Derivatives of phospholipids, the method of production thereof, pharmaceutical composition and a method of obtaining a pharmaceutical composition

 

(57) Abstract:

Describes compounds of formula I, where R5linear or branched C10- C24is an alkyl residue, which can contain from one to three double and/or triple relations; And represents a simple bond or one of the groups of formulae II-VI, and R7denotes a linear C1- C4is an alkyl group, and group II - VI is oriented so that the oxygen atom is linked to the phosphorus atom of the compound I, X denotes an oxygen atom or sulfur; AND1denotes a linear or branched C2- C10is an alkyl residue, R6-Y(R8R9R10), where R8, R9, R10the same or different, represent independently from each other hydrogen, linear, branched or cyclic C1- C6-alkyl residue, or two residue can form a loop, while Y represents P, As, Sb, or Bi. These compounds of formula I possess anti-tumor and/or protivolakoznoe activity. The method consists in the fact that the compound of formula VII, where R5X and As stated above, is subjected to the interaction with phosphorus oxychloride, in the environment of a solvent or in his absence, the product on the pots above, and then carry out the hydrolysis. The proposed pharmaceutical composition having antitumor and/or protivolakoznam action, containing as active principle at least one compound of formula I in an effective amount, and a method of obtaining a pharmaceutical composition having antitumor and/or protivolakoznam action, comprising mixing an effective amount of one or more compounds of General formula I with one or more pharmaceutically acceptable targeted supplements and subsequent processing of the resulting mixture in a conventional dosage form. 4 c. and 2 C.p. f-crystals.

This invention relates to pharmaceutically valuable substances and comes with high pharmaceutical activity of derivatives of phospholipids, the method of their derivation containing their medicines and how to obtain this tool.

Long-chain alkylphosphocholine with antimicrobial activity describes Cape AP and other Nippon Kayaku Kaishi, 9, 1452/1984/.

European patent application N 108565 /applicant: TakedF/

< / BR>
where R1denotes an aliphatic hydrocarbon residue with 8 to 30 C atoms ,

the remains of R2, R32R3R4denotes a cyclic ammonium group; and

n denotes 0 or 1.

For these compounds is indicated antitumor activity and antifungal activity.

According to the invention offers the derivatives of phospholipids of the General formula (1)

< / BR>
and R5denotes a linear or branched alkyl residue with 10 to 24 C-atoms, which can also contain one to three double bonds;

A denotes a single bond or one of the groups of formulae II - VI:

-CH2-CH2-CH2-O- (II);

-CH2-CH2-O- (III);

< / BR>
< / BR>
< / BR>
and R7denotes a linear alkyl group with 1-4 C-atoms, which may also be branched.

Group /II/ - /VI/ are oriented so that the oxygen atom bound to the phosphorus atom of the compound /1/;

X denotes an oxygen atom or sulfur, or NH, when A represents a simple bond;

X denotes an oxygen atom or sulfur, when A is a compound of the formula groups /II/ - /VI/;

A1denotes a linear or branched alkyl residue with 2 to 10 C-atoms, which may be unsaturated, and which may be substituted with halogen or hydroxyl groups;
svetlanna or cyclic alkyl residue with 1-6 C-atoms, which may be the same or different, or hydrogen;

and Y represents P, As, Sb or Bi

Proposed according to the invention compounds can be used for therapy of tumors and for the treatment of skin and autoimmune diseases.

For the treatment of diseases caused by protozoa, suitable, for example, the compounds of formula I with Y value As and Sb. Moreover, all compounds particularly suitable as anti-neoplastic diseases.

Proposed according to the invention compound suitable for the treatment of blood diseases such as anemia, which may occur in combination with tumor diseases. Further proposed according to the invention compounds can be used for therapy of bone disease such as osteoporosis.

Further, the compounds of formula I can be used for therapy of viral diseases and bacterial infections.

The compounds are characterised by low toxicity. Thus, the compounds according to example 3 with the introduction of disposable pills mouse has LD50more than 1470 mg/kg body weight.

Compounds according to the invention receive according to the method described below.

The first stage of the method consists in uzasadnij simple cyclic ethers, acyclic ethers, saturated hydrocarbons with 5-10 C atoms, liquid aromatic hydrocarbons, which can also be substituted by halogen (especially chlorine), or mixtures of the above solvents or without solvent, if necessary in the presence of normal for this purpose, the basic substance.

As halogenated hydrocarbons consider, for example, hydrocarbons having 1-6 C atoms, where one or more or all of the hydrogen atoms may be replaced by chlorine atoms. For example, using methylene chloride, chloroform, telengard, chlorobenzene, dichlorobenzene. If we are talking about substituted by halogen aromatic hydrocarbons, they are preferably substituted by one or two halogen atoms.

As saturated cyclic ethers can be used, for example, ethers, 5-6-membered ring which consists of carbon atoms and one or two atoms of oxygen. Examples of such ethers are tetrahydrofuran and dioxane.

Acyclic ethers consist of 2-8 C atoms and are liquid. For example, take into account: diethyl ether, Diisobutyl ether, methyl-tert.-butyl ether, Diisobutylene hydrocarbons, which consist of 5-10 carbon atoms and are liquid. For example, take into account pentane, hexane, heptane, cyclohexane.

As aromatic hydrocarbons consider, for example, benzene and alkyl substituted benzenes and alkyl substituents consist of 1-5 C-atoms.

