Methods of obtaining 9-aminocamptothecin, intermediate products and method of production thereof

 

(57) Abstract:

9-amino-camptothecin formula I is produced by interaction with diasterous agent restored the compounds of formula II with the formation of the compounds of formula IV, which consistently nitrous and restore the nitro-group with simultaneous removal of the halogen in the compound of formula V. the Method allows to retalitate 12-nitro-derivatives in the process through the conversion of 9-amino - simple and mild conditions, providing high yields and purity of the reaction products. 4 C. and 6 C.p. f-crystals.

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The invention relates to a new process for the preparation of 9-amino-20/S/-camptothecin formula /I/

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which is a well-known anti-cancer agent: Wani and others J. Med. Chem, 1987, 30, 1774-1779; Hsiang and others, Cancer Res., 49, 4385-4389, August 15, 1989; Cancer Res., 49, 1465-1469 March 15, 1989.

Fully synthetic methods to obtain 9-amino - camptothecin widely described /USA-A 4894456 and US-A-5053512/. Total synthesis of the product, however, undesirable and unsuitable for large-scale production because it includes too many stages in the process, which makes the synthesis too long and, especially, too expensive.

Semi-synthetic method POLUChENNOGO product camptothecin: Cancer Chemothetapy Report part I, volume 54, No. 6, Dec. 1970, 461-470, J. Med. Chem., 1980, 23, 554-560, Science, volume 246, November 1989, 1046-1048. The specified synthetic approach involves the nitration of camptothecin natural origin with subsequent recovery of 9-nitro-derivatives. This nitration, however, initially gives a 70/30 mixture of unwanted 12-nitro-derivatives of camptothecin /70%/ and the desired 9-nitro-derivatives of camptothecin /30%/. Therefore, 9-nitro-derivatives only receive the minimum amount.

After the separation of the two products of the nitration 12-nitro-derivatives, which in itself is biologically inactive /see for example, C. Wani, Nicholas A. W., Wall, M. E., J. Med. Chem., 1986, 29, 2358/ must then be removed, resulting in an increase in the problems associated with waste treatment. A significant deficiency relating to the removal of unwanted by-product of 12-nitro-derivatives, is especially fundamental for krupnomasshtabnogo production, as they collect large amounts of unnecessary 12-nitro-derivatives and requires its removal.

Moreover, following this synthetic approach required large quantities of natural camptothecin, which is a very expensive product for the production of small quantities of the desired protracta sufficient quantities of the desired compound. Therefore, there is a need in way to increase the performance and outputs in comparison with the above synthetic approach to 9-amino-camptothecin.

We have developed a new method that meets this objective and at the same time solves the problems associated with waste arising in obtaining the appropriate quantities of unwanted 12-nitro-derivatives. According to this invention, this 12-nitro-derivatives recyclist in the process through the conversion of 9-amino-camptothecin simple and mild reaction conditions, providing high yields and purity of the reaction products.

Thus, the present invention provides a new method to produce 9-amino-camptothecin formula /I/ based on 12-nitro-camptothecin formula (II) in accordance with the stages illustrated in scheme 1 below:

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where X represents a group which can be removed by recovery.

The method includes the recovery transformation 12-nitro-derivatives of the formula /II/ 12-amino derivatives of formula /III/. This is an intermediate connection, in turn, converted into the corresponding diazopropane that "in Situ" is converted into a compound of the formula the Nitration 12-substituted derivative of formula /IV/ proceeds with high selectivity and yields the corresponding 9-nitro-12-substituted derivative of the formula /V/. Subsequent recovery of the compounds of formula /V/ 9-amino - camptothecin the compounds of formula (I) may be performed either in one stage, leading directly to the compound of formula (I) or in two stages, restoring the connection formula /V/ to the compounds of formula /VI/ and then restoring the connection formula /VI/ to the compounds of formula (I). There is no need to allocate the connection formula /VI/.

In the patent JP-A-59-51289 noted above and in the published literature /see, for example, Chem. Pharm. Bull. 1991, 39, 3183/, disclosed a large part of the chemistry of the molecule camptothecin, including conversion of the 12-amino group to the corresponding 12-galoidoproizvodnykh, but it was used only for the purpose of synthesis of compounds for biological evaluation. Biological unsuitability 12-substituted compounds /see, for example, Crow R. T., D. M. Crothers, J. Med. Chem., 1992, 35, 4160/ and chemical difficulties prevented any attempt to possible further modifications of 12-substituted derivatives of camptothecin.

