Soluble in water phosphonoacetate the difficult esters of alcohols or phenols, the pharmaceutical compositions based on them, the method of anesthesia and the treatment of neoplastic diseases

 

The invention relates to new water-soluble postneoliberalism the difficult esters of alcohols and phenols. Describes phosphonoacetate esters of formula I:

where R-O - is a residue of pharmaceutical compounds containing alcohol or phenol, with the exception of Taxol and Taxol derivatives, R1is hydrogen or an alkali metal ion or a protonated amine, or protonated amino acid2is hydrogen or an alkali metal ion or a protonated amine, or protonated amino acid, n is an integer 1 or 2; m is an integer and has a value of at least 1; and their pharmaceutically acceptable salts. It also describes the intermediate compounds and methods for their preparation, pharmaceutical composition having anastasiadis action, a pharmaceutical composition having antitumor activity, the method of anesthesia and the treatment of neoplastic diseases. The technical result - the present invention provides a water-soluble form of medication, containing alcohol and phenol. 11 N. and 9 C.p. f-crystals, 4 Il.

The present invention against the aromatic difficult hydroxyl group. In particular, the present invention relates to new water-soluble phosphonoacetate esters of pharmaceutical preparations containing sterically-hindered alcohol or phenol, such as camptothecin, propofol, etoposide, vitamin E and cyclosporine A. the Present invention also relates to intermediate products used to obtain the final prodrugs, as well as to pharmaceutical compositions containing the new compounds.

Successful delivery to the patient a pharmaceutical preparation is extremely important in the treatment of diseases. However, the use of many proven in the clinic drugs with known properties is limited due to their very low solubility in water. Because these drugs have low solubility in water, they must be incorporated with sarestoniemi pharmaceutical excipients, including surfactants. These surfactants have been shown to cause side effects in humans, which limits the safety of these drugs in clinical conditions and their use for the treatment of several diseases.

For example, camptothecin is a natural product isolated from the bark of the Chinese is o, conducted in several animal models, in relation to the main types of tumors, such as tumors of lung, breast, ovary, pancreas, colon and stomach cancer, and malignant melanoma. Camptothecin inhibits cell enzyme DNA topoisomerase I and induces a cascade of reactions leading to apoptosis and programmed cell death. Topoisomerase I is a vital enzyme in the nucleus of the cell, responsible for the organization and modulation of the topological structure of DNA, which determines the ability of cells to reproduce, transcriptio and restoration of genetic information.

A serious disadvantage of camptothecin is its extremely low solubility in water. In order to carry out biological tests, it is necessary to dissolve the compound in a strong organic solvent (DMSO) or to make the drug in the form of a suspension in Tween 80: saline solution, which is undesirable when therapeutic treatment of humans. Recently in the United States were approved two analog camptothecin with medium solubility in water for the treatment of progressive ovarian cancer (Cosmegen, Hycamtin) and kolorektalnog disadvantages, are cyclosporine A (CsA), propofol, etoposide and Vitamin E (alpha-tocopherol). Similar to camptothecin, CsA has within its structure sterically hindered alcohol, in this case it is a secondary alcohol. CsA is administered in the composition of the mixture of Cremophor EL/ethanol.

An example of a sterically constrained, poorly water-soluble phenol is propofol representing the anesthetic.

Propofol prepared for intravenous clinical use in vivo in the form of an emulsion oil/water. Propofol is not only poorly soluble in water, but it also causes pain at the injection site. This pain can be reduced by using lidocaine. Due to the fact that propofol used in the form of an emulsion, it becomes difficult and challenging introduction to the composition of other medications, however, changing the physical properties of the composition, such as increasing the size of the droplets of oil may result in lung embolism, etc. are Soluble in water and chemically stable prodrug of propofol may provide some advantages. Such a composition could be a simple aqueous solution, which could be mixed with other drugs. If PraxisNote, due to the media. Other difficultly soluble in water steric hampered by Fanelli representing anticancer drugs are etoposide and Vitamin E (alpha-tocopherol).

The present invention provides a water-soluble form of medication, containing alcohol or phenol, such as camptothecin or propofol. As camptothecin, the compounds according to the present invention represent his phosphonoacetate esters in the form of the free acids and their pharmaceutically acceptable salts. The solubility of the acids and salts facilitates the preparation of pharmaceutical compositions. All prodrugs according to the present invention exhibit superior solubility in water compared with the corresponding original drug. Methods developed for compounds of the present invention can be useful for turning and many other water-insoluble medical agents, with aliphatic or aromatic difficult hydroxyl group, in their water-soluble derivatives.

This invention comprises new compositions. The invention relates to water-soluble postneoliberalism derived farmacevt>

The above formula I is a derivative of ROH, where ROH is a medicine containing alcohol or phenol, such as camptothecin, propofol, etoposide, vitamin E and cyclosporine A. In the above formula I, n represents the integer 1 or 2. When n has the value 2, ROH is preferably a phenolic pharmaceutical product, such as propofol. Also this may include some drugs, for which it is impossible to prepare a form for injection due to their inherent very low solubility in water. These include danazol, methyltestosterone, ethenol, atovaquone (danazol, methyltestosterone, iodoquinol, atovaquone). R1represents hydrogen or an ion of an alkali metal including sodium, potassium or lithium, or a protonated amine or protonated amino acid or other pharmaceutically acceptable cation. R2represents hydrogen or an ion of an alkali metal including sodium, potassium or lithium, or a protonated amine or protonated amino acid or other pharmaceutically acceptable cation. After intravenous or oral administration derivatives of the formula I turned back into the original drugs through hydrolysis and/or with the help of the drugs in the water, which show good activity and solubility in water.

Another objective of the present invention to provide pharmaceutical compositions based on water-soluble compounds, which contain a certain amount of the compounds of formula I and a pharmaceutically acceptable carrier.

In addition, the present invention is to develop a derivative drugs, having good stability at pH levels, suitable for the manufacture of pharmaceutical compositions, but quickly collapsing in vivo under dastem physiological conditions, i.e., potentially acting as prodrugs.

Brief description of drawings

Fig.1 illustrates the enzymatic conversion of prodrugs of propofol in propofol in vitro.

Fig.2 illustrates the change in the concentration of propofol in the blood over time, starting with the introduction of the prodrug of propofol or Diprivanin experiments on dogs.

Fig.3 illustrates the enzymatic conversion of prodrugs of camptothecin in camptothecin in experiments in vitro.

Fig.4 illustrates the relationship between the concentration of camptothecin in the plasma of prodrugs of camptothecin and camptothecin in organic cosolvent in experiments on rats.

Detailed product description product the and, following definitions are used.

"Phosphono-" means the group-P(O)(OH)2and phosphonoacetate" or "phosphonoacetate ether" means, generally, a group-och2The OP(O)(OH)2. "Methylthiomethyl" refers to the group-CH2SCH3. The present invention also encompasses compounds in which n=2, so that "phosphono-di(oxymethyl) ether" in General means a group-och2Och2The OP(O)(OH)2.

The definition of "the rest of camptothecin" means the residue containing the inner frame camptothecin with twenty carbon atoms, including two nitrogen atom and four oxygen atom, as shown below, in the above structural formula with absolute configuration.

The numbering system above, is a system used for the corresponding derivatives of camptothecin, and it is used throughout the description. For example, the definition C20 refers to the carbon atom number "20".

The definition of "similar camptothecin" refers to the connection of the inner frame camptothecin. It should be clear that the analogues of camptothecin cover compounds, including, but not limited to, the following: topotecan (Topotecan), coming from facin (9NC), GI 147211, coming from company Glaxo Wellcome, and DX-8951f (the previous six analogues camptothecin currently undergoing clinical trials and they are described in a review published in the Pacific West Cancer Fund by author Claire McDonald (December 1997).

In addition, several other analogues of camptothecin, also not limiting analogues included in the description by referencing Sawada et al., Current Pharmaceutical Design, Vol.1, No. 1, pp 113-132, and US patents 5646159, 5559235, 5401747, 5364858, 5342947, 5244903, 5180722, 5122606, 5122526, 5106742, 5053512, 5049668, 4981968 and 4894456.

Several pharmaceutical compounds, including related derivatives camptothecin contain more than one hydroxyl group, such as 10-hydroxycamptothecin, topotecan, and some others listed in the above links. It should be clear that the present invention can be applied to more than one hydroxyl group. In this case, it can be made by introducing protection for additional hydroxyl group before the formation of a derivative.

The definition of "phosphonate group" means residues, which can be used to block or protect the functional phosphonopropyl. Preferably, such protective groups include groups that m is phosphonoacetate groups include, for example, benzyl (denoted "EAP"), tert.-boutelou, allyl group.

The definition of "pharmaceutically acceptable salt" means a salt of the metal or amine salt of acid phosphonopropyl, in which the cation does not make a significant contribution to the toxicity or biological activity of active substances. Suitable metal salts include lithium, potassium, sodium, calcium, barium, magnesium, zinc and aluminum salts. The preferred salts are sodium and potassium salts.

Suitable salts of amines are, for example, salts of ammonia, tromethamine, triethanolamine, Ethylenediamine, glucamine, N-methylglucamine, glycine, lysine, ornithine, arginine, ethanolamine and these are just a few examples. Preferred salts of amines are the salt of lysine, arginine, N-methylglucamine, and tromethamine.

