] cyclopentane

Melting point: 151 - 159oC.

Elemental analysis (for C23H22N4O8)

Calculated: C (%) 57,26; H (%) 4,60; N (%) OF 11.61;

Found: C (%) 57,35; H (%) 4,70; N (%) 11,30.

The data of mass spectrometry (m/z): 481 ([M - H]-)

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,75 - 1,90 (2H, m), 2.05 is - is 2.30 (4H, m), 4,71 (4H, s), 4,90 - of 5.05 (2H, m), 6,93 (4H, d), from 7.24 (2H, sh.C.), 12,42 (2H, sh.sec.)

Example 19.

(a) in the same manner as described in example 10 (a), received the following connection.

TRANS-1,3-Bis-[4-(hydroxyquinolyl)phenoxy]cyclopentane

The data of mass spectrometry (m/z): 344 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,95 - of 2.20 (6H, m), 3,91 (4H, s), 3.95 to to 4.15 (2H, m), 4,70 - 4,85 (2H, m), PC 6.82 (4H, d), 7,18 (4H, d)

(b) in the same manner as described in example 11 (b), received the following connection.

TRANS-1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] cyclopentane

The data of mass spectrometry (
: 1,74 - of 1.78 (2H, m), 1,80 - of 1.95 (2H, m), 1,95 is 2.10 (2H, m), 4,30 (4H, s), 4.75 V - 4,85 (2H, m), at 6.84 (4H, d), 7,16 (4H, d).

Example 20.

(a) in the same manner as described in example 10 (a), received the following connection.

1,8-Bis-[4-(hydroxyquinolyl)phenoxy]octane

The data of mass spectrometry (m/z): 389 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,25 - 1,50 8H, m) of 1.65 and 1.75 (4H, m), of 3.78 (4H, s) to 3.92 (4H, t), 6,83 (4H, d), 7,21 (4H, d)

(b) in the same manner as described in example 11 (b), received the following connection.

1,8-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]- phenoxy]octane

Melting point: 160 - 163oC.

Elemental analysis (for C26H30N4O8)

Calculated: C (%) 59,31; H (%) 5,74; N (%) AT 10.64;

Found: C (%) 59,22; H (%) 5,88; N (%) 10,29.

The data of mass spectrometry (m/z): 525 ([M - H]-)

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,25 - 1,45 (8H, m) of 1.65 and 1.75 (4H, m), of 3.95 (4H, t), 4,70 (4H, s), 6,92 (4H, d), from 7.24 (4H, d), 12,40 (2H, sh.sec.)

Example 21.

(a) in the same manner as described in example 10 (a), received the following connection.

2,2-Bis-[4-(hydroxyquinolyl)phenoxy]ethyl ester

The data of mass spectrometry (m/z): 34 3,74 - is 3.82 (4H, m), of 3.78 (4H, s) 4,07 (4H, t), of 5.84 (2H, s), 6.87 in (4H, d), of 7.23 (4H, d).

(b) in the same manner as described in example 11 (b), received the following connection.

2,2-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy]ethyl ester

Melting point: 92 - 95oC.

Elemental analysis (for C22H22N4O9)

Calculated: C (%) 54,34; H (%) 4,94; N (%) 10,56;

Found: C (%) 54,05; H (%) 4,91; N (%) 10,51.

The data of mass spectrometry (m/z): 485 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 3,81 (4H, t), 4,11 (4H, t), 4,71 (4H, s), to 6.95 (4H, d) to 7.25 (4H, d), 12,45 (2H, sh.sec.)

Example 22

(a) in the same manner as described in example 10 (a), received the following connection.

1,2-Bis-[4-(hydroxyquinolyl)phenoxy]ethane

The data of mass spectrometry (m/z): 305 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: of 3.97 (4H, s), 4,10 - 4,50 (2H, m), 4,30 (4H, s), to 6.95 (4H, d), 7,34 (4H, d)

(b) in the same manner as described in example 11 (b), received the following connection.

1,2-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy]ethane

Melting point: 203 - 206oC.

Elemental analysis (for C20H18N4is etree (m/z): 441 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,32 (4H, s), 4.72 in (4H, s), 6,99 (4H, d), 7,27 (4H, d), 12,42 (2H, sh. C.)

Example 23.

(a) in the same manner as described in example 10 (a), received the following connection.

1,3-Bis-[4-(hydroxyquinolyl)phenoxy]propane

The data of mass spectrometry (m/z): 319 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 2,16 (2H, Quint), to 3.99 (4H, s), 3,90 - 4,20 (6H, m) 6,91 (4H, d), 7,31 (4H, d).

(b) in the same manner as described in example 11 (b), received the following connection.

1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]- phenoxy]propane

Melting point: 176 - 178oC.

Elemental analysis (for C21H20N6O8)

Calculated: C (%) 55,26; H (%) was 4.42; N (%) TO 12.28;

Found: C (%) 55,10; H (%) 4,33; N (%) 12,05.

The data of mass spectrometry (m/z): 455 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 2,16 (2H, Quint), 4,13 (4H, t), 4,71 (4H, t), 4,71 (4H, s), of 6.96 (4H, d), 7,25 (4H, d), 12,41 (2H, sh.sec.)

Example 24.

(a) in the same manner as described in example 10 (a), received the following connection.

1,10-Bis-[4-(hydro is)

: 0,90 - 1,90 (12H, m), 2,40 - 2,60 (4H, m), 3,80 (4H, m), 3,60 is 4.35 (6H, m), 6,83 (4H, s), 6,83 (4H, d), 7,22 (4H, d).

(b) in the same manner as described in example 11 (b), received the following connection.

1,10-Bis-[4-[(3,5-dioxo-1,2,4--oxadiazolidine-2-yl)methyl] - phenoxy] Dean

Melting point: 153 - 158oC.

Elemental analysis (for C28H34N4O8)

Calculated: C (%) 60,64; H (%) 6,18; N (%) 10,10;

Found: C (%) 60,55; H (%) To 6.22; N (%) 9,59.

