Polycyclic biocidal compounds and pharmaceutical composition based on them

 

(57) Abstract:

Usage: in medicine as anti-cancer agents. The inventive product-polycyclic biosignia the compounds of formula Ar CH2NR, where Ar is 2-benzo(b)oil [2,3-d] furan-6-yl, 2-benzo(b)oil(1,2-d)furan-5-yl, 2-[7-methyl-7H-benzo(C) carbazole-10-yl] -methyl ili-benzo(b)oil(2,1-d)furan-5-yl, and R-CH2OH-CCH3-CH2OH-group, monomethylamine or monoethylamine ethers, esters or their acid additive salts, and pharmaceutical composition thereof. Reagent 1: polycyclic compound of the formula Ar-CH=NR, where Ar and R above. Reagent 2: the restorer. Dose of 5 - 500 mg 2 S. and 2 C. p. F.-ly, 2 tab.

The invention relates to heteroalicyclic alkanoyl derivatives, which have a biocidal effect, and more particularly to aminoalcohols derived molecules containing heteroalicyclic ring system, to methods of their synthesis, their new intermediates, containing pharmaceutical compositions and to their use as biocidal agents, in particular anticancer agents.

In some classification systems using mice, it was found that two similar Nitra is imethyl)-metilenovuju group, also possess anti-tumor action.

The authors of the present invention have discovered a new class heteroalicyclic aromatic alkanols derivatives, which possess biocidal action.

Features compound of formula (I): ArCH2Other (1) monometallic or monoethylene ether. The compound of formula (1), including these ethers, contains a total of no more than 29 carbon atoms, and its ester and its salt, where Ar-6,6,6,5-tetracyclic aromatic ring system containing from 15 to 17 ring atoms, five-membered ring containing one heteroatom, possibly substituted by one or two substituents. R contains not more than 8 carbon atoms and is a group

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The class of aromatic ring systems, which is covered by the framework of the invention may include compounds of the following formulas, where Z heteroatom

6,6,6,5-tetracyclic ring system

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< / BR>
< / BR>
< / BR>
< / BR>
Z

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One of the preferred groups of compounds of the invention also includes compounds whose molecules Ar-cyclic system containing 15 or 17 of the ring is:

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One of the preferred classes of compounds of formula (1) class, the compounds of which the system is denoted by the symbol Ar, choose from the following:

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These cyclic systems respond to the following item:

Z NH

11-H-Benzo[a]carbazole 5-H-Benzo[b]carbazole 7-H-Benzo[c]carbazole

Z O

Benzo[b]oil[L,1-d]furan, Benzo[b]oil[2,3-d]furan, Benzo[b]oil[1,2-d] furan

Z S

Benzo[b] oil[2,1-d] thiophene Benzo[b] oil[2,3-d] thiophene Benzo[b]oil[1,2-d]thiophene

In a preferred variant of the side chain of CH2Other should be attached to the position:

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where Z SO, NMe or NEt.

A more preferred class of compounds of formula (1) class, the compounds which Ar represents a

where Z SO, NMe or NEt.

Preferably Ar represents 7H-benzo(C)carbazole-10-yl or benzo(b)oil[2,1-d]furan-5-yl.

Acceptable aromatic cycle is unsubstituted or contains only one Deputy. In a preferred variant of the aromatic cycle must be unsubstituted.

Acceptable compound of the formula ArCH2Other or onomatology or monotropy ether contains a total of not more than 28 carbon atoms.


2-[[(benzo[b] oil[2,1-d] thiophene-5-yl) methyl] amino]-2-methyl - 1,2-propandiol;

2[[(benzo[b] oil[2,3-d] furan-6-yl)me - Tyl]amino]-2-methyl - 1,3-propandiol;

2-[[(benzo[b] oil[1,2-d]furan-5-yl)me - Tyl]amino]-2-methyl - 1,3-propandiol;

2-methyl-2-[[7-methyl-7H-benzo[c]carb - angry-10-yl)methyl]amino] 1,3-propandiol;

2-[[(benzo[b] oil[2,1-d]furan-5-yl)me - Tyl]amino]-2-methyl - 1,3-propandiol;

their ethers and esters and their acid additive salt.

Salts, which are covered by the framework of the invention are salts of the compounds of formula (1) and salts ethers and esters of these compounds.

Esters and pharmaceutically useless salts of compounds of formula (1) can be used as intermediate products in the production and purification of the compounds of formula (1) and their pharmaceutically acceptable salts, which are also covered by part of the invention. So, the class of salts of compounds of formula (1), which can be used in accordance with the invention, include, but are not limited to, the products produced from inorganic (mineral) acids, in particular hydrochloric, Hydrobromic, sulfuric and phosphoric acids, and organic acids, in frequent is Monday, formic, lactobionic, Pantothenic acid, econsultancy, benzosulfimide, p-toluenesulfonic acid, naphthalene-2-sulfonic acids and ascorbic acid, and also amino acids, in particular glycine. Preferred are pharmacologically and pharmaceutically acceptable salts, in particular salts, which are soluble in a solvent that is acceptable for parenteral administration into the body, for example, hydrochloride, methanesulfonate and isocyanate.

Esters of compounds of formula (1) is obtained from the acids that are well known to specialists in this field as acceptable for obtaining esters. Usually they are esters derived from alkanovykh acids WITH1-C6or derivatives alkanovykh acids, for example acetic acid, propionic acid, n-butyric acid and somaclonal acid. Esters can be obtained by using all or only some of the hydroxyl groups contained in the molecules of compounds of formula (1).