In particular, the introduction of a nitro group in the 12-substituted derivative of this molecule is unknown and looks problematic, as it can lead to an increase in a mixture of derivatives with different regulation systems of the rings actually can and /VI/ should be marked that while restorative removing halogen atoms of the quinoline well know /see, for example, Jones G., The Chemistry of Heterocyclic Compouds, 32, 1 pages 604-611, where usually the presence of a base is considered useful in order to achieve a mild reaction conditions, on the contrary, despite decades of effort in chemistry camptothecin, nothing is known about deleting groups /for example, the removal of the halide groups/ derived camptothecin and, moreover, it is known that derivatives of camptothecin extremely sensitive to the basis, so to enlist the help of the Foundation will be considered to be problematic.

Unexpectedly, we found that it is possible, for example, the removal of the halogen atom from camptothecin in the presence of organic or inorganic non-nucleophilic base. The present invention includes this aspect, and is based on the observation of a very weak basicity and nucleophilic nature of the 9-amino group in the molecule camptothecin. Indeed, the restoration of the 9-nitro 9-nitro-12-substituted derivatives of the formula /V/ will give 9-amidofunctional and thus lead to the formation of 9-amino groups, which can then act as generated in situ weak non-nucleophilic base and wait, the presence of two substituents in para-position to each other in the connection formula /V/ will have unintended effects and may prevent or make very difficult dual-stage recovery: you can expect low outputs or decomposition of the desired product. In any case, the General synthetic scheme illustrated above combining the following sequence of reactions has never been reported and was not potentially suitable, and has not been recognized or implemented before.

The present invention provides a method of obtaining a 9-amino-camptothecin formula /I/

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this method, including:

1/ the recovery of the compounds of formula (II)

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thus obtaining a compound of formula (III

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2/ the transformation of compounds of formula (III into a compound of the formula /IV/

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where X represents a group which can be removed by recovery

3/ the interaction of the compounds of formula /IV/ nitrous agent, thus obtaining the compound of the formula /V/

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where X has the meaning as defined above, and

4/ restore in a single phase compound of the formula /V/, thus obtaining the 9-amino-camptothecin formula /I/, or Vice versa,

5/ restore is designated above, and

6/ reductive removal of the group X of the compound of the formula /VI/, thus obtaining the 9-amino-camptothecin formula /I/.

Preferably, the group X represents halogen, such as Cl, I, Br or F, preferably Cl or Br.

The recovery of the compounds of formula (II) in the compound of formula (III can be carried out, for example, with the appropriate reducing agent or by catalytic regeneration with appropriate catalysts in the presence of appropriate reducing agents. For example, it may be performed as described in J. March, Advanced Organic Chemistry, Third Edition, 1103. For example, the recovery may be carried out with reducing agents, such as, for example, SnCl2or other metals, or salts of metals such as, for example, Zn, or Fe, or their salts, in an appropriate solvent, such as, for example, dilute or concentrated aqueous solution of HCl, dilute aqueous solutions of a proton acid, water, ethanol, methanol or mixtures thereof, at a temperature of from about -20oC to about 60oC, during the period, which may vary from several minutes to several days, such as from about 5 minutes to about 3 days, for example from 4 hours droppy, such as, for example, palladium, platinum oxide, rhodium or ruthenium, in the presence of molecular hydrogen or sources of hydrogen, such as, for example, triethylammonium, formic acid, hydride tributyl tin, cyclohexadiene, etc., in an appropriate solvent, such as, for example, dimethylformamide /DMF/, MeOH, acetic acid, CHCl3, dioxane or mixtures thereof at a temperature of from about 0oC to about 100oC, in the course of time from a few minutes, such as from 5 minutes, as long as you do not stop the consumption of H2for example, about 3 days and at a pressure from about 1 atmosphere to about 100 atmospheres.

The transformation of compounds of formula (III into a compound of the formula /IV/ may be conducted with an appropriate reagent, such as, for example, halogen copper /I/, through education gazoprovodnogo that there is no need to isolate from the reaction mixture. The reaction of diazotization can be carried out by use of appropriate diastereomer agents, such as, for example, NaNO2or organic nitrite in aqueous dilute solutions of proton acids, such as, for example, HCl, HBr or H2SO4or in organic solvents at temperatures from about -20oC to OK the example from about 5 minutes to about 24 hours. The resulting solution may then be subjected to interaction with halogen copper /I/ in the amount of from about stoichiometric to a large excess, for example up to 10-fold molar excess, such as, for example, CuCl or CuBr, or iodide ions, optionally in the presence of an aqueous solution of the corresponding kaleidotrope acid, which can be used as solvent, at temperatures from about 0oC to about 100oC, over time, that may vary from several minutes to one day, such as from about 5 minutes to about 1 day.