The data of mass spectrometry (m/z): 553 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,20 - 1,40 (12H, m), 1,60 - 1,75 (4H, m), of 3.95 (4H, t), 4,70 (4H, t), 6,92 (4H, d), from 7.24 (4H, d), 12,41 (2H, sh.C)

Example 25.

(a) in the same manner as described in example 10 (a), received the following connection.

1,11-Bis-[4-(hydroxyquinolyl)phenoxy]undecane

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 0,90 - 1,90 (14H, m), 2.40 a - to 2.65 (4H, m), 3,83 (4H, s), 3,60 - 4,20 (6H, m), at 6.84 (4H, d), of 7.23 (4H, d)

(b) in the same manner as described in example 11 (b), received the following connection.

1,11-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] - phenoxy]undecane

Melting point: 122 - 125oC.

Spectrum of nuclear magnetic resonanceof 26.

(a) in the same manner as described in example 10 (a), received the following connection.

1,12-Bis-[4-(hydroxyquinolyl)phenoxy]dodecan

The data of mass spectrometry (m/z): 445 ([ M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,00 - 1,90 (20H, m), 3,60 - 4,10 (10H, m) 6,86 (4H, d), 7,27 (4H, d)

(b) in the same manner as described in example 11 (b), received the following connection.

1,12-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy]dodecan

Melting point: 220 - 228oC.

The data of mass spectrometry (m/z): 558 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 1,20 - of 1.45 (16H, m), 1,63 is 1.75 (4H, m), 3,93 (4H, t) to 4.52 (4H, s), 6,83 (4H, d), 7,20 (4H, d)

Example 27.

(a) in the same manner as described in example 10 (a), received the following connection.

1,5-Bis-[4-(hydroxyquinolyl)phenoxy]-2,2,3,3,4,4 - hexafluoropentane

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 3,81 (4H, s), 4.72 in (4H, t), of 5.89 (4H, s), 6,99 (4H, d), 7,28 (4H, d)

(b) in the same manner as described in example 11 (b), received the following connection.

1,5-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenyl] -2,2,3,3,4,4-Huck

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,74 (4H, s), 4,78 (4H, t), was 7.08 (4H, d), 7,30 (4H, d), to 12.44 (2H, sh. C.)

Example 28.

(a) When cooled to -70oC 24 ml of a 1.6 M solution of utility in hexane was added dropwise 40 ml of a solution of 6.48 in g 4-bromthymol in tetrahydrofuran. After stirring 1 hour at -70oC in the reaction mixture was added dropwise 20 ml of the solution to 4.33 g of N,N-dimethyl-N',N', dimethoxyisoflavone in tetrahydrofuran. After stirring 2 hours at -70oC the reaction mixture was diluted with 1 N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was recrystallized from a mixture of hexane-ethyl acetate, getting 3,18, 1,3-ditoluylmethane.

The data of mass spectrometry (m/z): 315 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: to 2.42 (6H, s), 7,39 (4H, d), 7,71 (4H, d), 7,76 (1H, t), 7,95 - 8,02 (3H, m)

(b) In 60 ml 1,82 g of 1,3-ditoluylmethane in carbon tetrachloride was added, and 2.27 g of N-bromosuccinimide and 0.15 g of azoisobutyronitrile. Reactionism. The solvent is evaporated under reduced pressure and educated the residue was recrystallized from a mixture of hexane-ethyl acetate, getting 1.63 g of 1,3-bis(4-bromomethylphenyl)benzene.

The data of mass spectrometry (m/z): 471 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,80 (4H, s), the 7.65 (4H, d), 7,76 - 7,86 (5H, m), 7,99 - 8,08 (3H, m)

(c) in the same manner as described in example 12 (c), received the following connection.

1,3-Bis-[4-[(1-benzyloxyaniline)methyl]benzoyl]benzene

Parent compound: 1,3-bis-(4-bromomethylphenyl)benzene

The data of mass spectrometry (m/z): 643 ([M + H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 4,71 - 4,72 (4H, m), 4.75 V - of 4.77 (4H, m), 7,28 - 7,49 (14H, m), 7,60 - 7,74 (5H, m), 7,98 - 8,18 (3H, m).

(d) using hydroxycarbamide compounds obtained in the same manner as described in example 12 (d), in the same manner as described in example 10 (c), received the following connection.

1,3-Bis-(4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]benzyl]benzene

Parent compound: 1,3-bis-[4-[(1-benzyloxyaniline)methyl] benzoyl] benzene

Melting point: 230oC (decomposition).

The data of mass-BR> : 3,88 (4H, s), of 4.45 (4H, s), 7,01 (2H, d), 7,12 - 7,21 (10H, m)

Example 29.

(a) in the same manner as described in example 12 (c), received the following connection.

1-Benzyloxy-1-(4-nitrobenzyl)urea

Starting compound: 4-nitrobenzylamine, benzyloxycarbonyl.

The data of mass spectrometry (m/z): 302 ([M + H]+)

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 4,71 (2H, s), was 4.76 (2H, s), of 5.24 (2H, sh.C.), 7,27 - 7,40 (5H, m), 7,47 (2H, d), 8,18 (2H, d)

10% Palladium on coal (0.3 g) was added to 80 ml of the solution was 4.76 g of 1-benzyloxy-1-(4-nitrobenzyl)urea in ethyl acetate. The reaction mixture was stirred overnight at normal pressure in a hydrogen atmosphere and then insoluble substances were removed by filtration. After evaporation of the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (eluent: chloroform-methanol, 10:1) getting to 1.82 g of 1-(4-aminobenzyl)-1-benzyloxycarbonyl.

The data of mass spectrometry (m/z): 272 ([M + H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: of 4.54 (2H, s) and 4.65 (2H, s), 5,19 (2H, sh.C.), of 6.65 (2H, d), 7,17 (2H, d), 7,26 - 7,29 (2H, m), 7,33 - 7,37 (3H, m).