The compounds of formula (1), their ethers, esters and salts can be obtained by any method known as the method of obtaining compounds of similar structure. For example, the compounds of formula (1) can beingolea Ar and R are defined above, or suitably protected derivatives thereof, with the subsequent removal of the protective groups where this is necessary.

Conditions of reactions and reagents for these reactions are well known in the art. You can create any conditions and to use any reagents that do not cause the recovery of the aromatic cyclic system. Conversion of compound (II) or its suitably protected derivatives can be performed by the recovery agent, followed by removal of protective groups, if necessary. The recovery process is conveniently performed using metal hydride, in particular sociallyengaged, sodium borohydride, laborgerate sodium, or catalytic hydrogenation, typically by means of hydrogen in the presence of metal catalysts, in particular palladium or platinum, or using well-known equivalent reagents (March J. Advanced Organic Chemistry. New York: McGraw hill, 1977, S. 819-820). Such reversal is conveniently carried out with the use of the compounds of formula ArCH= NR in the form of its solution in an inert solvent or mixture of solvents that are compatible with the reducing agent, when non-extremal temperatures, for example 0-80aboutUsually when connelley solvents include ethers (tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane), possibly in the presence of a hydrocarbon co-solvent (toluene, benzene or hexane).

In the case of sodium borohydride, and the like reagents class acceptable solvents include alcohols (ethanol, methanol or isopropanol), possibly in the presence of a hydrocarbon co-solvent (toluene, benzene or hexane or ether co-solvent (diethyl ether or tetrahydrofuran).

In the case of cyanoborohydride and similar reagents class acceptable solvents include those described as used for sodium borohydride, and recovery is usually carried out in the presence of acid, usually glacial acetic acid or ethanolic hydrochloric acid (R. Hutchins etc. Organic Preparations and Procedures International, 1979, 11, 201).

In the case of catalytic hydrogenation class acceptable solvents include alcohols (for example methanol and ethanol), possibly in the presence of a hydrocarbon co-solvent (for example toluene or benzene or ether co-solvent (for example diethyl ether or tetrahydrofuran), possibly in the presence of acid (such as glacial acetic acid or ethanolic hydrochloric acid is t-protected derivatives of compounds of the formula ArCH=NR. Acceptable protected groups must be compatible with the reducing agent and can be easily removed under conditions that do not result in destruction. These include, for example, benzyl group, tetrahydrofuranyl and isopropylidenebis ethers.

It is often convenient not to isolate the compound of the formula ArCH=NR, and to carry out the reaction of the compound ArCHO connection with NH2R, where the values of the symbols Ar and R are defined above, and subjecting the thus obtained compound of the formula Agsn=NR recovery at the place of use. The reaction of compounds ArCHO with NH2R is also conveniently carried out under conditions using reagents that are well known to specialists in this field, for example in the presence of acid, in particular sulfonic acids, i.e., p-toluenesulfonic acid, in an environment suitable inert solvent, for example an aromatic hydrocarbon, in particular toluene, with azeotropic removal of water, followed by treatment restorative agent in an appropriate solvent, in particular ethanol or methanol. Alternatively, the connection ArCH=NR obtained in the equilibrium conditions in the environment acceptable solvent, can be subjected to recovery at the place of use with the s ArCHO may be in the form of a protected aldehyde, for example acetal, which under reaction conditions performs the function of aldehyde. Connection ArCHO can be synthesized by reaction of the corresponding polycyclic aromatic hydrocarbon with familyroom agent, in particular with this, which is released in the reaction between tin tetrachloride and Cl2CHOCH3or equivalent reagents or other standard formulirowki reagents using procedures that are known to specialists in this field, for example by reaction of Gatterman-Koch [CO/HCl/AlCl3/ Cu/Cl] reaction of Gatterman [HCN/HClZnCl2] and the reaction of Vilsmeier [POCl3/Ph N/Me/CHO or POCl3/Me2NCHO]

Connection ArCHO can be obtained from the corresponding aromatic heterobicycle replaced with an appropriate functional group and conversion of this functional group aldehyde group by known methods. The class of suitable functional groups include ADHD, CH3, COR19where R19primary or secondary alkyl WITH1-C6group, COOH or its derivative, in particular a residue of ester, amide or carboxylic acid, or SP.

In the case where the aromatic heteropolyacid contains ZAT nature of the substituent on the ring. In that case, if the Deputy is a halogen atom, raw materials can be obtained by direct treatment of aromatic heterobicycle palodiruyut agent (chlorine, bromine or SO2Cl2or indirectly, for example by reaction of Sandmaier Hodgson, H. H. Chem. Rev. 1947, 40, 251). In that case, if the Deputy is alkyl, it is possible to conduct the reaction of the aromatic heterocycle with the appropriate reagents under conditions of normal reactions Friedel-(Olan G. A. Triedel Crafts and Related Reactions, Vol.1-3. Ner York: Interscience, 1963-1965).

The compounds of formula NH2R can also be obtained by methods known in the art. In the case when the values of the symbol R is defined above, can be obtained by the reaction of NO2R, where R is a group of the formula

with the appropriate aldehyde, more comfortable with acetaldehyde or formaldehyde, and then recovery easier by using hydrogen and a metal catalyst (for example, a catalyst containing platinum) in an appropriate solvent, easier glacial acetic acid.

2. Reconnection Ar.CO. Other, where the values of the symbols Ar and R are defined above and the hydroxyl group is protected, followed by removal of protective groups with hydroxyl groups, where this neo as agents, which are used in the reduction reaction of this type and do not recover aromatic ring system, for example, hydride reagent, in particular sociallyengaged, in an inert solvent, in particular in a simple ether, i.e., tetrahydrofuran, at a non-extremal temperatures, for example 0-100aboutUsually at the boiling point of simple ether under reflux.

