Derivatives phenanthridine, a pharmaceutical composition having antitumor activity, the method of inhibiting the growth of cancer cells

 

(57) Abstract:

The invention relates to new derivatives of phenanthridine General formula A, where R1substituted or unsubstituted lower aliphatic hydrocarbon group, R is an aliphatic hydrocarbon chain having 2 to 6 carbon atoms, which may be optionally substituted by a Deputy selected from the group comprising lower alkyl group, halogen or a hydroxy-group, each of Y and Z independently represents hydrogen, hydroxy or lower alkoxygroup, or Y and Z together with the formation of methylenedioxy or phenyl ring, and X-- acid residue or a residue hydrogen acid, and a derivative of phenanthridine General formula V, where R1, R, Y, Z are defined above for the formula A. in Addition, the disclosed salt of 2,3-(methylenedioxy)-7-hydroxy-8-methoxy-5,6-propane-benzo[C] phenanthridine, a pharmaceutical composition having antitumor activity, and a method of inhibiting the growth of cancer cells on the basis of the presented compounds. The invention can be used in medicine as an anticancer drug. 5 S. and 3 C.p. f-crystals, 7 PL.

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The technical field

Infusion is ewnetu and as expected, which is an effective drug and its pharmaceutical use.

Background of the invention

Currently in chemotherapy to treat patients with cancer use of alkylating agents, metabolic antagonists, antibiotics, plant alkaloids, etc.

It is known that the chloride or iodide, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxy-benzo[C] phenanthridine described in Chem. Pharm. Bull., 33, 1963, and antitumor activity (Japanese patent KOKAI 2-243628 and 3-184916). Derived benzo[C]phenanthridine and its antitumor activity is also described in Japanese patent KOKAI 5-208959.

Malignancy has many characteristics. Moreover, the application of these antitumor agents causes a resistance to them. Thus, there is a need to develop a new anticancer agent.

Description of the invention

The authors of this invention have discovered a new derivative of phenanthridine, having a structure formed by linking nitrogen atom in position 5 with the carbon atom in position 6 through aliphatic hydrocarbon chain, adjacent to them, and also found that the new production is ogicheskom metabolic reactions. These properties are derived phenanthridine, as found, are extremely favorable for application in medicine, so they are the basis for the present invention.

Thus, the present invention relates to a new derivative of phenanthridine represented by the General formula (A):

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where R1substituted or unsubstituted lower aliphatic hydrocarbon group;

R is an aliphatic hydrocarbon chain having 2 to 6 carbon atoms, which may be optionally substituted by a Deputy selected from the group comprising lower alkyl group, halogen and a hydroxy-group;

each of Y and Z independently represents hydrogen, hydroxy or lower alkoxygroup; or Y and Z together with the formation of methylenedioxy or phenyl ring;

X-- acid residue or a residue hydrogen acid.

The present invention further relates to a new derivative of phenanthridine represented by the General formula (I):

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where R1substituted or unsubstituted lower aliphatic hydrocarbon group;

R is a lower aliphatic hydrocarbon chain having 2 to 6 carbon atoms, which may be optional the BR>
each of Y and Z independently represents hydrogen, hydroxy or lower alkoxygroup; or Y and Z together with the formation of methylenedioxy or phenyl rings.

The present invention further relates to pharmaceutical compositions comprising, as active ingredient, a compound represented by the General formula (A) or (B), together with a pharmacologically acceptable carrier.

The present invention further relates to an antitumor agent comprising, as active ingredient, a compound represented by the General formula (A) or (B), together with a pharmacologically acceptable carrier.

The present invention further relates to the compound represented by General formula (A) or (B) for use in pharmaceutical compositions in the form of the active ingredient.

The present invention further relates to the use of compounds represented by the General formula (A) or (B) upon receipt of a pharmaceutical composition for the treatment or prevention of tumors.

The present invention further relates to a method of treatment or prevention of tumors involving the introduction of human connection represented by the General formula (A) or (B) in effect and with the present invention, the lower aliphatic hydrocarbon group includes, for example, alkyl group having 1-5 carbon atoms, and alkenylamine group having 3-5 carbon atoms. Examples of such alkyl groups having 1-5 carbon atoms, are methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, etc. Examples alkenylamine group having 3-5 carbon atoms are allyl, 2-butenyl, 3-methyl-2-butenyl, etc., These lower aliphatic hydrocarbon groups may be optionally substituted, and examples of such substituents are a hydroxy-group, C1-C5alkoxygroup, C1-C5alkoxycarbonyl group, acetyl group, halogen, carnemolla group or phenyl group, optionally substituted by a methoxy group.

Specific examples of the aliphatic hydrocarbon group which may be substituted or not substituted, are methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, 2-hydroxypropyl, allyl, 2-butenyl, 3-methyl-2-butenyl, methoxycarbonylmethyl, isopropoxycarbonyloxymethyl, carbamoylmethyl, benzyl, 4-methoxyphenethyl, vermeil, trifluoromethyl etc., Particularly preferred are methyl, ethyl, allyl, 2-hydroxyethyl, 2-methoxyethyl, 2-who in carbon in the General formula (A) and (C) in accordance with the present invention, which may be substituted by the Deputy selected from the group comprising lower alkyl group, halogen and a hydroxy-group, includes, for example, substituted or unsubstituted polymethene group having 2-6 carbon atoms. The lower alkyl group as Deputy aliphatic hydrocarbon chain is an alkyl group having 1-5 carbon atoms, e.g. methyl, ethyl, propyl, 1-propyl, butyl, tert-butyl, pentyl etc. Preferred examples of the substituent are methyl and ethyl. Examples of the halogen atom are fluorine, chlorine, bromine and iodine.

Specifically aliphatic hydrocarbon chain having 2 to 6 carbon atoms which may be substituted or not substituted, refers to-CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2CH(OH)CH2-,

-CH2CHFCH2-, -CH2CF2CH2-, -CH2SSSN2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-,

-CH2CH2CH2CH2CH2CH2and so on, Especially preferred is unsubstituted polymethene circuit having 3-4 atoms of carbon is ormula (a) and (b) in accordance with the present invention an example of the lower alkoxygroup is alkoxygroup, having 1-5 carbon atoms, such as methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy, tert-butoxy, pentox and so on, preferably, alkoxygroup having 1-3 carbon atoms, such as methoxy, ethoxy, n-propoxy or ISO-propoxy.

The remainder of the acid X-in the General formula (A) in accordance with the present invention means the remainder of the acid, forming a normal salt, for example, X-represents a halogen ion such as chloride ion, bromide, iodide or fluoride, or sulfate ion, nitrate or p-toluensulfonate. The remainder of the hydrogen acid means the residue of the acid forming the salt of the hydrogen of the acid. The remainder of the hydrogen of the acid contains 1 or 2 of the hydrogen atom, for example, hydrosulphate ion, ion anydataset and so on, Among them ion chloride and hydrosulphate ion are particularly preferred.

In this invention, preferred examples of such compounds are compounds of General formulas (a) and (b) in which R1represents methyl, ethyl, allyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, carbamoylmethyl or trifluoromethyl, R represents an unsubstituted polymethene circuit having 3-4 carbon atoms, a Y and Z together with can be obtained in the following processes, which are divided into two types. Each of the processes explained below.

1. The synthesis of compounds represented by the General formula (A), where R1- methyl (hereinafter referred to as the synthesis of type 1 in the General formula (A)):

(a) Compound of General formula (A), where R1is methyl, can be synthesized in accordance with the following reaction scheme 1.

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In the initial compounds of General formula (1), Y and Z have the same meaning as in General formula (a) and (B). The original compound of General formula (1), where each of Y and Z independently represents hydrogen, hydroxy or lower alkoxygroup, or Y and Z together with the formation of methylenedioxy, i.e., derivatives of 7-benzyloxy-8-methoxy-benzo[C] phenanthridine, can be synthesized using the method described in Japanese patent KOKAI 5-208959.