Nitration of compounds of formula /IV/ obtaining the compounds of formula /V/ can be done with nitrous agent such as, for example, nitric acid, a mixture of nitric and sulphuric acids, or other nitrous agents, such as, for example, potassium nitrate or nitric acid and boron TRIFLUORIDE, such as the monohydrate nortryptaline /see, for example, Olah, G. A. and other Synthesis 1085, 1992/ or nitric acid/ triftormetilfullerenov anhydride /ibid, 1087, 1992/, at a temperature of from about -20oC to about 100oC, over time, that may vary from several minutes to several days, as, for example, from about 5 minene formula /V/ in the compound of formula (I) can be performed with appropriate reducing agents, such as, for example, molecular hydrogen or triethylammonium, formic acid, anti-hydride, cyclohexadiene, etc. in the presence of appropriate catalysts or in the homogeneous condition, for example, in the presence of salts of palladium or platinum and the corresponding phosphorus or nitrogen ligand, or in the heterogeneous condition, for example, in the presence of palladium, platinum oxide, platinum, rhodium or ruthenium alone or deposited on an appropriate substrate, such as, for example, for coal, CaCO3at BaSO4aluminum and so on, in an appropriate solvent, such as, for example, DMF, MeOH, acetic acid, CHCl3, dioxane or mixtures thereof, at a temperature of from about 0oC to about 100oC, over time, that may vary from about 1 hour to about 3 days, and at a pressure from about 1 atmosphere to about 100 atmospheres, optionally in the presence of inorganic or organic bases.

On the contrary, if the recovery of the compounds of formula /V/ in the compound of formula (I) is carried out in two separate stages, the first stage can be performed with appropriate reducing agents such as, for example, those described above for single-stage vaselka minutes to several hours, such as from about 5 minutes to about 24 hours, if desired, separating the intermediate derived formula /VI/ and then spending a further stage of recovery of the compounds of formula /VI/, following the same recovery procedure described above for the recovery of the compounds of formula /V/ in a single phase, or with reagents that give the radical removal of halides, such as, for example, n-Bu3Sn H in the presence of a radical initiator, such as 2,2'-azobisisobutyronitrile /AEBN/ or christinamilian, etc., in appropriate solvents such as, for example, benzene, toluene, CHCl3, acetonitrile, DMF or their mixtures, at a temperature which may vary from room temperature to the temperature of phlegmy solvent, during the period of time from several minutes to several hours, such as from about 5 minutes to about 24 hours.

Preferred reducing agents for recovery of the compounds of formula II to the compounds of formula (III represent, for example, SnCl2in dilute or concentrated aqueous HCl at a temperature of from about 0oC to about 60oC during the period of time from about 1 hour to about 2 days or catalytic is the temperature from about room temperature up to about 60oC during the period of time from about 1 hour to about 24 hours and a hydrogen pressure from about 1 ATM to about 10 ATM.

Preferred reagents for the conversion of compounds of formula (III into a compound of the formula /IV/ represent, for example, NaNO2, amyl nitrate, tert-butylnitrite or organic nitrite in aqueous or organic solvents, such as, for example, concentrated HCl or HBr, diluted HCl or HBr, DMF, dioxane or CH2Cl2at a temperature of from about -20oC to about 60oC during the period of time from about 10 minutes to about 12 hours. The resulting solution may then interact with halogen copper in an amount of from stoichiometric to 10 equivalents, such as, for example, CuCl or CuBr, or iodide ions, optionally in the presence of aqueous solutions of the respective kaleidograph acids, which can be used as solvents, at temperatures from about room temperature from about room temperature to about 80oC, over time, that may vary from several minutes to several hours, such as from about 5 minutes to about 12 hours.

Preferred reagents for the conversion of compounds of formula /IV/ connection is the monohydrate nortryptaline, or nitric acid /triftormetilfullerenov anhydride at a temperature of from about -20oC to about 60oC, during the time from several minutes to several hours, such as from about 5 minutes to about 24 hours.

Preferred reducing agents for recovery of the compounds of formula /V/ in the compound of the formula /I/ in one stage are molecular hydrogen, triethylammonium, formic acid or cyclohexadiene in the presence of appropriate catalysts, such as palladium, platinum oxide, and rhodium as such or on the substrate at an angle, CaCO3, BaSO4silicon or aluminum, in an appropriate solvent, such as, for example, DMF, MeOH, acetic acid, CHCl3, dioxane, or mixtures thereof, optionally in the presence of an appropriate organic base such as pyridine or 2,6-alkylpiperidines pyridine, such as, for example, 2,6-lutidine, etc. or inorganic bases, such as, for example, sodium carbonate or calcium, etc. at a temperature from about room temperature to about 80oC, during the time from about 1 hour to about 2 days, at a pressure from about 1 ATM to about 50 ATM, and more preferably from about 1 to about 10 reagents for the first stage are the same reagents, as described above, to restore the compounds of formula /V/ in one stage, for a shorter period of time, for example during the time from about a few minutes, such as 5 minutes to about 6 hours, if desired, separating the intermediate derived formula /VI/ and then performing the second stage of recovery of the compounds of formula /VI/, following the same recovery procedure described above for the recovery of the compounds of formula /V/ at one stage.