Connection Ar. CO.Other can be obtained by reaction of the appropriate acid (ArCOOH) or its corresponding reactive acid derivative, such as galodamadruga, acid, in an inert solvent, with an amine NH2R, whose hydroxyl groups may secure, for example in the case where the connection NH2R is diola, isopropylidene group.

Thus obtained compound Ar.CO.Other appropriately restore the site and remove the protective group, if necessary, obtaining the compound of formula (1). The compounds of formula ArCOOH can be obtained by methods which are known to any expert in this field.

Both alternative method above can be described by the following reaction scheme:

Ar __ ArCH3__ ArC"ptx2">

Compounds of the present invention have a biocidal effect, such as the toxicity of some living cells, which are harmful to mammals, for example in relation to pathogens and tumors. Toxicity against pathogenic microorganisms demonstrated, for example, an action against one or more of the following cell types: viruses (e.g. Herpes simplex 1/vero Candida albicaus fungi), protozoa (e.g. Eimeria tenella and Trichomonas vaginalis bacteria (e.g. Mycoplasma smeg matis and Streptococcus pyogenes and helminths (e.g Nippostrongylus brasiliensis and Brugia pahangi). Antitumor activity of compounds of formula (1) has been demonstrated in a number of verification tests and foremost activity against ascitic leukemia R/0.

Preferred compounds of formula (1) are compounds that have anti-tumor activity. Action against ascitic tumors, including R/0, is evident from the observations to reduce the number of tumor cells in mammals (such as mice, have ascitic tumors) and, consequently, to increase the life expectancy of these animals in comparison with animals of the control group, untreated, is puhala after treatment of mammals using the compounds of the present invention in comparison with tumors in animals of the control group, which has not been subjected to such treatment. The compounds of formula (1) also exhibit activity against murine tumors, in particular against libopenal leukemia R/0, 1210 lymphoid leukemia, milanodisco B16 melanoma, mastocytoma R, fibrosarcoma M AY/2, colon adenocarcinoma 38, rhabdomyosarcoma M and carcinoma of the lung Lewis.

Action in one or more tests on the tumor is an indicator of antitumor activity in humans (Coldin A. Methods in Cancer Research ed Devita VT and H. Busch. New York: Academic Press, 1979, 16, 165)

There are compared R/0, which have become resistant to the action of the following clinically used agents: citizenoriented, doxorubicin, cyclophosphamide, L-phenylalanine mustard, methotrexate, 5-fluorouracil, actinomycin D-CIS-Platin and bigliettinobomboniera. Compounds of the present invention exhibit high activity against these tumors, having such a resistance to the drug, in the implementation of procedures for the above R/0.

It was found that the compounds of formula (1) possess activity against human tumor cells in primary cultures of lung, technicak, breast, kidney, melanoma, Neizvestnyi the term "cancer" is taken as a synonym of the term "malignant tumor" or more commonly used term "tumor" in all cases, except as specifically noted). This procedure, in which it was found that to prevent the formation of colonies of tumor cells, that is, replication of tumor cells by drugs is consistent with clinical antitumor activity in humans.

The compounds of formula (1), which possess anti-tumor activity, tested in vitro using DNA (this property is determined by viscometric methods, using the procedure (Wilson W. D.) and other Nucleic Acids Researoh, 1954, 4, 2697), and log P calculated by the method (C. Hansch and A. Leo. Substituent Constauts for Correlation Analysis in Chemiistry and Biologi. New York, 1979), the value of which is in the range from-2.0 to +2,5.

Compounds of the present invention can be used to treat tumors. Thus, it is proposed a method of treatment of tumors in animals, including mammals, in particular humans, in the exercise of which is provided for introduction into the body of a clinically effective amount of the compounds of formula (1) in a pharmaceutically acceptable form one or more times per day or other appropriate schedule oral, rectal, parenteral or local application. In addition, we offer soy is VA.

The amount of the compounds of formula (1) necessary to achieve the desired effect as biological controls may vary and is ultimately determined by the practice of a physician or veterinarian. Among the factors that need to be taken into account include the stage of the disease, route of introduction into the organism and the nature of education, the body weight of the mammal, surface area, age and General condition, as well as the specific compound, which must be entered in the body. Acceptable effective antitumor dose is in the range of approximately 0.1-120 mg/kg body weight, preferably 1.5 to 50 mg/kg, such as 10-30 mg/kg Total daily dosage can be used as a single dose, divided into several doses, for example 2 to 6 doses, which does not give injected into the body or administered by intravenous infusion over a chosen period of time. So, for a mammal weighing 75 kg daily dosage is approximately 8 9000 mg, and the typical daily dose of 2000 mg In the case, when there is a fractional multiple of the dose, the treatment usually can be carried out by introduction into the body of 500 mg of the compounds of formula (1) four times a day as pharmaceutic compound of formula (1), its simple ether, ester or salt) can be introduced into the body individually, this active compound is used preferably in the form of a pharmaceutical preparation. Compositions of the present invention for medical purposes include activetestsuite substance together with one or more pharmaceutically acceptable carriers for him and other therapeutic components. Carriers (excipients) must be pharmaceutically acceptable in the sense of compatibility with other components of the composition and not to have an undue influence on the recipient.

Thus, it is proposed pharmaceutical composition comprising a compound of formula (1) (in the form of its free base, simple ester or complex ether derivative or in the form of a pharmaceutically acceptable acid product), together with a pharmaceutically acceptable carrier for him.