(c) Under ice cooling 15 ml to 0.70 is)-1-benzyloxycarbonyl and 0.71 g of triethylamine in dichloromethane. The reaction mixture was stirred over night at room temperature and then mixed with 1 N hydrochloric acid. Educated thus the crystals were separated by filtration, washed successively with water and dichloromethane and then dried, obtaining 1,54 amide, N,N'-bis-[4-[(1-benzyloxyaniline)methyl] phenyl]isophthalic acid.

The data of mass spectrometry (m/z): 673 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,51 (4H, s), and 4.75 (4H, s), 6,53 (4H, s), 7,27 (4H, d), 7,33 - 7,42 (10H, m), 7,68 (1H, t) to 8.12 (2H, d), 8,51 (1H, s), the 10.40 (2H, s).

(d) ammonium Formate (2 g) and 0.3 g of 10% palladium on coal was added in 30 ml of dimethylformamide and 30 ml of a solution of 1.53 g of amide N,N'-bis-[4-[(1-benzyloxyaniline)methyl] phenyl] isophthalic acid in ethanol. The reaction mixture was stirred over night at room temperature and then insoluble substances were removed by filtration. The solvent is evaporated under reduced pressure and the obtained residue was added water. The thus obtained insoluble substance was separated by filtration, washed successively with water and diethyl ether and then dried, obtaining 0.52 g of amide-N,N'-bis-[4-[(1-hydroxyurea)methyl]phenyl]isophthalic acid.

Ditrani standard TMS)

: of 4.45 (4H, s), 6.35mm (4H, s), 7,28 (4H, d), to 7.67 to 7.75 (5H, m) to 8.14 (2H, d), 8,53 (1H, s), was 9.33 (2H, s), the 10.40 (2H, s).

(e) in the same manner as described in example 10 (c), received the following connection.

Amide N,N'-bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenyl]isophthalic acid

Parent compound: amide N,N'-bis-[4-[(1-hydroxyurea)- methyl]phenyl] isophthalic acid

Melting point: 300oC (decomposition).

The data of mass spectrometry (m/z): 543 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6internal standard TMS)

: 4,78 (4H, s), 7,35 (4H, d), of 7.70 (1H, t), 7,81 (4H, d), 8,14 (2H, d), 8,53 (1H, s), 10,50 (2H, s), to 12.44 (2H, s)

Example 30.

(a) in the same manner as described in example 10 (c), received the following connection.

1,3-Bis-[4-[[1-(4-methoxybenzyloxy)ureido]methyl]benzoyl]benzene

Starting compound: 1,3-bis-(4-bromomethylphenyl)benzene,

4-methoxybenzylidene

The data of mass spectrometry (m/z) 703 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: to 3.73 (6H, s), to 4.62 (4H, s), 4,71 (4H, s), to 6.58 (4H, s), make 6.90 (4H, d), 7,32 (4H, d), the 7.43 (4H, d), 7,74 to 7.75 (5H, m), 7,98 - 8,02 (3H, m).

(b) Under cooling with ice and 10 ml of anisole and 40 ml triperoxonane acid domovladenie ice for 30 min and then at room temperature for 6 hours. The solvent is evaporated under reduced pressure and the obtained residue was mixed with diethyl ether. Educated thus the crystals were separated by filtration and dried, obtaining 0,79 g of 1,3-bis-[4-[(1-hydroxyurea)methyl]benzoyl]benzene.

The data of mass spectrometry (m/z 463 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,63 (4H, s), 6,44 (4H, s) of 7.48 (4H, d), 7,76 - 7,79 (5H, m), 7,99 - of 8.04 (3H, m), 9,48 (2H, s).

(c) in the same manner as described in example 10 (c), received the following connection.

1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]benzoyl]benzene

Parent compound: 1,3-bis-[4-[(1-hydroxyurea)methyl]benzoyl]benzene

Melting point: 183 - 185oC.

The data of mass spectrometry (m/z): 513 ([M - H]-).

Spectrum of nuclear magnetic resonance (DNSO-d6, internal standard TMS)

: is 4.93 (4H, s), 7,56 (4H, d), 7,79 (1H, t), 7,83 (4H, d), 8,01 - of 8.06 (3H, m), to 12.52 (2H, s).

Example 31.

(a) in the same manner as described in example 10 (a), received the following connection.

1,3-Bis-[4-(hydroxyquinolyl)phenoxy]-4-nitrobenzene

The original compound is 1,3-bis-(4-formylphenoxy)-4-nitrobenzene

The data of mass spectrometry (m/z): 3,82 (4H, W.), of 6.25 (1H, d), to 6.58 (1H, DD), at 6.84 (2H, d), 6,86 (2H, d), 7,13 (2H, d), 7,20 (2H, d), 7,89 (1H, d)

(b) in the same manner as described in example 10 (b), received the following connection.

1,3-Bis-[4-[(1-hydroxyurea)methyl]phenoxy]-4-nitrobenzene

Parent compound: 1,3-bis-[4-(hydroxyquinolyl)phenoxy]-4-nitrobenzene

The data of mass spectrometry (m/z): 484 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,51 (2H, s) to 4.52 (2H, s) 6,38 (4H, s), to 6.58 (1H, d), 6,76 (1H, DD), 7,11 (2H, d), 7,12 (2H, d), 7,33 (2H, d), 7,35 (2H, d), 8,14 (1H, d), 9,36 (1H, s), 9,38 (1H, s).

(c) in the same manner as described in example 10 (c), received the following connection.

1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy]-4-nitrobenzene

Parent compound: 1,3-bis-[4-[(1-hydroxyurea)methyl]phenoxy]-4-nitrobenzene

Melting point: 187 - 189oC (MeOH).

Elemental analysis (for C24H17N5O10)

Calculated: C (%) 53,84; H (%) 3,20; N (%) 13,08;

Found: C (%) 53,83; H (%) 3,26; N (%) 12,95.

The data of mass spectrometry (m/z): 534 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,79 (2H, s), to 4.81 (2H, s) 6,70 (1H, d), 6,85 (1H, DD), 7,12 (2H, d), 7,20 (2H, d), 7,40 (2H, d), the 7.43 (2H, d), 8,17 (1H, d) is E.