Preferred reagents for the removal of halogen radicals are n-Bu3SnH in the presence of radical initiators, such as AIBN or christinamilian and so on , in appropriate solvents such as benzene, toluene, CHCl3, acetonitrile, DMF or mixtures thereof at a temperature from about room temperature to the temperature of phlegmy solvent, for a time from about several minutes to several hours, such as from 5 minutes to 24 hours.

Mild reaction conditions, describing the method of the present invention, allow to save /S/ configuration when C20the compounds of formula (II) end connection 9-amino-camptothecin formula /I/.

The original connection of the formula (II) is Izv its scope also the way to obtain 9-amino-camptothecin formula /I/ reaction

a/ nitration of camptothecin formula /VII/

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obtaining a mixture of 9-nitro-20 /S/-camptothecin 12-nitro-20 /S/-camptothecin,

b/ division 9-nitro-20 /S/- camptothecin from 12-nitro-20 /S/-camptothecin,

c/ restore selected 9-nitro-20 /S/-camptothecin obtaining thereby a 9-amino-20 /S/-camptothecin,

d/ recycle dedicated 12-nitro-20 /S/-camptothecin through these stages of method /1/-/4/ or stage of the way /1/ by /3/, /5/ and /6/ obtaining thereby a 9-amino-camptothecin.

A further purpose of the present invention is a method of obtaining camptothecin above formulas /VII/, including recovery groups deleting X from the compound of the above formula /IV/.

Reductive removal of the group X of the compound of the formula /IV/ obtaining camptothecin formula /VII/ can be performed using appropriate reducing agents selected from, for example, molecular hydrogen or, for example, triethylammonium, formic acid, cyclohexadiene, etc. in the presence of appropriate catalysts, such as palladium, platinum oxide, platinum, rhodium or ruthenium as such or on the substrate at an appropriate material, such is kasna acid, CHCl3, dioxane or mixtures thereof, in the presence of an appropriate organic base such as pyridine or 2,6-alkylpiperidines pyridine, such as, for example, 2,6-lutidine, etc. at a temperature of from about 0oC to about 100oC, during the time from about 1 hour to about 3 days and at a pressure from about 1 ATM to about 100 ATM.

Preferred reducing agents, if in connection formula /IV/ X represents halogen, are molecular hydrogen, triethylammonium, formic acid or cyclohexadiene in the presence of appropriate catalysts, such as palladium, platinum oxide, platinum and rhodium as such, or on the substrate, coal, CaCO3, BaSO4, silicon or aluminum, DMF, MeOH, acetic acid, CHCl3, dioxane or mixtures thereof, at a temperature from about room temperature to about 80oC, during the period of time from about 1 hour to about 24 hours, in the presence of organic bases, preferred are pyridine and 2,6-lutidine, and at a pressure from about 1 ATM and up to about 50 ATM, and more preferably from about 1 ATM to about 10 ATM.

9-amino-camptothecin formula /I/ and camptothecin formula /VII/ are useful in catastophry colon and rectal tumors. Therefore, the connection can be used to improve the condition of a patient suffering from this cancer. They can also be useful to facilitate such cancers.

An effective amount of 9-amino-camptothecin or camptothecin can be thus introduced to the owner who needs it, usually the man. The active compound may be introduced by appropriate means, for example, orally or parenterally, such as intravenously. Dose in an amount of from 0.1 to 60 mg of active compound can be introduced this way person per kg of body weight. The preferred dose is from 1 to 40 mg per kg of body weight.

9-amino-camptothecin formula /I/ or camptothecin formula /VII/ may be incorporated for administration in a pharmaceutical composition with a pharmaceutical carrier or diluent. Can be applied to any appropriate carrier or diluent, depending on route of administration. The composition of the appropriate type described in the patent US-A 5106742 and WO 91/05556.

The following examples illustrate the production of intermediate compounds and compounds of the present invention, but not limit the scope of the invention.

Example 1.

12-amino-20th HCl /300 ml/ add anhydrous SnCl2/a 41.9 g/ at 0-5oC and the resulting mixture was continuously stirred at room temperature overnight. The solid is filtered off and washed with small amounts of concentrated HCl. Then the yellow solid is suspended in water and the pH adjusted to about 2 by the addition of solid sodium bicarbonate portions. Collect the solid by filtration, washed with water until neutral, then with ethanol and diethyl ether. After drying receive a 10.5 g specified in the title compound.

1H-NMR /DMSO-d6/ , M. D.: 0,88 /3H, t, J=7.2 Hz/, 1,83 /2H, m, 5,22 /2H,/, 5,40 /2H,/, to 6.19 /2H, Shir.with/, 6,50 /1H/, 6,9 - 7,4 /3H, m/, 8,44 /1H, s/.

