Thioxanthone compounds and pharmaceutical composition having antitumor activity

 

(57) Abstract:

Describes the new thioxanthone compounds of General Formula /I/, where the values of R1, R2, R8, Q, specified in paragraph 1 of the formula or its pharmaceutically acceptable salt, acid additive salt or solvate. The compounds of formula I possess anti-tumor activity. Also described composition on the basis of the above compounds with antitumor activity. 5 C. and 16 h.p. f-crystals, 8 PL.

The invention relates to new 1-//(dialkylamino)alkyl/-amino/-4-substituted, thiaxanthene-9-Onam, pharmaceutical compositions containing thiaxanthene, methods of treatment of tumor thiaxanthene and methods of treatment of cancer in mammals compositions containing thioxanthone.

Nabin and Elsheikh /J. Pharm. Sci., 54, 1672-1673 /1965/ describe 1-//2-(diethylamino)ethyl/amino/-4-(diethylamino)- methyl/thioxanthen-9-it is, however, this connection has not been shown.

In U.S. patent 3745172 (Colins and Rosi) first described intermediate product for the synthesis of fungicides and bactericides structure:

< / BR>
and anthelmintic and antibacterial agent structure:

< / BR>
In U.S. patent 3312598 (Rosi and Perusotti) patented 1-//2-(diethylamino)ethyl/Amie.

Blans, and French /J. Med. Chem 6, 185-191 1963/ disclose the synthesis of a series thioxanthenes attributed to lucantoni, and the results of tests of these compounds against leukemia and two solid tumors. Among the above compounds represented by compounds of structure

< / BR>
where R is methyl, methoxy, ethoxy.

Yarinski and Freele /Journal of Tropical Medicine and Hygiene 73, 23-27 (1970)/ open

< / BR>
as antihistamines agent.

N-/2-(dimethylamino)ethyl/-9-oxo-9H-thioxanthen-4-carboxamid monohydrochloride described in the publication /Palmer et al., J. Med. Chem. 31, 707-712 (1988)/, was tested against cells P388 leukemia in vitro against leukemia Guinea pigs /L 1210/, and in vivo against leukemia cells P388, the result of which was fitted with a small probability of its use as an antitumor agent.

In U.S. patent 4539412 (Archer) describes compounds of formula:

< / BR>
where X = S:

R1and R2is independently selected from lower Akilov, and simultaneously are selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinil and N-substituted piperazinil; and

R3-H or hydroxyl.

and where for X = 0:

R1and R2is individually selected from lower Akilov and at the same time is SUP>-H or hydroxyl.

These compounds are useful as antitumor agents.

Compounds of General formula:

< / BR>
R=C2H5, R' = H, R" = CH2OH /example 1/;

R=CH3, R' = OH, R" = CH2OH /example 2/;

R=C2H5, R' = H, R" = CH2OCONHCH3/example 4/;

R=CH3, R' = OH, R" = CH2OCONHCH3/example 5/;

R=C2H5, R' = H, R" = CH2OCONHC6H5/example 23/;

R=C2H5, R' = H, R" = CH2OCONHC3H7/example 24/;

R=C2H5, R' = H, R" = CH2OCONHC4H9/example 25/;

R=C2H5, R' = H, R" = CH2OCOCH3/example 26;/

R=C2H5, R' = H, R" = CH2OCOCH3/example 27 and/ or

R=C2H5, R' = H, R" = CH2OCOC6H3(NO2)2/example 28/

and the results of the testing of these compounds for anti-tumor and/or antihistorical activity described in the publication Archer, etc. /J. Med. Chem/ 31, 254-260 (1988)/.

In accordance with this invention provides compounds of General formula I:

< / BR>
where (I) n = 2 or 3;

R1and R2- independently from each other lower alkyl;

Q is a residue selected from the group consisting of CH2OTHER3CH7CH2N(C2H5)CHO, CH2N(R4) P(O) (O-lower alkyl)2CH2= CH-N(R9)(R10), CH2N(R4)C(O)OR47CH2N(R4)C(O)CF3.

R3hydrogen or lower alkyl;

R4hydrogen, lower alkyl or Ar;

R5hydrogen, lower alkyl or Ar;

R6hydrogen or lower alkyl;

R7lower alkyl or Ar;

R8hydroxyl;

Ar is phenyl or phenyl substituted with stands, methoxy, hydroxy, halogen or nitro-group; and

R9and R10- independently from each other lower alkyl; or

(2) Q is a residue selected from the group consisting of CH2N(R4)SO2R7CH= N-Ar, C(O)NR5R6CH2N(R4)C(O)R7CH2N(R4)P(O) (O-lower alkyl)2CH2N(R4)C(O)CF3and CH2N(R4)C(O)OR7; R8is hydrogen, lower alkyl, lower alkoxy or hydroxyl; Ar is phenyl, substituted by hydroxyl; and n, R1, R2, R4, R5, R6and R7- take the values defined in part /1/ provided that one or more of R4, R5or R7- Ar, or

Q is a residue selected from the group consisting of CH2N=CH-N(R9)(R10), CH2N(R4, R1, R2, R4, R7, Ar, R9and R10- take the values defined above in paragraph (1); or their pharmaceutically acceptable acid additive salt or solvate;

The compounds are useful for treating tumors in mammals.

The term "lower alkyl" used herein includes linear, branched or cyclic hydrocarbons containing four or more carbon atoms. The term "halogen" includes bromo, chloro and fluoro. The term "lower alkoxy" includes linear or branched alkoxy substituents having from one to four carbon atoms, e.g. methoxy, ethoxy, propoxy, ISO-propoxy, butoxy, fluorine-butoxy etc.

The preferred compounds defined under part /1/, are compounds in which Q represents a residue selected from the group consisting of CH2OTHER3CH2N(R4) SO2R7CH2NHCHO,-CH-N-Ar, C(O)NR5R6,

CH2N(R4)C(O)R7CH2N(C2H5)CHO and

CH2N(R4)P(O) (O-lower alkyl)2and R4is hydrogen or lower alkyl, especially when Ar is phenyl or phenyl substituted with stands, methoxy, halogen or nitro group. Especially predpochli methyl and R7- lower alkyl, in particular 1-//2-(diethylamino)ethyl/amino/-4-(methylamino)methyl)-7 - gidrometeocenter-9-he and N-//1-(2-(diethylamino)ethyl)amino/-7-hydroxy-9-exoticisation-4-yl/methyl/ methanesulfonamide.

The preferred compounds defined under part /3/, are compounds in which R8is hydrogen, lower alkyl or lower alkoxy; R4is hydrogen and Ar is phenyl or phenyl substituted with stands, methoxy, halogen or nitro-group. Especially preferred are compounds in which n is 2 and R1and R2are both ethyl, and R8is hydrogen or methoxy group, particularly compounds in which R7is lower alkyl. The most preferred compounds are methyl N-//1-//2-(diethylamino)ethyl)amino)-9-exoticisation-4-yl/methyl/carbamate and methyl N-//1-//2-(diethylamino)ethyl)amino/-7-methoxy-9-exoticisation-4 - yl/methyl/carbamate.

The invention also relates to compositions for the treatment of tumors and cancers in mammals, which contain compounds of formula I and pharmaceutically acceptable excipients or diluents.

The invention further relates to a method of using the compounds of formula I for the treatment of tumors in mammals, which is in Oia, the compounds of formula I for the treatment of cancer in mammals, which is the introduction to the mammal the composition of the compounds of formula I and pharmaceutically acceptable excipients or diluents.

The synthesis of compounds of this invention may be broadly represented as shown in schemes a and B and C (see the end of the description).

The compounds of formula III /formula I in which Q is - CH=N-Ar/ can be synthesized by heating the aldehyde of formula II with approximately one equivalent of the appropriate aniline in an inert azeotropic solvent, preferably xylene or toluene, to the boiling point.

The compounds of formula IV can be obtained from the aldehyde of formula II by heating to 150 - 185oC in the presence of from about 5 to about 17 equivalents of formic acid in formamide, N-alkylphosphine or N-Ar-formamide, which here is used as a solvent. Conditions for this reaction Lacerta well known. The compounds of formula V get further acid hydrolysis of formamide.

The compounds of formula VI /formula I in which Q is CH2N(R4)SO2R7/ can be synthesized by sulfonylamine amine slight excess of the lower alkylsulfonyl or arylsulfonyl memom solvent, such as dichloromethane, in excess of base, such as triethylamine, at a temperature of from about 0oC to about room temperature.

On the other hand, the compounds of formula VI, where R4is lower alkyl, can be synthesized by sulfonylamine Amin V, in which R4- hydrogen, as described above, followed by treatment of the resulting sulfonamida VI, in which R4is hydrogen, an excess of base, preferably sodium hydride, in an appropriate solvent, such as tetrahydrofuran or N,N-dimethylformamide, followed by treatment with an excess of a suitable galoidoproizvodnykh lower alkyl at a temperature of from about 0oC to a temperature corresponding to the boiling point of the used solvent.

Carboxamide formula IX can be synthesized by the reaction of aldehyde II with 5 - to 6-fold excess of hydroxylamine hydrochloride in pyridine, optionally containing co-solvent, with subsequent dehydration of the oxime /VII/ by treatment with excess acetic anhydride and heated in an inert high-boiling solvent, such as xylene, and finally, partial hydrolysis of the nitrile /VIII/ in concentrated sulfuric acid. In fact the van to the corresponding acid in 16% alcoholic KOH, and the acid may be condensed with an appropriate amine using well known methods.

The compounds of formula X /formula I in which Q is CH2N(R4)C(O)R7/ can be synthesized by acylation of amine V with an excess of acid chloride is lower alkyl or aryl chloride acid in a suitable solvent, preferably pyridine, optionally in the presence of co-solvent, preferably dichloromethane, at a temperature of from about 0oC to approximately the 50oC.

The compounds of formula XII /the formula I in which Q represents CH2= CHN(R9)(R10)/can be synthesized by treatment of an amine of formula V with an excess of dimethylacetal of the formula (MeO)2CHN(R9)(R10) at a temperature of approximately 60oC.

The compounds of formula XIII /the formula I in which Q represents CH2N(R4)-C(O)CF3/ can be synthesized by treatment of an amine of the formula V in a suitable solvent, preferably dichloromethane, the excess solution triftoratsetofenona formula CF3C(O)X, in which X is halogen, preferably of triftoratsetata, in a suitable solvent, preferably toluene, at a temperature of about 0omay be synthesized by treatment of amine V with an excess of a suitable gaelicforum formula R7OC(O)X, in which X is halogen, preferably chlorine, in excess of base, preferably triethylamine, in a suitable solvent such as dichloromethane or chloroform, at a temperature of from about 0oC to about room temperature.