It is also proposed a method of obtaining a pharmaceutical composition, in accordance with which is provided the combination of the compounds of formula (1), simple or complex ester, or its pharmaceutically acceptable salt with a pharmaceutically acceptable carrier for him.

Predlagaemye the compounds of formula (1), its simple or complex ester, or its pharmaceutically acceptable salt with a pharmaceutically acceptable carrier for him.

Although suggest that the antitumor activity of compounds of formula (1) peculiar to them when they are in free base form, it is often convenient to introduce such compounds in the body in the form of acid adducts of such compounds of formula (1). Such compositions include compositions suitable for ingestion by oral, rectal or parenteral routes (including subcutaneous, intramuscular and intravenous injections). Preferred are such compositions, which are intended for introduction into the body orally or parenterally.

Such compositions can be a drugs in dosage form, which can be prepared according to any method well known in the art Pharmacopoeia. In all such methods provides phase alignment activitiesthese substance with a carrier that includes one or more auxiliary components. Typically such compositions are prepared homogeneous or thorough mixing an active substance with a liquid carrier or Tonio, the product molded in the form of the desired drug.

Compositions of the present invention, it is acceptable for introduction into the body through the mouth, can be a discrete dosage unit, in particular capsules, pills, tablets or pellets, each of which contains a given number activitiesthese substances, powder or granules, a suspension in an aqueous liquid or non-aqueous liquid, in particular syrups, elixirs, emulsions or the metered fluid.

Tablets can be manufactured by extrusion or molding, you can use one or more auxiliary components. Molded tablets may be made by extrusion using the appropriate equipment, in which the active substance is used in a thin form, in particular in the form of powder or granules, possibly mixed with a binder component, lubricant additives, inert diluent, surface active agent or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of powdered activitiesthese substances with any acceptable media.

The syrup can be prepared by adding the active deistvii any auxiliary components. Such accessories may include flavoring or flavoring agents, agents inhibiting crystallization of sugar, or agents that increase the solubility of any other component, in particular polyhydric alcohol such as glycerin and sorbitol.

Compositions for rectal insertion into the body can be made in the form of a suppository with a conventional filler, in particular with cocoa butter.

Composition that is acceptable for parenteral administration into the body, usually comprise sterile water, the active drug substance, which is the preferred option should be isotonic relative to the recipient's blood. Such compositions must be a solution of the pharmaceutically and pharmacologically acceptable acid adduct compounds of formula (1), (solution) is isotonic relative to the recipient's blood. For example, such compositions can contain distilled water, 5% dextrose in distilled water or salt, and a pharmaceutically and pharmacologically acceptable acid adduct compounds of formula (1), which has an appropriate solubility in such solvents, for example cleaners containing hydrochloride Izet is also concentrated solutions or solid materials, containing compound formula (1), which upon dilution with an appropriate solvent to form a solution that is acceptable for parenteral administration into the body, as described above.

In addition to the above components, the compositions of the present invention can include one or more auxiliary components selected from the class of diluents, buffers, flavoring or flavoring, preservatives (including antioxidants) and the like.

All of the above solvents represented products varieties for reactions, so they were used without further purification, except for those procedures, which are shown below. Tetrahydrofuran (THF) was dried by distillation using a sodium-potassium alloy in a stream of nitrogen and immediately after that, used. The toluene was distilled using dihydride calcium in a stream of nitrogen and stored over molecular sieves 3A. As the chemicals used products varieties for reactions without any further purification in all cases, except as specifically allowed. Full name and address of the suppliers of reagents and chemicals are given at the first mention, hereinafter referred to in abbreviated form.

The drug is RA Waters Prep LC. System 500 using two 500-gram columns of silica gel (silicon dioxide) in all cases, except as specifically allowed. The columns of silicon dioxide, which is used for cleanup operations, represented the columns of silica gel for instant chromatography (Merck Co.Inc. Merck Chemical Division. Rahway, new Jersey, 07065 silica gel 60, 230-400 mesh mesh.). Funnel fused glass corresponding volume about 3/4 of the height filled with silica gel and evenly placed by Asturiana on the outer wall of the funnel. Then on top of the silica gel was placed a piece of filter paper and the upper part is evenly applied to the solution of the material to be cleaned. Careful vacuum with filter flask contributed to the rapid advancement of eluent through the column of silica gel. The fraction of the respective volumes were combined as required and directed for further manipulation.

A similar procedure shows the melting temperature (TPL.), solvent for recrystallization and the data of elementary analysis (all elements were analyzed with a difference of 0.4% from the expected value). Noted all the changes that were related to the procedure, in the th NMR (1H, 13C), IR and mass spectrograms for all new products corresponded to the expected and proposed structures. Provisions that have been defined for structural isomers were clearly established near the PMR-spectrograms, where 0 is a singlet, M multiplet, d doublet, DD double doublet, t triplet, q Quartet, W wide. All final products were dried in vacuum under a residual pressure of 20 mm RT.article at the same temperature overnight (12-16 h).

P R I m e R 1. 2-[[benzo(b)oil[2,1-d]thiophene-5-ylmethyl]-amino]-2-methyl - 1,3-propertiesmetaltheme.