In the description and in the claims the term-och2The OP(O)(OH)2as the implies, covers both concepts and the free acid and its pharmaceutically acceptable salts, unless the context indicates specifically that means only the free acid.

One aspect of the present invention provides derivatives of pharmaceutical preparations containing alcohol and phenol, as shown in formula I: the STU reactions presented in figure 1:

Scheme 1

where ROH is a medicine containing alcohol or phenol, such as camptothecin, propofol, etoposide, vitamin E, cyclosporine A. it Should be clear that the above path is one of the alternative paths. Alternative routes will become apparent when their disclosure in the description and in the examples.

The above scheme can be illustrated by using the connection of camptothecin. It should be understood that these regimens are applicable for other compounds covered by formula I and the above, in accordance with the present invention. Accordingly, another aspect of the present invention is the provision of analogues of camptothecin according to the formula II:

which include the free acid, where Z represents hydrogen, and their pharmaceutically acceptable salts, where Z is a metal or amine.

Alternative formula II includes decollate, where Z is a metal or amine in both cases.

Predpochtitelnye pharmaceutically acceptable salts of the compounds of formula II are alkali metal salts, including lithium, sodium and potassium salts; and salts of amines, including the most preferred embodiment of the invention derivatives of camptothecin formula II include the following compounds:

(20)-O-phosphonomethylglycine, (20)-O-phosphonomethylglycine mono - or disodium salt, (20)-O-phosphonomethylglycine mono - or dikalova salt, (20)-O-phosphonomethylglycine mono - or VIRGINIAVA salt, (20)-O-phosphonomethylglycine mono - or Deliziosa salt, (20)-O-phosphonomethylglycine mono - or di-N-methylglucamine salt and (20)-O-phosphonomethylglycine mono - or garitaonandia salt.

The compounds of formula II can be obtained directly from camptothecin (shown as ©-HE) in accordance with the sequence of reactions shown in scheme 2:

Scheme 2

The compound of formula III (methylthiomethyl ether, MTM ether) can be obtained by processing camptothecine the sulfoxide /acetic anhydride/acetic acid.

In the second stage of the process represented in scheme 2, methylthiomethyl ether is converted into the corresponding protected phosphonoacetate ether (compound of formula (IV). This stage is carried out by processing MTM ether N-iodosuccinimide and protected phosphate NORD(O)(OR)2. At the third stage phosphono protective group is removed, resulting in the compounds of formula II. For example, suitable zasoby the process of obtaining the compounds of formula (1) according to scheme 2 in more detail is shown in figure 3.

Scheme 3

In the first stage of the free hydroxyl group of camptothecin turn to the appropriate methylthiophenyl group (-och2SC3). This transformation can be carried out by reaction with dimethylsulfoxide in the presence of acetic anhydride and acetic acid. This method, known as reaction Pummer (Pummer reaction), was successfully applied Bristol-Myers Squibb for methyldiethylamine Taxol (EP 0604910 A1, Bioorg. Med. Chem. Lett., 6, 1837, 1996). Usually, to obtain methylthiomethyl ether the reaction is carried out at room temperature for 24-72 hours.

In the second stage of the reaction chain methylthiomethyl ether is converted into the corresponding protected phosphonoacetate ether. It is a well known transformation was applied successfully Bristol-Myers Squibb for phosphonomethylglycine Taxol (EP 0604910 A1, Bioorg. Med. Chem. Lett., 6, 1837, 1996). Thus, the compound of formula III is treated with N-iodosuccinimide and protected phosphoric acid, such as Dienzenhofer. The reaction is carried out in an inert organic solvent, such as tetrahydrofuran, and halogenated hydrocarbons such as methylene chloride and in the presence of molecular sieves. N-Iodosuccinimide and protected phosphoric acid and the chain protective phosphonic group are removed. Removing the protection is carried out using known from the prior art methods, such as catalyzed by alkaline or acid hydrolysis, hydrogenolysis, recovery and the like. For example, catalytic hydrogenolysis can be used to remove the benzyl phosphonoacetic groups. Description of methods of remove protection can be found in various handbooks, such as T. W. Green and P. G. M. Wutz, Protective groups in organic synthesis, J. Wiley publishers. New York, NY, 1991, pp.47-67.

Basic salts of the compounds of formula II can be formed using any of the available methods, including the interaction of the compounds of formula II in the form of the free acid with a metal base or an amine. Suitable base metals include hydroxides, carbonates and bicarbonates of sodium, potassium, lithium, calcium, barium, magnesium, zinc and aluminum; and suitable amines include triethylamine, ammonia, lysine, arginine, N-methylglucamine, ethanolamine, procaine, benzathine, dibenzylamine, tromethamine (TRIS), chloroprocaine, choline, diethanolamine, triethanolamine and the like. Basic salt can be further purified chromatography followed by lyophilization or by crystallization.

Compounds in accordance with the present invention are phosphonoacetate EPE is Cesky acceptable salts, they show improved water solubility compared to the parent compounds, thus allowing to obtain a more suitable pharmaceutical compositions. Although this has not been confirmed theoretically, however, it appears that phosphonoacetate esters in accordance with the present invention are prodrugs of the original pharmaceutical products; phosphono-exatly the residue is cleaved upon contact with phosphatase in vivo, with subsequent generation of the initial (parent) connection. As shown above, the compounds of the present invention are effective pharmaceutical and therapeutic agents.

For example, the compounds of formula II in accordance with the present invention can be used similarly to camptothecin. Structure prodrug of camptothecin presented above. Thus oncologist, a specialist in the field of cancer treatment will be able to determine without additional experiments, suitable treatment is the use of compounds in accordance with the present invention. Dosage, method, and schedule of administration of the compounds according to the invention are not strictly defined and will vary depending on when the on; the dose may, for example, be in the range from about 0.1 to about 100 mg/kg body weight or from about 5 to 500 mg/m2. The compounds of formula II may be introduced orally; oral dose may be in the range from about 5 to about 500 mg/kg body-weight. The dose used in practice may vary depending on the specific composition, route of administration, as well as the specific location of lesions, the master carrier and the type of tumor, which is subjected to the treatment. When determining the dosage taken into account the many factors that influence the activity of drugs that include age, gender, diet and physical condition of the patients.

Another example is the prodrug of provola having the formula I of the present invention. Structure prodrug of provola below:

In the above formula prodrugs of provola Z has the values that are represented in the above formula II. Thus, the anaesthetist, a specialist in the field of anaesthesia, is able to determine, without additional experiments, the appropriate timing of introducing the compounds of the present invention. Dosage, method, and timing of introducing connections at izobreteniya formula I, such a prodrug of provola may be introduced by any suitable means, preferably parenterally; the dose may, for example, be in the range from about 0.5 to about 10 mg/kg, administered in accordance with input methods General anesthesia or maintain a period of General anesthesia. On the other hand, the compound of formula I may be introduced by parenteral injection, in this case, the dosage may, for example, be in the range from 2 μg/kg/min up to 800 µg/kg/min in the introduction according to the methods that exist to maintain the period of General anesthesia, initiating and maintaining MAC or ICU sedation.

The present invention also provides a pharmaceutical composition comprising a pharmaceutically effective amount of the compounds of formula I in combination with one or more pharmaceutically acceptable carriers, eccipienti, diluents or adjuvants. For example, the compounds in accordance with the present invention can be introduced into the formulations in the form of tablets, pills, powders, capsules, injections, solutions, suppositories, emulsions, dispersions, food additives and other suitable forms. They can be made in the form of sterile solid compositions, for example, liofilizat to be diluted with sterilized water, physiological saline solution or a mixture of water and an organic solvent, such as propylene glycol, ethanol and the like or other sterile environment for injection immediately before parenteral administration.

Conventional pharmaceutically acceptable carriers are, for example, mannitol, urea, dextrans, lactose, not restored sugar, potato and maize starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethylcellulose, poly(vinyl pyrrolidone), calcium carbonate, etiloleat, isopropylmyristate, benzyl benzoate, sodium carbonate, gelatin, potassium carbonate, salicylic acid. Pharmaceutical compositions may also contain non-toxic auxiliary substances such as emulsifying agents, preservatives, wetting agents and the like, as for example, monolaurate sorbitol, triethanolamine, polyoxyethylene, monostearate, glyceryltrinitrate, dioctylsulfosuccinate, vegetable oils, polyalkylene glycols, ethylcellulose, poly(vinyl pyrrolidone), calcium carbonate, etiloleat, isopropylmyristate, benzyl benzoate, sodium carbonate, gelatin, potassium carbonate, silicic acid. Pharmaceutical compositions may also include non-toxic additives, the lithate of sorbitol, the triethanolamine oleate, monostearate polyoxyethylene, tripalmitin glycerin, sodium dioctylsulfosuccinate and the like.