The aldehyde II can be obtained by the method described in U.S. patent 3294803, i.e. the oxidation of MnO2alcohol obtained by the method described in U.S. patent 3711512, or the method described below in the examples.

Simple chemical transformations, common and well-known qualified specialists in the field of chemistry can be used to replace the functional groups of the compounds of the present invention, for example, dealkylation lower-alkyl-arolovich esters with the corresponding phenol derivatives.

The compounds of formula I are used both in free base form and in the form of an acid additive salts, and both forms are covered by this invention. An acid additive salt in some cases are more convenient form for use, but in practice the use of the salt form is essentially equal to the main form. Acids which can be used to obtain kisut acceptable from a medical point of view, salt, i.e. salts, the anions of which are relatively innocuous to the animal organism when using salt in the medical dose, so that beneficial effects inherent in the free base has not been tampered with side effects attributed to the anions. Acceptable for practical use salts of this invention are hydrochloride, fumarate, toluensulfonate, methanesulfonate or maleate. However, in the field of the present invention are other acceptable from a medical point of view salts formed other mineral or organic acids. Acid additive salts of the basic compounds are produced either by dissolving the free base in an aqueous alcohol solution containing the appropriate acid and the release of salt by evaporation of the solution, or by the interaction of the free base with an acid in an organic solvent, in this case salt is allocated immediately planted a second solvent or can be obtained by evaporation of the solution. Despite the fact that the salts of the basic compounds that are acceptable from a medical point of view, are preferred, the scope of the present invention are all acid-salt additive. All acid additive salts are useful in image quality is only as an intermediate product, as for example when the salt is obtained only for the purpose of purification or identification, or when it is used as an intermediate product to obtain the salt, acceptable from a medical point of view, methods of ion exchange.

The structure of compounds of this invention was determined by the method of synthesis and one or more of: elementary analysis and by IR, UV and NMR spectroscopy. The direction of the reactions and the identity and homogeneity of the products was assessed by thin-layer chromatography /TLC/ or gas chromatography /GC/. The melting temperature is given in degrees Celsius /oC/ and are uncorrected. Starting materials are either commercially available or can be obtained fairly well-known methods.

Hereinafter the invention will be illustrated by the following examples, without however, limiting the invention.

Example 1. 1-//2-(Diethylamino)ethyl/amino/-4- (N-vinylformamide)thioxanthen-9-he.

(I: R1=R2=C2H5; Q = CH=N-C6H5; R8= H; n = 2).

A mixture of 17.7 g /50 mmol/ 1-//2-(diethylamino)ethyl/amino-9 - oxo-thioxanthen-4-carboxyaldehyde and 15.1 g /150 mmol/ aniline in 100 ml of toluene is boiled in the Isopropylamine in the ratio 10 : 10 : 2 shows, that the reaction was incomplete. The toluene is distilled off, add 25 ml of aniline and the mixture is boiled for 4 hours. 50 ml of xylene is added and the reaction mixture is boiled again for 3 hours. The solvent and excess aniline is removed under vacuum, the residue is recrystallized from benzene, resulting in a gain to 19.9 g of a technical product. As a result of recrystallization of the product from approximately 1.5 l of hexane get to 15.8 g /86%/ product with so pl. 125 - 126oC.

Example 2. N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite-4 - yl/methyl formamide.

(I: R1=R2=C2H5; Q = CH2NHCHO; R8= H; n = 2).

A solution of 35.4 g /0,1 mol/ 1-//2-(diethylamino)ethyl/amino-9 - oxo-thioxanthen-4-carboxyaldehyde, 420 ml of formamide and 50 ml /1 mol of formic acid is heated to 160oC and kept at this temperature for 1 hour. The reaction mixture is cooled, poured into 2 liters of water and alkalinized approximately 50 ml of sodium hydroxide /35%/. Resinous precipitate is filtered and dried under vacuum. The dried precipitate was dissolved in about 1.5 liters of hot ethyl acetate, treated with charcoal and crystallized by cooling. The product is filtered, washed with ethyl acetate and dried with receives/methyl-N-methylformamide.

(IV: R1=R2=C2H5; R4= CH3; R8= H; n = 2).

By a method similar to that described in example 2, the gain of 24.6 g of N-methylformamide out of 35.4 g /0,1 mol/ 1-//2-(diethylamino)ethyl/amino - 9-exoticisation-4-carboxaldehyde, 394 g of N-methylformamide and 50 ml of formic acid. The product is recrystallized from 150 ml of acetone to obtain a product with a melting point 127 - 130o.

Example 4. 4-(Aminomethyl)-1-//2-(diethylamino)ethyl/amino/- thioxanthen-9-he

(I: R1=R2=C2H5; Q = CH2NH2; R8= H; n = 2).

A solution of 24.4 g /64 mmole/ formamide example 2 in 240 ml of 2 N. hydrochloric acid is heated on a steam bath for 1 hour. The reaction mass was then cooled to room temperature, alkalinized 35% aqueous solution of sodium hydroxide and the resulting yellow precipitate are filtered. The product is dissolved in benzene, treated with charcoal, dried with magnesium sulfate, filtered and azeotrope dried to remove traces of moisture. The dried residue is recrystallized from methanol and isopropanol with the addition of ethereal hydrochloric acid. The resulting solid is recrystallized from methanol to obtain 10.6 g of product with a temperature of the Teal/thioxanthen-9-he

(I: R1=R2=C2H5; Q = CH2NHCH3; R8= H; n = 2).

Method that exactly matches the one described in example 4, receive a 10.5 g of methylamine hydrochloride hemihydrate of 14.6 g /37 mmol/ N-methylformamide of example 3 and 150 ml of 2 N. hydrochloric acid. The product melts at 241 - 243o.

Example 6. N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite-4-yl/methyl/methanesulfonamide.

(I : R1= R2=C2H5; Q = CH2NHSO2CH3; R8= H; n = 2).

The solution 10,65 g /30 mmol/ free base amine, obtained in example 4 in 100 ml of pyridine cooled in an ice bath and add to it in one portion to 4 g /35 mmol/ methanesulfonamide. The mixture is stirred for 2 hours at room temperature and poured to 750 ml of water containing 2 g of sodium hydroxide. Dark yellow precipitate is collected, washed and left to dry under vacuum overnight. The second portion is produced by adding an excess of sodium hydroxide to the filtrate and filtering the obtained solid substance. Precipitates are combined and, after drying, recrystallized from benzene to obtain 6.4 g of methanesulfonamide with so pl. 169-170o.

Example 7. 1-//2'-(Diethylamino)ethyl/AMI (n = 2).

Suspension 74 g /a 0.23 mol/ 1-//2-(Diethylamino)ethyl/amino/- 9-oxo-thioxanthen-4-carboxaldehyde and 74 g /1,06 mol/ hydroxylamine hydrochloride in 400 ml of pyridine and 400 ml of ethanol is boiled for 0.5 hour to obtain a homogeneous solution, add 70 ml of water. The solution is heated for another 2 hours and left on for 14 hours at room temperature. The resulting crystalline oxime was filtered and receive with a quantitative yield of product with so pl. 215-218oC.

123 g of the oxime heat up quickly on the steam bath in 180 ml of acetic anhydride to obtain a solution. The solution is cooled, add 100 ml of 1.8 M HCl in ether and the resulting suspension was dissolved in 500 ml of diethyl ether. The suspension is maintained at a temperature of 0owithin 14 hours and filtered. Balance /123 g, so pl. 109-112oC/ suspended in 250 ml of xylene and boil for 20 minutes. The mixture is cooled and filtered to obtain from 71.3 g of the nitrile with so pl. 265oC.

10 g of the nitrile is stirred in 200 ml of concentrated H2SO4at room temperature for 3 days. The reaction mixture is neutralized with concentrated NH4OH and the residue filtered. The residue is mixed with a warm mixture of ethyl acetate and ethyl alcohol, filtered and kristallizuyutsya one g/equivalent of HCl in ethanol. Get 6 g of amide hydrochloride with so pl. 271-272o.

Example 8. N-//1-//-(Diethylamino)ethyl)amino/-9 exotikite-4-yl/methyl/ N-methylmethanesulfonamide.

(I : R1=R2= C2H5; Q = CH2N(CH3)SO2CH3; R8= H; n = 2).

A solution of 1.5 g /3.5 mmole/ methanesulfonamide obtained in example 6 in tetrahydrofuran (THF /THF/ /60 ml/ cooled to 0oC in an ice bath and added 0.16 g /4.0 mmole/ NaH. The reaction mixture was warmed up to room temperature, stirred for 10 minutes, then add methyliodide - 0.25 ml /4.0 mmole/. The reaction mixture was stirred at room temperature for 24 hours, then the solvent is removed under vacuum. The residue was subjected to purification by the method of column chromatography on silica by elution with chloroform /100%/ then 1% Isopropylamine/chloroform to obtain 1,15 g /74%/ N-methylmethanesulfonamide in the form of a yellow powder with so pl. 175-177oC. the Free base is treated methanesulfonic acid in methanol to obtain methansulfonate salt so pl. 194 - 195,5oC /designated hereinafter as example 8a/.

Example 9. N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite-4-yl/methyl/vinylsulfonate.

Example 10. N-//1-//2-(Diethylamino)ethyl/amino/-9-oxo-thioxanthen - 4-yl/-methyl/ndimethylacetamide.

(I : R1=R2= C2H5; Q = CH2NHC(O)CH3; R8= H; n = 2).

By a method similar to that described in example 2, to obtain 2.3 g /52%/ ndimethylacetamide in a solid orange color of 4.15 g /11,7 mmole/ free base of the amine of example 4, pyridine /60 ml/ acetylchloride /0,82 ml, 11,53 mmole/. The product is recrystallized from acetone to obtain a solid substance with a melting point 182 - 183oC.

Example 11. N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite - 4-yl/methyl/benzamid.

(I : R1= R2= C2H5; Q = CH2NHC(O)C5H6; R8=H; n = 2).

By a method similar to that described in example 6, get 1,02 g /68%/ benzamide as a yellow powder from 1,17 g /3,29 mmole/ free base amine of ftografii on silicon dioxide, elwira chloroform, starting with 100% chloroform to 1% Isopropylamine/chloroform, followed by recrystallization from ethyl acetate. The product melts at 161 - 163oC.

Example 12. N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite - 4-yl/diethyl/phosphoamide.

(I : R1=R2=C2H5; Q = CH2NHP(O)(OC2H5)2; R8= H; n = 2).

A solution of 2.28 g /6,48 mmole/ free base of the amine of example 4, CH2Cl2/50 ml/ triethylamine /2 ml/ at 0oC is treated with diethylphosphoramidite /1.0 ml, 6.9 mmole/. The reaction mixture is stirred for 2 hours at 0oC, then 1 hour at room temperature. The solvent is removed under vacuum, the residue was subjected to purification by the method of column chromatography on silica, elwira with ethyl acetate /100%/, then 5% methanol/ethyl acetate and finally with a mixture of methanol/Isopropylamine/ ethyl acetate in the ratio 5/5/90 to obtain 2.28 g /72%/ diethylformamide in a solid yellow color with so pl. 108 - 110oC after recrystallization from ethyl acetate.