As basic substances, as for the reaction of phosphorus oxychloride with alcohol, misperton or an amine, and subsequent interaction with the salt of phosphonium, STIBINE or Mismaloya, take into account amines, for example, aliphatic amines of the formula NR6R7R8and R6, R7and R8are identical or different and denote hydrogen or C1-C6-alkyl or aromatic amines as pyridine or picoline. Further, it is possible to apply, for example, quinoline, Diisopropylamine, isoquinoline, triethylamine, base Hunga /Hunig, Kissel, Chem. Ber. 91 /380/ 1958/.

When the reaction of interaction with the salt of phosphonium, STIBINE or Mismaloya necessary here, the main substances can be added simultaneously or also before the introduction of salt phosphonium, STIBINE or Mismaloya. For this reaction in each case, the required solvent; i.e., if the first stage of reakce phosphorus oxychloride to alcohol, DiSpirito or amine is, for example, 1,5:1 - 0,8:1.

If the reaction of phosphorus oxychloride with alcohol, respectively, misperton or amine is carried out in the presence of a basic substance, the amount of the basic substance is, for example, 1-3 mol, per 1 mole of POCl3.

For further interaction with the salt of phosphonium, STIBINE, or Mismaloya used amount of the basic substance is, for example, 1-5 mol, per 1 mol of the alcohol, teopista or amine.

The reaction temperature in the interaction of phosphorus oxychloride with alcohol, misperton or amine ranges from -30 to +30oC, preferably from -15 to 0oC, in particular between -10 and 0oC.

This reaction is, for example, 0.5 to 5 hours, preferably 1-3 hours, in particular 1,5-2 hours. If the reaction is carried out in the presence of a basic substance, it flows in a General fast /around 30 minutes/.

The resulting product, without isolation and purification in an inert solvent is injected into the interaction with the salt of phosphonium, stibane, arsonia or Mismaloya formula

OH - A1- R6,(VIII)

where A1and R6have the above values.

Consistent with this, phosphonium salt, STIBINE or Mismaloya add portions or immediately fully.

As the acid salt of phosphonium, STIBINE or Mismaloya take into account salts with inorganic acids /as, for example, sulfuric acid, hydrochloric acid/; next, salts with organic acids such as, for example, acetic acid, p-toluensulfonate and the like.

This stage reaction is carried out in an inert solvent. As solvents are taken into account such as that used for the interaction of phosphorus oxychloride with alcohol, misperton or an amine, if this interaction is carried out in a solvent.

Then added dropwise base material dissolved in one of these solvents or without solvent.

Preferred as solvents for the main substances used here halogenated hydrocarbons, saturated cyclic ethers, acyclic ethers, saturated hydrocarbons with 5-10 C atoms, liquid aromatic hydrocarbons or mixtures of the above solvents. Here we are talking about such solvents that can be applied to the interaction of phosphorus oxychloride is. It is necessary that the temperature was maintained in the range 0-40oC. preferably 10-30oC, especially 15-20oC.

The reaction mixture is then stirred during 5-30oC, preferably at 15-25oC /for example, for 1-40 hours, preferably 3-15 hours/.

Hydrolysis of the reaction mixture is performed by adding water, and the temperature must be maintained at 10-30oC, preferably 15-30oC, especially 15-20oC.

The above reaction mixture to hydrolysis may contain basic substances. As such basic substances take into account the carbonates and bicarbonates of alkali and alkaline earth metals.

For a complete hydrolysis and then stirred for further 0.5 to 4 hours, preferably 1-3 hours, in particular 1.5 to 2.5 hours at a temperature of 10-30oC, preferably 15-25oC, in particular 18-22oC.

The reaction solution is then washed with a mixture of water with alcohols /preferably aliphatic saturated alcohols with 1-4 C-atoms which may also contain the main substance. The ratio of components in a mixture of water: the alcohol may be, for example 5 to 0.5, preferably 1-3 /volume/.

As of the alkaline earth metals, and ammonia /for example, aqueous ammonia/. Especially preferably 3% aqueous solution of sodium carbonate.

If necessary, you can then carry out the washing of the reaction solution with an acidic solution. Acid washing is preferably carried out to remove unreacted main parts of the reaction solution, especially when using methylene chloride as solvent.

The wash solution consists of a mixture of water with alcohols. Preferably take into account a mixture of saturated aliphatic alcohols with 1-4 C-atoms, and if necessary they can be acidic substance. The ratio of components in a mixture of water : the alcohol may be, for example, 5 to 0.5, preferably 1 to 3 /volume/.

As the acidic substance washing liquid take into account, for example, hydrochloric acid, sulfuric acid, or tartaric acid and citric acid. Especially preferred 10% aqueous hydrochloric acid solution.

Then again washed with a mixture of water with alcohols. Preferably take into account a mixture of saturated aliphatic alcohols with 1-4 C-atoms, and if necessary they can even predpochtitelno 1-3.

The washed phase and then combine the usual manner, dried, and then the solvent [preferably under reduced pressure, for example, 5-100 hPa], if necessary after addition 150-1000 ml, preferably 300-700 ml, particularly between 450 and 550 ml, aliphatic alcohol /per 1 mol of dry product/ remove.

As alcohols preferably take into account the saturated aliphatic alcohols with chain length 1-5 C-atoms. Especially preferred as alcohols while n-butanol, isopropanol. The purpose of this alcohol treatment is more complete removal of residual water.

The thus obtained product can be cleaned in the usual way (for example, by chromatography, recrystallization/.

Compounds according to the invention are also described below.