The following experimental part all temperatures are Celsius (C), unless explicitly. Spectral characteristics in accordance with nuclear magnanim resonance (NMR) belong to the chemical shift (), expressed in parts per million (ppm) relative to tetramethylsilane was (TMS) as a standard. The relative area defined for various shifts in the spectral data of proton NMR, corresponds to the number of hydrogen atoms contained in each functional group in the molecule. The nature of the chemical shift related to the multiplicity is indicated as a broadened singlet (BS), broadened doublet (dB), broadened triplet (BT), broadened Quartet (BKV), singlet (s), multiplet (m), doublet (d), Quartet (q), triplet (t), doublet of doublet (DD), doublet of triplet (dt), and doublet of Quartet (DQC). To remove the NMR spectra of the used solvent, such as acetone-d6(deuterated acetone) DMSO-d6(predeterminedthreshold), D2O (deuterated water), l3(deuterochloroform) and other suitable deuterated resthouse:

MS (mass spectrometry); HRMS (mass spectrometry high resolution); AC (acetyl); Ph (phenyl); FAB (strong atomic bombing); min (minutes); h or hrs (h(si)); NIS (N-iodosuccinimide); DMSO (dimethylsulfoxide); THF (tetrahydrofuran).

The following examples are intended to illustrate the synthesis of the most characteristic compounds in accordance with the present invention, however, they should not be regarded as limiting the scope of the invention in any way. Specialist in this field can take the following methods at no additional eksperimentirovaniya on the synthesis of compounds included in the scope of the present invention, but are not disclosed in this description. For example, in the above examples, some salt, but the salt should not be considered as limiting. This is illustrated by the fact that everywhere repeated application of silver salts dibenzylamine. At the same time can be used instead of the silver salt, other salts, as salts of Tetramethylammonium or other salts of alkali metals.

EXAMPLES

1. Synthesis of O-Phosphonoacetate

Ia. Synthesis of O-methylthiotetrazole:

To a stirred suspension of Hydra is giving more than 15 minutes propofol (1.1 ml 97%, 5.7 mmol). Then the reaction mixture was stirred at room temperature for an additional 30 minutes. Then to this mixture is added dropwise chlorodimethylsilyl (550 μl of 95%, 6.2 mmol) and then stirred at room temperature. After 20 hours the reaction mixture is distributed under stirring between water (10 ml) and benzene (20 ml). The aqueous layer was separated and extracted with benzene (10 ml). Benzene fraction unite, washed with water (23 ml), dried over sodium sulfate and evaporated under reduced pressure. The obtained oily residue purified by column chromatography (silica gel, hexane, then 4:1 hexane/chloroform), giving 1,15 g (85% yield) of the named compound as a colourless oil.

EIMS: [M+] m/z 238.

1H NMR (300 MHz, CDCl3,): 1.24 (d, J=6.9 Hz, M), 2.37 (s, 3H). 3.37 (hept, J=6.9 Hz, 2H), 4.86 (s, 2H), 7.12 (s, 3H).13With NMR (75 MHz, CDCl3,): 15.40, 23.98, 26.68, 78.12, 124.04, 125.05, 141.74, 152.20.

Ib. Synthesis of O-chloromethylpyridine:

To a stirred solution of O-methylthiotetrazole (3.00 g, 12.5 mmol) in dry methylene chloride (30 ml), which is kept in an argon atmosphere, add a 1M solution of SO2Cl2in symes stirred for 10 minutes at the same temperature and then for three hours at room temperature. The solvent is evaporated under reduced pressure and the brown residue in the form of oil purified using flash chromatography on a column (silica gel, 1:20 hexane/ethyl acetate), giving 2.36 g (83% yield) of the named compound as a yellow oil.

CIMS (NH3):[M]+m/z 226, [MH+NH3]+m/z 244.

1NMR (300 MHz, CDCl3,): 1.22 (d, J=6.9 Hz, M), 3.35 (hept, J=6.9 Hz, 2H), 5.76 (s, 2H), 7.15 (m, 3H).13With NMR (75 MHz, CDCl3,) 23.93, 26.84, 83.34, 124.34, 125.95, 141.34, 150.93.

IC. Synthesis of dimensional ether O-phosphonoacetate (path-1):

A mixture of O-chloromethylpyridine (2.20 g, 9.7 mmol), dibenzylamine silver (3.85 g, 10.0 mmol) and dry toluene (50 ml) is heated under reflux in an argon atmosphere for 45 minutes. The mixture is then cooled to room temperature and filtered.

After the solvent is evaporated in vacuum, the oily residue purified using flash chromatography on a column of silica gel (9:1 hexane/ethyl acetate and then 1:1 hexane/ethyl acetate), giving 4.43 g (98% yield) of the named compound as a yellow oil.

CIMS (NH3): [MN]+m/z 469, [MN+ NH3]+m/z 486.

1H NMR (300 MHz, CDCl3,): 1.17 (d, J=6.8 Hz, N), 3ub>,): 23.79, 26.57, 69.15, 69.23, 94.14, 94.20, 124.07, 125.62, 127.70, 128.44, 135.42, 135.51, 141.50,151.07.

IC. Synthesis of dimensional ether O-phosphonoacetate (alternative path 1)

To a stirred solution of O methylthiotetrazole (1.45 g, 6.08 mmol) in dry methylene chloride (15 ml) in an argon atmosphere at 0-5To add a 1M solution of SO2Cl2. in dry methylene chloride (6.5 ml, 6.5 mmol) over five minutes. The reaction mixture is stirred for 10 minutes with 5And three hours at room temperature. The solvent is then evaporated under reduced pressure. The remaining oil is dissolved in toluene (ACS grade, 20 ml), add dimensionful silver (3.50 g, 9.1 mmol) and the resulting mixture is heated under reflux for 45 minutes. The brown reaction mixture is cooled to room temperature and filtered. The solvent is then evaporated in vacuum, the oily residue purified by column chromatography (9:1 hexane/ethyl acetate, then 1:1 hexane/ethyl acetate), giving 2.41 g (85% yield) of the named compound as a yellow oil. The compound obtained has the same Rf(TCX) and1NAMR spectrum (300 MHz, l3that reliable 0167.gif">

To a stirred suspension of sodium hydride (41 mg, 60% dispersion in mineral oil, 1.02 mmol) in dry dimethoxyethane (1.5 ml) in an argon atmosphere is added dropwise to propofol (200 μl, 97%, 1.04 mmol) over 5 minutes and the resulting mixture was stirred for additional 15 minutes. The obtained homogeneous solution is added dropwise to a stirred solution chloroiodomethane (4.0 ml, 53 mmol) in dry dimethoxyethane (4 ml) over 15 minutes. The reaction mixture is stirred for two hours, filtered and then the solvent and excess chloroiodomethane evaporated. The remaining oil is dissolved in toluene (HPLC-grade, 10 ml). To the specified solution add dimensionful silver (400 mg, 1.04 mmol) and the resulting mixture is heated under reflux for 10 minutes. Then the reaction mixture is cooled to room temperature and filtered, the solvent evaporated in vacuum. The oily residue is purified using flash chromatography on a column of silica gel (9:1 hexane/ethyl acetate and then 1:1 hexane/ethyl acetate), giving 205 mg (42% yield) of the named compound as a yellow oil. The resulting product has the same Rf(TCX) and1NAMR spectrum (300 MHz, Dl3that authentic sample.

In relation to the above reaction Sa, can be used with other reagents. For example, when you need the connection of the formula I n=2, chloridometer can be replaced by such a connection, as X-CH2-O-CH2-CL, where X is easily tsepliaeva group.

IC. Synthesis of dimensional ether of O phosphonoacetate (alternative path - 3):

To a stirred solution of o methylthiotetrazole (91 mg, 0.38 mmol) in dry methylene chloride (2 ml) in an argon atmosphere add powdered activated molecular sieves 4 A(100 mg) and then a solution of dibenzylamine (127 mg, 0.45 mmol) and N-iodosuccinimide (102 mg, 95%, 0.43 mmol) in tetrahydrofuran (2 ml). The reaction mixture was stirred at room temperature for one hour, filtered and diluted with methylene chloride (30 ml). The resulting solution was washed with sodium thiosulfate solution (2 ml of 1M solution), saturated sodium hydrogen carbonate solution (3 ml), brine (5 ml), dried over a mixture of sodium sulfate and magnesium sulfate, filtered and concentrated in vacuo. The oily residue is purified by column chromatography on silica gel (1:1 hexane/ethyl acetate), giving 120 mg (67% yield) of the named compound as a yellow oil. The resulting product has the same Rf(TCX) and1 is dipropiona

To a solution of propofol (38 mg, 97%, 0.21 mmol) in methylene chloride (1 ml) is added tetrabutylammonium bromide (10 mg, 0.03 mmol) and sodium hydroxide solution (40 mg, 1 mmol) in water (0.2 ml). The heterogeneous mixture is stirred for 15 minutes. Then add a solution of chloromethyl of dibenzylamine (104 mg, 0.32 mmol) in methylene chloride (1 ml) and the reaction mixture is vigorously stirred for eight hours. The mixture is then diluted with methylene chloride (10 ml), washed with water (2 ml), dried over sodium sulfate, filtered and evaporated in vacuum. The oily residue is purified using flash chromatography on a column of silica gel (hexane, 20:1 hexane/ethyl acetate 10:1 hexane/ethyl acetate), giving 44 mg (45% yield) of the named compound as a yellow oil. This product has the samef(TCX) and1NAMR spectrum (300 MHz, Dl3that authentic sample.