Example 13. N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite - 4-yl/methyl/N-ethylformate.

(IV: R1= R2= C2H5; R4= C2H5oC and kept at this temperature for 4 hours. Then the reaction mixture is cooled, poured into water and alkalinized with 10% sodium hydroxide. The resulting solid is collected by filtration and washed with water. The solid residue is extracted with a mixture of chloroform/water, the organic layer separated and dried Na2SO4. The solvent is distilled off under vacuum and the residue purified by radial chromatography elwira a mixture of Isopropylamine/methanol/ethyl acetate in a ratio of 0.1:1:98 to receive 1,32 g /57%/ N-ethylformate in a solid orange color with so pl. 75 - 77o.

Example 14. 1-//2-Diethylamino ethyl/amino/-4-(ethylamino)methyl/thioxanthen-9-he

(I : R1=R2= C2H5; Q = CH2NHC2H5; R8= H; n = 2).

By a method similar to that described in example 4, to obtain 1.29 g /92%/ ethylamine in the form of the dihydrochloride of 1.3 g /3.2 mmole/ N-ethylformate of example 13 and 10.8 ml of 2 N. hydrochloric acid. The product is recrystallized from a mixture of ethanol/tetrahydrofuran, after which it has a melting point of 160oC /colour / div./

Example 15 1-//2-Diethylamino/ethyl/amino/-4- (dimethylamine is SUB>H5; Q = CH2N = CHN(CH3)2; R8= H; n = 2).

N-//1-//2-(Diethylamino)/ethyl/amino/-2-exoticisation-4-yl/methyl/formamid /3 g/ is diluted with 50 ml of 2n. HCl and the solution is heated on a steam bath for 90 minutes. The mixture is cooled, alkalinized to pH 10 with 35% aqueous sodium hydroxide and extracted into chloroform. The organic layer is separated, filtered through K2CO3, evaporated in vacuum and the resulting technical product used in the reaction with dimethyltrimethylene, which flows at a temperature of 60oC during the night. Excess DMF-dimethylacetal removed under vacuum, the desired title compound purified by thin layer chromatography /silica gel; chloroform: and-C3H7:CH3OH = 98:1:1/. The products obtained are dissolved in 2.5 M HCl /C2H5OH / 100 ml, cooled in an ice bath, filtered and dried, resulting in a gain of 2.38 g 1//2-(diethylamino)-ethyl/amino/-4- (dimethylaminomethylene)-thioxanthen-9-she trihydrochloride in a solid orange color, so pl. 258 - 260oC.

Example 16. N-//1-//2-Diethylamino ethyl/amino/-O-akateeminen - 4-yl/= methyl/triptorelin.

(I : R1= R2= C2H5; Q = CH2oC is treated with triftoratsetilatsetonom /14,75 ml 0,61 M solution in toluene; 9.0 mmole/, the reaction mixture is stirred for 90 minutes. The mixture is evaporated under vacuum and the residue purified by thin layer chromatography /silicagel; C2H5OCOCH3/100%/, then 2% Isopropylamine/ethyl acetate/ and then recrystallized from ethyl acetate to obtain 2,52 g /68%/ product in free base form with so pl. 189 - 190oC /example 16/. The free base is dissolved in methanol and treated methanesulfonic acid /0.55 g, 5.72 mmole/ getting methansulfonate with so pl. 152 - 154oC after recrystallization from acetone /example 16a/.

Example 17.

(a) a Mixture of thiosalicylic acid /50,14 g of 0.33 mol/ and acetate of copper /5.0 g/ DMSO /500 ml bring to a boil and portions add the potassium carbonate /54,3 g/. Then the syringe is injected into a mixture of 3-brotherbear /42 ml of 0.36 mol/ and the mixture is boiled for 3 hours. The reaction mixture was poured into water, treated with charcoal and filtered through celite. The filtrate is acidified with concentrated HCl and the resulting precipitates are filtered, washed with water and dried under vacuum at 60oC obtaining 75,0 0oC with stirring 2-/(3-chlorophenyl)thio/benzoic acid /75,00 g 0,28 mol/ hour. After that, the mixture is stirred for further 2 hours, poured into a concentrated solution of NH4OH /500 ml/ water /2.5 l/, the resulting precipitates are filtered, washed with water and dried under vacuum at 60oC obtaining 65.9 g /95%/ mixture of 1-chloro and 3-chlorothioxanthone-9-ones.

(C) a Mixture of 1-chloro - and 2-chlorothioxanthone-9-ones /14,01 g, 56,8 mmole/, pyridine /20 ml/ diethylaminopropylamine /5,13 g, 39.4 mmole/ boil until then, while the reaction will not work completely. Heating is removed, the solvent is distilled off under vacuum, the residue is placed in chloroform and purified by the method of column chromatography on silica, elution first with chloroform to remove unreacted 3-chloridometer, and then a 5% solution of Isopropylamine in chloroform with getting 5.10 g/54%/ 1-//3-(diethylamino)propyl/amino/thioxanthen-9-it is in the form of orange resinous substance.

(g) a Mixture of 1-//3-diethylamino propyl/amino/thioxanthen-9-it /5.10 g, 15,0 mmole/, formalin /160 ml/ 5 N. acetic acid /0.8 ml/ heated to 90oC and kept at this temperature for 16 hours, add additional amounts of acetic acid /0,20 ml/, zadow. After that, the mixture is diluted with water, alkalinized 5 N. NaOH solution and extracted with chloroform. The organic layer is dried Na2SO4and passed through a column of silicon dioxide, elwira first 2% solution of methanol in chloroform and then a mixture of Isopropylamine/methanol/chloroform in the ratio 2/2/96 obtaining 3,82 g /69%. 1-//(diethylamino)propyl/amino/-4-hydroxymethylcytosine-9-it is in the form of an orange-brown resinous substance.

(d) 1-//3-Diethylamino propyl/amino/-9 exotikite-4-carboxaldehyde.

(II: R1= R2=C2H5; R8=H, n = 3).

A mixture of 1-//3-(diethylamino)propyl/amino/-4-hydroxymethylcytosine-9-it /3,82 g/, toluene /60 ml/ and manganese oxide /7.5 g/ boiled for 6.5 hours. The mixture is cooled to room temperature, filtered through celite and the filtrate evaporated under vacuum to obtain 3,3 g /87%/ product as a brown oil.

/e/ 1-//-(Diethylamino)propyl/amino/-4-(methylaminomethyl)thioxanthen-9-he dihydrochloride 3/2 hydrate.

(I: R1=R2=C2H5; Q=CH2NHCH3; R8=H; n=3).

Solution 1-//3-(diethylamino)propyl/amino/-9 oxathiolane-4 - carboxaldehyde/ 3.3 grams, 8,96 mmole/ and 3 g of formic acid in 50 mirouet in chloroform /3 x 150 ml/. The organic layer is dried with sodium sulfate, evaporated under vacuum, the technical product in the form of oil dissolved in 3 BC aqueous solution of hydrochloric acid /50 ml and heated on the steam bath for 3 hours. The mixture is then cooled, alkalinized 30 ml of aqueous 35% NaOH solution, extracted in chloroform /h ml/, the organic layer dried with sodium sulfate and evaporated under vacuum to obtain a brown oil, which was purified by thin layer chromatography /silicagel; 5% triethylamine/diethyl ether, then 5% (C2H5)3N/a ethyl acetate, then triethylamine:methanol:ethyl acetate=5:5:90/ obtaining 1.1 g of 1-//3-(diethylamino)propyl/amino/-4-(methylamino)/-4-methylaminomethyl thioxanthen-9-it is in the form of a transparent resinous substances orange. This product is converted into the corresponding dihydrochloride interaction with 6 N. HCl in diethyl ether to obtain 1.04 g of the dihydrochloride 3/2 hydrate in the form of a yellow powder with so pl. 222 - 224oC.

Example 18.

(a) a Mixture of 1-chloro and 3-chlorothioxanthone-9-ones /20 g/, pyridine /40 ml/ and N-dimethylethylenediamine /11 ml/ boil for about 22 hours, then the solvent is removed under vacuum. The residue connect c technical provoznoj chromatography on silica, elwira first chloroform, then 1% solution of Isopropylamine in chloroform to obtain a 13.4 g of 1-//2-(dimethylamino)ethyl/amino/thioxanthen-9-it.

(b) a Mixture of 1-//2-(dimethylamino)/ethyl/amino/-thioxanthen-9-it /13 g 0,044 mol/, 37% formalin /390 ml/ 5 N. acetic acid /6,5 ml/ heated to 100oC and kept at this temperature for 8.5 hours, then leave for two days, and then again heated to 100oC and kept at this temperature for several hours. The mixture was poured into ice-cold water, alkalinized 35% NaOH solution and extracted with chloroform. The organic layer was washed with brine, dried with sodium sulfate and evaporated under vacuum. The residue was subjected to purification by the method of column chromatography on silica, elwira in series: 25%-s ' solution CHCl3in hexane; 50% solution of chloroform in hexane; 75% solution of chloroform in hexane; 100% chloroform; 0.5% solution of Isopropylamine in chloroform; 1% solution of Isopropylamine in chloroform; 2% solution of Isopropylamine in chloroform and a mixture of Isopropylamine:methanol:chloroform in the ratio 2:2:96 obtaining 9.2 grams/64%/ 1-//2-(dimethylamino)ethyl/amino/-4 - hydroxymethyl thioxanthen-9-it.

() 1-//2-(Dimer>8=H; n=2).

A mixture of 1-//2-(dimethylamino)ethyl/amino/-4-(hydroxymethyl) thioxanthen-9-it /9.2 grams, 0,028 mol/ toluene /322 ml/ heated to approximately the 60oC, and then added to the mixture of the manganese dioxide /MnO2, 16 g/, the mixture is heated to 60oC and kept at this temperature for 1 hour. The mixture is filtered and the filtrate evaporated under vacuum to obtain 7.9 g /87%/ product.

(g) N-//1-//2-(Dimethylamino)ethyl/amino/-9 exotikite-4-yl/ methyl/formamid.

(I: R1=R2=CH3; Q=CHNHCHO; R8=H; n=2).

A mixture of 1-//2-dimethylamino ethyl/amino/-9 exotikite-4 - carboxaldehyde /4,75 g/, formamide /66,5 ml/ and formic acid /7,6 ml/ heated to 170oC and kept at this temperature for 4 hours. The mixture was poured into ice-cold water /250 ml/ alkalinized 35% NaOH solution and extracted with chloroform. The organic layer is washed with water /twice/, then with a sodium chloride solution once, the solution is dried with sodium sulfate and evaporated under vacuum to obtain 6.2 g of product.