In a round bottom flask equipped with a magnetic stir bar, a refrigerator, a thermometer, a trap Dean-stark tube for nitrogen and a bubbler, downloaded 4.94 g benzo (b) oil (2,1-d) thiophene-5-carbaldehyde (18,83 mmol, SISA pharmaceutical the laboratories, Inc. 763 Coucord Avenul Cambridge, Massachusetts, 02138), 1.98 g of 2-amino-2-methyl-1,3-propane diol (18,83 mmol Aldrich), 0.1 g of p-toluenesulfonic acid, monohydrate, and 200 ml of toluene. The mixture is stirred at the boiling temperature with removal of water for 2.5 hours or until until stopped the formation of water, which was extracted with 3 portions of 500 ml of ethyl acetate. An ethyl acetate extracts were collected. A large part of the toluene is then removed by distillation. is vision. In the reaction mixture in one portion was added 0,712 g (18,83 mmol) of solid Na borohydride (MRV of Manufacturing Chemists, Inc. 2909 Aigheand Ave, Cincinnati, HE 45212). Next, bath with ice was removed, the reaction mixture was allowed to warm to room temperature and then was stirred overnight. The reaction mixture was acidified using 10% hydrochloric acid and in a rotary evaporator removed the solvents. The crude solid product was subjected to shaking in 300 ml of 1 N. hydrochloric acid, filtered, washed with hydrochloric acid, was subjected to vacuum filtration to a moist condition and washed with 300 ml of diethyl ether. Then the material was dissolved in 200 ml of methanol, was filtered solution was podslushivaet 1 l of 1 n solution of hydrate of sodium oxide. The washing liquid with the solid white material was combined, filtered, washed with three portions of 500 ml of saturated sodium chloride solution, dried over 25 g of potassium carbonate (Mallinckrodt), filtered and concentrated in a rotary evaporator to obtain a white solid product. This latter was dissolved in a mixture of 200 ml of absolute ethanol with 3 ml of methansulfonate (99,5% Morton Thiokol, Inc. Alpha products, PO BOX 299, 152 Andover Street, Danvers, Massachusetts, 01923), the solution of Professor shall Arial three recrystallize from ethanol-hexane in the ratio of 1:3, the result obtained 2-[benzo(b)oil(2,1-a)thiophene-5-ylmethyl] -amino-2-methyl - 1,3-propertiesmetaltheme with TPL221-222aboutWITH 1H-NMR (80 MNz/d6-DMSO/ 8,66 (Shir. WITH2H, NH), 8,66 (s, 1H,), 8,48-7,56 (m, 8H, Az-H), 5,63 (Shir.T. 2H, HE), 4,85 (Shir. m, 2H, Az2-) of 3.77 (Shir. s, 4H-CH2IT), to 2.35 (s, 3H, CH3SO3-), of 1.39 (s, 3H, -CH3).

P R I m m e R 2. 2-[(benzo)b(naphthol)2,3-d-furan-6-ylmethyl)-amino]-2-methyl-1,3-propandiol.

2A. Benzo (b) oil (2,3-d)furan-6-carbaldehyde.

Benzo(b)oil(2,3-d) SISA has been formirovanie in accordance with the procedure of A. Rieche and other Chem Ber, 1960, 93,88. By thin-layer chromatographic analysis, it was found that the crude aldehyde consists of a single isomer. Purification by chromatographic treatment using silica gel and toluene, followed by recrystallization from a mixture of methylenechloride with hexane allowed achieving a 58% yield of pure material, which, as it was established NMR spectral analysis, represented benzo(b)oil(2,3-d)furan-6-carbaldehyde) with TPL169-171,5aboutC, 1H-NMR (300 MNz) (DCl3) 11,23 (c,1H, CHO), 9,39 (d, 1H, J1,2=8,8 HzH7), 8,51 (s, 1H, H11), 8,01 (d, 1H, J=6.8 cm HzH13), to 7.61 (d,IH, J=7,8 H H10), 7,58-7,52 (2D,D. D. 2N, N8,9), 7,41 (D. D. D. 1H, J1,27,5 HzI , J2,3=6,3 HzJ2,4-1,5 HzH2).

2B. 2-[(benzo)b(oil(2,3-d-furan-6-ylmethyl)-amino]-2-methyl - 1,3-propertiesmetaltheme.

Using the procedure of restorative amination described in example 1, benzo(b)oil(2,3-d)furan-6-carbaldehyde (2A) and 2-amino-3-methyl-1,3-propane diol (Aldrich) was obtained 2-[(benzo)(b)oil(2,3-d-furan-6-ylmethyl)- -amino]-2-methyl-1,3-propertiesmetaltheme, 0,4 H2O s TPL. 187-190aboutC (a mixture of ethanol-diethyl ether),

1H-NMR (300 MN) (d6-SO) 8,82 (s,1H, Ar-H11), 8,66 (Shir. s, 2H, -NH), 8,35, 8,29, 8,19, (3d, 3H, J=8H, Ar-H1,4,10),7,78, (W,H. J=8 HzAr H7), 7,76-7,46 (m, 4H, Ar-H2,3,5,8,9), 5,63 (Shir. W.2N-HE), to 4.98 (Shir. m, 2H, ArCH2), to 3.73 (Shir.s, 4H, -CH2HE, of 2.30 (s, 3H, CH3SO3), to 1.38 (s, 3H, -CH3).

P R I m e R 3. 2-[(benzo)(b)oil(1,2-d furan-5-ylmethyl)-amino]-2-methyl - 1,3-propandiol.

3A. -benzo(b)oil(1,2-d)furan-5-carbaldehyde.

Benzo (b)oil(1,2-d)furan)SISA has been formirovanie in accordance with the procedure of A. Rieche and others in Chem Ber. 1960, 93. By thin-layer chromatographic analysis, it was found that raw al is of silicon oxide and toluene, followed by recrystallization from a mixture of methylenechloride with hexane allowed achieving a 39% yield of pure material, which, as it was established NMR spectral analysis, represented benzo(b)oil(1,2-d)-furan-5-carbaldehyde with TPL143-145aboutC.