Example 2

12-amino-20 /S/-camptothecin

A solution of 12-nitro-20 /S/-camptothecin /1 g/ DMF /100 ml/ hydronaut at atmospheric pressure and room temperature in the presence of 10% Pd /C/0.25 g/ as long as you do not stop the consumption of H2. The resulting suspension was diluted with an equal amount of DMF and filtered. The solution was concentrated in vacuo to a small volume and collect the precipitated solid by filtration, washed with standard and ether. Specified in the title of the product is obtained as yellow solids /0.8 g/.

It has the same Patria /2.4 g/ 30 ml of water are added to a solution of 12-amino-camptothecin /9 g/ in 18% HCl /650 ml/ at 0-5oC under stirring. After 30 minutes the reaction mixture was added dropwise into the flask containing CuCl /12.2 g/ and 18% HCl /250 ml at a temperature of 70oC. Heating continued for 1.5 hours. Then the reaction mixture was poured into ice water and the aqueous mixture extracted with methylene chloride. The solvent is removed in vacuum and the solid substance add /absorb/ ether and again filtered to obtain 5.5 g specified in the title of the product.

1H-NMR /DMSO-d6/ , M. D.: 0,89 /3H, t, J=7,3 Hz/, 1,86 /2H, m, of 5.29 /2H,/, 5,42 /2H,/, 6,57 /1H/, of 7.36 /1H/, 7,66 /1H, t, J=7.9 Hz/, 8.0 to 8.1 README /2H, m, 8,75 /1H, s/.

Example 4

12-bromo-20 /S/-camptothecin

Sodium nitrate /2.4 g/ 30 ml of water is added to a 12-amino-20 /S/-camptothecin /9 g/ 16% HBr /650 ml/ at 0-5oC under stirring. After 30 minutes the reaction mixture was added dropwise into the flask containing CuBr /21,3 g/ and 16% HBr /250 ml at a temperature of 70oC. Heating continued for 1.5 hours. The reaction mixture was poured into ice water and the aqueous mixture extracted with ethyl acetate. After evaporation of the solvent, the pure product emit precipitation with ether. Specified in the title of the product is obtained as yellow solids /6,1 g/.

1H-NMR /DMSO-d6/, , M. D.: 0,88 /3H, t, J=712-chloro-20 /S/-camptothecin

12-chloro-20 /S/-camptothecin /5 g/ dissolved/ suspended in concentrated H2SO4/70 ml and cooled to 0-5oC with mechanical stirring. Added dropwise 70% HNO3/2,7/ ml in the reaction mixture for 20 minutes and then the reaction flask allowed to warm to room temperature. Continue stirring over night at room temperature. The reaction mixture was poured into water with ice and collect the yellow solid substance by filtration, washed with water, ethanol and ether. After drying receive 4 g specified in the title of the product.

1H-NMR /DMSO-d6/, , M. D.: 0,89 /3H, t, J=7.2 Hz/, 1,86 /2H, m, 5,34 /2H,/, 5,44 /2H,/, 6,61 /1H,, 7,39 /1H/, 8,24 /1H, d, J=8,3 Hz/, 8,48 /1H, d, J=8,3 Hz, which 9.22 /1H, s/.

Example 6

9-nitro-12-bromo-20 /S/-camptothecin

12-bromo-20 /S/-camptothecin /5.5 g/ dissolved /suspended in concentrated H2SO4// 80 ml and cooled to 0-5oC with mechanical stirring. In the reaction mixture for 20 minutes, added dropwise 70% HNO3/3,1 ml/ and then the reaction flask allowed to warm to room temperature. Stirring is continued overnight at room temperature. The reaction mixture was poured into water with ice and collect Sanogo in the title of the product.

1H-NMR /DMSO-d6/, , M. D.: 0,88 /3H, t, J=7,3 Hz/, 1,87 /2H, m/ 5,35 /2H,/, 5,44 /2H,/, 6,61 /1H/, 7,40 /1H/, 8,39 /1H, d, J=8,4 Hz/, 8,45 /1H, d, J=8,4 Hz/, 9,2 /1H, s/.

Example 7

9-amino-12-chloro-20 /S/-camptothecin

A solution of 9-nitro-12-chloro-20 /S/-camptothecin /3 g/ DMF /50 ml/ hydronaut at atmospheric pressure and temperature in the presence of 10% Pd/C//0.1 g/ in 2 hours. The reaction mixture is filtered and the solution concentrated in vacuo. The residue is subjected to chromatographicaliy on a column of silica gel, getting mentioned in the title link /2.5 g/.