(d) 4-(Aminomethyl)-1-//2-(dimethylamino)ethyl/amino/-9 exotikite-9-he dihydrochloride/2 hydrate.

(I: R1=R2=CH3; Q=CH2NH2; R8=H; n=2).

A mixture of N-//1 is uderjivayut at this temperature for 1.5 - 2 hours. The reaction mixture was poured into ice water, alkalinized 35% NaOH solution and extracted with chloroform. The organic layer is washed with water /twice/, then brine /once/, dried with sodium sulfate and evaporated under vacuum. The residue was subjected to purification by the method of column chromatography, elwira sequentially with ethyl acetate, 0.5% solution of triethylamine in ethyl acetate, 2% solution of triethylamine in ethyl acetate, 1 - 2% solution of Isopropylamine in ethyl acetate and finally with a mixture of methanol:Isopropylamine: chloroform in the ratio 2:(1 - 2):(97 - 96) with the receipt of 3.3 g /58%/ product in the form of free base. A portion of the free base is dissolved in methanol and treated with concentrated HCl /3,3 ml/ methanol /6 ml/ obtaining 1.2 g of product in the form dihydrochloride/2 hydrate with so pl. 213oC /colour / div./.

(e) N-//1-//2-(Dimethylamino)ethyl/amino/-9-exoticisation-4 - yl/methyl/methanesulfonamide methanesulfonate.

([I: R1=R2=CH3; Q=CH2NHSO2CH3; R8=H; n=2).

4-(Aminomethyl)-1-//2-(dimethylamino)/ethyl/amino/-9 exotikite-9-it/ 2 g, 6 mmole/ in 30 ml of dry pyridine was stirred at room temperature to obtain a solution. The solution is cooled in an ice bath, d is for 1 hour at room temperature. The reaction mixture is poured into 500 ml of water containing 0.51 g of hydrococone sodium, extracted with chloroform, the organic layer washed twice with water and brine, dried with anhydrous sodium sulfate. The mixture is filtered and evaporated under vacuum. Balance /2.5 g/ carry in diethyl ether, filtered, dried to obtain 2 g of the product with so pl. 126 - 127oC. the Free base is dissolved in methanol and treated methanesulfonic acid /0,48 g/ obtaining 2.0 g /67%/ product in the form of a salt methanesulfonic acid so pl. 168oC (decomp./.

Example 19.

(a) by a Method similar to that described in example 17// get 6,83 g 1-//3-(dimethylamino)propyl/amino/thioxanthen-9-it is from a mixture of 1-chloro - and 3-chlorothioxanthone-9-ones /br15.15 g, 61.4 mmole/, pyridine /20 ml/ dimethylaminopropylamine /6,01 g, 59.1 mmole/.

(b) by a Method similar to that described in example 17/g/, get 6,74 g/90%/ 1-//3-(dimethylamino)propyl/amino/-4-(hydroxymethyl)- thioxanthen-9-it 1-//3-(dimethylamino)propyl/amino/thioxanthen-9-it /6.8 g, of 21.9 mmole/, formalin /175 ml of glacial acetic acid /0.75 ml/.

() 1-//3-(Dimethylamino)propyl/amino/-9 exotikite-4 - carboxaldehyde.

(II: R1=R2=CH3; R8=H; n=3).

Method, the number is-9-it /6.7 g/, toluene /80 ml/ and manganese dioxide /12,15 g/. The product was subjected to purification by the method of column chromatography on silica, elwira first chloroform /100%/, and then a 1% solution of Isopropylamine in chloroform.

(g) N-//1-//3-dimethylamino)propyl/amino/-9 exotikite-4 - yl/methyl/N-methylformamide.

(IV: R1=R2=CH3; R4=CH3; R8=H; n=3/.

A mixture of N-methylformamide /50 ml/, formic acid /5,2 g/ and 1-//3-dimethylamine/propyl/amino/-9 exotikite-4-carboxaldehyde /4,14 g, 12,16 mmole/ boiled for 3 hours. The mixture is diluted with water to 250 ml/, alkalinized 35% NaOH solution and extracted with chloroform /h ml/. The organic layer is dried with sodium sulfate, passed through a filter with silicon dioxide, elwira chloroform /100%/, then 2% solution of Isopropylamine in chloroform to obtain 3,93 g /84%/ product.

(d) 1-//3-Dimethylamino)propyl/amino/-4-(methylaminomethyl) thioxanthen-9-he dihydrochloride monohydrate.

(I: R1=R2=CH3; Q=CH2NHCH3; R8=H; n=3).

The solution previously obtained N-methylformamide /a 3.83 g, 10 mmole/ in 40 ml of 3 N. HCl is kept on the steam bath for 3 hours, neutralized with 35% NaOH solution and cooled in Leda the rez silica gel, elwira first chloroform, then 1% solution of Isopropylamine in chloroform to obtain 2.38 g of the desired amine in the form of resinous substances orange. The product is converted into the corresponding salt of hydrochloric acid by dissolving in methanol and treating it with concentrated hydrochloric acid, resulting in a gain of 0.98 g of the dihydrochloride monohydrate with so pl. 228 - 229oC.

Example 20.

(a) N//2-(Dimethylamino)ethyl/amino/-9 exotikite-4-yl/ methyl/N-methylformamide.

(IV: R1=R2=CH3; R4= CH3; R8= H; n = 2).

A mixture of 1-//2-(dimethylamino)ethyl/amino-9-exoticisation-4 - carboxaldehyde /4,75 g of 0.15 mol/ N-methylformamide /48 ml/, formic acid is heated to 170oC for 4.5 hours and then left at room temperature for approximately 64 hours. The reaction mixture was poured into water /250 ml/, alkalinized 35% NaOH solution, extracted with chloroform /three times/. The organic layer was separated, washed with water two times, then brine, and dried with sodium sulfate. The solvent is distilled under vacuum to obtain 5.75 g of product.

(b) 1-//2-(Dimethylamino)ethyl/amino/-4-/(methylamino)- methyl/thioxanthen-9-he dihydrochloride/4 hydrate.

(the y in example 19/d/, obtain 1.8 g of 1-//2-(dimethylamino)ethyl/amino/-4-/(methylamino)methyl/thioxanthen-9-he of 5.7 g /15.4 mmole/ corresponding to the N-methylformamide of example 20 (a) and 50 ml of 2 N. HCl, after purification of the free base by the method of thin-layer column chromatography /silica gel, chloroform, 0.5% solution Isopropylamine in chloroform/. The free base was transferred to the salt form of the dihydrochloride 5/4 hydrate treatment of concentrated hydrochloric acid in methanol to obtain 1.8 g /30%/ product with so pl. 177oC /colour / div./

Example 21.

(a) N-//1-//3-(Dimethylamino)propyl/amino/-9 exotikite - 4-yl/methylformamide.

(I: R1=R2=CH3; Q = CH2NHCO; R8= H; n = 3).

Solution 1-//3-(dimethylamino)propyl/amino-9-exoticisation-4 - carboxaldehyde /3.6 g; 10,57 mmole/ 50 ml of formaldehyde containing 3.6 g of formic acid, boiled for 1.5 hours and then left at room temperature overnight. The reaction mixture is diluted with water to 400 ml/, alkalinized 3 ml of 5 n NaOH solution, intensively stirred for 30 minutes, the resulting precipitate is filtered, washed with water and dried, resulting in a gain of 3.1 g /79%/ product as a yellow powder.

(b) 4-Aminomethyl-1-//3-(dimethylamino)propyl/amino/t is the thief of formamide example 21 (a) - /2,98 g; 8,07 mmole/ in 40 ml of 3 N. HCl is heated on the steam bar for 4 hours, then allowed to cool to room temperature, cooled in an ice bath, neutralized to pH 8 5 N. NaOH solution. The resulting homogeneous mixture is extracted with chloroform /5 x 100 ml, the organic layer dried with sodium sulfate and filtered through a layer of silica gel /elwira first 5% solution of triethylamine in diethyl ether, then 1 to 5% solution of isopropanol in chloroform/ obtaining 2.3 g /83%/ product in the form of oil is light yellow in color.

(in) N-//1-//3-(Dimethylamino)propyl/amino/-9 exotikite - 4-yl/methanesulfonamide methanesulfonate 1/2 hydrate.

(I: R1=R2=CH3; Q = CH2NHSO2CH3; R8= H; n = 3).

To a cold solution of the amine of example 21 /b/, cooled in an ice bath, with /2.2 g, 6,44 mmole/ pyridine add methanesulfonanilide /0.51 ml, 6,59 mmole/ and the resulting mixture was stirred at room temperature overnight. The mixture is diluted with chloroform, passed through a thick layer of silicagel, elwira 5% solution of triethylamine in ethyl acetate, obtaining 1,32 g N-//1-//3-(dimethylamino)propyl/amino/-9 exotikite - 4-yl/methanesulfonamide in the form of a yellow powder. The free base play of 1.38 g of the methanesulfonate salt 1/2 hydrate in the form of a solid orange color with so pl. > 107oC.

Example 22. N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite-4-yl/methyl/N-methylethanolamine methanesulfonate.

(I: R1=R2=C2H5; Q = CH2N(CH3)SO2C2H5; R8= H; n = 2).

The solution 2,03 g /5,49 mmole/ 1-//2-(diethylamino)ethyl/amino/- 4-(methylamino)methyl/-thioxanthen-9-it /obtained by the method described in example 5/ triethylamine in 45 ml of methylene chloride cooled to 0oC and treated with acanaloniidae /0.74 g, 5,76 mmole/. After keeping the resulting solution for 15 minutes at 0oC, the reaction mixture was stirred at room temperature for 72 hours. The mixture is evaporated under vacuum, the residue is dissolved in chloroform and purified passing through a layer of silica gel /chloroform, then 1% solution of triethylamine in chloroform/, the result 2,43 g /96%/ N-//1-//2-(diethylamino)ethyl/- amino/-9 oxathiolane-4-yl/methyl/N-methylethanolamine. The sulfonamide is recrystallized from ethyl acetate and treated methanesulfonic acid in isopropanol to obtain a product in the form of a salt methanesulfonic acid so pl. 159 - 161oC.

Example 23. N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite-4-yl/m>HSO2C6H4-p-OCH3; R8= H; n = 2).