In addition to the above reactions IC (an alternative path - 4) it should be noted that the reagent:

can be generally represented by the following formula:

where X represents a removable group, R3and R4each represents a hydrogen atom, an organic or seargant or remove any other group. Examples of protective groups for phosphate protective groups include groups that temporarily block the reactivity of the phosphate group and allow for selective substitution using nucleophilic substitution reactions. Examples of such blocking groups include, but are not limited to, benzyl, allyl, tertiary bootrom and isopropyl, ethyl and-cyanoethyl.

IC. Synthesis of dimensional ether O-phosphonoacetate (alternative path - 5):

To a stirred suspension of sodium hydride (36 mg, 60% dispersion in mineral oil, 0.91 mmol) in dry dimethoxyethane (2 ml) in an argon atmosphere is added dropwise to propofol (172 μl, 97%, 0.90 mmol) over five minutes. The resulting mixture was stirred at room temperature for an additional 20 minutes. Then to the mixture add a solution of bis-(dibenzylamino) acetal of formaldehyde (500 mg, 0.88 mmol) in dry dimethoxyethane (3 ml). The reaction mixture was stirred at room temperature for 20 hours and then at 70With 2.5 hours. The mixture is then filtered and the solvent evaporated in vacuum. The oily residue is purified using flash chromatography on a column of silica gel (hexane, 10:1 hexa is This product has the same Rf(TCX) and1NAMR spectrum (300 MHz, CDCl3that authentic sample.

Id. Synthesis of O-phosphonoacetate:

To a solution of dimensional ether O-phosphonoacetate (115 mg, 0.245 mmol) in methanol (10 ml) is added palladium on coal (10%, 20 mg). The mixture is stirred in hydrogen atmosphere (1 ATM) for 1.5 hours. The catalyst was removed by filtration through celite and the filtrate evaporated under reduced pressure, giving 70.5 mg (100% yield) of the named compound as a colourless oil, unstable in the case of storage at room temperature.

FABMS-(GLY): [M-N]-m/z 287.

1H NMR (300 MHz, acetone-d6,): 1.19 (d, J=6.8 Hz, M), 3.46 (Sextus, J=6.8 Hz, 2H), 5.45 (d, J=9.7 Hz, 2H), 7.15 (m, 3H).13With NMR (75 MHz, acetone-d6,): 24.2178, 27.1496, 94.63, 94.65, 124.08, 126.30. 142.46, 152.32.

The Oia. Synthesis of disodium salt of O-phosphonoacetate:

To a solution of dimensional ether O-phosphonoacetate (1.05 g, 2.24 mmol) in tetrahydrofuran (100 ml) is added water (5 ml) and palladium on coal (10%, 300 mg). The resulting mixture is stirred in hydrogen atmosphere (1 ATM) for 1 hour. The catalyst was removed by filtration through celite, and the filtrate treated with a solution of hydroca xtraceroute with diethyl ether (33 ml). The aqueous layer was evaporated to dryness (in a stream of argon or on a rotary evaporator and the obtained solid is dried overnight in a vacuum, washed with diethyl ether (44 ml), hexane (24 ml) and dried again in a vacuum, which allows to obtain 655 mg (93% yield) of the named compound as a white powder. FABMS-(GLY): [M-2Na+H]-, m/z 287.

1H NMR (300 MHz, D2O,): 1.22 (d, J=7.0 Hz, M), 3.46 20 (hept, J 6.9 Hz, 2H), 5.27 (d, J=7.5 Hz, 2H), 7.28 (m, 3H).

II. Synthesis of O-phosphonomethyl-alpha-tocopherol

IIa. Synthesis of dimensional ether O-phosphonomethyl-alpha-tocopherol:

To a solution of chlorotrimethylsilane (323 mg, 0.98 mmol), alpha-tocopherol (409 mg, 97%, 0.92 mmol) and tetrabutylammonium bromide (301 mg, 0.92 mmol) in benzene (5 ml) is added an aqueous solution of sodium hydroxide (150 mg in 0.2 ml of water, 3.7 mmol). The resulting reaction mixture was stirred at room temperature for two hours in an argon atmosphere. The mixture is then diluted with benzene (10 ml), washed with water (33 ml), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The brown oily residue purified using flash HVIDE yellow oil.

FABMS+(NBA): [M]+m/z 720.

1H NMR (500 MHz, CDCl3,): 0.85 (m, N), 1.21 (s, 3H), 1.27 (m, 24N), 1.75 (m, 2H), 2.06 (s, 3H), 2.11 (s, 3H), 2.14 (s, 3H). 2.54 (t, J=6.8 Hz, 2H), 4.97 (m, 4H), 5.20 (d, J=9.3 Hz, 2H), 7.31(m, 10H).

IIb. Synthesis of O-phosphonomethyl-alphato-koverola:

To a solution of dimensional ether O-phosphonomethyl-alpha-tocopherol (88 mg, 0.12 mmol) in tetrahydrofuran (10 ml) is added palladium on coal (10%, 15 mg). The mixture is stirred in hydrogen atmosphere (1 ATM) for 10 minutes (as shown by TLC analysis, the reaction ends after 5 minutes). The catalyst was removed by filtration through celite, the filtrate evaporated under reduced pressure and then dried in vacuum. A named connection receive 70 mg (100% yield) as a brown oil, which is unstable at room temperature.

FABMS+(NBA): [M]+m/z 540, [M + Na]+m/z 563; (NBA + Li)+: [M + Li]+m/z 547

II c. Synthesis of disodium salt of O-phosphonomethyl-alpha-tocopherol

To a solution of dimensional ether O-phosphonomethyl-alpha-tocopherol (100 mg, 0.14 mmol) in tetrahydrofurane (10 ml) is added palladium on coal (10%, 18 mg). The mixture is stirred in hydrogen atmosphere (1 ATM) for 5 minutes. The catalyst was removed by filtration cher straut in diethyl ether (2 ml). The ether solution is treated with an aqueous solution of sodium hydroxide (11.2 mg in 100 ml of water, 0.28 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. The ether phase was removed and the aqueous phase washed with diethyl ether (33 ml) and then dried in vacuum for 20 hours, giving 73 mg (89% yield) of the named compound as a gray solid.

FABMS+(TG/G): [MN]+m/z 585, [M + Na]+m/z 607

Synthesis of water-soluble derivatives of camptothecin also will be further described in detail below:

III. Synthesis of 20-O-Phosphonomethylglycine

IIIa. Synthesis of 20-O-methylthiosemicarbazone:

To a suspension of camptothecin (5.0 g, 14.3 mmol) in dimethyl sulfoxide (250 ml) is added acetic anhydride (125 ml) and acetic acid (35 ml). The heterogeneous mixture was vigorously stirred at room temperature for 24 hours, poured onto ice (800 ml), stirred for 30 minutes and then extracted with methylene chloride (4100 ml). The combined extracts methylene chloride washed with water (2100 ml) and dried over magnesium sulfate. Methylene chloride is removed under reduced pressure giving a brown solid.make 10-fold excess of hexane, then incubated over night in the fridge. Precipitated precipitated solid is filtered off, washed several times with hexane and dried, giving 5.38 g (92% yield) of the named compound as a light brown powder.D20-123,6(0.55, l3).

FABMS+(NBA): [MH]-, m/z 409.

1NAMR (400 MHz, CDCl3,): 0.93 (t, J=7.2 Hz, 3H), 2.11 (Sextus, J=7.6 Hz, 1H), 2.29 (Sextus, J=7.6 Hz, 1H), 2.30 (s, 3H), 4.58 (s, 2H), 5.33 (s, 2H), 5.40 (d, J=17.2 Hz, 1H), 5.62 (d, J=17.3 Hz, 1H), 7.48 (s, 1H), 7.69 (t, J=7.1 Hz, 1H), 7.86 (t, J=7.1 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.42 (s, 1H).

13With NMR (75 MHz, SO3,): 7.76, 14.89, 33.90, 49.92, 66.68, 71.02, 76.57, 97.51, 122.63, 128.02, 128.09, 128.30, 129.71, 130.64, 131.11, 145.14, 146.10, 148.88, 152.27, 157.43, 169.34, 169.73.

IIIb. Synthesis of dimensional ether 20-O-phosphonomethylglycine

To a well stirred suspension of 20-O-methylthiosemicarbazone (1.00 g, 2.44 mmol) and powdered activated 4 a molecular sieves (5 g) in tetrahydrofuran (20 ml) is added a suspension of N-iodosuccinimide (2.00 g, 95%, 8.44 mmol) and dibenzylamine (2.20 g, 7.83 mmol) in methylene chloride (12 ml). The resulting mixture was vigorously stirred at room temperature for 30 minutes, filtered.gif">15 ml), water (220 ml), brine (50 ml) and dried over magnesium sulfate. The mixture is filtered and the solvent evaporated under reduced pressure. The brown oily residue purified using flash chromatography on a column of silica gel (98:2 ethyl acetate/methanol) and dried in vacuum overnight, giving 1.19 g (76% yield) of the named compound as a yellow foam.D20-43.1(0.55, l3).

FABMS+(NBA): [MH]+m/z 639.