1,3-Bis-[4-(hydroxyquinolyl)phenoxy]-5-chlorobenzene

Parent compound: 1,3-bis-(4-formylphenoxy)-5-chlorobenzene

The data of mass spectrometry (m/z): 387 ([M + M]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: a 3.87 (4H, s), of 6.52 (1H, t), is 6.78 (2H, d),? 7.04 baby mortality (4H, d), 7,40 (4H, d)

(b) in the same manner as described in example 10 (b), received the following connection.

1,3-Bis-[4-[(1-hydroxyurea)methyl]phenoxy]-5-chlorobenzene

Parent compound: 1,3-bis-[4-(hydroxyquinolyl)phenoxy]-5 - chlorobenzene

The data of mass spectrometry (m/z): 473 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: to 4.52 (4H, s) 6,38 (4H, s), 6.35mm (1H, t), 6,69 (2H, d), 7,07 (4H, d), 7,34 (4H, d), 9,37 (2H, s).

(c) in the same manner as described in example 10 (c), received the following connection.

1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy]-5-chlorobenzene

Parent compound: 1,3-bis-[4-[(1-hydroxyurea)methyl]phenoxy]-5-chlorobenzene

Melting point: 84 - 86oC (diisopropyl ether).

Elemental analysis (for C24H17N4O8Cl H2O)

Calculated: C (%) 53,10; H (%) of 3.53; N (%) 10,32; Cl (%) 6,53;

Found: C (%) 53,08; H (%) 3,47; N (%) resonance (DMSO-d6, internal standard TMS)

: 4,79 (4H, s), is 6.61 (1H, t), to 6.80 (2H, d), 7,13 (4H, d), 7,40 (4H, d).

Example 33.

(a) in the same manner as described in example 10 (a), received the following connection.

2,6-Bis-[4-(hydroxyquinolyl)phenoxy]benzonitrile

Parent compound: 2,6-bis-(4-formylphenoxy)benzonitrile

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 3,91 (4H, s), 6,56 (2H, d), to 7.15 (4H, d), 7,30 (1H, m), 7,46 (4H, d)

(b) in the same manner as described in example 11 (b), received the following connection.

2,6-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] benzonitrile

Parent compound: 2,6-bis-[4-(hydroxyquinolyl)phenoxy]benzonitrile

Melting point: 173 - 175oC (ethanol-water).

Elemental analysis (for C25H17N5O81/2H2O)

Calculated: C (%) 57,26; H (%) of 3.46; N (%) 13,35;

Found: C (%) 57,20; H (%) 3,47; N (%) 13,13.

The data of mass spectrometry (m/z): 514 ([M - H]-).

Spectrum of nuclear magnetic resonance (DSO-d6, internal standard TMS)

: 4,84 (4H, s), of 6.66 (2H, d), 7,25 (4H, d), 7,47 (4H, d), EUR 7.57 (1H, t).

Example 34.

In the same manner as described in example 11 (b), received the following connection.


Melting point: 175 - 177oC (ethanol-water).

The data of mass spectrometry (m/z): 514 ([M - H]-)

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,80 (2H, s), to 4.81 (2H, s), 7,53 (1H, s), is 6.78 (1H, d), 7,16 (2H, d), 7,20 (2H, d), 7,38 (2H, d), the 7.43 (2H, d), 7,89 (1H, d)

Example 35.

(a) in the same manner as described in example 10 (a), received the following connection.

1,3-Bis-[4-(hydroxyquinolyl)phenoxy]-5-methoxybenzoyl

Parent compound: 1,3-bis-(4-formylphenoxy)-5-methoxybenzo

The data of mass spectrometry (m/z): 348 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: to 3.73 (3H, s), of 3.96 (4H, s), 6,29 (3H, m) to 7.00 (4H, d), 7,30 (4H, d)

(b) in the same manner as described in example 11 (b), received the following connection.

1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] -5-methoxybenzoyl

Parent compound: 1,3-bis-[4-(hydroxyquinolyl)phenoxy] -5-methoxybenzoyl

Amorphous

The data of mass spectrometry (m/z): 519 ([M - H]-).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: is 3.82 (3H, s), was 4.76 (4H, s), 6,18 (1H, s), 6,36 (2H, s), 6,97 (2H, d), 7,29 (2H, d)

Example 36.

(a) in the same manner as described the ol

Parent compound: 1,3-bis-(4-formylphenoxy)-5-torbenson

The data of mass spectrometry (m/z): 371 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 3,86 (4H, s), 6.35mm (1H, m), 6,44 (1H, d), 6,56 (1H, d), 7,03 (4H, d), 7,39 (4H, d)

(b) in the same manner as described in example 11 (b), received the following connection.

1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] -5-torbenson

Parent compound: 1,3-bis-[4-(hydroxyquinolyl)phenoxy]- 5-torbenson

Melting point: 182 - 184oC (methanol).

Elemental analysis (for C24H17N4O8F)

Calculated: C (%) 56,70; H (%)3,37; N (%) 11,02; F (%) 3,74;

Found: C (%) 56,58; H (%) 3,51; N (%) 10,97; F (%)3,72.

The data of mass spectrometry (m/z): 507 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,79 (4H, s), 6,44 (1H, s), 6,62 (2H, d), 7,12 (4H, d), 7,39 (4H, d), 12,45 (2H, sh.sec.)

Example 37.

In the same manner as described in example 11 (b), received the following connection.

1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy]-4-Brabanthal

The source connection of 1,3-bis-[4-(hydroxyquinolyl)phenoxy]- 4-Brabanthal

Amorphous

Data mass is Standart TMS)

: was 4.76 (4H, sh.C.), 6,74 (1H, s), 6,79 (1H, DD), 7,00 (2H, d), was 7.08 (2H, d), of 7.36 (2H, d), 7,73 (1H, d).

Example 38.

(a) in the same manner as described in example 10 (a), received the following connection.