1H-NMR (300 MNz) (DCl3) of 10.50 (s, 1H, Cho), and 9.3 (d,1H, J=7,3 HzH4), 8,68 (d, 1H, J 7,3 H, H1), 8,42, (d, 1H, J 6HzH11), 8,24 (S, 1H, H6), 7,82-7,49 (m, 5H, H2,3,8,9,10).

3V. 2-[(benzo)(b)oil(1,2-d)furan-5-ylmethyl)-amino] -2-methyl-1,3-propertiesmetaltheme.

Using the procedure of restorative amination described in example 1, benzo(b)oil(1,2-d)(furan-5-carbaldehyde (3A) and 2-amino-2-methyl-1,3-propane diol (Aldrich) was obtained 2-[(benzo(b)oil(1,2-d)furan-5-ylmethyl)-amino] -2-methyl - 1,3-propertiesmetaltheme with Tpl.215-217aboutWith (a mixture of ethanol-diethyl ether).

1H-NMR (300 MNz) (d6-SO) to 8.94 (D. 1H,J=8H, Ar-H1), 8,75 (Shir.with 2N-NH), 8,63 (D. 1H, J= 8H, Ar-H11), 8,44 (d, 1H, J=8H, Ar-H4), 8,20 (c, 1H, Ar-H6), of 7.90-of 7.55 (m, 4H, Ar-H2,3,9,10), the ceiling of 5.60 (sh.with. 2N-HE), 4,82 (Shir. m, 2H, ArOH3-), to 3.73 (Shir.with. 4H-CH2IT), 2,32 (s,3H, CH3SO3), of 1.36 (s, 3H-CH3).

P R I m e R 4. 2-methyl-2-[(7-methyl-7H-benzo(c)carbazole-10-yl)- marked)-amino]-1,3-propandiol.

4A. 7-methyl-7H-benzo(c)carbazole.

6.6 g 7H-benzo (the complete dissolution of the added 7,56 g dimethylsulfate. The mixture was stirred for several minutes, after which TLC analysis using silica and toluene showed that the reaction is complete. The reaction mixture was poured into 2 l of a 1 n solution of hydrate of sodium oxide and mixed. The thus obtained solid material was collected by filtration, was dissolved in 300 ml of toluene and subjected to passage through a column of silica (50.8 x 50.8 mm), elwira toluene. The fractions containing the product boiled away the dryness, the solid mass was dissolved in 400 ml of methylene chloride and diluted with hexane. Concentration in vacuo allowed to obtain 5.0 g of a white solid, which was filtered and washed with pentane. Additionally 1.06 g of product (total yield amounted to the 6.06 g, 87%) received additional maturation and further concentration of the filtrate. The data of elemental analysis for C17H13N:

calculated: C 88,28 H 5,67 N 6,06%

found: 88,31 N 5,68 N 6,01%

4B. 7-methyl-7H-benzo(C)carbazole-10-carbaldehyde.

5.8 g of 7-methyl-7H-benzo(C)carbazole was dissolved in methylene chloride and treated at 13.0 g of the chloride of tetravalent tin in a stream of nitrogen. This mixture was cooled and added dropwise 3,74 g of alpha, alpha-dichlorodimethyl afire boiling under reflux for 15 minutes Thin-layer chromatographic analysis using silicon dioxide and toluene showed the completeness of the reaction. The reaction mixture is cooled, added to 300 ml of water and was stirred for 2 hours Biphasic mixture was filtered, provided the organic layer and boiled away its dry. The residue was dissolved in 100 ml of toluene and was Polyanovo through a column of silica (127 x 76.2 mm) with toluene. Suirvey ninth liter contained the main isomer, and this liter and tenth liter (suirvey dichloromethane) were combined and boiled away the dryness. The residue was dissolved in 200 ml of dichloromethane, was filtered and diluted with pentane in a 1:1 ratio. The solution is evaporated until then, until the start of crystallization. Added additional amount of pentane and the volume was reduced to 150 ml Filtering allowed to obtain 3,83 specified in the header of the product as a pale yellow solid with TPL164-165aboutWith the net, as shown by thin layer chromatographic analysis. The data of elemental analysis for C18H13N:

calculated: C 83,37 H of 5.05 N OF 5.40%

found: 83,19 N 5,07 N ARE 5.36%

From 3 to 8 liters of fluid, elyuirovaniya from a column of silica, combined and boiled away the dryness. The solid material rastvoritelyu product, which was dissolved in 200 ml of dichloromethane, diluted with 200 ml of hexane and concentrated to obtain 0.55 g of crystalline yellow solid product, which, as found by NMR spectrographic analysis consisted of a 7-methyl-7H-benzo(C)carbazole-5-carbaldehyde with TPL210-213aboutC. elemental analysis Data for C18H13NO:

calculated: C 53,37 H of 5.05 N OF 5.40%

found: C 83,43 H 5,08 N 5.37 PERCENT

4C. 0.3 hydrate 2-methyl-2-[(7-methyl-7H-benzo(C)carbazole-10-yl(methyl)-amino] 1,3-propeciageneric.

The specified connection obtained by the method similar to described in example 1 from 7-methyl-7H-benzo(C)carbazole-10-carbaldehyde and 2-amino-2-methyl-1,3-propane diol; TPLwas 229-230aboutWith (decomposition, the mixture of methanol with diethyl ether in the ratio 1:3). The data of elemental analysis for C22H15N2O2C1,0,3 H2ABOUT:

calculated: C 67,70 H 6,61 N 7,18 Cl remaining 9.08%

found: C 67,61 H 6,53 N 7,17 Cl 9,05% 1H-NMR (MNz) (d6DMSO) 9,2-8,97 (m, 4H, Ar H1,11, NH), 8,2-of 7.24 (m, 5H, Ar H2,3,5,6,9), the ceiling of 5.60 (Shir.with. 2H, HE), 4,46 (Shir. m, 2H, Ar CH2-), Android 4.04 (s, 3H, -NCH3), 3,71 (Shir.with. 4H, -CH2IT), 1,34 (C. 3H, CH3).