1H-NMR /DMSO-d6/ , M. D.: 0,87 /3H, t, J=7.2 Hz/, 1,86 /2H, m, 5,28 /2H,/, 5,42 /2H,, 6,30 /2H, Shir.with/, 6,56 /1H/, 6,75 /1H, d, J=8,4 Hz/, 7,31 /1H/, 7,66 /1H, d, J=8,4 Hz/, 8,89 /1H, s/.

Example 8

9-amino-20 /S/-camptothecin

A solution of 9-nitro-12-chloro-20 /S/-camptothecin /3 g/ DMF /50 ml/ hydronaut at atmospheric pressure and temperature in the presence of 10% Pd/C/0.1 g/ in 48 hours. The reaction mixture is filtered and the solution concentrated in vacuo. The residue is subjected to chromatographicaliy on a column of silica gel with obtaining specified in the title compounds /1.5 g/.

1H-NMR /DMSO-d6/ memorial plaques: 0,87 /3H, t, J=7,3 Hz/, 1,85 /2H, m, 5,26 /2H,/, 5,41 /2H,/, 6,11 /2H,/, 6,50 /1H/, 6,79 /1H, m, 7,28 /1H/, 7,3 - 7,5 /2H, m, 8,33 /1H, s/.

Example 10

9-amino-20 /S/-camptothecin of 9-amino-12-chloro-20 /S/-camptothecin

The reaction is carried out similarly as in example 8, to obtain specified in the title compound as a yellow solid, which was identical with the authentic product.

Example 11

20 /S/-camptothecin of 12-chloro-20 /S/-camptothecin

The reaction is carried out similarly as in example 8, except that the reaction is carried out in the presence of pyridine and the reaction mixture hydronaut within 12 hours. Specified in the title of the product produce by using column chromatography. The product was identical with the authentic sample of the product.

Example 12

20 /S/-camptothecin of 12-bromo-20 /S/-camptothecin

The reaction is carried out similarly as in example 11, except that the reaction is carried out for 6 hours, to obtain specified in the title of the product, which was identical to the authentic sample of the product.


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receiving, thus, the compounds of formula III

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2) turn the compound of formula III with diastereomer agent into the corresponding compound of formula IV

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where X represents a halogen atom;

3) nitrous compound of formula IV nitrous agent with obtaining the compounds of formula V

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where X is the specified value,

and 4) restore the nitrogroup and at the same time using a reduction reaction of removing the halogen atom in the compound of formula V with 9-amino-camptothecin formula I or, alternatively, 5) restore the connection of the formula V, thus obtaining a compound of formula VI

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where X is the specified value,

and 6) reduction reaction removes the halogen atom from the compounds of formula VI to obtain 9-amino-camptothecin formula I.

2. The method according to p. 1, characterized in that the stage 1 is performed with the use of SnCl2, Zn or Fe as a reducing agent or by catalytic hydrogenation using palladium, platinum oxide, platinum, rhodium or ruthenium.

3. The method according to any of the preceding paragraphs, characterized in that the stage 2 carry out the diazotization of the compounds of formula III, vaimoisa fact, what nitrouse agent in stage (3) is selected from nitric acid; a mixture of nitric and sulphuric acids; potassium nitrite; nitric acid and nortryptaline and nitric acid and triftormetilfullerenov anhydride.

5. The method according to any of the preceding paragraphs, characterized in that the reducing agent used in stage 4, or reducing agents used in stage 5 and 6, which are selected from molecular hydrogen, triethylammonium formate, formic acid, hydride and anti-cyclohexadiene.

6. The method according to any of the preceding paragraphs, characterized in that exercise a) narisovanie of camptothecin formula VII

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obtaining a mixture of 9-nitro-20(S)-camptothecin and 12-nitro-2-(S)-camptothecin; (b) separate 9-nitro-20(S)-camptothecin from 12-nitro-20(S)-camptothecin; (c) restore the selected 9-nitro-20(S)-camptothecin obtaining thereby a 9-amino-20(S)-camptothecin and (d) conducting management dedicated 12-nitro-20(S)-camptothecin through the specified stage of the method (1) to (4) or through the specified stage of the way(1) - (3), (5) and (6) obtaining thus 9-amino-20(S)-camptothecin.

7. A method of obtaining a 9-amino-camptothecin formula I under item 1, characterized in that conduct: (i) the restoration of the Alenia group X by recovery of the compounds of formula VI, as defined under item 1, with the connection specified formula VI does not necessarily receive the recovery of the compounds of formula V under such conditions as to obtain the connection formula VI.

8. The method according to p. 7, characterized in that the compound of formula V is produced by interaction of the compounds of formula IV, as defined under item 1, with nitrous agent, and the compound of formula IV is not necessarily obtained by conversion of the compounds of formula III, as defined under item 1, with compounds of formula III do not necessarily receive the recovery of the compounds of formula II, as defined in paragraph 1.

9. The compound of formula V or VI

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where X is defined in paragraph 1.