A solution of 1.40 g /3.94 mmole/ 4-(aminomethyl)-1-//2- (diethylamino)ethyl/amino/thioxanthen-9-it /obtained by the method described in example 4/ in 30 ml of chloroform containing 1.5 ml of triethylamine, cooled to 0oC and treated with p-methoxybenzenesulfonamide /0,83 g, was 4.02 mmole/. After keeping the reaction mixture at 0oC for 10 minutes, the reaction mixture was stirred at room temperature for 2 hours. The chloroform is distilled off under vacuum, the residue is dissolved in 100 ml of methylene chloride containing 1 ml of triethylamine and treated with additional p-methoxybenzenesulfonamide /0,85 g/ under stirring at room temperature. The mixture is evaporated under vacuum, the residue is subjected to cleaning, passing through a layer of silica gel /1% triethylamine in chloroform/, with the receipt of 1.57 g of N-//1-//2-diethylamino ethyl/amino/-9 exotikite-4-yl/methyl/-p-methoxybenzenesulfonamide. The sulfonamide process methanesulfonic acid /0.3 g/ in a mixture of isopropanol/isopropanol/methanol to obtain 1.07 g of salt methanesulfonic acid so pl. 133 - 137oC.

Example 24. N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite - 4-yl/methyl/tinsulanond methanesulfonate.

(I: R1=R2=C2H5; Q = CH2N(C2H5)SO2CH3; R8= H; n = 2).

A solution of 2.10 g /5,48 mmole/ 1-//2-(diethylamino)ethyl/amino/- 4-/(ethylamino)methyl/-thioxanthen-9-it /obtained by the method described in example 14/ in 30 ml of methylene chloride cooled to 0oC, treated with 2 ml triethylamin the century The solvent is distilled off under vacuum, the residue is dissolved in chloroform and the solution is purified by passing through a layer of silica gel /elwira chloroform, and then 2% solution of triethylamine in chloroform/. As a result of recrystallization from ethyl acetate, followed by drying receive 1,11 g /44%/ product in the form of a yellow powder with so pl. 172 - 176oC.

Example 26. N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite-4-yl/methyl/-3,4-dichlorobenzenesulfonate 1/2 hydrate

(I: R1=R2=C2H5; Q = CH2NHSO2C6H33,4 - dichloro; R8= H; n = 2).

To a solution of 3,4-dichlorobenzenesulfonate /1.84 g, 7.5 mmole/ in 35 ml of dry pyridine add 2.5 g /7 mmole/ 4-aminomethyl-1-//2-(diethylamino)ethyl/amino/thioxanthen-9-it /obtained by the method described in example 4/ under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 15 minutes and then leave for approximately 72 hours. The reaction mixture was poured into 75 ml of water containing 0.75 g of NaOH and extracted with chloroform. The organic layer is washed twice with water and brine, dried with sodium sulfate. The chloroform is distilled off under vacuum, the residue is recrystallized from ethanol to obtain 1.24 g N-//1-//2-(Diet the base is dissolved in methanol and treated methanesulfonic acid in methanol to obtain methanesulfonate 1/2 hydrate with so pl. 55oC /colour / div./

Example 27. N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite-4-yl/methyl/-2-forbindelsesfaneblad.

(I: R1=R2=C2H5; Q = CH2NHSO2C6H4-2-F; R8= H; n = 2).

A solution of 1.36 g /a 3.83 mmole/ 4-(aminomethyl-1-//2- (diethylamino)ethyl/amino/thioxanthen-9-it /obtained by the method described in example 4/ in 25 ml of methylene chloride containing 1 ml of triethylamine, cooled to 0oC and treated with 2-forbindelsesfanebladet /0.84 g, 4,32 mmole/, after which the reaction mixture is stirred for several hours. The solvent is distilled off under vacuum, the residue is dissolved in chloroform and purified by thin-layer chromatography /silica gel : chloroform, then 1% solution of triethylamine in chloroform/. The solvent is removed under vacuum and recrystallization from ethyl acetate receive 1,08 g /55%/ product in the form of a powder orange with so pl. 125 - 127oC.

Example 27. N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite-4-yl/methyl/N-propylaminosulfonyl.

(I: R1=R2=C2H5; Q = CH2N(C3H7)SO2CH3; R8= H; n = 2).

Oil of 0.2 g of 60% dispersion of sodium hydride in mineiros nitrogen add dry dimethylformamide /40 ml/, and then 2 g N-//1-//2-(diethylamino)ethyl /amino/-9 exotikite-4-yl/methyl/methanesulfonamide /example 6/, whereupon the mixture is heated to a temperature of 50oC and kept at this temperature for 2 hours. After that, the mixture is cooled in an ice bath for 15 minutes and added 0.87 g of propyliodide in a small amount of dimethylformamide and leave the mixture under stirring overnight. The mixture is then mixed with 35 ml of water, filtered, the residue washed with water and dried /50oC/ 0.1 mm /P2O5/ to obtain 2.17 g of product with tons of dps, 142 - 143oC.

Example 29. N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite-4-yl/methyl/-N-methyl-benzosulfimide methanesulfonate.

(I: R1=R2=C2H5; Q = CH2N(CH3)SO2C6H5; R8= H; n = 2).

A solution of 5.32 g /14.4 mmole/ 1-//2-(diethylamino)ethyl/amino/- 4-/(methylamino/methyl/-exoticisation-9-it /obtained by the method described in example 5/ in 100 ml of methylene chloride cooled to 0oC and treated with triethylamine /5 ml/ benzosulphochloride /2 ml, 15,67 mmol/, after which the mixture is stirred for 2 hours. The mixture is evaporated under vacuum and the residue was subjected to purification, passing through the layer of silicagel /elwira first with chloroform, and the Board. The product is dissolved in ethyl acetate, the solvent is removed under vacuum and get the 6.06 g /83%/ N-//1-//2-(diethylamino)ethyl/amino/-9 exotikite-4 - yl/methyl/N-methylbenzenesulfonamide. The sulfonamide /2.5 g/ suspended in isopropanol and treated methanesulfonic acid /0.51 g/, resulting in a gain 2,63 g of salt methanesulfonic acid so pl. 171 - 174oC.

Example 30.

(a) To a mixture of m-anise acid /250 g, 1,67 mol/ and acetic acid /1 : 1/ add bromine /85 ml/, and then water /1 1/. The mixture is heated to boiling, cooled in an ice bath, the resulting precipitates are filtered and washed with water, the result is 305,7 g /79%/ 2-bromo-5-methoxybenzoic acid so pl. 154 - 156oC.

(b) To a mixture of 3-chlorothiophenol /20 g, was 0.138 mol/, acetate of copper /1.8 g/ and dimethylformamide /200 ml/ type K2CO3/23 g/. The mixture is heated to 150oC for 35 - 20 minutes, then added in several portions of 2-bromo-5-methoxybenzoic acid /35,8 g, 0,155 mol/. The mixture is heated and maintained under heating overnight, then poured into water /600 ml/ filter, treat the filtrate with charcoal, filtered and diluted with hydrochloric acid. The resulting precipitates are filtered, washed with water, dried at tempera what Noynoy acid.

(C) To the cooled sulfuric acid /89 ml/ under nitrogen atmosphere add 2/(3-chlorophenyl)thio/-5-methoxybenzoic acid /27 g, 0,092 mole,/ portions for 1.5-2 hours. The mixture is stirred at room temperature overnight, poured into water /900 ml/ containing conc. NH4OH /218/ ml and cooled. The resulting precipitates are filtered and dried at 50oC under vacuum over P2O5, resulting in a gain of 21 g /42%/ mixture of 1-chloro and 3-chloro-7-methoxy-thioxanthen-9-it.

(g) a Mixture of 1-chloro and 3-chloro-7-detoxification-9-it /20.7 g/, pyridine /69 ml/ diethylaminoethylamine /16,1 g, O,138 mol/ heated to 115oC under a nitrogen atmosphere and maintained at these conditions for 2 hours. The solvent is removed under vacuum and the residue purified by the method of column chromatography on silica, elwira first chloroform /100%/, and then a 1% solution of Isopropylamine in chloroform to obtain 11,22 g 1//2-(diethylamino)ethyl/amino-7-detoxification-9-it.

(d) a Mixture of 1-//2-(diethylamino)ethyl/amino/-7-detoxification-9 - it /11.2 g, 0,031 mole,/, 37% formaldehyde /277 ml/ 5 N. acetic acid /4,6 ml/ heated to 100oC and kept at this temperature for 3 hours. The reaction mixture was cooling gap is/three times/, washed with brine and dried with sodium sulfate. The solvent is removed under vacuum and the residue purified by the method of column chromatography on silica, elwira 25% (solution of chloroform in hexane, then with 0.5% (solution Isopropylamine in chloroform, resulting in a gain of 8.8 g/73%/ 1-//2-diethylamino ethyl/amino/-4-hydroxymethyl-7-detoxification-9-it.

(e) 1-//2-(diethylamino)ethyl/amino/-7-methoxy-9-exoticisation-4 - carboxaldehyde.

(II: R1=R2C2H5; R8=7-OCH3; n=2).

Solution 1-//2-(diethylamino)ethyl/amino/4-(hydroxymethyl)- 7-detoxification-9-it /8.8 g, is 0.023 mol/ toluene /268 ml/ heated to 60oC under a nitrogen atmosphere, then add MnO2/13,2 g/. The mixture was kept under heating overnight, filtered, the filtrate evaporated under vacuum, resulting in a gain 7,05 g /81%/ product.

(W) N-//1-//2-(diethylamino)ethyl/amino/-7-methoxy-9-exoticisation- -4-yl/methyl/N-methylformamide.

(IV: R1=R2=C2H5; R4=CH3; R8=7-OCH3; n = 2).

Solution 1-//2-(diethylamino)-ethyl/amino/-7-methoxy-9 - exoticisation-4-carboxaldehyde /3 g of 7.8 mmole/ and 1.5 ml of formic acid 25.5 ml of N-meillon mixture was poured into 160 ml of a mixture of ice water alkalinized 35% NaOH solution and extracted three times with chloroform. The organic layer was washed with water twice and brine, dried with sodium sulfate, the solvent is distilled off under vacuum, resulting in a gain of 3 g /89,9%/ product.

(C) 1-//2-(Diethylamino)ethyl/amino/-4-(methylamino)-methyl/-7 - detoxification-9-he.

(I: R1=R2=C2H5; Q = CH2NHCH3; R8=7 - OCH3; n = 2).

N-Methylformamide obtained in example 30 (R) /3.0 g/, 2 N. hydrochloric acid in water /24 ml/ heated to 100oC and stirred under nitrogen atmosphere for two hours. Then the mixture is cooled, poured into 125 ml of ice water, alkalinized 35% (aqueous solution Paon, extracted with chloroform, and then washed twice with water, then brine. The organic layer is dried with sodium sulfate and evaporated under vacuum, resulting in a gain of 3.1 g of a technical product. The product is treated with diethyl ether and the filtrate is purified on a few thin-layer chromatographic columns/silicagel, elution: 50% mixture of hexane and chloroform, then with chloroform, and finally, of 0.25 - 0.5% (solution Isopropylamine in chloroform - column 1; chloroform, then with a mixture of Isopropylamine: methanol: chloroform in a ratio of 1:1:98 - column 2; chloroform, then 0.5% is p 31.