1H NMR (400 MHz, CDCl3,): 0.91 (t, J=7.4 Hz, 3H), 2.09 (Sextus, J=7.4 Hz, 1H), 2.26 (Sextus J=7.4 Hz, 1H), 5.06 (m, 4H), 5.28 (m, 3H), 5.35 (d, J=17.0 Hz, 1H), 5.48 (HT, J=10 10.5 Hz, 1H), 5.64 (d, J=17.3 Hz, 1H), 7.59 (s, 1H), 7.67 (t, J=7.0 Hz, 1H), 7.80 (t, J=7.1 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 8.13 (q, j=8.5 Hz, 1H), 8.35 (s, 1H).

13With NMR (100 MHz, CDC13,): 7.73, 29.53, 32.49, 49.86, 66.74, 69.37, 69.44, 78.48, 88.99, 89.04, 98.09, 121.55, 127.65, 127.70, 127.90, 128.01, 128,25, 128.35, 128.36, 129.62, 130.48, 130.97, 135.45, 135.55, 145.47, 145.82, 148.76, 152.15, 157.18, 168.67.

IIIc. Synthesis of 20-O-phosphonomethylglycine:

To a solution of dimensional ether 20-O-phosphonomethylglycine (500 mg, 0.78 mmol) in tetrahydrofuran (100 ml) and water (5 ml) is added palladium on coal (10%, 500 mg). The mixture is stirred in hydrogen atmosphere (1 aannie the filtrate evaporated under reduced pressure. The obtained solid green washed with diethyl ether (220 ml), hexane (50 ml), dried in vacuum and then dissolved in hot methanol (60 ml). The solution is filtered, concentrated under reduced pressure to a residual volume of 10 ml. After standing at room temperature for one hour, the solution is placed in the refrigerator overnight. Formed during the night the crystalline precipitate is filtered off and dried in vacuum, giving 155 mg of the named compound as a yellow solid. The filtrate is concentrated to a volume of ml -1, which is kept in the refrigerator for one hour, which gives an additional 28 mg of product. Total yield: 183 mg (51%).

FABMS+(NBA): [MH]+, m/z 459, [M+Na]+m/z 481.

1H NMR (400 MHz, D2O,): 0.95 (t, J=7.5 Hz, 3H), 2.25 (m, 2H), 4.98 (d, J=5.0 Hz, 2H), 5.14 (2xd, J=9.3 Hz, 1H), 5.22 (2xd, J=8.9 Hz, 1H), 5.48 (d, J=17.0 Hz, 1H), 5.60 (d, J=16.9 Hz, 1H), 7.54 (s, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.77 (t, J=7.2 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 8.01 (d, J=8.5 Hz, 1H), 8.44 (s, 1H).

The chemical structure and purity of the product was also determined using the1NAMR spectroscopy of its disodium salt formed from an acid and two molar equivalents of sodium bicarbonate in2O.

IIIc. Synthesis of 20-O-phosphonomethylglycine (alternatives is 0 mg, 0.78 mmol) in tetrahydrofuran (100 ml) and water (5 ml) is added palladium on coal (10%, 500 mg). The mixture is stirred in hydrogen atmosphere (1 ATM) for 30 minutes. The catalyst was removed by filtration through celite. Celite is washed with tetrahydrofuran (2100 ml) and the combined filtrates treated with an aqueous solution of sodium hydrogen carbonate (97 mg in 2 ml of water, 0.78 mmol). THF evaporated under reduced pressure, water heterogeneous residue diluted with water (10 ml) and extracted with ethyl acetate (23 ml). Receives a yellow homogeneous solution, which was acidified with hydrochloric acid (10%) until pH=1. The resulting residue is filtered off and dried in vacuum overnight, giving 145 mg (41% yield) of the named compound as a yellow solid.

IIId. Synthesis of disodium salt of 20-O-phosphonomethylglycine:

To a suspension of 20-O-phosphonomethylglycine (5 mg, 10.9 μmol) in deuterium oxide (0.5 ml) add sodium hydroxide solution in deuterium oxide (50 ál from 0.44 M solution = 22 mmol). A heterogeneous mixture is subjected to destruction by ultrasound in a few minutes, which gives a yellow homogeneous solution of the above product.

lNAMR (400 MHz, D2O, after 10 min, 96% Lac=5.4 Hz, 1H), 5.18 (DD, J=7.6, J=5.5 Hz, 1H), 5.45 (d, J=16.7 Hz, 1H), 5.59 (d, J=16.8 Hz, 1H), 7.34 (t, J=7.1 Hz, 1H), 7.41 (s, 1H), 7.60 (m, 2H), 7.81 (d, J=8.3 Hz, 1H), 8.17 (s, 1H).

IIId. Synthesis of disodium salt of 20-O-phosphonomethylglycine (alternate path (I):

To a solution of dimensional ether 20-O-phosphonomethylglycine (78 mg, 0.122 mmol) in tetrahydrofuran (10 ml) and water (3 ml) is added palladium on coal (10%, 80 mg). The mixture is stirred in hydrogen atmosphere (1 ATM) for 30 minutes. The catalyst was removed by filtration through celite, and the filtrate is treated with an aqueous sodium hydrogen carbonate solution (20 mg in 0.5 ml water, 0.238 mmol). The yellow precipitate is filtered off, washed with methylene chloride and dried in vacuum, giving 35 mg (57% yield) of the named compound (pale brown solid) in the form of mixtures thereof in the form of a lactone (82%) and carboxylate (18%) (1H NMR).

IIId. Synthesis of disodium salt of 20-O-phosphonomethylglycine (alternative path 2):

To a solution of 20-O-phosphonomethylglycine (500 mg, 0.78 mmol) in tetrahydrofuran (100 ml) and water (5 ml) is added palladium on coal (10%, 500 mg). The mixture is stirred in hydrogen atmosphere (1 ATM) for 30 minutes. The catalyst was removed by filtration through celite. Celite is washed tetrahydro the 0.72 mmol). The tetrahydrofuran evaporated under reduced pressure, and the residue is dissolved in water (15 ml). A heterogeneous mixture is extracted with ethyl acetate (215 ml) and diethyl ether (20 ml) and the resulting aqueous homogeneous solution is evaporated to dryness in a stream of argon at room temperature. The residue is dried in vacuum overnight, giving 290 mg (80% yield) of the named compound (solid orange) in the form of a mixture in the form of lactate (60%), and carboxylate (40%) and small amounts of by-products (defined using the1H NMR).

IIIe. Synthesis monosodium salt 20-O-phosphonomethylglycine:

To continuously destroyed by ultrasound suspension 20-O-phosphonomethylglycine (5 mg, 10 mmol) in deuterium oxide (0.5 ml) is added dropwise a solution of sodium hydroxide in deuterium oxide until it reaches the full homogenization (21 μl 0.44 M solution = 9.2 mmol). Receives a yellow homogeneous solution of these compounds.

1H NMR (400 MHz, D2O,): 1.00 (t, J=7.2 Hz, 3H), 2.23 (m, 2H), 4.40 (d, J=18.8 Hz, 1H), 4.50 (d, J=18.8 Hz, 1H), 5.10 (DD, J=9.7, J=5.9 Hz, 1H), 5.26 (DD, J=9.0, J=6.1 Hz, 1H), 5.39 (d, J=16.7 Hz, 1H), 5.50 (d, J=16.7 Hz, 1H), 7.20 (t, J=7.3 Hz, 1H), 7.28 (s, 1H), 7.46 (m, 2H), 7.66 (d, J=8.4 Hz, 1H), 8.02 is yuno destructible suspension 20-O-phosphonomethylglycine (5 mg, 10 µmol) in deuterium oxide (0.5 ml) is added dropwise a solution of L-lysine in deuterium oxide (25 µl of a 0.43 M solution = 10.7 µmol) until it reaches the full homogenization. Receives a yellow homogeneous solution of these compounds.

1H NMR (400 MHz, D2Oh, 94% lactone, 6% carboxylate,): 1.02 (t, J=7.2 Hz, 1H), 1.49 (m, 2H), 1.73 (m, 2H), 1.88 (m, 2H), 2.25 (m, 2H), 3.03 (t, J=7.5 Hz, 2H), 3.76 (t, J=6.0 10 Hz, 1H), 4.43 (d, J=19.0 Hz, 1H), 4.52 (d, J=18.9 Hz, 1H), 5.11 (DD, J=9.7, J=5.8 Hz, 1H), 5.27 (DD, J=9.2, J=5.8 Hz, 1H), 5.41 (d, J=16.7 Hz, 1H), 5.53 (d, J=16.7 Hz, 1H), 7.23 (t, J=7.4 Hz, 1H), 7.30 (s, 1H), 7.49 (m, 2H), 7.68 (d, J=8.4 Hz, 1H), 7.04 (s, 1H).

IIIg. Synthesis of arginine salt 20-O-phosphonomethylglycine

To continuously destroy suspension of 20-O-phosphonomethylglycine (5 mg, 10 µmol) in deuterium oxide (0.5 ml) is added dropwise a solution of L-arginine in deuterium oxide (27 μl of 0.40 M solution = 10.8 mmol) until it reaches the full homogenization. Receives a yellow homogeneous solution of these compounds.

