Esters estramustine or their pharmaceutically acceptable salts and method of production thereof

 

(57) Abstract:

Usage: as an oral anticancer agents. The inventive product: esters estramustine formula (see Fig.), where R1- H, alkyl (C1-C4, R2- H, alkyl (C2-C4, R3- H, alkyl (C1-C4n = 0, 1, 2, or their pharmaceutically acceptable salts. Output: 80 - 90%. Reagent 1: estramustin. Reagent 2: amino acid HOOC-CHR1-(CH2)n-NR2R5where R1, R2have the specified values, R5=R3or a protective group. Reaction conditions: in the midst of methylene chloride and in the presence of dicyclohexylcarbodiimide, for removing the protective group hydronaut hydrogen over palladium on coal. 2 S. and 3 C.p. f-crystals, 4 PL.

< / BR>
The invention relates to new esters estramustine and the way they are received, namely esters of the General formula I:

< / BR>
(I) where R1hydrogen atom, a lower alkyl WITH1-C4;

R2a hydrogen atom, a lower alkyl WITH1-C4;

R3a hydrogen atom, a lower alkyl WITH1-C4; or R2and R3together-CH2-CH2-CH2-CH2-,

n is 0,1 or 2

or their pharmaceutically acceptable salts, having protivoop rastvorimye calcium salt and is suitable for oral administration in the treatment of prostate cancer.

Synthesis of conduct esterification estramustine amino acid of General formula:

HOOC--(CH2)n-NR2R5where R5=R3or a protective group,

with the product of General formula II:

< / BR>
(II) where R4the group-NR2R5< / BR>
c followed by removal of the protective group to obtain the desired product I.

Estramustin, östra-1,3,5(10)-triene-3,17-diol-3-N, N-bis(2 - chloroethyl)carbamate and its various esters are well known as anti-cancer agents. One of them, 17-extramathematical (EMFs) has been studied more widely, and its aqueous solution (estracyt") is now widely used in the treatment of prostate cancer. The problem with oral administration EMF is in the interaction with ions of calcium contained in food and drink. In the presence of calcium ions EMF gives precipitates and forms insoluble complex which is not absorbed by the digestive tract and thus has very little activity in the body. There have been several attempts to solve the problem, as relatively the pharmaceutical obtaining EMF salts, and estramustine. However, it was not possible to find such modification EMFs for oral administration, which would bespeco-estramustine, what gives water-soluble sodium salt of EMFs in the absence of calcium ions.

Esters of amino acids for pharmaceutical purposes described. However, these esters of alcohols, although containing a steroid skeleton, have a structure quite different from the patterns estramustine.

P R I m e R 1. 17-estramustine the CHLOROACETATE.

Estramustin (4.4 g 0.01 mol) dissolved in toluene (100 ml). Chlorocatechol (1.7 g, 0.015 mol) was added to the solution and heated at 70oC for 1.5 hours, the Solvent is then removed in a vacuum evaporator at 30oC. the Residue is treated with ethanol and the product crystallizes. The product is filtered and washed with several milliliters of ethanol. The CHLOROACETATE after drying at room temperature, melts at 95oC. Yield of 4.9 g

P R I m m e R 2. 17-estramustine bromoacetate.

This compound is obtained by a method similar to that described in example 1 from estramustine and bromoacetamide, so pl. 109oC.

P R I m e R 3. 17-estramustine N-methyliminodiacetic hydrochloride.

17-estramustine the CHLOROACETATE (5,2 g 0.01 mol) dissolved in acetonitrile (40 ml) at room temperature. Methylamine (3.1 g 0.1 mol) is dissolved in cold acetonitrile and added at 0oC. After 3 h, wt is water washed with 50 ml of water, setting each time the pH of the sodium bicarbonate solution 7-9. The organic phase is dried with anhydrous sodium sulfate and remove the solvent. The residue is dissolved in acetonitrile (40 ml) and the precipitated N-methyliminodiacetic by adding a solution of hydrogen chloride in ether (0.012 mol). Formed a voluminous precipitate, which after stirring for several minutes breaks up into fine crystals. The product is filtered and washed with a mixture of ethyl acetate and acetonitrile 1:1. Then the hydrochloride is dried under vacuum at room temperature for 24 h, the Output of 3.7, So pl. 226oC C decomp. NMR spectroscopy shows that the product has the structure estramustin 17-N-acetate.

P R I m e R 4. 17-estramustine N-acetate methanesulfonate and ethanesulfonate.

Using the method described in example 3, except for the application of solutions methansulfonate and econsultancy acid in the air instead of hydrogen chloride in ether were obtained methanesulfonate and aconsultant, so pl. 212aboutC and 170aboutRespectively.

P R I m e R 5. 17-estramustine N-R3-N-R3-aminoacetate hydrochloride.

Esters having the substituents R2and R3described in table.1. From 17-estramustine of bromoacetate with COI is chlorid and methanesulfonate.

Estramustin (4.4 g 0.01 mol) and N-tert.-butoxy carbonyliron (1.75 g, 0.01 mol) is dissolved in methylene chloride (35 ml). Add dicyclohexylcarbodiimide (2.1 g, 0.01 mol) and 4-dimethylaminopyridine (0.1 g, 0.001 mol) and the reaction mixture is stirred 3 hours Forming dicyclohexylphosphino removed by filtration and the solvent evaporated. The oily residue is dissolved in acetonitrile (10 ml) and added acetonitrile (40 ml) containing hydrogen chloride (0.03 mol) and stirred the mixture for 16 hours the Resulting precipitate is filtered off and recrystallized from a mixture of ether-methanol. Output 3.2 g 17-estramustine of aminoacetate hydrochloride (so pl. 220oC, the connection 6.1), as confirmed by NMR spectroscopy. The same method, except methanesulfonic acid instead of hydrogen chloride and the absence of crystallization obtained 17-estramustine aminoacetate meanswhat (connection 6.2), so pl. 206aboutC.