10. The method of producing camptothecin formula VII

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characterized in that the compounds of formula IV

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where X represents a halogen atom,

delete a group X recovery.

 

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7 cl, 4 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I)CE, wherein "-----" means a bond, V represents CH, and U represents CH or N, or "-----" means a bond, V represents CR6 and U represents CH, or also "-----" means a bond, V represents N and U represents CH, or "-----" is absent, V represents CH, and U represents CH2, NH or NR9; R0 represents H, or provided "-----" means a bond, can also represent C1-3alkoxygroup; R1 represents H, halogen, cyanogroup, C1-3alkyl or ethinyl; R2 represents H, acetyl or a group of formula -CH2-R3; R3 represents H, C1-3alkyl or C1-3hydroxyalkyl; R4 represents H, or provided n is other than 0, and R5 means H, can also represent OH; R5 represents H, C1-3alkyl, C1-3hydroxyalkyl, C1-3aminoalkyl, C1-3alkoxyC1-3alkyl, carboxyl group or C1-3alkoxycarbonyl; R6 represents C1-3hydroxyalkyl, carboxyl group, C1-3alkoxycarbonyl or a group -(CH2)q-NR7R8, wherein q is 1, 2 or 3 and each of R7 and R8 independently represents H or C1-3alkyl, or R7 and R8 together with a nitrogen atom to which they are attached, form a pyrrolodinyl or piperidinyl ring; R9 represents C1-3alkyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl; A represents -(CH2)p-, -CH2CH2CH(OH)- or -COCH2CH(OH)-; G represents a phenyl group which is mono- or disubstituted in m- and/or n-position(s)by substitutes independently specified C1-4alkyl, C1-3alkoxygroup and halogen, or G means a group of one of formulas below G1 and G2, wherein Q means O or S, and X means CH or N; and each Y1, Y2 and Y3 represents CH, or one of Y1 and Y3 represents N, and the other one represents CH; and n is equal to 0, provided A represents -CH2CH2CH(OH)- or -COCH2CH(OH)-, and n is equal to 0, 1 or 2, provided A represents (CH2)p, wherein p is equal to 1, 2, 3 or 4, provided a sum of n and p is then equal to 2, 3 or 4; or a pharmaceutically acceptable salt of this compound.

EFFECT: compound of formula (I)CE or its pharmaceutically acceptable salt are applicable as a therapeutic agent for preventing or treating a bacterial infection.

29 cl, 2 tbl, 202 ex

Organic compounds // 2591194

FIELD: chemistry.

SUBSTANCE: invention relates to specific substituted condensed with heterocycle gamma-carbolynam of formula I, where X is -N(H)- or -N(CH3) and Y represents -C(H)(OH)-; and formula III, where X is -N(CH3)-, -N(H)-; and R1 is selected from -C(O)-C-1-5alkyl, -C(O)-C-6alkyl, -C(O)-C7alkyl and -C(O)-C9alkyl in free form, in form of solid substance, in form of pharmaceutically acceptable salts and/or in substantially pure form, as well as to pharmaceutical compositions based on these compounds.

EFFECT: treating diseases involving 5-HT2A receptor, carrier serotonin (SERT) and/or path, involving dopamine D2 receptor system signal.

30 cl, 2 dwg, 2 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

FIELD: organic chemistry of heterocyclic compounds, biology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of the general formula (1): or (2): or their pharmaceutically acceptable salts, N-oxides or hydrate possessing physiologically active properties, in particular, eliciting ability to induce apoptosis in tumor cells causing their death. In the general formula (1) or (2) X represents sulfur or oxygen atom; Y represents sulfur atom, group -SO, group -SO2, group -NH or group -NR6; R1 represents aryl, substituted aryl, heteroaryl; R2 and R5 represent hydrogen atom, alkyl, allyl, substituted benzyl, group -CH2-C(O)R3, group -CH2-C(O)NR3R4 wherein R3, R4 and R6 represent inert substitute. Also, invention relates to new combinatory libraries for search compound-leaders and candidates for medicinal compounds preparing by screening the combinatory libraries.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic synthesis.

SUBSTANCE: invention relates to synthesis of camptotecin analogues from 2'-amino-5'-hydroxypropiophnone corresponding to AB ring portion of camptotecin structure and tricyclic ketone converted into CDE ring portion in camptotecin structure. Preparation of 2'-amino-5'-hydroxypropiophnone comprises following steps: (1) preparing compound (b) by mixing compound (a), benzylation agent, and a base followed by stirring mixture obtained in solvent on heating under reflux; (2) preparing compound (c) by dropwise adding Grignard reagent to compound (b) under an inert gas atmosphere; (3) preparing compound (d) by mixing compound (c) with an oxidant and stirring resulting mixture; and (4) preparing compound (e) via catalytic reduction of compound (d) (see scheme 1 below). Intermediate compounds (c') and (d') are described. Also described is a method for preparing tricyclic ketone to provide efficient complete synthesis of camptotecin serving as starting compound for irinotecan hydrochloride and a various types of camptotecin derivatives as well as for stable preparation of camptotecin and its derivatives. Scheme 1: .