This method consists in the introduction in the interaction of the cyclic complex Trevira phosphoric acid with the compound of the formula X or XI. Cyclic ester of phosphoric acid get according to European patent N 108565 by reacting a cyclic acid chloride complex diapir phosphoric acid with alcohol.

The compound of formula IX:

< / BR>
and "m" = 2 or /X/

YR6R7R8/X/;

[values radicals and indices, see formula /1/].

As inert solvents take into account aliphatic NITRILES, such as acetonitrile, propionitrile; further, polar solvents, such as N-organic, dimethylformamide, dimethylacetamide.

The reaction temperature is 30-140oC, preferably 50-120oC, especially 70-100oC.

You can work at atmospheric pressure and also at elevated pressure, and the pressure is 1000-2000 hPa, preferably 1000-1750 hPa and in particular 1000-1500 hPa.

The duration of the reaction is 0.5 to 4 hours; when working at elevated pressure, for example, at 1500 hPa and 85oC; the duration of the reaction is 2 hours.

In addition, the compounds according to the invention can also be obtained below way.

The interaction of activated derivatives of esters of phosphoric acid.

This method consists in the introduction into the interaction hydrogen phosphate with compounds of General formula /XIII/:

< / BR>
moreover, in the formula /XIII/ R5, X, A, A1and R6have the above meanings;

Z denotes tosylate, the mesilate and triflate.

As the dehydrating means in the condensation reaction can be applied carbodiimide as, for example, dicyclohexylcarbodiimide.

As solvents for the variant of the method take into account the aprotic, polar solvents such as acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-organic and chlorinated hydrocarbons.

Temperature is, for example, 20-80oC, particularly preferably 40-60oC. the Duration of the reaction is, for example, 4 hours.

Compounds according to the invention are also those that the compound of General formula /XII/, which is activated on aliphatic residue ester of phosphoric acid

(XII)

where Z1- chlorine, bromine, mesilate, toilet, or iodine

/other symbols have the above meanings/, enter into interaction with the compound of the formula /X/ or formula /XI/.

This reaction is carried out in a known manner without solvent or in an inert solvent at a temperature of 50-150oC. as solvents take into account those specified in method 2.

After the above reaction EWRM, Ag2CO3and with reason, for example, Carbondale alkali and alkaline earth metals or organic amines. As solvents are aliphatic alcohols, such as methanol, ethanol and isopropanol. It is possible to work at elevated temperatures.

When all reactions should be observed in the chemistry of ORGANOMETALLIC substances exclusion of moisture and oxygen.

All four methods can be performed by carrying out additional purification stages. Clearance above the compounds obtained can be realized by the fact that the residue that is obtained after evaporation of the reaction medium, if necessary under reduced pressure, dissolved in an organic solvent /preferably in a lower alcohol with a water content of 0-4%, as for example, methanol, ethanol, isopropanol, n-butanol/ and treated with joint H-OH ion exchanger or sequentially with acidic and basic ion exchangers. The obtained filtrate in this case mixed with the joint H-OH-exchanger, for example, as AmberliteMV 3, for example, for 1-5 hours, preferably 2 hours, at a temperature of 10-50oC, preferably 20oC. Instead of the joint H-OH ionoobmennika.

As ion exchangers can be applied all insoluble solids, which contain ionoobmennaya group.

Acidic ion exchangers are those which contain, for example, acidic groups, as sulfonylurea group, carboxyl group. Examples are ion exchangers with sulfoxylate groups on a polystyrene matrix, as for example, Amberlite1R 120; DowexHCR; DuoliteC 20 or LewatitS 100. Weak-acid ion exchangers are, for example, such that based on the matrix of polyacrylic acid as, for example, AmberliteIRC 76, DuoliteC 433 or ReliteCC, contain the carboxylic acid group.

As basic ion exchangers take into account, for example, such that the polymer matrix of /for example, polystyrene matrix is/ are primary, secondary, tertiary or Quaternary amino group such as, for example, DuoliteA 101; DuoliteA 102; DuoliteA 348; DuoliteA 365; DuoliteA 375; Amberlite1RA 67; DuoliteA 375; Amberlite1RA 458 and DuoliteA 132.

Joint H-OH-ion is a mixture of acid and alkali is berliteMB 6.

However, it is necessary to refer to Ullmann''s Encyclopedia of Inductrial Chemistry, 5th edition /1989/, I. And 14, S. 450, which explains all commercially available ion exchangers that can be used in the cleaning method.

After removal of substances with ion-exchange resin is evaporated under reduced pressure (for example, 20 Torr to 200 Torr/ 40-70oC and then recrystallized from halogenated hydrocarbons, saturated aliphatic ketones, mixtures of alcohols to ketones or of saturated or aromatic hydrocarbons.

As halogenated hydrocarbons for recrystallization take into account, for example, hydrocarbons having 1-6 C atoms, where one or more or all of the hydrogen atoms may be replaced by chlorine atoms. For example, you can apply methylene chloride, chloroform, telengard, chlorobenzene.

As spirits take into account the saturated aliphatic alcohols with 1 to 6 C-atoms and 1 to 3 hydroxyl groups. As ketones take into account the saturated, aliphatic ketones with 3-6 C-atoms.

The ratio of components in a mixture of alcohol:ketone is from 1:1 to 1:5 /volume/. Particularly preferred mixture of ethanol with acetone in the ratio 1:1 /about the nd petroleum ether, toluene, xylene, ethylbenzene.

Proposed according to the invention the compounds of formula /1/ low toxicity with good antitumor activity. For example, the compound according to example 1 in experiment on L 1210-culture cells has EC90= 2.9 μg/ml.