1H NMR (400 MHz, D2O): 1.02 (t, J=7.1 Hz, 1H), 1.66 (m, 2H), 1.89 (m, 2H), 2.25 (m, 2H), 3.20 (t, J=6.8 Hz, 2H), 3.77 (t, J=6.0 Hz, 1H), 4.40 (d, J=19.0 Hz, 1H), 4.49 (d, J=18.8 Hz. 1H), 5.12 (DC, J=9.7, J=6.0 Hz, 1H), 5.29 (DD, J=8.8, J=6.1 Hz, 1H), 5.40 (d, J=16.7 Hz, 1H), 5.51 (d, J=16, 7 Hz, 1H), 7.20 (t, J=7.3 Hz, 1H), 7.29 (s, 1H), 7.47 (m, 2H), 7.66 (d, J=8.3 Hz, 1H), 8.03 p>To continuously destroy suspension of 20-O-phosphonomethylglycine (5 mg, 10.9 μmol) in deuterium oxide (0.5 ml) is added dropwise a solution of (D)-N-methylglucamine in deuterium oxide (21 μl 0.51 M solution = 10.7 µmol) until it reaches the full homogenization. Receives a yellow homogeneous solution of these compounds.

1H NMR (400 MHz, D2O,): 1.02 (t, J=7.3 Hz, 3H), 2.25 (m, 2H), 2.78 (s, 3H), 3.20 (m, 2H), 3.65 (m, 2H), 3.80 (m, 3H), 4.11 (m, 1H), 4.44 (d, J=18.9 Hz, 1H), 4.53 (d, J=19.0 Hz, 1H), 5.12 (DD, J=9.8, J=5.9 Hz, 1H), 5.27 (DD, J=9.2, J=5.9 Hz, 1H), 5.41 (d, J=16.7 Hz, 1H), 5.53 (d, J=16.7 Hz, 1H), 7.23 (t, J=7.4 Hz, 1H), 7.49 (m, 2H), 7.69 (d, J=8.4 Hz, 1H), 8.05 (s, 1H).

IV. Synthesis of 4’-O-phosphonoacetate:

The IVa. Synthesis of dimensional ether 4’-O-phosphonoacetate:

To a solution of chlorotrimethylsilane (670 mg, 2.05 mmol), etoposide (300 mg, 0.51 mmol) and tetrabutylammonium bromide (164.4 mg, 0.51 mmol) in tetrahydrofuran (0.5 ml) is added powdered potassium carbonate (352.4 mg, 2.55 mmol). The reaction mixture is vigorously stirred at room temperature for 35 minutes. The mixture is then directly purified by chromatography on a column of silica gel (30:1 methylene chloride/methanol) give 272 mg (61% yield) of the named+ m/z 879.

1H NMR (400 MHz. Dl3,): 1.41 (d, J=5.0 Hz, 3H), 2.79 (broadened with 1H), 2.86 (m, 1H), 2.97 (broadened s, 1H), 3.30 (DC, J=14.2, J=5.3 Hz, 1H), 3.35 (m, 2H), 3.45 (t, J=8.5, J=8.0 Hz, 1H), 3.59 (m, 1H), 3.66 (s, 6N), 3.74 (m, 1H), 4.19 (m, 1H), 4.20 (t, J=8.5, J=8.0 Hz, 1H). 4.42 (DD, J=10.3, J=9.1 Hz, 1H), 4.60 (d, J=5.2 Hz, 1H), 4.64 (d, J=7.6 Hz, 1H), 4.76 (q, J=5.0 Hz, 1H), 4.92 (d, J=3.4 Hz, 1H), 5.03 (DD, J=7.3, J=4.3 Hz, 4H), 5.54 (DD, J=11.7, J=5.1 Hz, 1H), 5.59 (DD, J=11.3, J=5.1 Hz, 1H), 5.99 (d, J=3.5 Hz, 2H), 6.26 (s, 2H), 6.51 (s, 1H), 6.84 (s, 1H), 7.33 (m, 10H).

13With NMR (75 MHz, CDCl3,): 20.21, 37.49, 41.00, 43.78, 56.07, 66.32, 67.87, 67.97, 69.06, 69.14, 73.01, 73.29, 74.47, 79.70, 92.55, 92.62, 99.70, 101.57, 101.72, 107.89, 109.13, 110.55, 127.82, 127.97, 128.15, 128.35, 128.43. 132.40, 133.08, 135.68, 135.78, 136.49, 147.14, 148.73, 152.18, 174.90.

IVb. Synthesis of 4’-O-phosphonoacetate:

To a solution of dimensional ether 4’-O-phosphonoacetate (20.5 mg, 0.023 mmol) in tetrahydrofuran (2 ml) is added palladium on coal (10%, 5 mg). The mixture is stirred in hydrogen atmosphere (1 ATM) for 10 minutes. The catalyst was removed by filtration through celite and the tetrahydrofuran evaporated under reduced pressure. The resulting residue is dried in vacuum, giving 16 mg (100% yield) of the named compound as a white solid.

FABMS+(NBA): [MH]+m/z 699.

1H NMR (400 MHz, Dl3/DMSO-d6,VIc. Synthesis diatremes salt of 4’-O-phosphonoacetate

To a solution of dimensional ether 4’-O-phosphonoacetate (200 mg, 0.227 mmol) in tetrahydrofuran (10 ml) is added palladium on coal (10%, 45 mg). The mixture is stirred in a stream of hydrogen (1 ATM) for 25 minutes. The catalyst was removed by filtration through celite. The filtrate is evaporated under reduced pressure, and the residue is dried in vacuum. The resulting white solid was dissolved in aqueous sodium hydrogen carbonate solution (2.9 ml, 0.136 M=0.394 mmol). Received a heterogeneous mixture is mixed with activated carbon, stirred for a few minutes and then filtered through a filter with a pore size of 40 microns. A homogeneous, colorless filtrate lyophilized that gives 140 mg (96% yield) of the named compound as a white solid with more than 95% conserved stereochemistry.

FABMS+(NBA): [MN]+m/z 743, [M - Na +2H]+m/z 721, [M - 2Na +3H]+m/z 699.

1H NMR (400 MHz, D2O,): 1.37 (d, J=5.1 Hz, 3H), 3.10 (m, 1H), 3.37 (DD, J=8.9, J=8.0 Hz(d, J=7.8 Hz, 1H), 4.91 (q, J=5.0 Hz, 1H), 5.13 (d, J=3.0 Hz, 1H), 5.26 (HT, J=5.3, J=3.3 Hz, 1H), 5.28 (HT, J=5.3, J=3.3 Hz, 1H), 5.98 (d, J=10.5 Hz, 2H), 6.40 (s, 2H), 6.58 (s, 1H), 7.00 (s, 1H).

13With NMR (125 MHz, D2O,): 22.13, 40.74, 43.56, 46.11, 59.12, 68.70, 70.41, 72.40, 75.46, 75.95, 76.95, 82.46, 94.87, 102.88, 103.66, 104.62, 111.14. 112.82, 113.23, 130.73, 135.45, 135.74, 140.22, 149.56, 151.43, 154.94, 166.36, 181.61.

31P NMR (200 MHz, D2O,): with (2.19).

V. Synthesis phosphonomethoxy agents

Va. Synthesis of chlorotrimethylsilane

To heated under reflux solution chloroiodomethane (25 g, 97%, 0.14 mol) in toluene (HPLC-grade, 30 ml) add dimensionful silver (7.0 g, 0.018 mol) in several portions over 20 minutes. The reflux continued for 1 hour. Then the reaction mixture is cooled to room temperature and filtered. The solvent is evaporated under reduced pressure. The oily residue is purified using flash chromatography on a column of silica gel (7:3 hexane/ethyl acetate), giving 3.63 g (62% yield) of the named compound as a yellow oil.

FABMS+(NBA): [MN]+m/z 327

1H NMR (300 MHz, CDCl3,): 5.10 (d, J=8.0 Hz, 4H), 5.63 (d, J=15.7 Hz, 2H), 7.36 (s, 10H).

13With NMR (mg, CDCI3,6.gif">

To a stirred solution of p-toluensulfonate silver (600 mg, 2.15 mmol) in dry acetonitrile (3 ml) add chloromethylmethylether (150 mg, 0.46 mmol) in argon atmosphere. Then the reaction mixture is stirred for 21 hours at room temperature. The solvent is removed and the residue extracted with ether (33 ml). The combined extracts filtered, evaporated and dried in vacuum, giving 210 mg (99% yield) of the named compound as a white solid.

EIMS:[MH]+m/z 463.

1H NMR (300 MHz, CDCl3,): 2.37 (s, 3H), 4.91 (2 x d, J=7.9 Hz, 4H), 5.61 (d, J=14.2 Hz, 2H), 7.29 (m, N), 7.78 (d, J=8.4 Hz, 2H).

With reference to the above reaction Vb, taking into account the explanations given in IC above, reagent:

can be generally represented by the following formula:

where all the symbols have the meanings given above.

Vc. Synthesis of formaldehyde bis(dibenzalacetone)-acetal:

To a solution of diiodomethane (4 ml, 50 mmol) in dry toluene (15 ml) add dimensionful silver (3.0 g, 7.8 mmol). The resulting mixture was heated under reflux for 15 minutes in an argon atmosphere. The mixture was then cooled to room tempera is matography on a column of silica gel (1:1 hexane/ethyl acetate and then ethyl acetate) to give a yellow oil, which is then crystallized that give 1.97 g (90% yield) of the named compound as a white solid, so pl. 39-42C.