P R I m e R 7. 17-estramustine amino-propionate hydrochloride.

The following salts were obtained using the method described in example 6

17-estramustine 2-1-aminopropionic hydrochloride, T. pl. 248oC from N-tert.-butoxycarbonyl-L-alanine.

17-estramustine 3-aminopropionic hydrochloride, T. pl. 223

To estramustine (4.4 g, 0.01 mol) dissolved in methylene chloride (30 ml) was added N-benzyloxycarbonylglycine (2.2 g, 0.01 mol) dicyclohexylcarbodiimide (0.12 g 0.001 mol). The mixture is stirred at room temperature for 2 h Formed of DICYCLOHEXYL urea is filtered off, the filtrate is washed with hydrochloric acid (2M, 10 ml), water (10 ml), sodium carbonate solution (1M; 25 ml) and again water (25 ml) and dried with sodium sulfate. The solvent is evaporated in a rotary evaporator. The remaining oil is dissolved in ethanol (125 ml). Added palladium on coal (1 g, the palladium content of 5%) and treated with a mixture of hydrogen at room temperature and atmospheric pressure. When the reaction ceases, the mixture is filtered and the solvent evaporated. The residue is dissolved in acetonitrile (75 ml). Add methansulfonate acid (1 g, 0.01 mol). After 18 h stirring the residue is filtered off, washed with acetonitrile and dried at room temperature. Exit 17-estramustine aminoacetate methansulfonate 3,7, so pl. 204aboutC.

P R I m e R 9. 17-estramustine 4-(N,N-dimethylamino) butyrate hydrochloride.

To estramustine (4.4 g 0.01 mol) in methylene chloride (50 ml) was added 4-dimethylaminobutyric hydrochloride (1.3 g, 0.01 mol). The solution to the eat in ethanol solution and recrystallized from a mixture of ethanol-ether. The output of 6.5, So pl. 205aboutC. As confirmed by NMR spectroscopy, the product is a 17-estramustine 4-(N, N-dimethylamino)butyrate hydrochloride.

P R I m e R 10. Interaction with calcium ions.

The solution: 0.3 M dietansulfonat calcium. Calcium carbonate (1,38 g 15 mmol) is dissolved by adding 1 n solution econsultancy to obtain a constant pH of 5.3. The solution was diluted with water to 50 ml

Solution: 0.03 M dietansulfonat calcium. One part of the solution And diluted with 9 o'clock water.

Solution:0.05 M acetate buffer pH 4.5. Glacial acetic acid (3.0 g 0.05 mol) is dissolved in 800 ml of water, and titrate with 1 M sodium hydroxide solution to a pH of 4.5 and dilute to 1 liter of the Test compound is dissolved in 50 ml of solution C. the Pure solution is formed after a few minutes. After 5 minutes of entering the equimolar amount of calcium ions added to solution a or B. For mixture observed 3 h (see tab.3).

The results show that the new compounds in the presence of calcium ions do not give any precipitate at a concentration 10 times greater than the concentration estramustine phosphate disodium salt, necessary for the immediate formation of insoluble calcium salts extremisten phosphatase estramustine on dogs.

Various formulations was administered orally to a group of four greyhounds. The dose was equivalent to 140 mg estramustine phosphate. Animals were not fed prior to the adoption of the dose and gave them 50 ml of 0.01 M hydrochloric acid after the adoption. Blood samples were analyzed on estramustin using gas chromatography.

We used the following recipe:

1. An aqueous solution of disodium salt of phosphate estramustine.

2. An aqueous solution of compound 6.2.

3. An aqueous solution of compound N 4.2.

4. An aqueous solution of 7.2 connection.

Table.4 shows the area under the curve of concentration change estramustine in the blood plasma of dogs at the time. Average values were 5462, 118 60, 83 62 and 174+83 ng/MLC for estramustine phosphate compounds 6.2, 4.2 and 7.3, respectively.

Used several doses. The obtained values extrapolated to a dose equivalent dose of other compounds.

P R I m e R 12. Recipes, simple tablets. I:Connection 6.2 mg 160 Starch, 15 mg Polyvidone, 8 mg Ethanol III:Starch, 15 mg magnesium Stearate 2 mg

I mix and granularit with solution II. After drying and sieving through a sieve of 1 mm was added III. The mixture is pressed into tablets weighing 200 mg.

1. The esters of astrod, lower alkyl WITH1WITH4;

R3hydrogen, lower alkyl WITH1WITH4or R2and R3together CH2-CH2-CH2-CH2-;

n is 0,1 or 2,

or their pharmaceutically acceptable salts.

2. The method of producing esters estramustine General formula I

< / BR>
where R1hydrogen, lower alkyl WITH1WITH4;

R2hydrogen, lower alkyl WITH1WITH4;

R3hydrogen, lower alkyl WITH1WITH4or R2and R3together CH2-CH2-CH2-CH2-;

n is 0,1 or 2,

or their pharmaceutically acceptable salts, characterized in that carry out the etherification estramustine amino acid of General formula

HOOC CHR1(CH2)nNR2R5,

where R5=R3or not necessarily protective group,

with the product of General formula II

< / BR>
where R4group NR2R5,

which then removing the protective group to obtain compounds of General formula I.

3. The method according to p. 1, characterized in that the receive connections, where n=0.

4. The method according to PP. 1 and 2, characterized in that the receive connection R1the hydrogen.

5. The method according to PP.1 and 2, characterized in that the hydrogen methyl or ethyl radical.

 

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