EFFECT: expanded synthetic possibilities in camptotecin derivatives series.

5 cl, 17 tbl, 33 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel polycyclic compounds of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7, cycle A, cycles B, X, Y and Z have values given in the invention claims and in description of the claim, and to their pharmaceutically acceptable salts also. Proposed compound possess an antitumor activity and can be used in treatment of oncological diseases. Also, invention relates to a pharmaceutical composition based on these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

23 cl, 1 tbl, 57 ex

FIELD: medicine; pharmacology.

SUBSTANCE: new annelated asaheterocycles include pyrimidine fragment of general formula I in the form of free bases or pharmaceutically acceptable salts. Compounds of this invention possess properties of PI3 kinase inhibitors. In general formula I X represents oxygen atom or sulphur atom; Z represents oxygen atom, R1 represents hydrogen atom or optionally substituted C1-C6alkyl, or Z represents nitrogen atom together with bound carbon atom forming through Z and R1 optionally substituted annelated imidazoline cycle; R2 represents optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, possibly annelated with 5-6-term heterocyclyl containing heteroatoms chosen from oxygen and nitrogen, optionally substituted 5-6-term heterocyclyl containing heteroatoms chosen from nitrogen, oxygen and/or sulphur, possibly annelated with phenyl ring. Invention also concerns method of production of compounds, pharmaceutical compositions and medical products.

EFFECT: effective application for preparation of medical products for oncologic therapy.

14 cl, 3 dwg, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, specifically to 4-substituted-3-(1-alkyl-2-chloro-1H-indol-3-yl)furan-2,5-diones of general formula I , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R3=phenyl, naphthyl, 2-phenyl-1-ethenyl, thienyl, furyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, synthesis method thereof and use as compounds capable of photochemical generation of stable fluorophores of formula II, which can be used, for instance in information storage systems, particularly as photosensitive components of material for three-dimensional recording and storage of information. The invention also relates to novel 4,5-substituted-6-alkyl-1H-furo[3,4-c]carbazole-1,3(6H)diones of general formula II , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R4=H, R5=phenyl, R4, R5=benzo, naphtho, thieno, furo, pyrrolo, benzothieno, benzofuro, indolo, method for synthesis of said compounds and use as fluorophores.

EFFECT: obtaining novel compounds and possibility of using said compounds as fluorophores.

14 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: compounds, which have formula I , in which A, B, R1, R1a, R2, R3, R4, R5 R6, R7 and R8 have values given in description and are inhibitors of receptor tyrosinkinases, useful in treatment of diseases, mediated by class 3 and class 5 receptor tyrosinkinases. It has been also discovered that specific compounds of the claimed invention are Pim-1 inhibitors. Also claimed is method of obtaining formula I compound.

EFFECT: increase of compound efficiency.

27 cl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel spirocyclic azaindole derivatives of formula I: , where: one of A stands for N, and the other ones stand for CR7-10; W stands for NR4; X stands for O, S; R1 and R2, independently on each other stand for H; C1-5-alkyl each time saturated, branched or unbranched, non-substituted or monosubstituted with -OC1-6alkyl; phenyl, thienyl, morpholinyl, benzothiophenyl or benzodioxilyl, each time non-substituted or monosubstituted with F, C1-6alkyl; or 5-membered heteroaryl, containing three nitrogen atoms as heteroatoms, substituted with C1-3alkyl; bound with C1-3-alkyl group phenyl non-substituted or monosubstituted with F or C1-6alkyl; R4 stands for H; R5 stands for H; R6 stands for H; R7, R8, R9 and R10 stand for H or CP3; in form of siastereomers, mixtures of diastereomers or separate diastereomer; bases and/or salts of physiologically compatible acids. Compounds are suitable for treatment of a number of diseases, for instance, pain, stress, depressions, etc. Described is method of their obtaining.

EFFECT: compounds are suitable for treatment of a number of diseases, for instance, pain, stress, depressions.

11 cl; 1 tbl; 34 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) where values of substituents are given in description, possessing inhibiting activity with respect to cathepsin K as well as to pharmaceutical compositions for treating diseases, associated with cysteine protease activity and to methods of inhibiting cathepsin K in mammals, requiring such treatment by introduction of efficient amount of compound to mammal.

EFFECT: claimed is application of formula (I) compound or its pharmaceutically acceptable salt in manufacturing medication for application in cathepsin K inhibition in a warm-blooded animal.

10 cl, 45 ex, 5 dwg

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