3,5-Bis-[4-(hydroxyquinolyl)phenoxy]-N,N-dimethylaniline

Source connection: 3,5-bis-(4-formylphenoxy)-N,N-dimethylaniline

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: is 2.88 (6H, s), 3,90 (4H, s), of 5.84 (1H, t), 6,14 (2H, d), 6,93 (4H, d), 7,21 (4H, d).

(b) in the same manner as described in example 11 (b), received the following connection.

3,5-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] -N,N-dimethylaniline

Source connection: 3,5-bis-[4-(hydroxyquinolyl)phenoxy] - N,N-dimethylaniline

Amorphous

The data of mass spectrometry (m/z): 534 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 2,84 (6H, s), to 4.38 (4H, s), of 5.81 (1H, s), 6,11 (2H, s), to 6.95 (4H, d), 7,28 (4H, d).

Example 39.

(a) in the same manner as described in example 10 (a), received the following connection.

2,6-Bis-[4-(hydroxyquinolyl)phenoxy]pyridine

Parent compound: 2,6-bis-(4-formylphenoxy)pyridine

The data of mass spectrometry (m/z): 354 ([M + H]+)

WITH WHOM(4H, d) of 7.82 (1H, t).

(b) in the same manner as described in example 11 (b), received the following connection.

2,6-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy]pyridine

Parent compound: 2,6-bis-[4-(hydroxyquinolyl)phenoxy] pyridine

Amorphous

The data of mass spectrometry (m/z): 490 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,47 (4H, s), 6,59 (2H, d), was 7.08 (4H, d), 7,31 (4H, d), to 7.84 (1H, t)

Example 40.

(a) in the same manner as described in example 10 (a), received the following connection.

1,3-Bis-[4-(hydroxyquinolyl)phenoxy]-4-chlorobenzene

Parent compound: 1,3-bis-(4-formylphenoxy)-4-chlorobenzene

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

/ : 3,99 (4H, sh.C.), 6,6 - 6,8 (2H, m), 6,93 (4H, d-like), 7,22 - 7,53 (5H, m).

(b) in the same manner as described in example 11 (b), received the following connection.

1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] -4-chlorobenzene

Parent compound: 1,3-bis-[4-(hydroxyquinolyl)phenoxy] -4 - chlorobenzene

Amorphous

The data of mass spectrometry (m/z): 523 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, B1.

(a) in the same manner as described in example 10 (a), received the following connection.

1,3-Bis-[2-fluoro-4-(hydroxyquinolyl)phenoxy]benzene

Parent compound: 1,3-bis-(2-fluoro-4-formylphenoxy)benzene

The data of mass spectrometry (m/z): 389 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6internal standard (TMS)

: a 3.87 (4H, s), is 6.54 (1H, s), is 6.61 (2H, d), 7,15 - 7,21 (4H, m), 7,33 (1H, t), of 7.36 (2H, d)

(b) in the same manner as described in example 11 (b), received the following connection.

1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]-2 - fervency] benzene

Parent compound: 1,3-bis-[2-fluoro-4-(hydroxyquinolyl)phenoxy]benzene

Melting point: 160 - 162oC (CH3CN - H2O).

Elemental analysis (for C24H16N4F2O81/4H2O)

Calculated: C (%) 54,30; H (%) 3,13; N (%) 10,55; F (%) 7,16;

Found: C (%) 54,49; H (%) 3,30; N (%) 10,34; F (%) 6.89 In.

The data of mass spectrometry (m/z): 525 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,81 (4H, s), of 6.65 (1H, s) 6,70 (2H, d), 7,21 - 7,28 (4H, m), 7,33 (1H, t), 7,40 (2H, d).

Example 42.

(a) in the same manner as described in example 10 (a), received the following connection.


Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: of 3.96 (4H, s), about 6.5 - 6.8 (3H, m), 7,00 (2H, d), 7,15 - 7,33 (3H, m), 7,43 (2H, s).

(b) in the same manner as described in example 11 (b), received the following connection.

1,3-Bis-[2-chloro-4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] benzene

Parent compound: 1,3-bis-[2-chloro-4-(hydroxyquinolyl) phenoxy] benzene

Amorphous

The data of mass spectrometry (m/z): 558 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: to 4.46 (4H, s), to 6.58 (1H, t), 6,62 (2H, DD), 7,16 (2H, d), 7,30 and 7.36 (3H, m) to 7.50 (1H, s)

Example 43.

(a) in the same manner as described in example 10 (a), received the following connection.

1,3-Bis-[3-chloro-4-(hydroxyquinolyl)phenoxy]benzene

Parent compound: 1,3-bis-(3-chloro-4-formylphenoxy)benzene

The data of mass spectrometry (m/z): 421 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 4,10 (4H, s), and 6.6 and 7.1 (7H, m), 7,22 (1H, m), 7,34 (2H, d).

(b) in the same manner as described in example 11 (b), received the following connection.

1,3-Bis-[3-chloro-4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] benzene

The source is connected - ]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,49 (4H, d), to 6.80 (1H, s), 6,83 (2H, d), 7,06 (2H, DD), 7,16 (2H, d), 7,42 (1H, t), of 7.48 (2H, d).

Example 44.

(a) in the same manner as described in example 10 (a), received the following connection.

1,3-Bis-(4-Hydroxyeicosatrienoic)-5-methylbenzo

Parent compound: 1,3-bis-(4-formylphenoxy)-5-methyl-benzene

The data of mass spectrometry (m/z): 366 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 2,24 (3H, s, -CH3)

< / BR>
< / BR>
< / BR>
< / BR>
b) in the same manner as described in example 10 (b), received the following connection.

1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] -5-methylbenzoyl

Parent compound: 1,3-bis-[4-hydroxyeicosatrienoic)-5-methylbenzo

Elemental analysis (for C25H20N4C8)

Calculated: C (%) 59,52; H (%) 4,00; N (%) 11.11 IS;

Found: C (%) 59,42; H (%) 4,00; N (%) 11,06.

The data of mass spectrometry (m/z): 503 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: of 2.25 (3H, c-CH3)

< / BR>
< / BR>
< / BR>
< / BR>
Example 45.