EC90represents the effective concentration protivoopukholevaya substances, which in vitro inhibits the growth of cancer cells by 90% compared to the control experiment without addition of protivoopukholevaya substances.

Example 1

Internal salt of 2-[/(octadecylamine)hydroxyphosphonic/oxy]-As, As, As-trimethylarsine: [name according to nomenclature IUPAC] :

< / BR>
of 2.3 ml /25 mmol/ phosphorus oxychloride dissolved in 15 ml of chloroform, and at 0-5oC dropwise mixed with a solution of 6.1 g /22,5 mmol/ octadecanol in 25 ml of chloroform, which contains 8 ml of pyridine. Duration added is from 30 minutes to 1 hour. Stirred for further 1 hour at room temperature and then added at once to 7.4 g /30 mmol/ arsenomolybdate. To this solution was added dropwise 10 ml of pyridine so that the temperature did not exceed 20-25oC. after adding the optional stirred for 3 hours at room the art of water with methanol /1:1/, 20 ml of 3% sodium carbonate with methanol /1:1/, 20 ml of 3% citric acid with methanol /1:1/, and then 20 ml of a mixture of water with methanol /1:1/. The organic phase is dried over magnesium sulfate, concentrated and the residue treated with 96% ethanol. After filtering off mixed with 30 g of ion exchanger Amberkite MB.3. Sucked off through a mixture of diatomaceous earth with activated carbon, concentrated in vacuo and crystallized from acetone. Output: 2,54 g /23%/.

Elemental analysis are given in table. 1.

Thin-layer chromatogram [chloroform/methanol/1M sodium acetate in 25% ammonia = 70:40:10] : Rf = 0.53 per share.

Example 2

Internal salt of 2-[[(hexadecylamine)hydroxyphosphonic]oxy]-As, As, As-trimethylarsine: /name according to nomenclature IUPAC/:

< / BR>
Obtaining analogous to example 1 from 2,3 ml /25 mmol/ phosphorus oxychloride, 5.5 g /22,5 mmol/ hexadecanol, 8 - 10 ml of pyridine and 7.4 g /30 mmol/ arseniosiderite. Purification by treatment with 23 g of ion exchanger Amberlite MB 3 in 96% ethanol. Yield: 1.4 g /13%/.

Elemental analysis are given in table. 2.

Thin layer chromatogram (chloroform/methanol/1 M sodium acetate in 25% ammonia = 70:40:10): Rf = 0,48.

Example 3.

Internal salt of 2-[[(CIS-13-docosenoic)hydroxide is the iMER 1, of the 2.3 ml /25 mol of phosphorus oxychloride, 7,3 g /22,5 mmol/ erollover alcohol, 8 + 10 ml of pyridine and 7.4 /30 mmol/ arsenomolybdate. Purification by treatment with 23 g of ion exchanger Amverlite MB 3 in 95% ethanol. Output: 1,1,

Elemental analysis:

Calculated, %: C 55,28; H 10,31

Found, %:

C 54,98; H 10,19

C 55,08; H 10,30

Thin-layer chromatogram [chloroform/methanol/1 M sodium acetate in 25% ammonia = 70:40:10]:Rf=0.52 in.

Internal salt of 2-[[(octadecylamino)hydroxyphosphonic] oxy]P,P,P-trimethylphosphine /title according to the nomenclature of IUPAC/:

< / BR>
obtain analogously to example 1: 4.6 oz /50 mmol/ phosphorus oxychloride, 12.2 g /45 mmol/ octadecanol, 16+20 ml of pyridine and 12.1 g /60 mmol/ phospholinked. Purification by treatment with 50 g of ion exchanger Amberlite MB 3 in 96% ethanol. Yield: 2.1 g /10%/.

Elemental analysis are given in table. 3.

Thin layer chromatogram (chloroform/methanol/1 M sodium acetate in 25% ammonia = 70:40:10):Rf=0,43.

Example 5

Internal salt of 2-[[(hexadecylamine)hydroxyphosphonic] oxy]-P,P,P-trimethylphosphine:

< / BR>
Obtain analogously to example 1: 4.6 oz /50 mmol/ phosphorus oxychloride, 10,9 g /45 mmol/ hexadecanol, 16+20 ml of pyridine and 12.1 g /60 mmol/ postcoloniality analysis are given in table. 4.

Thin-layer chromatogram [chloroform/methanol/1 M sodium acetate in 25% ammonia=70:40:10]:Rf=0,43.

Example 6

Internal salt of 2-[[(CIS-13-docosenoic)hydroxyphosphonic] oxy]-P,P, P-trimethylphosphine:

< / BR>
Obtain analogously to example 1: 3.5 ml /38 mmol/ phosphorus oxychloride, and 11.2 g /34 mmol/ erollover alcohol, 12 + 15 ml of pyridine and 9.2 g /46 mmol/ phospholinked. Purification by treatment with 45 g of ion exchanger Amberlite MB 3 in 96% ethanol. Output: 1,9 g /11%/.

Elemental analysis are given in table. 5.

Thin layer chromatogram (chloroform/methanol/1 M sodium acetate in 25% ammonia = 70:40:10):Rf=0,47.

Example 7

Internal salt of 2-[[(octadecylamino)hydroxyphosphonic]oxy]-As, As, As-trimethylethylene:

< / BR>
Obtain analogously to example 1: 3.5 ml /38 mmol/ phosphorus oxychloride, was 9.33 g /35 mmol/ octadecanol, 12 + 5 ml of pyridine and 13.2 g /46 mmol/ triethyl-/2-hydroxyethyl)-Archibald. Purification by treatment with ion exchanger Amberlite MB 3 in 96% ethanol and subsequent column chromatography on silica gel using a mixture of CH2Cl2/CH3OH/25% ammonia = 70: 40:10. Output 3.39 /18%/.