The original compound of General formula (1), where Y and Z together with the formation of the phenyl ring, i.e., the derivative of 8-benzyloxy-9-methoxy-oil[2,3-C]phenanthridine, can be synthesized in accordance with reaction scheme 3, below.

In the General formula (D) M corresponds to R in the General formulas (a) and (b) is an aliphatic uglevodoroy chain, it is the fact that the lower alkyl group, halogen and a hydroxy-group; and W represents an iodine or bromine.

Haloalkene compound of General formula (D) can be synthesized in the usual way.

The compound represented by formula (C) can be obtained by heating compounds of General formula (1) and haloalkylthio compounds of General formula (D) in a solvent such as acetonitrile, etc. in the presence of the promoter of radical reactions, such as ORGANOTIN hydride, organosilane hydride and so on ; the radical reaction initiator such as 2,2'-azobis(isobutyronitrile) and so on; and acids, such as triperoxonane acid, with stirring.

The compound of General formula (C) is subjected to reaction with the acid chloride of the acid, such as methanesulfonate, p-toluensulfonate and so on, or acid anhydride, such as triperoxonane anhydride, etc. in an organic solvent in the presence of a base, such as triethylamine, etc. while cooling with ice to room temperature followed by treatment of the reaction mixture at a temperature from room temperature up to 110oFor cyclization.

Then carry out the removal of the protective group of the reaction product, preferably without isolation and purification of the product. Natialie 7-benzyl group can be carried out by treatment at room temperature to 100oIn acidic conditions using concentrated hydrochloric acid and so on,

The acid treatment is carried out by dissolving in a solvent the compound obtained by removing protection, and added to the acid solution such as hydrochloric, sulfuric, p-toluenesulfonic acid, etc., In General, the amount of acid is about 1-3 moles per mole of the compound.

In accordance with the above procedures may be obtained from a type 1 connection represented by the General formula (A).

(b) Connection type 1 in the General formula (A) can also be synthesized in accordance with the following reaction scheme 2.

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In the above reaction scheme W is an organic or inorganic salt of the metal; L - lower alkyl group; M' is an aliphatic hydrocarbon chain having 2 to 6 carbon atoms, which may be optionally substituted by a Deputy selected from the group comprising lower alkyl group, halogen and a hydroxy-group; a Q - protective group.

The reaction of compounds of General formula (1) with meteorous agent is conducted by heating and the absence of a solvent, or by dissolving in C6-C10hydrocarbon solvent such to the usual within 1-24 hours preferably 2-10 hours.

Can be used any metymirumi agent commonly used for N-methylation of the pyridine ring. It is preferable methylsulfonate used for methylation, for example, methylsiloxanes of benzosulfimide or methyltrichlorosilane. Specific examples include methyl p-toluensulfonate, methyl 2-nitrobenzenesulfonate and methyltrichlorosilane.

N-methylated thus the connection is mixed with a lower alcohol (L-OH), such as ethanol etc., preferably methanol, ethanol or n-propanol, usually at a temperature of from 0oC to room temperature in the presence of a base to obtain the compounds of General formula (E).

The connection represented by the General formula (E), is dissolved in an aprotic solvent, for example, hydrocarbon solvent such as benzene, toluene, xylene and so on; ether solvent such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran and so on; the solvent halide type, such as methylene chloride, 1,2-dichloroethane etc., Then the solution of the compound (E) add ORGANOMETALLIC compound of General formula (G) in an amount of 1-10 equimole, precocity boron ester. The reaction is carried out, stirring the mixture at a temperature(-)78-(+)50oWith, preferably, at a temperature of from -20oWith up to room temperature over a period of time from 5 minutes to 24 hours, preferably from 10 minutes to 10 hours.

ORGANOMETALLIC compound of General formula (G) can be any ORGANOMETALLIC compound used in conventional reactions of nucleophilic substitution. As the ORGANOMETALLIC compound is used, for example, organic compounds of lithium, magnesium, zinc, aluminum or copper, preference is given magnetogenesis connection. Specific examples of ORGANOMETALLIC compounds include 3-(tert-butyldimethylsiloxy)propylene bromide, 2-methyl-3-(tert-butyldimethylsiloxy)propylene bromide and 4-(tert-butyldimethylsiloxy)butylamine bromide.

The reaction product obtained in the above reaction, nucleophilic substitution, flavored with oxidation oxidizing agent, receiving the compound of General formula (F). The reaction can be used in a variety of oxidizing agents such as manganese dioxide, leads to compounds, which lead and dichlorodicyanoquinone (DDQ), preferably manganese dioxide. Reenie 1-120 minutes, preferably 5-60 minutes.

Removing the protective group in the compound of General formula (F) leads to the production of compounds of General formula (C). As a protective group commonly used substituents used to protect the hydroxy-group, for example, substituted methyl group, such as methoxymethyl, benzoyloxymethyl, tetrahydrofuryl, tert-butyl, n-methoxybenzyl, triphenylmethyl and so on; trialkylsilyl group, such as tert-butyldimethylsilyl, trimethylsilyl, and so on; acyl group such as acetyl, chloroacetyl, benzoyl, isobutyryl, etc. For removal of the protective group used the appropriate procedure for each protection group. For example, the removal of the protective group Q and a protective group type trialkylsilyl used to protect the hydroxy-group in M', carried out by adding to the reaction mixture of fluoride, such as tetrabutylammonium fluoride, potassium fluoride, cesium fluoride, etc. in a solvent such as tetrahydrofuran, acetonitrile, etc. and keeping at a temperature of 0-80oWith, preferably, 0oWith up to room temperature. Then the compound of General formula (C) is subjected to cyclization in the same manner as in reaction scheme 1. The removal of the protective group, and then acid OS) From compounds of General formula (1), used as starting compound in the reaction schemes 1 and 2, in accordance with reaction scheme 3 can be synthesized derivative of 8-benzyloxy-9-methoxy-oil[2,3-C] phenanthridine, in which Y and Z together form a phenyl ring.

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1-Aminoanthracene formula (J) and 2-benzyloxy-3-methoxy-6-halogenoalkane formula (K), which can be obtained by a method described, for example, J. C. S. Perkin I, 1221 (1976) and J. Org. Chem., 53, 1708(1988), is heated at a temperature of 80-110oWith toluene or benzene for 1-3 hours. The reaction mixture was concentrated, and water by-product is removed by azeotropic distillation with toluene or benzene. Preferably, fresh toluene or benzene is added to the concentrate, and the above procedure of heating with subsequent concentration of repeat 2-4 times to get digidratirovannogo condensation products of (Chippewa base) almost quantitatively. The condensed position degradirovannoi condensation products of restoring to obtain compounds of General formula (H).

Can be used any reducing agent capable of restoring the double bond carbon-nitrogen. Recovery is preferably carried out when the room is

In formulas (K) and (N) And represents a halogen atom.