(a) the same hydroxy)-4,6-dichlorobenzene

Parent compound: 1,3-bis-(4-formylphenoxy)-4,6-dichlorobenzene

The data of mass spectrometry (m/z): 421 ([M + H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
(b) in the same manner as described in example 10 (b), received the following connection.

1,3-Bis-[4-(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] -4,6-dichlorobenzene

Parent compound: 1,3-bis-(4-hydroxyeicosatrienoic)-4,6-dichlorobenzene

Melting point: 217 - 218oC.

.The data of mass spectrometry (m/z): 557 ([M - H]-)

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Example 46.

(a) in the same manner as described in example 10 (a), received the following connection.

1,3-Bis-(4-hydroxyeicosatrienoic)-4-ethylbenzene

Parent compound: 1,3-bis-(4-formylphenoxy)-5-ethylbenzene

The data of mass spectrometry (m/z): 381 ([M + H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 1,19 (3H, s, -CH2CH3), 2,62 (2H, K, -CH2CH3)

< / BR>
6,25 - 7, 50 (11H, m, phenyl)

(b) in the same manner as described in example 10 (b), Paul

Parent compound: 1,3-bis-[4-hydroxyeicosatrienoic)-4 - ethylbenzene

The data of mass spectrometry (m/z): 517 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: of 1.13 (3H, t, -CH2CH3, of 2.54 (2H,- CH2CH3)

< / BR>
6,50 - 7,40 (1H, m, phenyl)

Example 47

(a) in the same manner as described in example 10 (a), received the following connection.

3,5-Bis-(4-hydroxyeicosatrienoic)benzamide

Source connection: 3,5-bis-(4-formylphenoxy)benzamide

The data of mass spectrometry (m/z): 396 (M + H).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
(b) in the same manner as described in example 10 (b), received the following connection.

3,5-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy]benzamide

Source connection: 3,5-bis-[4-hydroxyeicosatrienoic)benzamide

The data of mass spectrometry (m/z): 532 ([M - H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Example 48.

(a) in the same manner as described in example 10 (a), received the following connection.

1,phenoxy)benzene

The data of mass spectrometry (m/z): 489 ([M + H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: was 4.02 (4H, s), 6,50 (1H, t), to 6.80 (2H, d), of 6.96 (2H, d), 7,31 (1H, t), was 7.45 (2H, d), 7,63 (2H, d).

(b) in the same manner as described in example 11 (b), received the following connection.

1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] -2 - triptoreline]benzene

Parent compound: 1,3-bis-[4-(N-hydroxyquinolyl) -2-triptoreline]benzene

Data mass of spetrometry (m/z): 625 ([N-H]-)

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: 4,88 (4H, s), 6,83 (1H, t), to 6.88 (2H, d), 7,18 (2H, d), 7,47 (1H, t), the 7.65 (2H, m), 7,76 (2H, s), 12,50 (2H, sh.sec.)

Example 49

(a) using hydroxylamine compounds obtained in the same manner as described in example 10 (a), received the following connection in accordance with the method of example 11(b).

1,3-Bis[2,6-debtor-4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy]benzene

Parent compound: 1,3-bis-(2,6-debtor-4-formylphenoxy)benzene

Melting point: above 300oC (decomposition)

The data of mass spectrometry (m/z): 561 ([M-H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6internal standard is but in example 10 (a), received the following connection.

1,3-Bis-[4-(N-hydroxyquinolyl)-3-triptoreline]benzene

Parent compound: 1,3-bis-(4-formyl-3-triptoreline)benzene

The data of mass spectrometry (m/z): 489 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 4,17 (4H, s), 6,55 (1H, d), to 6.80 (2H, d), 7,14 (2H, d), 7,31 - to 7.35 (3H, m), 7,55 (2H, d).

(b) in the same manner as described in example 11 (b), received the following connection.

1,3-Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] -3-triptoreline]benzene

Parent compound: 1,3-bis-[4-(N-hydroxyquinolyl)-3 - triptoreline)benzene

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: br4.61 (4H, s), 6.87 in - 6,90 (3H, m), of 7.36 - 7,39 (4H, m), 7,46 (1H, t), of 7.69 (2H, d).

Example 51.

(a) in the same manner as described in example 10 (a), received the following connection.

3-[4-(N-Hydroxyquinolyl)phenoxy] -N-[4-(N-hydroxyquinolyl)phenyl]-N-methylaniline

Source connection: 3-(4-formylphenoxy)-4-(4-formylphenyl) -N-methylaniline

The data of mass spectrometry (m/z): 366 ([M+H)+).

Spectrum of nuclear magnetic resonance (CDCl3, internal standard TMS)

: 3,2 what about in example 11 (b), received the following connection.

3-[4-[(3,5-Dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy]- N-[4-(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenyl-N-methylaniline

Source connection: 3-[4-(N-hydroxyquinolyl)phenoxy]-N- [4-(N-hydroxyquinolyl)phenyl]-N-methylaniline

The data of mass spectrometry (m/z): 502 ([M-H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

: of 3.25 (3H, s), 4,70 (2H, s), to 4.73 (2H, s), 6,51 (1H, d), 6,62 (1H, t), 6,74 (1H, d), 7,01 (2H, d), to 7.09 (2H, d), 7.23 percent - 7,27 (3H, m), 7,33 (2H, d).

Example 52.

(a) in the same manner as described in example 10 (a), received the following connection.

1,3-Bis-[4-(N-hydroxyquinolyl)phenoxy]benzene

Parent compound: 1,3-bis-(4-formylphenoxy)benzene

Melting point: 110 - 114oC

The data of mass spectrometry (m/z): 353 ([M+H)+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

/ : a-3.84 (4H, s), 5,98 (2H, s), 6,55 (1H, J=2,44 Hz), 6,69 (2H, DD, J= 2.44 and 8,32 Hz), 6,99 (4H, d, J=8,28 Hz), 7,24 (2H, s), 7,34 (1H, d, J=8,32 Hz), 7,35 (4H, d, J=8,28 Hz).