(a) N-//1-//2/(Diethylamino)ethyl/amino/-7-methoxy-9-oxo - thioxanthen-4-yl/methyl/formamid.

(I: R1=R2=C2H5; Q = CH2NHCHO; R8= 7 - OCH3; n = 2).

A mixture of 1-//2-(diethylamino)ethyl/amino/-7-methoxy-9-exoticisation - 4-carboxaldehyde /3.6 g, 0,0094 mol/ formamide /48 ml/ and formic acid /6 ml/ heated to 170oC under a nitrogen atmosphere and maintained at these conditions for 8 hours. The mixture was poured into ice-cold water, alkalinized 35% NaOH solution and extracted with chloroform. The organic layer was separated, washed with water twice, then brine and dried with sodium sulfate, then evaporated under vacuum to obtain 3.88 g of product.

(b) 4-Aminomethyl-1-//2-(diethylamino)ethyl/amino/7 detoxification-9-he.

(I: R1=R2=C2H5; Q = CH2NH2; R8= 7 - OCH3; n = 2).

A mixture of formamide obtained in example 31/a/, /3.88 g/ and 2 n aqueous hydrochloric acid and 32 ml/ heated to 100oC and stirred at this temperature for 2 hours under nitrogen atmosphere. Then the above mixture is cooled, poured into water, alkalinized 10% (aqueous NaOH solution, extracted with chloroform and washed first with water, then brine. About the product is dissolved in chloroform and purified using thin-layer chromatography /silicagel; elution first with a mixture of hexane: chloroform in the ratio of 50:50, then a 1% solution of Isopropylamine in a mixture of hexane:chloroform = 50:50 with the receipt of 1.75 g of the desired product.

(in) N-//1-//2-(Diethylamino)/ethyl/amino/-7-methoxy-9-exoticisation-4-yl/ methyl/methanesulfonamide.

(I: R1=R2=C2H5; Q = CH2NHSO2CH3; R8= 7 - OCH3; n = 2).

To a solution of 1.75 g /0,0045 mol/ amine example 31 /b/ 22.5 ml of pyridine, cooled in an ice bath, under nitrogen atmosphere with stirring, added dropwise to 0.39 ml of 0.005 mol,/ methanesulfonanilide in a small amount of pyridine and the resulting reaction mixture was stirred at room temperature for 2 hours. The mixture was then poured into 275 ml of water containing 0,38 g NaOH, extracted with chloroform and the organic layer washed with water and brine. The chloroform layer is dried with sodium sulfate, the solvent is distilled off under vacuum, the residue is dried under vacuum obtaining of 1.61 g /77%/ product with so pl. 144oC /colour / div./

Example 32.

(a) To a mixture of 3-chlorothiophenol /20 g was 0.138 mol/, acetate of copper /1,75 g/ and dimethylformamide /199 ml/ under nitrogen atmosphere are added in several portions K2CO3/23 g/. The mixture is heated to 150oC and that ml/, filtered, the filtrate is treated with charcoal and filtered again. The filtrate is acidified with conc. hydrochloric acid, extracted with chloroform, the organic layer washed with brine and dried with sodium sulfate. The solvent is distilled under vacuum, resulting in a gain of 28.9 g of 2-/(3-chlorophenyl)thio/-5-bromobenzoyl acid.

(b) a Mixture of 2-/(3-chlorophenyl)thio/-5-bromobenzoyl acid /28.4 g/, and concentrated sulfuric acid /80 ml/ stirred first at a temperature of 0oC and then at room temperature overnight. The mixture is poured into ice-cold water /850 ml/ containing conc. NH4OH /199 ml/ and formed as a precipitate product was filtered and dried at a temperature of 50oC under vacuum, resulting in a gain of 15.0 g of a mixture of 1-chloro and 3-chloro-7-bromooctane-9-ones.

(C) a Mixture of 1-chloro and 3-chloro-7-bromooctane-9-ones /13,6 g/ pyridine /108/ ml and N,N-diethylethylenediamine /16,3 ml/ heated to 115oC and kept at this temperature for 20 hours. The solvent is removed under vacuum, the residue was subjected to purification by the method of column chromatography on silica, elwira first chloroform /100%/, then 1% solution of Isopropylamine in chloroform, resulting in a gain of 9.3 g of 1-//2-(diethylamino)ethyl/amino/-37% solution of formaldehyde and 3.4 ml of 5 N. solution of acetic acid is heated to 100oC under a nitrogen atmosphere and maintained at these conditions during the night. The mixture is cooled to room temperature and the formed precipitate solids are filtered. The filtrate is diluted with water, alkalinized 35% (NaOH solution and extracted with chloroform. The organic layer was washed with brine, dried with sodium sulfate, the solvent is distilled off, resulting in a gain of 10 g of oil. The oil obtained is dissolved in methylene chloride, filtered, the solvent is distilled under vacuum and technical hydroxymethylene similar purified by thin-layer chromatography /silicagel; elution: 25%-s ' solution of chloroform in hexane, a mixture of chloroform: hexane = 1:1, then 25% solution of chloroform in hexane, chloroform /100%/ and then 0.5 to 1% solution of Isopropylamine in chloroform/, resulting in a gain of 3.2 g of 1-//2-(diethylamino)ethyl/amino/-4-(hydroxymethyl)-7-bromooctane - 9-it.

(e) 1-//2-(Diethylamino)ethyl/amino/-7-bromo-9-exoticisation-4-carboxaldehyde.

(II: R1=R2=C2H5; R8=7-Br; n = 2).

A mixture of 3.2 g /7,34 mol/ alcohol of example 32 /g/ and 4.3 g of manganese dioxide in 85 ml of toluene is heated to 60oC and videri the United filters evaporated under vacuum, resulting in a gain of 3 g solid yellow color. Solid yellow is treated with diethyl ether, filtered and dried to obtain 2.7 g /94,3%/ project with so pl. 145 - 146oC.

(W) N-//1-//2-(Diethylamino)ethyl/amino/-7-bromo-9-exoticisation-4-yl/methyl/ formamid.

(I: R1=R2=C2H5; Q = CH2NHCHO; R8=7-Br; n = 2).

A mixture of 2.7 g /6.2 mmole/ 1-//2-(diethylamino)ethyl/amino/-7 - bromo-9-exoticisation-4-carboxaldehyde, and 31.7 ml of formamide and 3.6 ml of formic acid is heated to 170oC under nitrogen atmosphere and stirred at this temperature for 8 hours. Then, the mixture is left at room temperature for 72 hours. The mixture is then poured into 150 ml of ice water, alkalinized 35% NaOH solution, the resulting solid product produce by filtration and washed with water. The solid product is dissolved in chloroform, washed with brine, dried with sodium sulfate, then the solvent is distilled under vacuum and obtain 2.85 g of the desired wavelengths in the form of a solid yellow-orange color with so pl. 132oC /decomp/.

(C) 1-//2-(Diethylamino)ethyl/amino/-4-(aminomethyl)-7-bromooctane-9-he.

(I: R1= R2= C2H5; Q = CH2NH2 the acid is heated to 100oC under nitrogen atmosphere and kept at this temperature for 2 hours, after which the mixture is left overnight at room temperature. The mixture is then poured into 200 ice water, alkalinized 35% sodium hydroxide solution and extracted with chloroform. The organic layer was washed with water and brine, dried with sodium sulfate and evaporated under vacuum, resulting in a gain 2.67 g of a dark oil. Dark oil is purified by thin layer chromatography /silicagel; 1250 ml of a mixture of hexane:chloroform in a ratio of 1:1, then 1% solution of Isopropylamine in a mixture of hexane-chloroform = 1:1/, resulting in a gain of 1.87 g /70%/ product with so pl. 79 - 83oC.

Example 33. N-//1-//2-(Diethylamino)ethyl/amino/-7-bromo-9 - exoticisation-4-yl/methyl/methanesulfonamide.

(I: R1= R2= C2H5; Q = CH2NHSO2CH3; R8= 7 - Br; n = 2).

1-//2-(Diethylamino)ethyl/amino/-4-(aminomethyl)-7-bromooctane-9-it /1 g, 2.3 mmole/ 11.5 ml of dry pyridine under a nitrogen atmosphere is stirred in an ice bath for 15 minutes, then added dropwise 0.2 ml /2.6 mmole/ methanesulfonanilide cooled pyridine and the resulting mixture was stirred at room temperature. The reaction mixture was pouring out is washed with water twice and brine and dried with anhydrous sodium sulfate. The mixture was then filtered, evaporated under vacuum, the residue is washed with ether, filtered, dried, resulting in a gain of 1.02 g of the product with so pl. 134 - 139oC.

Example 34. Methyl N-//1-//2-(diethylamino)ethyl/amino/-9 exotikite-4-yl/methyl/carbamate.

(I: R1= R2= C2H5; Q = CH2NHCOOCH3; R8= H: n = 2).

The solution to 2.94 g /8,27 mmole/ 4-(aminomethyl)-1-//2-(diethylamino)/ethyl/amino/thioxanthen-9-it /obtained by the method described in example 4/ in 50 ml of methylene chloride containing 5 ml of triethylamine, cooled to 0oC, add 0.7 ml /9,06 mmole/ methylcarbamate, the resulting mixture was stirred for 2.5 hours. The solvent is distilled off under vacuum, the residue is suspended in chloroform and purified by thin-layer chromatography /silicagel; elution with chloroform, then 1% solution of Isopropylamine in chloroform/, resulting in a gain of 2.36 g /69%/ product in a solid yellow color with so pl. 129 - 131oC.

Example 35. 1-//2-(Diethylamino)ethyl/amino/-4-/(methylamino)methyl/- 7-hydroxy-thioxanthen-9-he.

(I: R1= R2= C2H5; Q = CH2NHCH3; R8= 7-OH; n = 2).

A solution of 1.6 g /4 mmole/ 1-//2-diethylamino)ethyl/Amira HBr was heated to 110oC and kept at this temperature for 5 hours. After cooling, the reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with chloroform /h ml/. Resinous substance of a dark color, not soluble in water or chloroform is dissolved in methanol and combined with a solution of chloroform. The solvent is distilled under vacuum, resulting in a gain 1,67 g solid dark orange color. This product is purified by thin layer chromatography /silica gel: elution with a mixture of Isopropylamine: methanol: chloroform in a ratio of 1:1:98 - 1 column; silica: elution with a mixture of Isopropylamine:methanol:chloroform in the ratio 2:2:96 - column 2/, to obtain 0.56 g /36%/ product with so pl. 167 - 169oC.