P R I m e R 5. 2-(benzo(b)oil[2,1-d]furan-5-ylmethyl)-amino-2 - methyl-PROPANEDIOL in a stream of nitrogen in 400 ml of methylene chloride. Then to the solution was added 14, 59 g of the chloride of tetravalent tin, then was 4.02 g of alpha, alpha-dichlorodimethyl ether and the resulting mixture was stirred overnight, followed by boiling under reflux for 3 minutes Added 200 ml of water and the mixture was stirred over night. The organic layer was separated and boiled away the dryness. The residue was dissolved in 200 ml of toluene and was Polyanovo through a column of silica (88.9 x 76.2 mm) with toluene. Containing the product fractions were collected, boiled away the dryness, re-dissolved in 200 ml of methylene chloride, diluted with 500 ml of pentane and concentrated to a volume of 150 ml To the precipitate was added an additional 200 ml of pentane, and then the material was filtered, received 5.0 g of the desired compound with TPL. 118-121aboutS. filter has committed an additional $ 0.34 g of product. The data of elemental analysis for C17H10ABOUT2:

calculated: 82,91 N 4.09 TO%

found: 83,00 N 4,13%

These NMR spectrum was consistent with the product structure.

5V. 2-(benzo)(b)oil(2,1-d)furan-5-ylmethyl)-amino-methyl - 1,3-propandiol.

In accordance with the method similar to described in example 1 using benzo(a)the oil(2,1-a)furan-5-carboxamide guide and 2-SUP>With (a mixture of ethanol with diethyl ether in the ratio 1:1). The data of elemental analysis for C22H25NO6S:

calculated: C 60,23 H 5,93 N 3,19 S 7,31%

found: 60,22 N 5,93 N S 3,18 7,30% 1H-NMR (80 MNz) (d6-DMSO) 8,60 (Shir. with 2N-NH), 8,51 (S,1H, Ar-H6), 8,50-7,40 (m, 8H, Ar-H1,2,3,4,7,8,9,10) 5,63 (Shir. C. 2N-HE), 4,70 (Shir.with. 2H, CH2-), 377 (lat.with. 4H-CH2IT), a 2.36 (s, 3H, CH3SO3), 1,39 (C. 3H-CH3).

Test results of antitumor activity. Methods of evaluation of antitumor action of such compounds are those which are used in Timor Panel programme Development Therapeutics Program Division of cancer treatment National cancer Institute (Goldin A. et.al. Methods in Cancer Research. Academic Press, 1979, I. XVI, S. 165). To improve the efficiency of testing the level of dosage and the method of their introduction into the organism, some changes were made.

Test lymphoid leukemia R/0. As experimental animals used mice DM2-F, same sex, weighing 20 3 g / day 0 animals as the control group and the group that was exposed to treatment, intraperitoneal injection was administered a suspension of 106living tumor cells R/0. During each test, evaluate group of 6 animals. The test compounds used as drugs or saline solution containing 0.05% product Tween 80, or in distilled water containing 5% dextrose. These drugs were injected intraperitoneally on the 1st, 5th and 9th days in relation to implantation of tumor cells. Dosage was calculated in mg/kg depending on the weight of each individual animal; recorded the day of death of each animal was calculated averages for each group of animals groups, which were treated (T) and control groups (). The criterion of activity of the compounds was determined by the formula T/C x 100 120% of the test Results with R/0 are summarized in table. 1 and 2.

Data biological activity of ester derivatives:

1) 2,2-bis(methoxymethyl)-2-(((7-methyl-7H-benzo(C)carbazole-10-yl)methoxy)amino)ethanol NA Optimal dose

mg/kg T/C x 100%

100 150

2) 2-(ethoxymethyl)-2-(((7-methyl-7H-benzo(C)carbazole-10-yl-) methyl)amino)-1,3-propandiol NA Optimal dose

mg/kg T/C x 100%

85 115

3) 3-methoxy-2-methyl-2-(((7-methyl-7H-benzo(C)-carbazole-10-yl) methyl)amino)propanol NA Optimal dose

mg/kg T/C x 100%

100 190

4) (1,1-bis(methoxymethyl)ethyl) - (7-methyl-7H-benzo(C)carbazole-10-yl) methyl)amine Hcl Wholesale is a group of formula (1) in the form of methansulfonate 500,0 Pre gelatinizing corn starch 60,0 Nitroglycol starch 36,0 Stearate 4,0

The compound of formula (1) finely crushed and homogeneous mixed powder bases for the preparation of medicines, pre-gelatinization corn starch and sodium starch glycolate. Powders are moistened with purified water to form granules. The granules are dried and mixed with magnesium stearate. Then the composition is subjected to extrusion with molded tablets with a weight of approximately 600 mg each.

B. Tablet, mg Compound of formula (1) 500,0 Corn starch 70,0 Lactose 83,8 magnesium Stearate 4.2 Polyvinylpyrrolidone 14,0 Stearic acid 28,0

The compound of formula (1) finely crushed and homogeneous mixed with powdered bases for the preparation of medicines, corn starch and lactose. Powders are moistened with a solution of polyvinylpyrrolidone in purified water and denatured alcohol to form granules. The granules are dried and mixed with powdered stearic acid and magnesium stearate. Then the composition is subjected to extrusion with molded tablets with a weight of approximately 700 mg each.