(b) 1,3-Bis-[4-(N-hydroxyquinolyl)phenoxy]benzene (0.704 g) was dissolved in 21 ml of tetrahydrofuran, and then the solution was added with ice cooling in an argon atmosphere was added dropwise 0,354 ml chlorocarbon the ri room temperature. The solvent is evaporated under reduced pressure and the residue was chromatographically on a column of silica gel, receiving of 0.44 g of 1,3-bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] benzene fraction, buervenich a mixture of chloroform-methanol (30:1).

Physico-chemical properties of this compound showed that it is the same connection as the product of example 55 (b)

Example 53.

1,3-Bis-[4-(N-hydroxyquinolyl)phenoxy]benzene (1,76 g) was dissolved in 35 ml of tetrahydrofuran, the solution is then under ice cooling in an argon atmosphere was added dropwise of 1.65 g of n-butoxycarbonylamino. After stirring 30 min at the same temperature, the reaction mixture was added dropwise 1 N aqueous sodium hydroxide solution and stirring continued for 30 min at room temperature. After adding 1 N hydrochloric acid, the solvent is evaporated and the formed residue was chromatographically on a column of silica gel, obtaining 1.0 g of 1,3-bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy] benzene fraction, buervenich a mixture of chloroform - methanol (30:1).

Physico-chemical properties of this compound showed that it is the same connection as the product of example 55 (b).

Example 54.

Pheno is dropwise 1.24 g ethoxycarbonylethyl. After stirring for 3 hours at the same temperature was added to 1.41 g of 1,3-bis-[4-(N - hydroxyquinolyl)phenoxy]benzene and the stirring was continued for 1 hour. After adding 3 drops of triethylamine and then stirring 16 hours at 60oC in the reaction mixture under ice cooling was added dropwise 1 N aqueous sodium hydroxide solution and then the mixture was stirred for 1 hour at room temperature. It was mixed with 1 N hydrochloric acid, the solvent evaporated and then the residue was added water, obtaining 0.8 g of crude crystals. The crystals are then washed with diethyl ether and ethanol, gaining 0.4 g of 1,3-bis-[4- [(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy]benzene.

Physico-chemical properties of this compound showed that it is the same connection as the product of example 55 (b).

Example 55.

(a) 1,3-Bis-[4-(hydroxyquinolyl)phenoxy]benzene (1.06 g) was dissolved in 10 ml of tetrahydrofuran, the solution is then under ice cooling in an argon atmosphere was added dropwise to 0.66 ml ethoxycarbonylethyl. After stirring at this temperature for 2 h and 30 min educated thus the crystals were separated by filtration and washed with diethyl ether and ethanol, receiving 1, oC.

The data of mass spectrometry (m/z): 583 ([M+H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS)

< / BR>
7,32-7,38 (1H, m), 9,14 (2H, s), 9,95 (2H, s).

(b) 1,3-Bis-[4-[(2-(3-etoxycarbonyl-1-hydroxyanisole)methyl] phenoxy] benzene (0.85 grams) was dispersively 8.5 ml of tetrahydrofuran, at variance with ice cooling was added dropwise 1 N aqueous sodium hydroxide solution and then stirred for 30 min at room temperature. After adding 1 N hydrochloric acid, the solvent is evaporated under reduced pressure and then the residue was added water. Educated thus the crystals were separated by filtration and recrystallized from acetic acid, receiving 0.35 g of 1,3-bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy]benzene.

Melting point: 182-184oC.

Elemental analysis (for C24H18N4O8)

Calculated: C (%) 58,78; H (%) 3,70; N (%) 11,42;

Found: C (%) 58,77; H (%) A 3.83; N (%) 11,37.

The data of mass spectrometry (m/z) : 489 ([M-H]-)

Spectrum of nuclear magnetic resonance (DMSO-d6internal standard TMC)

< / BR>
Example 56.

(a) in the same manner as described in reference example 22 (b), received the following connection is the Tr NMR (CDCl3internal standard TMC)

: to 3.49 (3H, s), 7,19 (4H, d), 7,83 (4H, d), 9,90 (2H, s)

(b) in the same manner as described in example 10 (a), received the following connection.

Bis-(4-hydroxyaminobutyryl)methylamine

Spectrum of nuclear magnetic resonance (CDCl3internal standard TMC)

: 3,26 (3H, s) to 3.92 (4H, s), of 5.40 (2H, sh.C.), 6,94 (4H, d), 7,20 (4H, d).

(c) in the same manner as described in example 11 (b), received the following connection.

Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenyl]methylamine

The data of mass spectrometry (m/z) : 410 ([M-H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6internal standard TMC)

: of 3.27 (3H, s), 4.72 in (4H, s), 7,02 (4H, d), 7,25 (4H, d), 12,42 (2H, sh. C.)

Elemental analysis (for C19H17N5O6)< / BR>
Calculated: C (%) 55,47; H (%) 4,17; N (%) 17,02;

Found: C (%) 55,20; H (%) 4,08; N (%) 16,85.

Example 57.

(a) in the same manner as described in reference example 22 (b), received the following connection.

Bis-(4-formylphenyl)sulfide

The data of mass spectrometry (m/z) : 243 ([M+H]+).

Spectrum of nuclear magnetic resonance (CDCl3internal standard TMC)

: of 7.48 (4H, d), a 7.85 (4H, d), 10,00 (2H, s)

(b) in the same manner as described in example magnitnogo resonance (DMSO-d6internal standard TMC)

: a-3.84 (4H, s), 6,01 (2H, s), 7,20-7,40 (8H, m).

(c) in the same manner as described in example 11 (b), received the following connection.

Bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenyl]-sulfide

The data of mass spectrometry (m/z) : 413 ([M-H]-).

Spectrum of nuclear magnetic resonance (DMSO-d6internal standard TMC)

: 4,79 (4H, s), of 7.36 (8H, s), 12,46 (2H, sh.sec.)

Elemental analysis (for C18H14NO6S)

Calculated: C (%) 52,17; H (%) 3,41; N (%) 13,52; S (%) 7,74;

Found: C (%) 52,17; H (%) 3,47; N (%) 13,22; S (%) 7,73.