The compound of General formula (H) is subjected to cyclization (condensation reaction through the removal of kaleidotrope) in an organic solvent, using ORGANOTIN hydride compound, preferably Tripeptide (1-8 carbon atoms) compound of tin hydride, such as anti-hydride or hydride trioctylamine, or diplodonta (1-8 carbon atoms) compound of tin hydride, for example, hydride diphenylurea. As ORGANOTIN hydride compounds in this reaction, it is generally preferable to use the anti-hydride. The reaction can be carried out by dissolving the compounds of General formula (H) and 1-6 equimolar amount, preferably 2-3 equimolar amount, ORGANOTIN hydride compound in an organic solvent, preferably a hydrocarbon solvent with 6-10 carbon atoms, for example, toluene, xylene, benzene, etc. and heating the solution at 5-150oWith, preferably 80-130oWith over a period of time from 2 minutes to 4 hours, preferably 5-60 minutes, preferably in the presence of initiator radicals, such as 2,2'-azobis(isobutyronitrile), 2,2'-azobis(2-meth is camping, preferably, without extracting from it the condensed product is subjected to oxidative aromatization position (place) cyclization with an oxidizing agent. The reaction is carried out at a temperature of 0-120oWith, preferably, at a temperature of from room temperature to 100oFor 1-120 minutes, preferably 5-60 minutes, getting derived 8-benzyloxy-4-methoxy-oil[2,3-C]phenanthridine represented by the General formula (2). In this reaction can be used in a variety of oxidizing agents. Examples of oxidizing agents are manganese dioxide, leads to compounds, which lead, dichloromethane-benzoquinone (DDQ), especially preferred is manganese dioxide.

2. The synthesis of compounds represented by the General formula (A), where R1substituted or unsubstituted lower aliphatic hydrocarbon group other than methyl (hereinafter referred to as the synthesis of type 2 in the General formula (A)):

Connection type 2 in the General formula (A), where R1substituted or unsubstituted aliphatic hydrocarbon group other than methyl, represented by the following formula:

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where R2substituted or unsubstituted aliphatic hydrocarbon group other than methyl; a R, Y, Z and X-and the relevant procedures. That is, the compound of General formula (3):

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where R2substituted or unsubstituted aliphatic hydrocarbon group other than methyl; Y and Z have the meanings indicated in the General formula (A), is used as the source connection. The reaction is carried out in a manner similar to the reaction scheme 1 or 2, i.e., connection type 2 can be synthesized in accordance with reaction scheme 1 or 2, except that instead of the compounds of General formula (1) is used as a compound of General formula (3). To obtain compounds containing, for example, the hydroxy-group as a substituent on the aliphatic hydrocarbon group represented by R2in the connection type 2, represented by the General formula (A), use the connection with the hydroxy-group protected with a protective group, as R2in connection with the General formula (3). The protective group can be easily removed, as in reaction scheme 1 or 2.

When obtaining compounds of General formula (3) compound, in which Y and Z each independently represents hydrogen, hydroxy or lower alkoxygroup, or Y and Z together, forming methylendioxy, can be obtained by a method described in Japanese patent KOKAI 5-208959, using as source m is vodorodnaya group, other than methyl, in a manner similar to the method of obtaining the derivative of 7-benzyloxy-8-methoxy-benzo[C] phenanthridine General formula (1) shown in reaction schemes 1 and 2.

The original compound of General formula (4) can be obtained in a known manner by the synthesized 2-benzyloxy-3-hydroxybenzaldehyde obtained by the method described, for example, in J. C. S. Perkin I, 1221 (1976) and J. Org. Chem. , 53, 1708 (1988), and then the interaction of the reaction mixture with a compound of General formula (5):

R2-A1, (5)

where R2has the same meaning as in the formula (4), a a1- tsepliaeva group such as halogen atom, alkylsulfonyl group and so on, in an organic solvent in the presence or absence of a base.

In the General formula (3) compound, in which Y and Z are connected with the formation of the phenyl ring, i.e. compounds of General formula (6):

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where R2substituted or unsubstituted aliphatic hydrocarbon group other than methyl, can be obtained in a manner similar to the method of obtaining the derivative of 8-benzyloxy-9-methoxy-oil[2,3-C]phenanthridine in the above reaction scheme 3, except that as the starting compound used soedin, represented by the General formula (A), by reaction with base easily releases from its molecule one equivalent of acid. Thus, it can be obtained the following new structure derived phenanthridine represented by the General formula (I):

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where R1, R, Y and Z have the meanings indicated in the General formula (A). Alternatively, the compound of General formula (I) is easily transformed into a compound of General formula (A) in the reaction with acid.

The compound of General formula (I) is more soluble in lipids than the compound of General formula (A). However, it is believed that the compound of General formula (A) exerts its pharmacological action in the form of compounds of General formula (I) in vivo for the manifestation of antitumor activity. Moreover, the compound of General formula (V) plays the role of intermediary in the synthesis of compounds of General formula (A). Thus, in the reaction schemes 1 and 2 compound of General formula (V) obtained after removing the protection.

In the acid treatment of compounds of General formula (V) obtained after removal of the protective group, get a connection, General formula (A) in the reaction schemes 1 and 2. Also in the synthesis of compounds of type 2, represented by the General formula (A), corresponding to state acid treatment of compounds of General formula (I) receive the compound of General formula (A).

Connection in accordance with the present invention is characterized as described below chemical and biological properties.

Derivatives phenanthridine represented by the General formulas (a) and (b) contain a substituted or unsubstituted aliphatic hydrocarbon chain represented by R in the form of partial patterns. It was found that the cyclic structure is used for spatial protection of the site, which is thought to be has many chemical and biological reaction abilities in the known derivatives of benzo[C]phenanthridine, for example, gigajoules 2,3-(methylenedioxy)-5-methyl-7-hydroxyzi-8-methoxy-benzo[C]phenanthridine (Japanese patent KOKAI 5-208959), and therefore this feature provides improved resistance to chemical recovery and biological metabolic reactions.

For example, the known gigajoules 2,2-(methylendioxy) -5-methyl-7-hydroxy-8-methoxy-benzo[C] phenanthridine recovers rapidly in aqueous solution in the presence of cyanoborohydride sodium as the reducing agent, leading to the disappearance of phenanthridine for a few minutes. In addition, when conducting in vitro metabolic studies with ophys., 282, 183 (1990), observed obtaining metabolite. This product coincides with the recovered product obtained by the above chemical recovery.

Chloride 2,3-(methylenedioxy)-7-hydroxy-8-methoxy-5,6-propane-benzo[C]phenetidine, which is one of the compounds in accordance with the present invention, is treated with cyanoborohydride sodium in aqueous solution at room temperature. When compared with known above gigajoules 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxy-benzo[C] phenanthridine connection in accordance with the present invention disappears explicitly gradually. Moreover, metabolic study in vitro using liver homogenate (S9) derived from human liver, the metabolite is not formed, indicating that the connection is in accordance with the present invention is resistant to reductive metabolic reactions. Therefore, the connection in accordance with the present invention has a high resistance and therefore extremely useful as a drug.

Next, typical examples of the derived phenanthridine represented by the General formula (A) shown in table. 1. One of the measures.

When using the derived phenanthridine in accordance with the present invention of General formula (A) or (B) as a drug, pharmaceutical drugs and route of administration applicable to various known methods. This means that the derived phenanthridine in accordance with the present invention may be introduced parenterally, orally, intrarectally etc. Derived phenanthridine may have any form suitable for pharmaceutical drugs, including injections, powders, granules, tablets, suppositories, etc. In obtaining pharmaceutical compositions derived from phenanthridine, if necessary, can be used in a variety of excipients used in the production of medicine, namely, carriers and other additives such as a stabilizer, a preservative, a calming agent, emulsifier, etc., if only they have no harmful effects on the active ingredient.

In pharmaceutical preparations, the content of the derived phenanthridine submitted to the General formula (A) or (B) may vary within a wide range depending on the preparative form, but usually in the range of 0.01-100 wt. %, predpochitayut.

Dose derived phenanthridine represented by the General formula (A) or (B) may vary depending on the patient's condition and so on, but it is approximately 50-500 mg per day for an adult patient.

As indicated above, the derivative phenanthridine in accordance with the present invention, represented by General formula (a) and (B) possess anti-tumor activity both in vitro and in vivo, thus, it is expected that they will be effective in the treatment of cancer.