CIMS (NHC): [MN]+m/z 569.

1H NMR (300 MHz, Dl3,): 5.03 (d, J=7.9 Hz, 8H), 5.49 (t, J=14.3 Hz, 2H), 7.30 (m, 20N).

13With NMR (75 MHz, CDCl3,): 69.54, 69.61, 86.48, 127.88, 128.48, 128.55, 135.10, 135.20.

VI Synthesis of O-phosphonomethylglycine:

VIa. Synthesis of O-methylthiosemicarbazone:

To a suspension of cyclosporine a in dimethyl sulfoxide (250 ml) is added acetic anhydride (125 ml) and acetic acid (35 ml). The heterogeneous mixture was vigorously stirred at room temperature for 24 hours, poured onto ice (800 ml), stirred for 30 minutes and then extracted claritim a methylene (4100 ml). The combined extracts methylene chloride washed with water (2100 ml) and dried over magnesium sulfate. Methylene chloride is removed under reduced pressure, which leads to the formation of the target compounds. It then further purified using chromatography on silica gel.

VIb. Synthesis of dimensional ether O-phosphonomethylglycine:

15 ml), water (220 ml), brine (50 ml) and dried over sodium sulfate. The mixture is filtered and the solvent evaporated under reduced pressure. The residue is purified using flash chromatography on a column of silica gel.

VIc Synthesis of O-phosphonomethylglycine:

To a solution of dimensional ether O-phosphonomethylglycine And tetrahydrofuran (100 ml) and water (5 ml) is added palladium on coal (10%, 500 mg). The mixture is stirred in hydrogen atmosphere (1 ATM) for 35 minutes. The catalyst was removed by filtration through celite. Then celite washed with tetrahydrofurane (300 ml) and the combined extracts evaporated under reduced pressure. The obtained solid is washed with ether (220 ml), hexane (50 ml), dried in vacuum, and then dissolved in hot methanol (60 ml). The solution is filtered, concentrated at meshaut in the refrigerator overnight. The crystalline precipitate formed during the night, filtered and dried in vacuum, which leads to the said compound in the form of solids. The filtrate is concentrated to a volume of I ml and kept in the refrigerator for one hour, which gives an additional amount of product.

BIOLOGICAL TESTS

Compounds of the present invention are novel pharmaceutical agents; characteristic of the compounds of formula I were tested in the experiments to study their transformation in vitro and in vivo. In all of these studies prodrugs were transformed to the corresponding pharmaceutically active parent compound.

(1) evaluation of the solubility of the prodrugs of propofol in the water

The solubility of the prodrug of propofol is estimated as 500 mg/ml, based on data from the HPLC (high performance liquid chromatography, HPLC) analysis of a saturated aqueous solution.

(2) the Conversion of prodrugs of propofol in profol in vitro

Transformation in vitro prodrug of propofol in propofol carried out using alkaline phosphatase in the environment glycine buffer pH 10.4. Prepare 25 ml of a solution at 100 μg/ml prodrug of propofol in glycine buffer. One ml save to determine the zero mark in BP is propofol add 960 μl of a solution of alkaline phosphatase in glycine buffer with a concentration of 0.1 mg/ml, mix and return to the water bath. Samples with a volume of 1.5 ml selected through 5, 10, 20, 30, 40, 60, 90, 120, 180, 240, 300 and 360 minutes. To each sample immediately add 10 ál of glacial acetic acid to stop the enzymatic reaction. Samples analyzed by HPLC, which allows to determine the concentration of propofol and prodrugs of propofol. The results of transformation in vitro is shown in Fig. 1. These results show that the prodrug of propofol is a substrate for alkaline phosphatase.

(3) the Assessment of higher toxicity in rats.

A prodrug of propofol is prepared for intravenous injection with a concentration of 68 mg/ml in 0.9% sodium chloride injection, USP. This concentration is equivalent to 36 mg/ml of propofol. Before administration, the solution prodrugs of propofol filtered through 0.22 μm nylon membrane.

Studies of prodrugs of propofol in rats conducted with the use of two males, Harlen Sprague-Dawley, rats, weighing 820 and 650, Rat, weight 820 g, inject 200 ál of prodrugs of propofol intravenous (equivalent to 9 mg/kg of propofol) in the tail vein. Take a blood sample from the tail vein after about 12 minutes (using a heparinised syringe). Rat weighing 650 g dose medium sedative Metaphane(4) Pharmacokinetic studies in dogs

Pharmacokinetic study involving Diprivanor a prodrug of propofol, provide the dog with a substantial washout period between experiments. Concentrations of substances in the blood was determined using HPLC with fluorescence detection, while brain activity is studied using two taps for electroencephalography (EEG). Before introducing the dog dose, she put a bandage on eyes, ears, plug with cotton wool and feet tied to negate her movements, as well as other external influences, so that is most effective to observe the effects of propofol on electrc on hound dog weighing 13 kg Approximately 8 ml of blood taken before injection to use when constructing the standard curve as the zero time blood level. Dog gets Diprivan or prodrugs, equivalent to 7 mg/kg of propofol on the injection head in a vein.

Take blood samples of 2 ml from the head (but not from the veins into which the entered injection), jugular or saphenous vein of the leg (using a heparinised syringe) through 1, 3, 5, 10, 15, 20 and 30 minutes after injection. Blood samples are also taken through 60, 90, 120, 180, 240, 300, 360, 480 and 1440 minutes. Blood samples are extracted to immediately remove propofol after they took the dog. The dog is forced to starve approximately 20 hours before administered Diprivanor prodrugs of propofol. After 120 minutes of taking the blood sample and allow the dog to drink water. Food dog give after receiving a blood sample, corresponding to 480 minutes. Regular dogs diet is a diet Hills’ Science Maintenance. The dog is in a cycle of light/darkness, in which 12 hours a day is light.

The concentration of propofol in blood samples determined using HPLC with fluorescence detection. The results are presented in Fig 2. Ispolzovanie sample and the research process is as follows.

The blood sample of 1 ml add 10 ál of internal standard thymol (20 mg/ml) and 1 ml phosphate buffer (0.1 M, pH 7.2) through mixing after each addition. Then add five ml of cyclohexane and the samples stirred at 75 rpm for 20-30 minutes. The organic layer was separated by centrifugation for 1 minute at approximately 2000 rpm for Approximately 4.5 ml of the organic layer is placed in a tube containing 50 µl of the diluted solution of the hydroxide of Tetramethylammonium (TMAN) to approximately 1.8% (weight/volume). The solvent is evaporated to dryness in a stream of nitrogen and re-diluted with 200 μl of mobile phase A. the Samples are centrifuged at 15,000 rpm for 30 seconds to remove any particles, and the supernatant Inuktitut in device for HPLC. Samples for the standard curve is prepared by mixing 1 ml aliquot of the initial blood propofol at concentrations of 5, 1, 0.5, 0.1 and 0.01 μg/ml the standards are treated in the same way as the samples.

The HPLC system consists of the following components Shimadzu: LC-10AT pump, SCL-10A system controller, RF 353 fluorescence detector, SIL-10A autoprobing. The HPLC parameters as follows: excitation at 275 nm and emission at 320 nm; flow rate 1 ml/min; volume of injection is 3-30 μl depending the m inner diameter, the particle size of 5 μm. The mobile phase 60:40 (V/V) acetonitrile: 25 mm phosphate, 15 mm TVAR Buffer pH 7.1. The mobile phase 80:10:10 (V/V/V) acetonitrile:water:THF. Mobile phase used for the purification column after elution of thymol and propofol using mobile phase A (4.2 and 7.4 minutes, respectively).

The dog showed signs of narcosis after injection of both compounds, as shown by visual observation and EEG charts. The dog regained consciousness after anaesthesia induced by both compounds, 20-30 minutes. The levels of propofol in the blood as a result of injection prodrugs of propofol close to those that occur when Diprivan injection.

(5) evaluation of the solubility of the prodrugs of camptothecin in the water

The solubility of the prodrugs of camptothecin higher than 50 mg/ml, judging by the visual and HPLC analyses.

(6) Enzymatic studies of prodrugs of camptothecin (p-cpt)

16 µg/ml p-cpt destroy using acid phosphatase (0.02 units/ml p-cpt solution). As the environment of the use 0,09 M citrate buffer, pH 4.8 and a temperature of 37°C. the Transformation of p-cpt in camptothecin fixed with the help of HPLC.

The HPLC parameters:

Mr: 24% potassium phosphate buffer pH 4, 76% acetonitrile

Column: Bond RX-C18, 15 cm4.6 mm inner whom thou bull (Sigma). The results are presented in Fig. 3. The results show that the prodrug of camptothecin is a substrate for acid phosphatase.

(7) Pharmacokinetic studies of prodrugs of camptothecin using rats

Were conducted pharmacokinetic experiments involving the introduction of a dose of the composition of the prodrugs of camptothecin and camptothecin male species rats, Sprague-Dawley. Two compositions of prodrugs of camptothecin that were investigated consisted of prodrugs, dissolved in 15 mm phosphate, pH 4.0 and camptothecin dissolved in organic co-solvents. The essence of pharmacokinetic experiments is as follows:

The amount of the composition of the prodrugs of camptothecin or composition of camptothecin prepared with such concentration that the rat could get a dose equivalent to 1 mg of camptothecin per kg of weight. The composition is administered to the rat, using a cannula, which resides in the left jugular vein of a rat.