Century Capsules, mg Compound of formula (1) 500,0 Corn starch 50.0 Stearate 3,0

Finely ground compound of formula (1) is mixed with a powder to the more with stearic acid and the mass of semi-solid fill gelatin capsules.

, Syrup, mg Compound of formula (1) 250,0 Ethanol 250,0 Glycerin 500,0 Sucrose 3500,0 Aromatic or flavoring Needed

the amount of Dye Needed

the amount of Preservative 0.01% Of Purified water Required

number

to volume 5

The compound of formula (1) is dissolved in ethanol, glycerin, and portions of purified water. In another serving of hot purified water dissolve sucrose and preservative, then add the dye and dissolved. Both solution are mixed and cooled, then add flavoring or flavoring additive. In the final mass is added purified water. The resulting syrup is thoroughly mixed.

D. Preparation for intravenous injection.

The compound of formula (1) (methanesulfonate) 5.0 mg

Glycerin is the Amount needed

for isotonicity

Preservative 0,1%

Hydrochloric acid, or a hydrate Number needed for

of sodium oxide regulation of pH

Water for injection Quantity required

to a volume of 1 ml

The compound of formula (1) and the preservative is added to the glycerin and the portion of water for injection. The pH value is regulated addition of hydrochloric acid or hydrate of sodium oxide. Add water to dostigaeytsya by filtration through a membrane filter of 0.22 μm and in aseptic conditions, they fill a sterile 10-ml vials or test tubes.

1. Polycyclic biocidal compounds of formula

ArCH2NR,

where Ar is 2-benzo[b] oil[2,1-d]thiophene - 5-yl, 2-benzo[b]oil[2,3-d]furan-6-yl, 2-benzo[b] oil[1,2-d] furan-5-yl, 2-(7-methyl-7H-benzo[c]carbazole-10-yl)methyl or 2-benzo[b]oil[2,1-d]furan-5-yl;

R group CH2OH-CCH3-CH2OH,

monomethylamine or monoethylamine ethers, esters or their acid additive salt.

2. Pharmaceutical composition having anti-tumor activity, comprising an active substance and a pharmaceutically acceptable carrier, characterized in that the active substance use connection on p. 1 in an amount of 5 to 50 mg per dose.

3. The composition according to p. 2, characterized in that the active compound is 2-[methyl-2-(7-methyl-7H-benzo[c] carbazole-10-yl)methylamino]-1,3-potential or onomatology monotropy ether, ester or acid additive salt.

4. Polycyclic compounds of the formula ArCH=NR, where Ar and R have the specified values.

Priority signs:

15.11.84 when Ar is 2-benzo[b]oil[2,1-d]thiophene-5-yl, 2-benzo(b)oil[1,2-d] furan-5-yl, 2-benzo(b)oil[2,1-d]furan-5-yl and R - group ;

13.09.85 when Ar is 2-benzo(b)oil(2,3-d)furan-6-yl and 2-[7-methyl-7H-benzo(c)carbazole-10-yl]methyl, R GRU is

 

Same patents:

The invention relates to heteroalicyclic alkanols derived, and in particular to methods of obtaining new polycyclic biocidal compounds of General formula I

ArCH2Other where Ar is 2-benzo/b/oil/2,1-d/thiophene-5-yl; 2-benzo/db/oil/2,3-d/furan-6-yl; 2-benzo/b/oil/1,2-d/furan-5-yl; 2-/7-methyl, 7H-benzo/with/carbazole-10-yl/methyl, 2-/benzo/b/oil/2,1-d/furan-5-yl; R= -H3or their salts, which can be used as anticancer agents

The invention relates to a method for producing novel compounds that have biological activity similar to the activity retinova acid, more specifically, to methods and intermediate products used in the synthesis dogsleding acetylene compounds with similar retinova acid activity

The invention relates to new derivatives dihydroxyphenylpropionic General formula

where R is H; R1-NO2or R-NO2, R1-H, which possess antihypoxic and coagulation action

The invention relates to pharmaceutical industry and relates to a method of obtaining purpurine-18, used in medicine for treatment of cancer

The invention relates to polycyclic compounds, their pharmaceutical compositions and methods of their use in human diseases associated with impaired memory processes, diseases of the nervous system and/or depression, such as, but not limited to, degenerative changes in the nervous system

The invention relates to medicine, namely to pharmacology
The invention relates to medicine, in particular to Hematology, and concerns the development of new opportunities for new therapeutic drugs from the blood

The invention relates to heterocyclic derivatives having antibacterial activity, to processes for their preparation, to their containing compositions and to their use in medicine

The invention relates to new derivatives of benzopyran that have protivogipertenzin activity and can be used in the treatment and prevention of cardiovascular diseases

The invention relates to new chemical compound, specifically to 5H-3,4,6,7-tetrahydro-10-methoxy-5-methyl-6-(1', 1'-dioxide)-3'- metalorigin-4'-methoxy-benzo[B] thiophene-7 yl)-furo-[4.3.2

The invention relates to new chemical compound, particularly to a 10-methoxy-5-methyl-6-(1', 1'-dioxido-2' -meta-chlorvinyls-3'-hydroxy-4' -methoxy-benzo[b] thiophene-7-yl)-5H-3,4,6,7-tetrahydro[4,3,2-Q]-[3]benzazocine formula

(I) with an antidepressant

The invention relates to a method for producing novel compounds that have biological activity similar to the activity retinova acid, more specifically, to methods and intermediate products used in the synthesis dogsleding acetylene compounds with similar retinova acid activity
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