Further, the methods of obtaining the derivatives of phenanthridine in accordance with the present invention and their pharmacological action, and their pharmaceutical compositions are described in more detail by means of examples and examples of trials of pharmacological action. However, it is assumed that the present invention is not limited to only these examples.

Example 1

Synthesis of 6-(3-hydroxypropyl)-7-benzyloxy-8-methoxy-benzo [C] phenanthridine

7-Benzyloxy-8-methoxy-benzo[C]phenanthridine (obtained by the method described in Japanese patent KOKAI 5-208959, 284 mg, 0.78 mmol) suspended in acetonitrile (10 ml) and the resulting suspension add triperoxonane acid (60 μl, 0.78 mmol), 3-bromo-1-propanol (71 the donkey dissolution suspension to the solution add azobis(isobutyronitrile) (256 mg, 1.56 mmol) followed by heating with delegacia. An hour later the reaction mixture is allowed to cool down to room temperature, and then to it was added a saturated aqueous solution of acid sodium carbonate (60 ml) followed by extraction with methylene chloride. After washing the organic layer with a saturated aqueous solution of sodium chloride and drying over anhydrous sodium sulfate, the solvent is distilled off in vacuum. The residue passed through a column of silica gel (elwira a mixture of 1% methanol-methylene chloride). The main fraction is collected and concentrated in vacuo, obtaining 6-(3-hydroxypropyl)-7-benzyloxy-8-methoxy-benzo[C] phenanthridine in the form of a crude product (purity 50%, 142 mg, yield 21%) as a yellow-brown dry weight.

FAB-MS (positive.) m/z:

424 ([M+H]+), 366 ([M+H-CH3CH2CH2HE2]+)

333 ([M+N-benzyl]+);

1H-NMR (200MHz, Dl3) :

9,31 (1H, m), 8,51 (1H, d, J=9,3 Hz), 8,46 (1H, d, J=9,3 Hz), 7,95 (1H, d, J= 9,5 Hz), 7,94 (1H, m), to 7.77 (1H, m), 7,66 (1H, m), the 7.65 (1H, d, J=9,3 Hz), 7.62mm and 7.36 (5H, m), 5,23 (2H, s),

4,07(3H, s), 3,82(2H, t, J=6,9 Hz), to 3.64(2H, t, J=6,lHz), 2,24(2H, tt, J= 6.9 and 6,lHz).

Example 2

Synthesis of chloride 7-hydroxy-8-methoxy-5,6-propane-benzo[C] phenanthridine (compound a-1) (X-=CL-)

The crude product described in example 1, dissolved in methylene chloride (4 ml). To the solution add methanesulfonanilide (22 μl, 0.28 mmol) and N,N-diisopropylethylamine (50 μl, 0.28 mmol). The mixture is stirred at room temperature for 20 minutes. After adding to the reaction mixture of methanol (1 ml), the solution was concentrated in vacuo. The residue passed through a column of silica gel (elwira a mixture of 8% methanol-methylene chloride). The main fraction is collected and the solvent is distilled off in vacuum. For dissolution to the residue add acetic acid (1.6 ml) and concentrated hydrochloric acid (0.8 ml). The solution was stirred at 60oC in oil bath for 20 minutes. After cooling the reaction mixture to room temperature, there was added a saturated aqueous solution of acid sodium carbonate (160 ml), then extracted with methylene chloride. The organic layer is washed with water and dried over anhydrous sodium sulfate (containing the compound of General formula (In)). The organic layer was filtered to remove sodium sulfate. 4M solution of hydrogen chloride in dioxane is added to the filtrate until then, until the red-purple solution turns a Golden yellow. The solution was concentrated in vacuo. The residue is purified speakers chromatographed 59%) as a Golden yellow powder.

FAB-MS (positive.) m/z:

316 (M+)

1H-NMR (200 MHz, DMSO-d6) :

11,44 (1H, brs), 8,93 (1H, d, J=a 9.4 Hz), 8,93 (1H, m), 8,61 (1H, d, J= 9,2 Hz), 8,39 (1H, d, J= 9,2 Hz), 8,29 (1H, m), 8,15 (1H, d, J=and 9.1 Hz), 7,92-of 7.82 (2H, m), to 5.57 (2H, brt, J=7,2 Hz), to 4.23 (2H, brt, J=7,6 Hz), 4,10 (3H, s), 2.49 USD (2H, m).

Example 3

Synthesis of 2, 3-(methylenedioxy) -6- (3-hydroxypropyl) -7 - benzyloxy-8-methoxy-benzo[C]phenanthridine

2,3-(Methylenedioxy)-7-benzyloxy-8-methoxy-benzo[C] phenanthridine (obtained by the method described in Japanese patent KOKAI 5-208959) (1,228 g, 3.0 mmol) suspended in acetonitrile (48 ml), and then to the suspension add triperoxonane acid (231 μl, 3.00 mmol), 3-bromo-1-propanol (271 μl, 3.00 mmol) and Tris (trimethylsilyl) silane (1,85 ml of 6.00 mmol). The mixture was stirred at 80oC in an oil bath. After dilution of the suspension to the solution add azobis (isobutyronitrile) (0,985 g, 6,00 mmol.) followed by heating at reflux distilled. 90 minutes later, the reaction mixture is cooled to room temperature. Separating the precipitated crystals by filtration, the source material, 2,3-(methylenedioxy)-7-benzyloxy-8-methoxy-benzo[C]phenanthridine, get back in trifenatate (0,680 g). The filtrate was concentrated in vacuo and to the residue is added saturated aqueous solution of acid sodium carbonate (40 over anhydrous sodium sulfate, the solvent is distilled off in vacuum. The residue is purified column chromatography on silica gel (elwira a mixture of 10% ethyl acetate-toluene) to give 2,3-(methylenedioxy)-6-(3-hydroxypropyl)-7-benzyloxy-8-methoxy-benzo[C]phenanthridine (0,210 g, yield 15%) as a pale brown powder.

FAB-MS (positive.) m/z:

468 ([M+H]+), 377 ([M+H-benzil]+)

1H-NMR (200 MHz, Dl3) :

8,65 (1H, s), to 8.45 (1H, d, J=9,3 Hz), 8,31 (1H, d, J=and 9.1 Hz), 7,78 (1H, d, J=and 9.1 Hz), 7,60 (1H, d, J=9,3 Hz), EUR 7.57 (2H, dd, J=7,9 and 1.7 Hz), 7,49-7,37 (3H, m), 7,24 (1H, s), 6,11 (2H, s), a total of 5.21 (2H, s), 4,06 (3H, s); 3,76 (2H, t, J=7,0 Hz), 3,61 (2H, t, J=6,1 Hz), 2,22 (2H, tt, J=7.0 and 6.1 Hz).

Example 4

Synthesis of chloride 2,3-(methylenedioxy)-7-hydroxy-8-methoxy-5,6-propane-benzo[C]phenanthridine (compound a-4) (X-=CL-)

2,3-(Methylenedioxy)-6-(3-oksipropil)-7-benzyloxy-8-methoxy-benzo[C] phenanthridine (192 mg, 0.41 mmol. ) dissolved in methylene chloride (8 ml). To the solution add methanesulfonanilide (41 μl, of 0.53 mmol) and N,N-diisopropylethylamine (95 μl, of 0.53 mmol). The mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added methanol (1 ml) followed by concentration in vacuum, obtaining a yellow-brown syrup (530 mg). To the residue to dissolve add acetic acid (4 ml) and concentrated solenoidal to room temperature, and then concentrated in vacuo. The residue is dissolved in a solution of 5% methanol-methylene chloride (100 ml) and to the solution was added saturated aqueous sodium hydrogen carbonate solution (80 ml). The mixture is vigorously stirred until then, until the orange organic layer is completely converted into red-purple. The organic layer is separated and washed with water, and then dried over anhydrous sodium sulfate (containing the compound of General formula (In)). The organic layer was filtered to remove sodium sulfate. 4M Solution of hydrogen chloride in dioxane is added to the filtrate until then, until the solution is completely orange. The solution was concentrated in vacuo. The solution is purified column chromatography on silica gel (elwira mixture 8-12% methanol-methylene chloride) to give compound a-4 (X-=CL-) (112 mg, yield 69%) as a Golden yellow powder.