Example 58.

At room temperature 1,76 g metallocarboranes acid was added to a mixture of 910 mg of bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenyl] tiefer and 5 ml of dichloromethane and the mixture was stirred 15 hours. Thus formed crystals were separated by filtration, washed with dichloromethane and then dried, obtaining 730 mg of bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenyl]sulfon.

The data of mass spectrometry (m/z) : 445 ([M-H]+).

Spectrum of nuclear magnetic resonance (DMSO-d6internal standard TMC)

: 4,90 (4H, s), 7,60 (4H, d), of 8.00 (4H, d), 12,50 (2H, sh.sec.)

The structure of the compounds obtained in the examples in tabIe example N10 : 39%xxat the dose of 30 mg/day.

Connection example N13 : 44%xxat the dose of 30 mg3/day.

The toxicity of the compounds is low. Single application (600 mg/kg) compound of example N10 in rats and dogs did not lead to mortality.

Prescription example: tablet (1 mg)

The compound of the present invention weighing 7 grams mixed with 534,8 g of lactose. This mixture is ground into powder using proborazdelochnyh mill. Powdered mixture weight 541,8 g uniformly mixed with 135,1 g corn starch in a machine for coating fluidized bed granulation. To this add spray 210 g 10% solution of hydroxypropylcellulose for the implementation of the granulation. After final drying, the granules are passed through a 20 mesh, is mixed with 2.1 g of magnesium stearate and then produce tablets at the rate of 100 mg per tablet processing of the final granules in a rotary teletrauma car. Using the device for coating the finished tablets are sprayed 350 g of the solution for coating containing 20,3 g hydroxypropylmethylcellulose, 2.8 g of polyethylene glycol, 11.2 g of titanium oxide and 0.7 g of talc, thus obtaining film-coated tablets.

1. Derived bisexuality is jdy is fenelonov group, which may be substituted; L represents: (1) an oxygen atom, (2) a group represented by the formula

< / BR>
(3) a group represented by the formula-S(O)n-, (4) a group represented by the formula-CO-, (5) a group represented by the formula

< / BR>
(6) alkylenes group or alkenylamine group, which may respectively be interrupted by oxygen atom and/or sulfur atom and which may respectively be substituted, or (7) a group represented by the formula

< / BR>
R1is a hydrogen atom or a lower alkyl group; n is 0,1 or 2; R2is a hydrogen atom or a lower alkyl group; L1and L2the same or different from each other and each represents: (1) an oxygen atom, (2) a group represented by the formula

< / BR>
(R1has the above values), (3) a group represented by the formula-S(O)n- (n has the above values), (4) a group represented by the formula-CO-, (5) a group represented by the formula

< / BR>
(R2has the above values), or (6) alkylenes group or alkenylamine group, which may respectively be interrupted by oxygen atom and/or sulfur atom and which may respectively be substituted; and cycloalkenyl group, Allenova group is stuut, represent one or more substituents selected from the group consisting of halogen atom, lower alkyl group, lower halogenoalkanes group, lower alkoxygroup, ceanography, nitro, amino, lower alkylamino amino group, carbamoyl group and lower alkyl substituted carbamoyl group, and the substituents on L, L1and L2when he is present, represents a halogen atom, or a pharmaceutically acceptable salt.

2. Connection on p. 1, which

may be the same or different from each other, and each represents fenelonov group which may be substituted by one or more substituents selected from the group consisting of halogen atom, lower alkyl groups and halogen lower alkyl group, and L is 1) alkalinous group or alkynylamino group, which may respectively be interrupted by oxygen atom and/or sulfur atom and which may respectively be substituted by one or more halogen atoms, or 2) a group represented by formula

< / BR>
where L1and L2may be the same or different from each other, and each represents alkylenes group and the traveler may respectively be substituted by one or more halogen atoms, and represents cycloalkenyl group, Allenova group or peritendinous group, which may respectively be substituted by one or more substituents selected from the group consisting of halogen atom, lower alkyl group, halogen lower alkyl groups, lower alkoxygroup, ceanography, nitro, amino, lower alkyl substituted amino groups, carbamoyl group and lower alkyl substituted carbamoyl group.

3. Connection on p. 1, representing 1,3-bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl) methyl] phenoxy] benzene, or its pharmaceutically acceptable salt.

4. Connection on p. 1, predstavlyayushie a 1,4-bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy] -2-butene or its pharmaceutically acceptable salt.

5. Connection on p. 1, representing 1,9-bis-[4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl] phenoxy]nonan or its pharmaceutically acceptable salt.

6. Connection on p. 4, which has a geometric isomerism.

7. The pharmaceutical composition exhibiting hypoglycemic activity containing the active ingredient and pharmaceutically acceptable carrier, characterized in that as Achillea salt.

The priority for all values of radicals with L: a) lower Allenova group, an oxygen atom or a group represented by the formula where is a simple bond, a saturated or unsaturated carbon ring having 3 to 10 carbon atoms; P1, P2 is 0 or an integer from 1 to 3 30.04.93;

The priority for all values of radicals with L: b) Allenova group having from 1 to 12 carbon atoms or alkenylamine group having from 2 to 12 carbon atoms, which may likewise be interrupted by oxygen atom, or which may be respectively substituted by the group of lower alkyl or halogen atom - 29.12.93;

The priority for all values of radicals with L representing a group of the formula

< / BR>
a group of the formula-S(O)n-, a group of the formula-CO-, a group of the formula

< / BR>
alkylenes or alkenylamine group which may be interrupted by a sulfur atom, a group of the formula R1means a hydrogen atom or a lower alkyl group; n is 0, 1,2; R2is a hydrogen atom or a lower alkyl group; L1and L2: the same or different from each other and each represents an oxygen atom, a group represented by the formula (R1has the above values), a group represented by the formula-S-(O)n(n is the decree is related higher values) or alkylenes or alkenylamine group, which may respectively be interrupted by a sulfur atom; and cycloalkenyl group, Allenova group or peridiniella group, which may respectively be substituted - 26.04.94.

 

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