Example 36. Methyl-N-//1-//2-(diethylamino)/ethyl/amino/-7-methoxy - 9-exoticisation-4-yl/-methyl/carbamate.

(I: R1=R2= C2H5; Q = CH2NHCOOCH3; R8= 7-OCH3; n = 2).

To a solution of 1.55 g of 4-aminomethyl-1-//2-(diethylamino)ethyl/amino/-7 - detoxification-9-it /obtained by the method described in example 31/b// in 40 ml of chloroform containing 2 ml of triethylamine, cooled to 0oC add 0.45 ml of methylchloroform, poluchenogo thin-layer chromatography /silicagel: elution by chloroform, then 1% solution of triethylamine in a mixture of chloroform:hexane in a ratio of 1:1/ to obtain 1.2 g of product, recrystallization from ethyl acetate yields a 0,79 g solid bright yellow with so pl. 131 - 132oC.

Example 37. N-//1-(2-Diethylamino)ethyl/amino/-7-hydroxy-9 - exoticisation-4-yl/methyl/methanesulfonamide/4 hydrate.

(I: R1= R2= C2H5; Q = CH2NHSO2CH3; R8= 7-OH; n = 2).

To a solution of N-//1-(2-diethylamino)ethyl/amino/-7-methoxy-9 - exoticisation-4-yl/methyl/methanesulfonamide /0.5 g/ / obtained by the method described in example 31/in// in methylene chloride /45 ml/ -78oC add 1 BC BBr3in methylene chloride /1,71 ml/. Mixture is allowed to warm to room temperature, stirred overnight and then poured into ice water /250 ml/ containing 35% NaOH /8 ml/. The mixture is acidified with diluted hydrochloric acid, then alkalinized solid Na2CO3, and then extracted with ethyl acetate. The organic layer was separated, washed with brine, dried with sodium sulfate and evaporated under vacuum. The residue was subjected to purification by the method of column chromatography on silica, elwira 5% solution of methanol in ethyl acetate, in achiev Outil/amino/-6 - methylthionine-9-he.

(I: R1=R2= C2H5; Q = CH2NH2; R8= 6 - CH3; n = 2).

Assume that a method similar to that described in example 30 /parts a - e/, but replacing 4-methylbenzoic acid 3-methoxybenzoic acid in part a, can be obtained 1-//2-(diethylamino)ethyl/amino/-6-methyl-9-exoticisation-4-carboxaldehyde. Next assume that it can be converted into 4-(aminomethyl)-1-//2-(Diethylamino)ethylamino/-6-methyl-thioxanthen-9-he methods described in example 31 part a-B.

Examples 39 and 41.

Assume that the method described in example 34, replacing, if necessary, the appropriate amine of the formula V 4-(aminomethyl)-1-//2-(diethylamino)ethyl/amino/thioxanthen-9-it can be obtained the compounds of formula I (see below).

Example 42. 1-//2-(Diethylamino)ethyl/amino/-4-(methylamino methyl/-6 - methylthionine-9-he.

(I: R1= R2= C2H5; Q = CH2NCH3; R = 6 - CH3; n = 2).

The method described in example 30, part /W-z/, replacing 1-//2-(diethylamino)ethyl/amino/-6-methyl-9-exoticisation-4-carboxaldehyde 1-//-(diethylamino)ethyl/amino/-7-methoxy-9-exoticisation-4-carboxaldehyde can be obtained above the product.

1= R2= C2H5; Q = CH2NHSO2CH3; R8= 6-CH3; n = 2).

Assume that the method described in example 6, it is possible to obtain the above product of 4-(aminomethyl)-1-//2-(diethylamino) ethyl/amino/-6-methylthionine-9-it, pyridine and methanesulfonanilide.

Example 44. N-//1-//2-(Diethylamino)ethyl/amino/-7-methoxy-9 - exoticisation-4-yl/methyl/vinylsulfonate.

(I: R1= R2= C2H5; Q = CH2NHSO2C6H5; R8= 7-CH3O; n = 2).

Assume that a method similar to that described in example 31 part /in/ can be obtained above the product of 4-(aminomethyl)-1-//2-(diethylamino)ethyl/amino/-7-detoxification-9-it, pyridine and benzosulfimide.

Example 45.

(a) N-//1-//2-(Diethylamino)ethyl/amino/-9 exotikite-4 - yl/methyl/N-vinylformamide.

(IV: R1=R2= C2H5; R4= C6H5; R8= H; n = 2).

A mixture of 1-//2-(Diethylamino)ethyl/amino/-9 exotikite-4 - carboxaldehyde /3,40 g, 9,59 mmole/, formanilide /31 g/ and formic acid are heated to 160oC and kept at this temperature for 2 hours. The mixture is cooled, poured into water /200 ml/ l/ and the combined organic extracts are dried with sodium sulfate and passed through Florisil, elwira first chloroform /100%/, then a 5% solution of Isopropylamine in chloroform. The solvent is distilled off under vacuum and the residue purified by the method of column chromatography on silica, elwira 0.5 and 1%-governmental solutions Isopropylamine in chloroform, and double recrystallization from a mixture of benzene/hexane, resulting in a gain of 1.88 g of the desired product.

(b) 1-//2-(Diethylamino)ethyl/amino/-4-/phenylamino methyl/thioxanthen-9-he.

(V: R1= R2= C2H5; R4= C6H5; R8= H; n = 2).

A mixture of N-vinylformamide example 45/a/ /1.70 g, 3,70 mmole/ and 3 N. HCl /100 ml is heated on a steam bath for 1 hour. The mixture is then cooled, alkalinized 5 N. NaOH, extracted with chloroform /3 x 100 ml, the combined organic phases are dried with sodium sulfate and evaporated under vacuum. The residue was subjected to purification by the method of column chromatography on silica, elwira diethyl ether /100%/, then a 5% solution of Isopropylamine in the air; and then cleaned on the second column of silica, elwira 1% solution of Isopropylamine in the air, resulting in a gain of 0.80 g of the desired product with so pl. 133 - 135oC.

(in) N-//1-//2-(Diethylamino)EB/SUB>; Q = CH2N(C6H5)SO2CH3; R8= H; n = 2).

Assume that the above product can be obtained by the method similar to that described in example 22, 1-//2-(diethylamino)ethyl/amino/-4-/(phenylamino)methyl//thioxanthen-9-example 45/b/, methanesulfonanilide, methylene chloride and triethylamine.

Suggest that other compounds of General formula I can be obtained by methods similar to that shown in examples 1 to 14, substituting the appropriate 1-//2-(dialkylamino)ethyl/amino/- or 1//3(dialkylamino)propyl/amino/-9 exotikite-4-carboxaldehyde 1-//2-(dialkylamino)ethyl/amino/-9 exotikite-4-carboxaldehyde, or by a method similar to that shown in examples 15 to 45, but using a suitable 1-//(dialkylamino)alkyl/amino/-9 exotikite-4-carboxaldehyde. Many aldehydes and their precursors are described in U.S. patent 3294803.

Representative examples of compounds of this invention were tested for antitumor activity in mice in accordance with the following procedure.

Animals are selected and implanted them subcutaneously fragments tumors weighing from 30 to 60 mg of trataron 12-th size and again taken before selective distribution for replicaid from 1 to 5 days after implantation at a time when the number of tumor cells is relatively small /107up to 108units of cells/. For the treatment of diseases at a later stage chemotherapy lay to until the tumor reaches a relatively large size /200 - 300 mg/. For 90% of the animals the tumor reached 2.5 times the size. Measurement of tumors with calipers weekly /or twice a week for more rapidly growing tumors/. Mice decapitate, when the size of the tumors is 1500 mg /i.e. before the tumor can cause discomfort to the animal/. The weight of the tumors measured twice the dimension.

The treated and control groups examined, when the tumors of the control group reached approximately from 700 to 1200 mg /average group median group/. Determine the median weight of the tumors in each group/ including the absence of tumors/. The ratio Of (weight of the treated tumors to the weight of tumors in the control group) in % is an indicator of antitumor effectiveness: O/K, is equal to or less than 42%, is considered by the Department Estimates Medicine Division of Cancer Treatment National cancer Institute (Drug Evaluation Branch of the Division of Canser Treatment NCI) as a significant antitumor activity. O/K, less 10%, rassmatrivaia the group value/, exceeds 20%, or greater than 20% mortality from drugs, is regarded as extremely toxic dose.

The results of determination are shown in table 1 for adenocarcinoma of the pancreatic duct #3 and in table 2 for adenocarcinoma #38 of the colon.

The compound of example 5 was tested intravenous against a number of other tumors, as shown in table 3, and was active at a dose of 300 mg/kg when administered orally against colon adenocarcinoma 38.

The compound of example 6 was tested bolus intravenous injection against a number of other tumors, as shown in table 4.

The compound of example 8 was tested against a number of tumors, as presented in table 5.

The compound of example 36 was tested against a number of tumors, as shown in table 6.

The presented compounds of the invention were tested against mammary adenocarcinoma 16/C/PP, as shown in table 7.

Presents the compounds of this invention were tested against P388 leukemia resistant to the action of adriamycin, as shown in table 8.

The pharmaceutical compositions of this invention include one or more is acceptable carriers, adjuvants or diluents, which are defined together as carriers, for parenteral injection, for oral administration in solid or liquid form, for rectal or topical application, etc.

The composition can be administered to humans and animals oral, rectal, parenteral /intravenous, intramuscularly or subcutaneously/ vnutripolostno, intrawaginalno, administered intraperitoneally, locally /powders, ointments or drops or in the form of solutions for spraying the mouth and nose.

Composition applicable for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for obtaining sterile solutions or dispersions for injection. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyalcohol /propylene glycol, polyethylene glycol, glycerin, etc./ suitable mixture, vegetable oil such as olive oil/ organic esters used for injection, such as etiloleat. The proper fluidity can be maintained, for example, the use of coatings /membranes/ such as lecithin, registering These compositions can also contain adjuvants, such as preserving, wetting, emulsifying and dispersing agents. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc., you May need to introduce isotonic agents such as sugars, sodium chloride, etc., the extension of the absorption of the pharmaceutical forms suitable for injection can be achieved by using agents that slow down the absorption, for example, aluminum monostearate and gelatin.

If necessary, and to ensure a more efficient allocation of compounds can be introduced into the system slow release or system specified period of discharge, such as polymer matrices, liposomes, and microspheres. They can be sterilized, for example, by filtration through filter traps bacteria, or the introduction of sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or other sterile environment for injection immediately prior to use.