FAB-MS (positive.) m/z:

360 (M+), UVmaxnm:

(in 1M HCl) 438, 342, 320, 271, (in rn) 488, 347, 335, 278;

1H-NMR (200 MHz, DMSO-d6) :

8,72 (1H, d, J=9,2 Hz), 8,43 (1H, d, J=9,2 Hz), 8,24 (1H, s), 8,19 (1H, d, J=9,2 Hz), 8,03 (1H, d, J=9,2 Hz), 7,71 (1H, s), 6,33 (2H, s), vs. 5.47 (2H, brt, J=7,1 Hz), 4,16 (2H, brt, J=7,7 Hz), 4,06 (3H, s), of 2.44 (2H, m).

Example 5

Synthesis of 2,3-(methylenedioxy)-5-methyl-6-ethoxy-7-benzyloxy-8-methoxy-5,6-dihydrobenzo is authorized in Japanese patent KOKAI 5-208959) (4,487 g, 10,96 mmol.) and methyl 2-nitrobenzenesulfonate (4,30 g, 19,79 mmol.) dissolved in toluene (90 ml). The solution is stirred for 24 hours with heating at 110oC. After cooling the reaction mixture to room temperature, the precipitated crystals are separated by filtration, and then washed with toluene. The crystals are suspended in N, N-dimethylformamide (62 ml) and to the suspension is added pyridine (of 0.62 ml). The mixture was stirred at 60oC for 2 hours. After cooling the mixture to room temperature, the crystals are filtered and sequentially washed with toluene and hexane. Thus obtained Golden-yellow crystals suspended in ethanol (124 ml) and the suspension add 0.1 N aqueous sodium hydroxide solution (93 ml). The mixture is stirred until complete disappearance of Golden yellow. The obtained pale-brown crystals are filtered and washed with 50% aqueous ethanol, receiving 2,3-(methylenedioxy)-5-methyl-6-ethoxy-7-benzyloxy-8-methoxy-5,6-dihydrobenzo[C] phenanthridine (3,016 g, yield 59%) as a pale brown powder.

FAB-MS(positive.)m/z:

424 ([M-CH3CH2ON]+);

1H-NMR (200 MHz, Dl3) :

for 7.78 (1H, d, J=8,6 Hz), to 7.64 (1H, d, J=8,6 Hz), 7,63 (1H, s), 7,46 (1H, d, J=8,6 Hz), 7,58-7,33 (5H, m), 7,11 (1H, s), 7,06 (1H, d, J=8,6 Hz), S="ptx2">

Example 6

Synthesis of 2,3-(methylenedioxy)-5-methyl-6-[3-(tert-butultimately-siloxy)propyl]-7-benzyloxy-8-methoxy-5,6-dihydrobenzo [C] phenanthridine

In a dry flask magnesium (0,468 g, and 19.3 mmol) and to it add tetrahydrofuran (15 ml). A solution of 3-(tert-butyldimethylsiloxy)-propyl bromide (2,36 g, 9,63 mmol.) in tetrahydrofuran (15 ml), iodine (a few crystals) and 1,2-dibromethane (a few drops) are added in several portions to the mixture. The resulting mixture was stirred at room temperature for one hour. To the resulting solution was added a solution of 2,3-(methylenedioxy)-5-methyl-6-ethoxy-7-benzyloxy-8-methoxy-5,6-dihydrobenzo[C]phenanthridine (1.01 g, 2.3 mmol) in tetrahydrofuran, followed by stirring at room temperature for 2 hours. To the reaction mixture is added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer is separated, washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent is distilled off in vacuum. The resulting residue is purified column chromatography on silica gel (elwira mixture 33-66% methylenchloride), receiving 2,3-(methylenedioxy)-5-methyl-6-[3-(tzvetkova amorphous solid.

1H-NMR (200 MHz, DlC) :

of 7.69 (1H, d, J=8,6 Hz), to 7.64 (1H, s), EUR 7.57-to 7.35 (7H, m), to 7.09 (1H, s), of 6.96 (1H, d, J= 8,6 Hz), 6,05-of 6.02 (2H, m) to 5.17 (1H, d, J=11,4 Hz), 5,09 (1H, J= 11.4 in Hz), the 4.29 (1H, dd, J=9.5 and a 5.1 Hz), of 3.96 (3H, s), of 3.45 (2H, t, J=6,8 Hz), is 2.41 (3H, s), 1,80-of 1.53 (2H, m), 1,40-1,20 (2H, m), of 0.77 (9H, s), of 0.07 (3H, s), and 0.09 (3H, s).

Example 7

Synthesis of 2,3-(methylenedioxy)-6-[3-(tert-butyldimethylsiloxy)-propyl] -7-benzyloxy-8-methoxy-benzo [C] phenanthridine

After the dissolution of 2,3-(methylenedioxy)-5-methyl-6-3(tert-butyldimethylsiloxy) propyl] -7-benzyloxy-8-methoxy-5,6-dihydrobenzo[C]phenanthridine (871 mg, of 1.46 mmol) in toluene (30 ml) solution was added activated manganese dioxide (4,36 g). The mixture was stirred at 100oC for 2 hours. The manganese dioxide is removed by filtration, then the filtrate was concentrated in vacuo. The resulting residue is purified column chromatography on silica gel (elwira mixture 33-66% methylenchloride), receiving 2,3-(methylenedioxy)-6-[3-(tert-butyldimethylsiloxy) propyl] -7-benzyloxy-8-methoxy-benzo[C] phenanthridine (457 mg, yield 54%) as a colorless powder.

FAB-MS (positive.) m/z:

582 ([M+H]+)

1H-NMR (200 MHz, Dl3) :

8,73 (1H, s), 8,40 (1H, d, J=a 9.4 Hz), of 8.28 (1H, d, J=9,2 Hz), of 7.75 (1H, d, J=8,8 Hz), 7,60 is 7.50 (3H, m), 7,47-to 7.35 (3H, m), 7,22 (1H, s), 6,11 (2H, s), 5,16 (2H, s), was 4.02 (3H, s), 3.75 to 3,63 (4H, m), 2,32-2,18 (ethoxy-benzo[C]phenanthridine

After the dissolution of 2,3-(methylenedioxy)-6-[3-(tert-butyl-dimethylsiloxy)propyl] -7-benzyloxy-8-methoxy-benzo[C] phenanthridine (374,4 mg, 0,644 mmol.) in tetrahydrofuran (3.2 ml) to the solution was added tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 1.9 ml). The mixture is stirred over night at room temperature. To the reaction mixture, water is added, followed by extraction with methylene chloride. The organic phase is dried over anhydrous sodium sulfate, and then concentrated in vacuo. The resulting residue is purified column chromatography on silica gel (elyuirovaniya with methylene chloride) to give 2,3-(methylenedioxy)-6-(3-hydroxypropyl)-7-benzyloxy-8-methoxy-benzo[C]phenanthridine (263,7 mg, yield 88%) as colorless powder.

The data obtained in the research of this product, analytical methods, coincide with the data obtained in the study of product synthesized in accordance with example 3.