Elemental analysis are given in table. 6.

Thin layer of chromatose)hydroxyphosphonic]oxy]-As As, As-tritylimidazole:

< / BR>
Obtain analogously to example 1: 3.5 ml /38 mmol/ phosphorus oxychloride, 8,43 g /35 mmol/ hexadecanol, 12 + 15 ml of pyridine and 13.2 g /46 mmol/ trimethyl-/2-hydroxyethyl)-Archibald. Purification by treatment with ion exchanger Amberlite MBB in 96% ethanol and subsequent column chromatography on silica gel using a mixture of CH2Cl2/CH3OH/ 25% ammonia=70: 40:10. Output: of 2.26 g /13%/.

Elemental analysis are given in table. 7.

Thin-layer chromatogram /chloroform/methanol/25% ammonia=80:25:5/: Rf=0,57.

Example 9

Internal salt of 2-[[(CIS-13-docosenoic)hydroxyphosphonic]oxy]-As, As, As-tritylimidazole:

< / BR>
Obtain analogously to example 1; 3.5 ml /38 mmol/ phosphorus oxychloride, 11.4 g /35 mmol/ erollover alcohol, 12 + 15 ml of pyridine and 13.2 g /46 mmol/ trimethyl-/2-hydroxyethyl)-Archibald. Purification by treatment with 30 g of ion exchanger Amberlite MBB in 96% ethanol and subsequent column chromatography of silica gel using a mixture of CH2Cl2/CH3OH/ 25% ammonia = 70:4-:10. Output: 4,50 g (22%).

Elemental analysis are given in table. 8.

Thin layer chromatogram (chloroform/methanol/25% ammonia = 80:25: 5)Rf=0,57.

>/BR>Obtain analogously to example 1; from about 4.0 ml /38 mmol/ phosphorus oxychloride, 10.8 g /35 mmol/ octadecanol, 14 + 17 ml of pyridine and 13.2 g /53 mmol/ trimethyl-(2-hydroxyethyl)-Archibald. Purification by treatment with 30 g of ion exchanger Amberlite MBB in 96% ethanol and subsequent column chromatography on silica gel using a mixture of CH2Cl2/CH3OH/ 25% ammonia=70:40:10. Yield: 1.97 g /10%/.

Elemental analysis are given in table. 9.

Thin layer chromatogram (chloroform/methanol/ 25% ammonia=70:40:10): Rf=0,47.

Example 11

Inner salt of 3-[[(hexadecylamine)hydroxyphosphonic]oxy]-As, As, As-trimethylpropane:

< / BR>
Obtain analogously to example 1, from about 4.0 ml /43 mmol/ phosphorus oxychloride, 9.7 g /40 mmol/ hexadecanol, 14+17 ml of pyridine and 13.6 g /53 mmol/ trimethyl-(3-hydroxyethyl)-Archibald. Purification by treatment with 30 g of ion exchanger Amberlite MBB in 96% ethanol and subsequent column chromatography on silica gel using a mixture of CH2Cl2/CH3OH/ 25% ammonia = 70:40:10. Yield: 2.0 g (10%).

Elemental analysis are given in table. 10.

Thin layer chromatogram (chloroform/methanol/ 25% ammonia=70:40:10): Rf =0,47.

Example 12

Internal salt of 3[[(dokis 4,0 ml /43 mmol/ phosphorus oxychloride, 13,0 g /40 mmol/ erollover alcohol, 14+17 ml of pyridine and 13.2 g /53 mmol/ trimethyl-(3-hydroxyethyl)-Archibald. Purification by treatment with ion exchanger Amberlite MBB in 96% ethanol and subsequent column chromatography on silica gel using a mixture of CH2Cl2/CH3OH/ 25% ammonia = 70:40:10. Yield: 2.4 g (11%).

Elemental analysis are given in table. 11.

Thin layer chromatogram (chloroform/methanol/ 25-hydrated ammonia=70:40:10): Rf=0.50 to

Example 13

Inner salt of 3-[[(CIS-13-docosenoic)hydroxyphosphonic] oxy]-P,P, P-trimethylpropane:

< / BR>
Obtain analogously to example 1; from 4.2 ml /45 mmol/ phosphorus oxychloride, 13.8 g /42 mmol/ erollover alcohol, 14+18 ml of pyridine and 12.0 g /56 mmol/ trimethyl-(3-hydroxypropyl)-Archibald. Purification by treatment with 45 g of ion exchanger Amberlite MBB in 96% ethanol and subsequent column chromatography on silica gel using a mixture of CH2Cl2/CH3OH/ 25% ammonia =70:40:10. Output: 2,93 g (13%).

Elemental analysis are given in table. 12.

Thin layer chromatogram (chloroform/methanol/ 1 M sodium acetate in 25% ammonia 70:40:10):Rf=0.25 in.

Example 14

Inner salt of 3-[[(octadecylamino)hydroxyphosphonic] oxy]-P,P,P-trim the ol/ octadecanol, 14+18 ml of pyridine and 12.2 g /56 mmol/ trimethyl-(3-hydroxypropyl)-factorybased. Purification by treatment with 56 g of ion exchanger Amberlite MBB in 96% ethanol and subsequent column chromatography on silica gel using a mixture of CH2Cl2/CH3OH/ 25% ammonia = 70:40:10. Output: 2,27 g /11%/.