Blood samples are taken through the cannula constantly finds, in the right jugular vein of the rat. Both cannula before use washed with heparin saline solution, and they contain heparin saline throughout the experiment.

Rats give anesthesia using pentobarbital sodium per what about the research. During the experience of rats placed on a soft pad, heated to 37And tracheotomized. Take blood samples of approximately 150 µl to dose and through 1, 3, 5, 10, 15, 20, 30, 45, 60 and 90 minutes after administration to rats of compounds.

The blood samples are placed in microcentrifuge tubes and centrifuged for 20 seconds at approximately 15000 rpm

In other microcentrifuge tubes placed 50 μl aliquots of plasma from each blood sample. To the plasma, add 150 ál aliquot of chilled acetonitrile and the product is shaken for 5 seconds. Then add 450 ál aliquot of chilled phosphate (0.1 M, pH 7.2). The contents of the centrifuge tubes, shaken for 5 seconds and centrifuged for 20 seconds at approximately 15000 rpm, the Supernatant is placed in the sampler samples HPLC at 4With and analyze (injections of 50 ál).

The HPLC system consists of the following Shimadzu components: LC-10AT pump, SCL-10A system controller, RF-535 fluorescence detector, SIL-10A sampler samples (at 4C), and a HUNDRED-10A heating chamber is at a temperature of 30C).

The HPLC parameters as follows: excitation at 370 nm and emission at 435 nm; speed is iameter, the particle size of 5 μm. The mobile phase consisted of 75% 25 mm phosphate, pH 6.5/25% acetonitrile (V/V) with 25 mm dihydrophosphate tetrabutylammonium added as a reducing insinuante reagent.

As can be seen in Fig. 4, the prodrug provides levels of camptothecin in the blood plasma, which is equivalent to levels achievable with direct injection camptothecin in organic cosolvent. The drawing shows the average standard deviation for five rats, which were administered prodrug and six rats, which was introduced camptothecin.

Claims

1. Phosphonoacetate esters of the formula I

where R-O - is a residue of pharmaceutical compounds containing alcohol or phenol, with the exception of Taxol and Taxol derivatives,

R1is hydrogen, or an alkali metal ion or a protonated amine, or protonated amino acid;

R2is hydrogen, or an alkali metal ion or a protonated amine, or protonated amino acid;

n is the integer 1 or 2;

m is an integer and has a value of at least 1,

and their pharmaceutically receiving eticheskoe compound selected from the group consisting of camptothecin analogs camptothecin, propofol, etoposide, vitamin E and cyclosporine A.

3. Connection on p. 1, characterized in that the alkali metal ion for R1and R2each independently selected from the group including sodium, potassium and lithium.

4. A compound selected from the group including

Cyclosporine And

in which Z is chosen from the group consisting of hydrogen and alkali metal ion and an amine,

and their pharmaceutically acceptable salts.

5. Connection on p. 4, wherein Z is independently selected from the group consisting of sodium, tromethamine, triethanolamine, triethylamine, arginine, lysine, ethanolamine and N-methylglucamine.

6. The compound of formula III

where R-O - is a residue of pharmaceutical compounds containing alcohol or phenol, with the exception of Taxol or Taxol derivatives,

and it farmatsevticheskii acceptable salt.

7. Connection on p. 6, characterized in that the said compound is chosen from:

where R-O - is a residue of pharmaceutical compounds containing alcohol or phenol, with the exception of Taxol and Taxol derivatives;

Y is phosphonothioic group;

n is the integer 1 or 2,

and its pharmaceutically active salts.

9. Connection on p. 8, characterized in that the said compound is chosen from the

Cyclosporine And

where Y represents phosphono-protective group.

10. Connection on p. 8, characterized in that the specified phosphono-protective group selected from the group comprising benzyl group, tert.-boutelou group and allyl group, and other appropriate protective groups for the phosphonic group.

11. A method of obtaining a connection on p. 4, including the removal of phosphonothioic group of compounds of the following formula:

Cyclosporine And

where Y represents phosphorazidate group,

and selection of product.

12. A method of obtaining a connection on p. 6, include terasawa alcohol or phenol, with the exception of Taxol and Taxol derivatives, and their pharmaceutically acceptable salts with dimethyl sulfoxide in the presence of acetic anhydride and acetic acid, and the allocation of product.

13. A method of obtaining a connection on p. 8, including the interaction of the compounds of formula III

where R-O - is a residue of pharmaceutical compounds containing alcohol or phenol, with the exception of Taxol and Taxol derivatives, and their pharmaceutically acceptable salts,

N-iodosuccinimide and protected phosphoric acid formula NORD(O)(OY)2where Y represents phosphorazidate group, and the allocation of product.

14. The method according to p. 13, characterized in that phosphorazidate group selected from a group comprising benzyl group, tert.-boutelou group and allyl group.

15. Pharmaceutical composition comprising an effective amount of the compounds of formula I, represents a derivative of propofol, has anesthetic effects.

16. Pharmaceutical composition comprising an effective amount of the compounds of formula I, except for derivatives of propofol with antitumor activity.

17. The method of anesthesia, including the introduction of the patient, guideuse is a broad introduction to the patient an effective amount of a composition according to p. 16.

19. The method according to p. 18, characterized in that the said compound is administered orally.

20. The method according to p. 18, characterized in that the said compound is administered parenterally.

 

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where R= H, -COCH3or their salts; the way they are received by cultivation of the strain SANK 13899 (FERM BP-6851) a microorganism of the genus Phoma; strain SANK 13899 (FERM BP-6851) a microorganism of the genus Phoma; therapeutic or preventive agent against fungal infections; method of treating or preventing fungal infectious diseases

The invention relates to new polypeptide compounds of General formula [I]

< / BR>
where R1is hydrogen; arylamino(lower)alkanoyl, which may have one or more suitable substituents; aroyl substituted heterocyclic group that may have one or more suitable substituents; aroyl substituted with aryl having higher alkyl; aroyl substituted with aryl having lower alkyl; aryl(C2-C6)alkanoyl substituted with aryl having lower alkyl; lower alkanoyl, substituted unsaturated condensed heterocyclic group which may have one or more suitable substituents; lower alkanoyl, replaced by pyridium, which may have one or more suitable substituents; aminosidine group; Lexington; aroyl, replaced by heterocyclization, which may have one or more suitable substituents; lower alkanoyl, substituted cyclo(lower)alkyl which may have one or more suitable substituents; lower alkanoyl, replaced by tanila having a heterocyclic group which may have one or more suitable substituents; or nissila; R2is hydrogen or hydroxy; R3is hydroxy, hydroxysulfonic or lower alkoxy; R4is hydroxy or lower alkoxy, or their salts, having antifungal activity; two ways of obtaining compounds of General formula I; a pharmaceutical composition having anti-fungal activity, and to a method of prophylactic and/or therapeutic treatment of infectious diseases caused by fungi

The invention relates to new cyclic peptides of General formula 1

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where is a bridging group; E=H, halogen, -NO2, -NR8R8'or or13, R8and R8'each independently represents hydrogen or methyl; R13represents hydrogen or methyl; X - substituents on the phenyl ring, selected from hydrogen, halogen, -NR2or8; Z is one or more substituents on the phenyl ring, independently selected from hydrogen, halogen, -OR9or two groups Z may be taken together with the formation of a condensed aryl ring; R9is hydrogen or methyl; D

< / BR>
< / BR>
substituted or unsubstituted, imidazolyl; R2, R3, R4and R5each represents hydrogen, methyl, or any two radicals of R2, R3, R4and R5can be connected to form heterocyclic or heteroaryl ring; R = 1 to 3; and to a pharmaceutical composition having a selectivity for receptors MC-3 and/or MC-4 compared with other receptors melanocarcinoma

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< / BR>
where R2, R3denote H; R4= R5- Ar or R4= Ar, where R5- alkylen (C1-C6); Ar is unsubstituted phenyl; or R4= A, where A = (C1-C6)alkyl, and, if you have in mind remains optically active amino acids, these compounds include D-and L-forms, and their salts, method of production thereof, pharmaceutical composition having the ability to inhibit integrin containing as active ingredient a compound of the formula I

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-d-glyukopiranozil-l-ascorbic acid and its preparation" target="_blank">

The invention relates to a method of obtaining a new crystalline 2-0--D-glyukopiranozil-L-ascorbic acid of General formula I

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exhibiting enhanced stability during storage

The invention relates to new heteroaryl-alldifferent formulas (I) and (II) for compounds of formula (I) A=S if V=C; A=N, if B=N, R1is hydrogen or C1-C4alkyl, R2-R5-phenyl, R6and R7is hydrogen, n=0 or 1, R8-R11is hydrogen; compounds of f-crystals (II) A=N, if I=S, R1=C1-C4alkyl, A=C, if B= N, R1is hydrogen; A=N if I=N, R1=0; And=O, if=S, R1=0, R2-R5- phenyl, R8-R11is hydrogen or C1-C4alkyl

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