Example 9

Synthesis of 2,3-(methylenedioxy)-5-methyl-6-[4-(tert-butultimately-siloxy) butyl] -7-benzyloxy-8-methoxy-5, 6-dihydrobenzo [C] phenanthridine

2, 3-(Methylendioxy)-5-methyl-6-[4-(tert-butyldimethylsiloxy) -butyl] -7-benzyloxy-8-methoxy-5, 6-dihydrobenzo [with] phenanthro in example 8, except that instead of 3-(tert-butyldimethylsiloxy) propyl bromide in example 6 using 4-(tert-butyldimethylsiloxy) butyl chloride.

1H-NMR (200 MHz, Dl3) :

of 7.70 (1H, d, J=8,7 Hz), 7,63 (1H, s), 7,54 (1H, d, J=8,5 Hz), 7,54-7,32 (6N, m), to 7.09 (1H, s), of 6.96 (1H, d, J=8,6 Hz), 6,04-of 6.02 (2H, m) to 5.17 (1H, d, J=11,3 Hz), 5,09 (1H, d, J=11,3 Hz), the 4.29 (1H, dd, J=7.3 and a 6.5 Hz), of 3.96 (3H, s), of 3.48 (2H, dd, J=5,9 and 5.4 Hz), is 2.41 (3H, s), 1.56 to of 1.26 (2H, m), 0,87-0,83 (N, m), of 0.04 to 0.04 (6H, m).

Example 10

Synthesis of 2,3-(methylenedioxy)-6-[4-(tert-butyldimethylsiloxy) -butyl] -7-benzyloxy-8-methoxy-benzo [C] phenanthridine

After the dissolution of 2,3-(methylenedioxy)-5-methyl-6-[4-(tert-butyldimethylsiloxy)butyl]-7-benzyloxy-8-methoxy-5,6-dihydro-benzo[C]phenanthridine (300 mg, 0.49 mmol) in toluene (8 ml) solution was added activated manganese dioxide (1.5 g). The mixture is heated to deregulirovania within hours. After cooling to room temperature the reaction mixture is diluted with a solution of 10% methanol-methylene chloride (12 ml) followed by filtration. The filtrate was concentrated in vacuo. The resulting residue is purified column chromatography on silica gel (buyowner with methylene chloride) to give 2,3-(methylenedioxy)-6-[4-(tert-butyldimethylsiloxy)butyl] -7-benzyloxy-8-methoxy-benzo[C]phenanthridine (205 mg, yield 70%) as light is B>) :

a total of 8.74 (1H, s), 8,44 (1H, d, J=a 9.4 Hz), 8,31 (1H, d, J=and 9.1 Hz), to 7.77 (1H, d, J=8,8 Hz), 7,58 (1H, d, J=9,0 Hz), 7,60-of 7.55 (2H, m), 7,47-to 7.35 (3H, m), 7,24 (1H, s), 6,11 (2H, s) to 5.17 (2H, s), Android 4.04 (3H, s), to 3.64 (4H, m), a 2.01 (2H, m), 1,58 (2H, m), 0.88 to (N, m) 0,04 (6N, m).

Example 11

Synthesis of 2, 3- (methylenedioxy) -6- (4-hydroxybutyl) -7 - benzyloxy-8-methoxy-benzo[C]phenanthridine

After the dissolution of 2,3-(methylenedioxy)-6-[4-(tert-butyldimethylsiloxy) butyl] -7-benzyloxy-8-methoxy-benzo[C] phenanthridine (532 mg, 0.89 mmol) in tetrahydrofuran (6 ml) to the solution was added acetic acid (102 μl, 1.78 mmol. and tetrabutyl-ammonium fluoride (1M solution in tetrahydrofuran, of 1.78 ml). The mixture is stirred at room temperature. The reaction solution was concentrated in vacuo. The residue is diluted with methylene chloride (30 ml), then washed with water. After drying the organic phase over anhydrous sodium sulfate, the solution is distilled off in vacuum. The residue is purified column chromatography on silica gel (elwira a mixture of 1% methanol-methylene chloride) to give 2,3- (methylenedioxy)-6-(4-hydroxybutyl) -7-benzyloxy-8-methoxy-benzo[C] phenanthridine (372 mg, yield 87%) as light yellow needles.

FAB-MS (positive.) m/z:

482 ([M+H]+)

1H-NMR (200 MHz, Dl3) :

8,71 (1H, s), to 8.45 (1H, d, J=9,3 Hz), 8,31 (1H, d, J=9,0 Hz), to 7.77 (1H, d, J=9,0 H64-1,50 (2H, m).

Example 12

Synthesis of 2,3-(methylenedioxy)-7-hydroxy-8-methoxy-5,6-butano-benzo[C]phenanthridine chloride (compound a-7) (X-=CL-)

2,3-(Methylenedioxy)-6-(3-hydroxybutyl)-7-benzyloxy-8-methoxy - benzo[C] phenanthridine (252 mg, 0.52 mmol) dissolved in methylene chloride (10 ml). Methanesulfonanilide (80 μl, of 1.03 mmol.) and N,N-diisopropylethylamine (186 μl, 1.04 mmol) added to the solution. The mixture is stirred at room temperature for 20 minutes. After adding to the reaction mixture water (30 ml), the mixture is extracted with methylene chloride (30 ml). The organic phase is successively washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solvent is distilled off in vacuum. The residue is purified column chromatography on silica gel (elwira mixture 0-0,5% methanol-methylene chloride) to give the methanesulfonate (210 mg, yield 72%).

Methanesulfonate (186 mg, 0.33 mmol) dissolved in toluene (12 ml). The solution is heated to boiling point under reflux for two days. The reaction mixture was concentrated in vacuo. To the residue add acetic acid (3 ml) and concentrated hydrochloric acid (1.5 ml). A mixture of TRANS who intronaut in vacuum. The residue is dissolved in a solution of methylene chloride (50 ml) and to the solution was added saturated aqueous sodium hydrogen carbonate solution (50 ml). The mixture is vigorously stirred until then, until the orange organic layer will not turn completely to red-violet. The organic layer (containing the compound of General formula (V)) is separated and washed with water. To the organic phase, add methanol (10 ml) and 1M aqueous solution of hydrochloric acid (1 ml). The resulting solution was stirred (solution again becomes orange). The solution was concentrated in vacuo. The residue is purified column chromatography on silica gel (elwira a mixture of 8% methanol-methylene chloride) to give compound a-7 (X-=CL-) (86 mg, yield 64%) as an orange powder.

FAB-MS (positive.) m/z:

374 (M+), UVmaxnm:

(in 1M HCl) 446, 345, 325, 275,

(rn) 495, 353, 335, 283;

1H-NMR (200 MHz, Dl3) :

11,41 (1H, brs), 8,66 (1H, d, J=9,2 Hz), of 8.47 (1H, d, J=9,2 Hz), 8,19 (1H, d, J=8,8 Hz), with 8.05 (1H, d, J=9,0 Hz), of 7.90 (1H, s), of 7.70 (1H, s), of 6.31 (2H, s), 5,11 (2H, m), 4.26 deaths (2H, m), 4,08 (3H, s), 2,05-to 1.87 (2H, m), 1.85 to to 1.67 (2H, m).