Elemental analysis are given in table. 13.

Thin layer chromatogram (chloroform/methanol/1 M sodium acetate in 25% ammonia =70:40:10):Rf=0.50 in.

Example 15

Inner salt of 3-[[(hexadecylamine)hydroxyphosphonic] oxy]-P,P,P-trimethylpropane:

< / BR>
Obtain analogously to example 1; from 4.2 ml /45 mmol/ phosphorus oxychloride, 10.2 g /42 mmol/ hexadecanol, 14+18 ml of pyridine and 12.0 g /56 mmol/ trimethyl-(3-hydroxypropyl)-factorybased. Purification by treatment with 55 g of ion exchanger Amberlite MBB in 96% ethanol and subsequent column chromatography on silica gel using a mixture of CH2Cl2/CH3OH/ 25% ammonia=70:40:10. Yield: 1.86 g (10%).

Elemental analysis are given in table. 14.

Thin layer chromatogram (chloroform/methanol/ 1 M sodium acetate in 25% ammonia =70:40:10):Rf=0.50 in.

Example 16

Inner salt of 3-[[(nonadecanoic)hydroxyphosphonic]oxy]-P,P,P-trimethylethylene, 11 + 4 ml of pyridine and 8,64 g /43 mmol/ phospholinked. Purification by treatment with 25 g of ion exchanger Amberlite MBB in 96% ethanol and subsequent boiling 2 times in acetone. Yield: 1.85 g /12%/.

Elemental analysis are given in table 15.

Thin layer chromatogram (chloroform/methanol/ 1 M sodium acetate in 25% ammonia = 70:40:10:)Rf=0,58.

Example 17

Internal salt of 2-[[(asosiasi-)-hydroxyphosphonic]oxy]-P,P,P-trimethylethylene:

< / BR>
Obtain analogously to example 1; 3.2 ml /35 mmol/ phosphorus oxychloride, 9,63 g /32 mmol/ eicosanol, 11+14 ml of pyridine and 8,64 /43 mmol/ phospholinked. Purification by treatment with 25 g of ion exchanger Amberlite MBB in 96% ethanol and subsequent boiling 2 times in acetone. Yield: 0.02 g (7%).

Elemental analysis are given in table. 16.

Thin layer chromatogram (chloroform/methanol/ 1 M sodium acetate in 25% ammonia = 70:40:10):Rf=0.53 per share.

Example 18

Internal salt of 2-[[(nonadecanoic)hydroxyphosphonic]oxy]-As, As, As-trimethylethylene:

< / BR>
Obtain analogously to example 1; 4,6 ml /50 mmol/ phosphorus oxychloride, 12.8 g /45 mmol/ nonadecanone, 16+20 ml of pyridine and 14.7 g /60 mmol/ arsenomolybdate. Purification by treatment with 55 g ionoobmennaya chromatogram (chloroform/methanol/ 25% ammonia = 80:25: 5):Rf=0.45 in.

Example 19

Internal salt of 2-[[(asosiasi)hydroxyphosphonic] oxy] -As, As, As-trimethylethylene:

< / BR>
Obtain analogously to example 1; 4,6 ml /50 mmol/ phosphorus oxychloride, a 13.4 g /45 mmol/ eicosanol, 16+20 ml of pyridine and 14.7 g /60 mmol/ arsenomolybdate. Purification by treatment with 50 g of ion exchanger Amberlite MBB in 96% ethanol. Output: 2,81 g (12%).

Elemental analysis are given in table. 18.

Thin layer chromatogram (chloroform/methanol/25% ammonia = 80:25:5): Rf=0.45 in.

Example 20

Internal salt of 2-[[(heptadecanoic)hydroxyphosphonic]oxy]-As, As, As-trimethylethylene:

< / BR>
Obtain analogously to example 1; 4,6 ml /50 mmol/ phosphorus oxychloride, 11.5g /45 mmol/ heptadecanol, 16+20 ml of pyridine and 14.7 g /60 mmol/ arsenomolybdate. Purification by treatment with 35 g of ion exchanger Amberlite MBB in 96% ethanol and subsequent mixing in acetone. Yield: 1.20 g (6%).

Elemental analysis are given in table. 19.

Thin layer chromatogram (chloroform/methanol/ 1 M sodium acetate in 25% ammonia = 70:40:10):Rf=0.45 in.

Example 21

Internal salt of 2-[[(octadecylamino)hydroxyphosphonic]oxy]-P,P-diethyl-P-phenyl-ethylphosphonic:

< / BR>
Obtain analogously to example 1; and xitil)-phenyl-factorybased. Purification by treatment with 21 g of ion exchanger Amberlita MBB in 96% ethanol and twice recrystallized from acetone.

Output: 1,76 g (13%).

Elemental analysis are given in table. 20.

Thin layer chromatogram (chloroform/methanol/ 25% ammonia - 80:25: 5):Rf=0,37.

Example 22

Internal salt of 2-[[(CIS-13-docosenoic)hydroxyphosphonic]oxy]-P,P-diethyl-P-phenyl - ethylphosphonic:

< / BR>
Obtaining analogous to example 1 from 2,3 ml /25 mmol/ phosphorus oxychloride, 8.6 g /27 mmol/ erollover alcohol, 8 + 10 ml of pyridine and 7,28 g /27 mmol/ diethyl-(2-hydroxyethyl)-phenyl - factorybased. Treated with 30 g of ion exchanger Amberlita MBB in 96% ethanol and crystallized from acetone. Output: 2,53 g (17%).