Solid dosage forms for oral administration include capsules, tablets, Pilum inert customary excipient or carrier/, such as sodium citrate or dvuhkantnyj phosphate or /and/ diluents or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b /W/ binders, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and the Arabian gum, // moisturizers such as glycerin, /g/ dezinfeciruyuhimi /bulk/ agents, for example agar-agar, calcium carbonate, starch from potato or tapioca starches, alginic acid, certain complex silicates and sodium carbonate, /d/ inhibitor /inhibitors/ dissolution, for example, paraffin, /e/, absorption accelerators, such as Quaternary ammonium compounds, /W/ wetting agents, for example cetyl alcohol or glycerylmonostearate, /C/ absorbents, such as kaolin and bentonite, and lubricating agents, for example talc, calcium stearate, magnesium stearate, solid polyethylene glycols, nutriceuticals or mixtures thereof. In the case of capsules, tablets and pills dosage forms may also comprise buffering agents.

The percentage of active component in the composition and method of treatment of tumors or cancer may vary, so that was received appropriate doses. Enter each otdenie, the duration of treatment, age and weight of the patient, the ability of the active component, the susceptibility of the patient. Effective quantitative dose of the active component, thus, can be easily identified clinical study of all the criteria using the very best results in the interests of the patient.

For more examples.

(A) Tablet

Ingredient mg/tab.

The compound of example 15 - 50,0

Mannitol, USP - 223,75

Sodium crosscarmellose - 6,0

Corn starch - 15,0

The hypromellose, USP was 2.25

Magnesium stearate - 3,0

(B) Capsule

Ingredient mg/capsule.

The compound of example 16A - 10,0

Mannitol, USP - 488,5

Sodium crosscarmellose - 15,0

Magnesium stearate and 1.5

(C) Parenteral

Ingredient mg/ml

The compound of example 34 - 2,0

Dextrose - 39,5

Sterile water for injection Up to 1 mlya

1. Thioxanthone compounds of General formula I

< / BR>
where (1) n = 2 or 3;

R1and R2independently from each other lower alkyl;

Q is a residue selected from the group consisting of CH2OTHER3CH2N(R4)SO2R7CH2NHCHO, CH=N-Ar, C(O)NR5R6CH2N(R4)(R10), CH2N(R4)C(O)CF3and CH2N(R4)C(O)OR7; R3is hydrogen or lower alkyl;

R4is hydrogen, lower alkyl or Ar;

R5is hydrogen, lower alkyl or AG;

R6is hydrogen or lower alkyl;

R7is lower alkyl or AG;

R8is hydroxyl;

Ar is phenyl or phenyl substituted with stands, methoxy-, hydroxyl group, halogen or a nitro-group;

R9and R10independently from each other lower alkyl; or

(2) Q is a residue selected from the group consisting of CH2N(R4)SO2R7CH = N-Ar, C(O)NR5R6CH2N(R4)C(O)R7CH2N(R4)P(O) (O - lower alkyl)2CH2N(R4)C(O)CF3and CH2N(R4)C(O)OR7;

R8is hydrogen, lower alkyl, lower alkoxy or hydroxyl; AG - phenyl, substituted by hydroxyl;

n, R1, R2, R4- R7take the values defined above, provided that one or more of R4, R5, R7- Ah; or

(3) Q is a residue selected from the group consisting of CH2N=CHN(R9)(R10), CH2N(R4)C(O)CF3and CH2N(R4)C(O)OR7;

R8is hydrogen, lower alkyl, lower alkoxy or GI in paragraph (1),

or their pharmaceutically acceptable acid additive salt or solvate.

2. Connection on p. 1, where n = 2 or 3; R1and R2independently from each other lower alkyl, Q is a residue selected from the group consisting of CH2OTHER3CH2N(R4)SO2R7CH2NHCHO, SN = N-AG; C(O)NR5R6CH2N(R4)C(O)R7CH2N(C2H5)CHO, CH2N(R4)P(O)(O - lower alkyl)2CH2N=CHN(R9)(R10), CH2N(R4)C(O)OR7and CH2N(R4)C(O)CF3, R3is hydrogen or lower alkyl, R4is hydrogen, lower alkyl or AG, R5is hydrogen, lower alkyl or Ar, R6is hydrogen or lower alkyl, R7is lower alkyl or Ar, R8- Oh, Ah - phenyl or phenyl, substituted stands, methoxy, hydroxyl, halogen or a nitro-group, and R9and R10independently from each other lower alkyl; or pharmaceutically acceptable acid additive salt or solvate.

3. Connection on p. 2, where Q is a residue selected from the group consisting of CH2NR3CH2N(R4)SO2R7CH2NH, CH = N-Ar, C(O)NR5R6CH2N(R4)C(O)R7CH2N(C2H5)SNO, and CH2N(R< phenyl or phenyl, replaced by stands, methoxy, halogen or a nitro-group.

5. Connection on p. 4, where n = 2, R1and R2both ethyl, and R3is hydrogen or methyl and R7is lower alkyl.

6. Connection on p. 5, selected from the group consisting of 1-//2-(diethylamino)ethyl/amino/-4-/(methylamino)-methyl)- -7-gidrometeocenter-9-it N-//1-(2-(diethylamino)ethyl/ amino/-7-hydroxy-9-exoticisation-4-yl/methyl/methanesulfonamide.

7. Connection on p. 1, where n = 2 or 3, R1and R2independently from each other lower alkyl; Q is a residue selected from the group consisting of CH2N(R4)SO2R7CH = N-Ar, C(O)NR5R6CH2N(R4)C(O)R7CH2N(R4)P(O)(O - lower alkyl)2CH2N(R4)C(O)CF3and CH2N(R4)C(O)OR7, R4is hydrogen, lower alkyl or AG, R5is hydrogen, lower alkyl or AG, R6is hydrogen or lower alkyl, R7is lower alkyl or Ar, R8is hydrogen, lower alkyl, lower alkoxy or hydroxyl, and ar is phenyl, substituted by hydroxyl, provided that one or more of R4, R5or R7is Ar, or their pharmaceutically acceptable acid additive salt or solvate.

8. Connection on p. 1, where n = 2 or 3, RN= CH-N(R9)(R10), CH2N(R4)C(O)CF3and CH2N(R4)C(O)OR7, R4is hydrogen, lower alkyl or AG; R7is lower alkyl or Ar, R8is hydrogen, lower alkyl, lower alkoxy or hydroxyl, AG - phenyl or phenyl, substituted stands, methoxy, hydroxyl, halogen or a nitro-group, and R9and R10independently from each other lower alkyl, or their pharmaceutically acceptable acid additive salt or solvate.

9. Connection on p. 8, where R8is hydrogen, lower alkyl or lower alkoxy, R4is hydrogen and ar is phenyl or phenyl substituted with stands, methoxy, halogen or a nitro-group.

10. Connection on p. 9, where n = 2, R1and R2both ethyl, and R8is hydrogen or a methoxy group.

11. Connection on p. 10, where Q is CH2N=CH-N(R9)(R10and R9and R10both are stands.

12. Connection on p. 10, where Q is CH2N(O)OR7.

13. Connection on p. 12, where R7is lower alkyl.

14. Connection on p. 13, selected from the group consisting of methyl N-//1-//2-(diethylamino)ethyl/amino/-9-oxo-thioxanthen-4-yl/methyl/carbamate and methyl N-//1-//2-(diethylamino)ethyl/amino/-7-methoxy-9-exoticisation-4-yl/methyl/carbamate.

15. ptx2">

16. Pharmaceutical composition having antitumor activity, characterized in that it contains an effective amount of a compound according to any one of paragraphs. 1-14 and a pharmaceutically acceptable carrier or diluent.

17. The pharmaceutical composition according to p. 16, characterized in that suitable for the production of medicaments for the treatment of cancer in a mammal.

18. N-[[1-[[2-(Diethylamino)ethyl]amino]-7-methoxy-9-exoticisation-4-yl] methyl]formamide.

19. Pharmaceutical composition having antitumor activity, characterized in that it contains an effective amount of the compounds on p. 18 and a pharmaceutically acceptable carrier or diluent.

20. Connection on p. 18, which is useful for obtaining a drug for treating tumors in a mammal.

21. Connection on p. 18, which is useful for obtaining a drug for the treatment of cancer in a mammal.

 

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FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 cl, 2 tbl, 568 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compositions eliciting an antilipidemic effect and comprising inhibitor of bile acid transport in jejunum of the general formula (I): and inhibitor of HMG-CoA-reductase. Also, invention relates to a method for carrying out the combined therapy.

EFFECT: improved treatment method, valuable medicinal properties of compositions.

15 cl, 9 tbl, 1401 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

FIELD: pharmaceutical industry, in particular new bioactive chalcones.

SUBSTANCE: invention relates to new chalcones of formula I

, pharmaceutically acceptable salts or solvates thereof, wherein Ar is optionally substituted C5-C10-carbocycle group or 5- or 6-membered heterocycle group having sulfur atom in cycle, and Ar substituents are selected independently from Cl, Br, F, CN, SCH3 and OR10, wherein R10 is linear or branched C1-C6-hydrocarbon; R is OH or R10; R2 and R3 are independently phenyl, saturated linear or branched C1-C6-hydrocarbon, or R2 and R3 together with carbon atom attached thereto form 5- or 6-membered carbocycle group with the proviso, that in compounds where R is OH and both R2 and R3 are methyl, Ar is not phenyl, 4-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 3,4-dimethoxyphenyl, or 4-methoxyphenyl. Also disclosed are drug component for treatment or prophylaxis of neoplasm and pharmaceutical compositions with antiproliferation effect based on compounds of formula I.

EFFECT: new chalcone derivatives with value bioactive action.

26 cl, 2 tbl, 22 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new lipoic acid derivatives of general formula Ia

1, wherein n = 0-4, integer; -X-Y represents -O(CH2)r-, -CO-N(R3)-(CH2)r-, -N(R4)-CO-(CH2)r; -X'-Y' represents -(CH2)r-, -(CH2)r-N(R3)-(CH2)r-, -(CH2)r-CO-N(R3)-(CH2)2-; R3 and R4 are the same or different and represent hydrogen or alkoxycarbonyl; r = 0-4, integer; Ω represents piperazinyl, piperidyl or phenyl. Also disclosed are method for production the claimed derivatives and pharmaceutical composition, containing the same. Compounds are useful as NO-syntase inhibitors and/or reagents mediating redox state of thiol groups.

EFFECT: new lipoic acid derivatives.

7 cl, 17 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in stomatology in the topical anesthesia. The pharmaceutical composition comprising articaine hydrochloride and epinephrine hydrochloride and accessory substances, such as sodium metabisulfite, sodium chloride and water for injection involves additionally glycine and pH-regulating substance taken in the definite ratio of components. Invention provides preparing the preparation that is stable, non-toxic and doesn't cause allergic response reactions and elicits highly expressed infiltration and conducting anesthetic activity, good tissue tolerance and activity promoting to accelerated wound-healing in the post-operative period.

EFFECT: improved and valuable medicinal properties of composition.

3 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

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