Example 13

Synthesis of N-((2'-benzyloxy)-3'-methoxy-6'-bromobenzyl)-1-andriamena

2-Benzyloxy-3-methoxy-6 - bromobenzaldehyde (8,32 g, 23.2 mmol), obtained by the method described in J. C. S. Perkin I, 1221 (1976) and J. Org. Chem., Moshevani the solution is heated to boiling under reflux at 120oC for 2 hours. Continuing the heating at 120oWith, to the reaction mixture over three hours gradually add toluene (180 ml), and the solvent is distilled off. After cooling to room temperature, to the mixture of toluene (70 ml). When the cooling water to the mixture successively added complex dimethylaminoborane (1,03 g, 17.5 mmol) and acetic acid (30 ml). After stirring at room temperature for 75 minutes to the mixture while cooling water is added 1M aqueous solution of hydrochloric acid (130 ml). The reaction mixture is filtered. The filtrate is separated into the organic phase and aqueous phase. The aqueous phase is extracted with toluene (200 ml of 2) and this fraction is combined with the previously obtained organic phase. The combined mixture is dried over anhydrous sodium sulfate. The solvent is distilled off in vacuum. The residue is purified column chromatography on silica gel (elwira a mixture of 10% ethyl acetate-hexane) to give N-((2'-benzyloxy)-3'-methoxy-6'-bromobenzyl)-1-antillen (12,77 g, quantitative yield) as a yellow powder.

1H-NMR (200 MHz, Dl3) :

8,86 (1H, s), scored 8.38 (1H, s), 7,98 (2H, m), 7, 50-7,07 (10H, m), to 6.57 (1H, m), of 6.20 (1H, t, J=4,5 Hz), of 5.05 (2H, s), 4,47 (1H, s), of 4.44 (1H, s), 3,90 (3H, s).

Example 14

Synthesis of 8-benzyloxy-9-M0,81 g, 21,70 mmol.) in toluene (1 l) to the solution add hydride trioctylamine (19,95 g, 43,43 mmol.) and the temperature raised to 105oC. Then added to the mixture of 2,2'-azobis(2-methylbutyronitrile) (at 8.36 g, 43,46 mmol). The solution is heated to boiling under reflux for 2 hours at 120oC. After cooling to room temperature, to the resulting mixture are added activated manganese oxide (10,81 g). The mixture is stirred for 30 minutes. After addition of ethanol (200 ml), the reaction solution is filtered to remove manganese dioxide. The filtrate was concentrated in vacuo. The resulting residue is crystallized from a mixture solution of hexane-methylene chloride, receiving 8-benzyloxy-9-methoxy-oil [2,3-C] phenanthridine (Android 4.04 g, yield 45%) as a pale yellow powder.

FAB-MS (positive.) m/z:

416 ([M+H]+)

1H-NMR (200 MHz, Dl3) :

9,82 (1H, s), 9,65 (1H, s), 8,67 (3H, m), of 8.37-8,15 (3H, m), 7,94 (1H, d, J=9,3 Hz), 7,60 (4H, m), 7,40 (3H, m), to 5.35 (2H, s), 4,10 (3H, s).

Example 15

Synthesis of chloride 8-hydroxy-9-methoxy-6,7-propane-oil [2,3-C]phenanthridine (compound A-9) (X-=CL-)

8-benzyloxy-9-methoxy-oil[2,3-C] phenanthridine (231 mg, 0,56 mmol.) suspended in acetonitrile (80 ml) and the suspension add triperoxonane acid (43 μl, 0.56 to Mr>oC in an oil bath. After the dissolution of suspended matter to the solution add azobis(isobutyronitrile) (184 mg, 1.12 mmol.) followed by heating with delegacia. An hour later, the reaction mixture was cooled to room temperature. To the residue is added saturated aqueous solution of acid sodium carbonate (50 ml) and then extracted with methylene chloride. After washing the organic layer with water and drying over anhydrous sodium sulfate, the solvent is distilled off in vacuum. The residue passed through a column of silica gel (elwira a mixture of 1% methanol-methylene chloride). The main fraction is collected and the solvent is distilled off in vacuum. The residue is dissolved in toluene (3 ml) and to the solution was added activated manganese dioxide (100 mg). The mixture is stirred at room temperature for 90 minutes. The manganese dioxide is filtered off and the filtrate was concentrated in vacuo, to give crude 7-(3-hydroxypropyl)-8-benzyloxy-9-methoxy-oil[2,3-C]phenanthridine (83 mg) as a brown dry mass.

The crude product is dissolved in methylene chloride (3 ml). To the solution add methanesulfonanilide (13 μl, 0,17 mmol.) and N,N-diisopropylethylamine (30 μl, 0,17 mmol. ). The mixture is stirred at room temperature for 45 korichnevuu siropoo different mass. To this mass to dissolve add acetic acid (1.2 ml) and concentrated hydrochloric acid (0.6 ml). The solution was stirred at 60oC for 25 minutes in the oil bath. Then the reaction solution is cooled to room temperature and to it add a saturated aqueous solution of acid sodium carbonate (100 ml). The mixture is then extracted with methylene chloride. The organic phase is separated and washed with water, and then dried over anhydrous sodium sulfate (containing the compound of General formula (In)). The sodium sulfate is filtered off and the solution was added 4M solution of hydrogen chloride in dioxane to until the solution is completely orange. The solution was concentrated in vacuo. The residue is purified column chromatography on silica gel (elwira mixture 8-12% methanol-methylene chloride), and then gel-filtration chromatography (elwira aqueous solution of a mixture of 20% methanol -5 mm hydrochloric acid Sephadex LH-20) to give compound a-9 (X-=CL-) (10 mg, yield 4%) in the form of a Golden yellow powder.

FAB-MS (positive.) m/z:

366 ([M+H]+)

1H-NMR (200 MHz, DMSO-d6) :

11,43 (1H, brs), of 9.56 (1H, s), 8,88 (1H, s), 8,81 (1H, d, J=9,5 Hz), 8,61 (1H, d, J=9,2 Hz), of 8.47 (1H, d, J=9,2 Hz), 8,46 (1H, m), 8,24 (1H, m), 8,17 (1H, d, J=9,2 Hz), 1, 80-7,72 (2H, m), 5,77 (2H, brt, J=7,1 is accordance with the present invention were tested for antitumor activity, and the results are presented below. As shown below, the derivative phenanthridine represented by the General formula (A), prevent the growth of cancer cells.

1. Preventing the growth of cancer cells

Cancer cells HeLa S3 received from the uterus of the person, incubated at 37oC for 24 hours in 5% CO2. The analyzed connection then enter into contact with the cells for 72 hours. After that, cells stained of 0.05% methylene blue. From stained cells extracted pigment. Inhibition of cell growth is determined on the basis of the absorption at 660 nm, calculating the concentration of 50% growth inhibition (IC50). The results are presented in table. 2.

2. Anti-tumor effect on cancer cells in vivo

Murine leukemia cells R injected six-week CDF1 female mice at a dose of 105cells in the mouse. The next day after transplantation of the tumor they impose a single intravenous injection of 5% glucose aqueous solution of chloride 2,3-(methylenedioxy)-7-hydroxy-8-methoxy-5,6-propane-benzo[C] phenanthridine (compound a-4 in accordance with the present invention (X-= CL-)). Antitumor activity determined by comparing the ratio (T/C%) days CLASS="ptx2">

3. Acute toxicity

Acute toxicity was determined by intravenous injection of chloride 2,3-(methylenedioxy)-7-hydroxy-8-methoxy-5,6-propane-benzo[C] phenanthridine (compound a-4 in accordance with the present invention (X-=CL-)) a six-week CDF1 female mice. Animals survive even at the dose of 100 mg/kg, staying alive.

Example 16

Pharmaceutical compositions

After weighing 1 g 2, 3-(methylendioxy)-7-hydroxy-8-methoxy-5,6-propane-benzo[C] phenanthridine chloride (compound 4 in accordance with the present invention, X-=CL-), 1 g of Polysorbate and 1 g of Macrogol 400, these compounds is dispersed and dissolved in 100 g of sterile water for injection. The solution is filtered through a membrane filter. The filtrate was dispensed into the vials and lyophilized in the usual way, by receiving the drug for injection containing 50 mg per ampoule compound a-4 (X-=CL-).