Elemental analysis are given in table. 21.

Thin layer chromatogram (chloroform/methanol/ 25% ammonia = 80:25: 5):Rf = 0,37.

Example 23

Internal salt of 2-[[[(4'-dodecylthiomethyl)metiloksi]hydroxyphosphonic] oxy]-As, As, As-trimethylethylene:

< / BR>
Obtain analogously to example 1; 2.4 ml /26 mmol/ phosphorus oxychloride, 6.50 g /23 mmol/ dodecyltrichlorosilane, 9 + 12 ml of pyridine and to 7.59 g /31 mmol/ arsenomolybdate. Purification by treatment with 30 g of ion exchanger Amberlita M is L. 22.

Thin layer chromatogram (chloroform/methanol/1M/sodium acetate in 25% ammonia = 70:40:10) : Rf = 0,37.

Example 24

1-O-Octadecyl-2-O-methyl-rat-glycerophosphorylcholine:

< / BR>
Obtain analogously to example 1; 3.0 ml /33 mmol/ phosphorus oxychloride, 10.8 g /30 mmol/ 1-O-octadecyl-2-O-methyl-rat-glycerine, 11 + 13 ml of pyridine and 9.8 g /40 mmol/ arsenomolybdate. Purification by treatment with 55 g of ion exchanger Amberlita MBB in 96% ethanol and mixing with acetone. Output: of 5.83 g /33%/.

Elemental analysis are given in table. 23.

Thin layer chromatogram (chloroform/methanol/1M sodium acetate in 25% ammonia = 70:40:10):Rf = 0,57.

Example 25

1-O-Octadecyl-2-O-methyl-rat-glycerophosphocholine:

< / BR>
Obtain analogously to example 1; 4,6 ml /50 mmol/ phosphorus oxychloride, 16,1 g /45 mmol/ 1-O-octadecyl-2-O-methyl-rat-glycerine, 16 + 20 ml of pyridine and 12.1 g /60 mmol/ phospholinked. Purification by treatment with 45 g of ion exchanger Amberlite MBB in 96% ethanol and mixing with acetone. Output: 6,25 g /26%/.

Elemental analysis of the above table. 24.

Thin layer chromatogram (chloroform/methanol/1M sodium acetate in 25% ammonia = 70:40:10):Rf = 0.52 in.

Example 26
2Cl2/CH3OH/ 25% ammonia = 80:25:5. Containing products fraction is treated with diethyl ether and concentrated. Yield: 1.0 g /8%/.

Elemental analysis are given in table. 25.

Thin layer chromatogram (chloroform/methanol/1M sodium acetate in 25% ammonia = 70:40:10):Rf = 0,62.

Example 27

Octadecyl-/2-(A-methylarginine)-ethyl/-phosphate

< / BR>
The synthesis of compounds of the above formula is carried out as described in example 1. Take of 0.32 ml (3,50 mmole) of phosphorus oxychloride, 0.87 g (3,50 mmole) octadecanol, 11+14 ml of pyridine and 1.22 g (4,28 mmole) of 1-methyl-1-(2-hydroxyethyl)Arsenio-bromide. Purification is carried out by treatment with an ion exchanger Amberlite MB 3 which is taken in the amount of 2.5 g of 96% ethanol. Then carry out a chromatography on a column filled with silica gel, CH2Cl2/CH3OH/ 25% aqueous ammonia (70:40:10).

Yield 160 mg (10%).

Elemental analysis are given in table. 26.

Temperatu ammonia. 70:40:10). Rf=0,83.

According to the method described in example 1, the compound obtained of General formula I:

< / BR>
Name of compound (D-51117):

Internal salt of 2-[[(octadec-9-in-1 yloxy)hydroxyphosphonic]oxy]-P,P, P-trimethyl-ethylphosphonic.

Physico-chemical data for this connection:

Elemental analysis (D-51117 1,5 H2O) are given in table.27.

Rf= 0,50 (SiO2CH2Cl2/CH3OH/1M NaOAc in 25% of NH4OH 70:40:10) NMR (chemical shift Delta in ppm) (500 MHz, CDCl3) to 0.85 (3H, t, -CH3), of 1.30 (18H, m, -(CH2)n-), 1,45 (4 H, m, -CH2-CC-CH2-), of 1.57 (2H, p-CH2-), 2,12 (9H, d, -P+(CH3)3), a 2.75 (2H, m, -CH2-P+), of 3.78 (2H, q, CH2-OP(= O)(01-)-O-), 4,22 (2H, m, -O-P(=O)-O-CH2-C-P+).

The results of the biological tests are presented in table. 28.

Results suppression of leishmaniasis in vitro when used ALPs are presented in table. 29.

Description of the methods and results of tests for biological activity.

Ethers, lipids are an important class of membrane lipids at the leishmaniases and are used for fixing the coding glycolipids (e.g., LPG, GJPLS and so on) and glycoproteins (e.g., GP63) promastigotes and amastigotes cell blockin (HE-PC) on leishmaniosis metabolism, because it was assumed that such synthetic analogues are a new class of anticancer drugs and activate the metabolism of ethers of lipids and membrane function in cancer cells.

Protivolakozna in vitro activity of a number of analogues of ethers of lipids was compared with the activity of simple and complex esters of natural origin, as well as with the activity of already known drugs. Investigated the effects of infection with Leishmania mexicana and Leishmania donovani at the stage promastigotes on the skin and internal organs. After 24 hours of treatment Leishmania mexicana for different medicines obtained the following values LD50(ág/ml):

Pentostam >100; pentamidine 2,0; aminosidine 10,0; ester lipid 2-LPC 45,0; simple ether lipid Lpaf 27,0; analogues of simple ether lipid: 18 ET OCH31,5; ET PA >128; HE PC 2,0; compounds according to the invention:

in example 1 1,5

in example 4 0,7

in example 18 0,8

Activity against leishmaniasis all but one analogues of ethers of lipids was significantly higher than that of pentostam and aminosidine and almost the same activity pentamidine. On the contrary, complex and simple esters of lipids of natural origin 2-LPC and L-Paf demonstrator ether lipid ET PA was > 60 times less active than its structural homologues ET 18 OCH3or HE PC, suggesting the existence of a dependence of cytotoxicity on the structure in the studied class of complex and simple ether lipids.

Activity in vitro of this new class of drugs against leishmaniasis highly comparable and with the defeat of the skin, and when the lesion of the internal organs, and as in the case of intracellular amastigote, and in the case of extracellular promastigote. Thus, it can be considered confirmed the assumption about the mechanism of action, namely the activation of biosynthesis through the ethers of lipids and on the mechanism of signal transduction - RKS-braking.

Example 28 (capsules 100 mg)

Take 1000 g of one of the compounds according to the invention, and 684 g of lactose monohydrate GIVING 10, 345 g of microcrystalline cellulose HAVING 10, 60 g of talc, 15 g of highly disperse silica gel GIVING 10 and 6 g of magnesium stearate, sieved through a sieve with a mesh size of 0.8 mm and then mixed in the mixer for 45 minutes.

On 276 mg of this mass was dosed out on capsulotomy car in capsules of gelatin size 1. Each capsule contains 100 mg of the compounds according to the invention.

The mass is stirred in a suitable mixer for 10 minutes and then add 0.4 g of magnesium stearate, which is also pre-sifted through a sieve of 0.8 mm, the Mixture is again stirred for 5 minutes. The resulting tablets weight tabletirujut on tabletting machine into tablets with a diameter of 8 mm and a weight of 180 mg

1. Derivatives of phospholipids of the General formula I

< / BR>
where R5denotes a linear or branched C10- C24is an alkyl residue, which can contain from one to three double and/or triple links;

A represents a simple bond or one of the groups of formulae II - VI

- CH2- CH2- CH2- O - II

- CH2- CH2- O - III

< / BR>
< / BR>
< / BR>
and R7denotes a linear C1- C4is an alkyl group and group II - VI is oriented so that the oxygen atom is linked to the phosphorus atom of the compound I;

X denotes an oxygen atom or sulfur;

A1denotes a linear or branched C2- C10is an alkyl residue;

R6does

<, inany, branched or cyclic C1- C6-alkyl residue, or two residue can form a loop, while Y represents P, As, Sb or Bi.

2. Connection on p. 1 with antitumor and/or protivolakoznoe activity.

3. The method of obtaining compounds of General formula I

< / BR>
where R5, X, A, A1and R6have the values listed in paragraph 1,

characterized in that they are subjected to the interaction of the compound of General formula VII

R5- X - A - H, VII

where R5, X and A have the meanings specified in paragraph 1,

with phosphorus oxychloride in the environment of a solvent or in his absence, the resulting product is then subjected to interaction with the compound of General formula VIII

HO - A1- R6,

where A1and R6have the values listed in paragraph 1,

and then carry out the hydrolysis.

4. The method according to p. 3, characterized in that the resulting product is treated with H-OH-exchanger (co-H-OH-inromania), either simultaneously or sequentially acidic and/or basic ion exchanger.

5. Pharmaceutical composition having antitumor and/or protivolakoznam action, containing as active principle at craineau composition, having antitumor and/or protivolakoznam action, comprising mixing an effective amount of one or more compounds of General formula I on p. 1 with one or more pharmaceutically acceptable targeted supplements and subsequent processing of the resulting mixture in a conventional dosage form.

 

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1 ex

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SUBSTANCE: claimed method includes interaction of mixtures of natural phosphatides or components thereof, for instance, soybean or egg lecithin or animal phospholipids, or synthetic phosphatides, by reaction thereof with D phospholipase having transphosphatidylase activity in water medium.

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FIELD: medicine.

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54 cl, 25 dwg, 15 ex

FIELD: chemistry.

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EFFECT: design of methods of producing phospholipids, which avoid use of chromatography.

22 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to application for production of medication for prevention and/or treatment of radiolesion or lesion of trisubstituted glycerol compound, corresponding to formula where X is selected from phosphate and sulfate; R1 is selected from C16-C20alkyl, R2 is selected from C1-C3alkyl and C1-C3hydroxyalkyl, R3 is selected from hydrogen and C1-C3 alkyl, R4 is selected from C1-C3alkyl and C3-C6cycloalkyl, R5 is selected from hydrogen and methyl, or its enantiomer, or diastereomer, or pharmaceutically acceptable salt, and at least one pharmaceutically acceptable filling agent.

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12 cl, 3 dwg, 5 ex, 5 tbl

FIELD: chemistry.

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EFFECT: method enables to obtain a human breast milk substitute by processing readily available material and use thereof to make infant formula.

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FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmaceutical compositions containing synthetic oxidised lipids.

EFFECT: developing the method for using the oxidised lipids for treating and preventing the inflammation associated with the endogenous oxidised lipid.

39 cl, 11 tbl, 15 ex, 25 dwg

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