Example 17

Chemical recovery

Connection in accordance with the present invention (0.1 mg/ml aqueous solution, 0.1 ml) was diluted with methanol (0.1 ml). To the solution was added an aqueous solution of cyanoborohydride sodium (4 mg/ml 0,02 ml). The mixture allow to stand at room temperature. Reaction chromatography high resolution. As a control, the same reaction is subjected to sulfuric acid 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxy-benzo [C]phenanthridine. The results are presented in table 4.

Industrial applicability

The derived phenanthridine in accordance with the present invention exhibits antitumor activity, is resistant to chemical recovery and biological metabolic reactions and, therefore, it is extremely effective as a medicine.

As noted above, the materials of this application contain data of experiments in vitro and/or in vivo to compounds a-4 and a-7.

In addition, to confirm the implementation of the specified purposes other claimed compounds below, the Applicant shall submit the results of in vitro experiments for compounds a-1 and a-9 in cancer cells Hela S3.

Compounds a-1 and a-9 are chloride 7-hydroxy-8-methoxy-5,6-propanamine[s] phenanthridine and chloride 8-hydroxy-9-methoxy-6,7-propanoate[2,3-C]phenanthridine, respectively, as described in examples 2 and 15.

Connection - IC50(μm) Concentration of 50% inhibition

The compound a-1 (X-=CL-) - 0,15

The compound a-9 (X-=CL-) vivemos mouse leukemia R (see table. 5).

From the foregoing it becomes apparent that the claimed compounds other than a-4, also showing antitumor activity.

In addition, to confirm the implementation of the stated purpose of the claimed compounds in relation to other tumors, currently, the Applicant may submit the results of the experiment in vivo to compounds A-4 adenocarcinoma of the colon Colon 26 mouse and mouse malignant tumor B16 vaccinated mice.

i) adenocarcinoma of the Colon 26 mouse (see tab. 6).

ii) a Malignant tumor B16 mouse (see tab. 7).

In view of the foregoing it is clear that the claimed compounds exhibit anti-tumor activity in various tumors, such as adenocarcinoma of the Colon 26 mouse and mouse malignant tumor B16 vaccinated mice, non-cell leukemia.

1. The derived phenanthridine represented by the General formula

< / BR>
where R1substituted or unsubstituted lower aliphatic hydrocarbon group;

R is an aliphatic hydrocarbon chain having 2 to 6 carbon atoms, which may be optionally substituted by a Deputy selected from the group comprising lower alkali lower alkoxygroup; or Y and Z together with the formation of methylenedioxy or phenyl ring;

X-- acid residue or a residue hydrogen acid.

2. The derived phenanthridine represented by the General formula

< / BR>
where R1substituted or unsubstituted lower aliphatic hydrocarbon group;

R is a lower aliphatic hydrocarbon chain having 2 to 6 carbon atoms, which may be optionally substituted by a Deputy selected from the group comprising lower alkyl group, halogen and a hydroxy-group;

each of Y and Z independently represents hydrogen, hydroxy or lower alkoxygroup; or Y and Z together with the formation of methylenedioxy or phenyl rings.

3. Connection under item 1 or 2, in which R1is methyl, ethyl, allyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, carbamoylmethyl or trifluoromethyl; R is unsubstituted polymethene circuit having 3-4 carbon atoms; and Y and Z are combined together with the formation of methylenedioxy or phenyl rings.

4. Salt of 2,3-(methylenedioxy)-7-hydroxy-8-methoxy-5, 6-propane-benzo[C] phenanthridine.

5. Pharmaceutical composition having antitumor activity, soderjaschim.

6. The pharmaceutical composition according to p. 5 for inhibiting the growth of cancer cells.

7. The compound according to any one of paragraphs. 1-4 as an active ingredient in pharmaceutical compositions for PP.5-6.

8. Method of inhibiting the growth of cancer cells comprising the administration to a human an effective dose of a compound according to any one of paragraphs.1-4.

 

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The invention relates to medicine, namely to methods of prevention vestibulovegetativnymi disorders in terms of impacts that cause motion sickness

The invention relates to medicine, namely to the creation of medicines for parenteral use

The invention relates to new bis(Amida)nitrogen-containing tricyclic carboxylic acids f-crystals (I), where each X, which may be the same or different in the molecule, represents-CH= or-N=, each of R1-R4that may be the same or different, represents H, C1-C4-alkyl, NH2WITH1-C4-alkoxy, phenyl, phenoxy, other, N(R)2, CF3or halogen, R1-C4-alkyl, each of R5and R6- N or C1-C4-alkyl, Z is (CH2)nN(R7)(CH2)n, (CH2)nN(R7)(CH2)N(R7)(CH2)n, (CH2)nNH(CH2CH2)NH(CH2), R7- N or C1-C4-alkyl, n and m = 1-4, or their pharmaceutically acceptable salts, with the exception of connections, where each X Is N; each of R1- R6- N, carboxamidine part attached in position I of each ring phenazine and Z is (CH2)2NH(CH2)2, (CH2)3NH(CH2)3, (CH2)3NH(CH2CH2)2NH(CH2)3,

(CH2)2NH(CH2)2NH(CH2)2or (CH2)3NH(CH2)2NH(CH2)3

The invention relates to a method for producing pharmaceutically acceptable salt of clavulanic acid of formula I by reacting clavulanic acid or its salts, in particular amine salt, with the source of cations capable of forming pharmaceutically acceptable salts of clavulanic acid, in particular potassium salt, isobutyl alcohol (2-methyl-1-propanol) as a solvent in the presence of water

The invention relates to a new method of obtaining the acridine-carboxamide of the formula (I), where R1, R2, R5, R6x, Y are defined in the claims, which involves the cyclization of the compounds of formula (II) processing of boron TRIFLUORIDE or a suitable complex at its base in a suitable solvent to obtain tetrafluoroborate salt of the formula (IIIa) followed by treatment of the salt with inorganic base in EtOAc or CH2Cl2with the formation of the compounds of formula (III), and the processing of either (i) the compounds of formula (III) primary alkylamino formula (IV), or (ii) carboxylic acid obtained by hydrolysis of compounds of formula (III) in alkaline conditions, the primary alkylamino formula (IV) in the presence of a suitable binding agent to obtain the compound (I) and, optionally, translation of one of the compounds of formula (I) into another compound of formula (I) and/or its pharmaceutically acceptable salt

The invention relates to new derivatives of piperidineacetate-2-it General formula I, where R1and R2each independently from each other represents an unsubstituted or once substituted phenyl residues, substituents which may be OA, Hal, NH2, OTHER3; R3denotes-CO-alkyl, where alkyl has 1 to 7 carbon atoms; And indicates WITH1-C6alkyl; Hal denotes F, CL, Br or J

The invention relates to an inhibitor semipretioase - derived imidazo [1,5-a] pyridine, containing containing structural unit (link) of General formula (I), where R1and R2represent hydrogen, R3and R4independently represent hydrogen, (1-6C) alkyl or together form =CH-NR5R6and R5and R6represent (1-6C) alkyl; X is hydrogen, R7, acetyl, PMC, R7-SO2N-protecting group, where R7is (1-12C) alkyl or (1-14C) aryl; R3represents a bond, D-Tig, Atc, D - amino acid with a hydrophobic side chain; R2is Pro, Gly, Val, Jle, 2,4-Me P2O, 3,3-Dmp, Jlc, Thr, Hyp, 2,2-Dmt or 5,5-Dmt; or R2is the link in case when R3is a bond, and X is R7-SO2-; or R2and R3together represent a structure similar to a dipeptide having the formula (II), in which the positions marked with asterisks may be condensed with a benzene ring and in which R9is hydrogen; or its pharmaceutically acceptable salt

The invention relates to methods of reducing the level of TNFin mammals and connections that are applicable for this purpose
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