Derivatives 17,20-epoxides pregnana, methods for their preparation, connection

 

(57) Abstract:

The invention relates to new derivatives of 17,20-epoxides Pregnana, to a method for their production and to their use as intermediates in the synthesis of biologically active products, specifically to derived 17,20-epoxides of General formula I

< / BR>
where R-=0, -OH, and In the remains of

< / BR>
and K=O, or group

< / BR>
or

< / BR>
where n=2,3;

R1-the remainder of the ether or of ester,

wavy lines indicate a mixture of isomers. The new compounds may find application in medicine. 6 C. and 5 C. p. F.-ly.

The subject of this invention is new derivatives of 17,20-epoxides Pregnana receiving them, their application to obtain cortisone derivatives and intermediate compounds.

More specifically, the invention relates to compounds of formula (I)

< / BR>
where

R - radical oxo or hydroxy, and loops A and B is the remainder of

< / BR>
< / BR>
where

K is the radical oxo or a group protecting the oxo radical of the formula

< / BR>
where

n is 2 or 3;

R1- the remainder of the ester or ether complex;

K' - oxo radical or a protecting group, type the oxime, hydrazone or semicarbazone,

wavy lines symbolize the mixture is, capable of blocking position 3 in this form, in particular it can be an alkyl radical with 1 to 6 carbon atoms, a radical of alkoxylalkyl with 3 to 8 carbon atoms, an aryl radical with 6-10 carbon atoms or the radical aralkyl with 7 to 12 carbon atoms.

When R1- alkyl radical, it is, for example, methyl radical, ethyl, propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, pentyl or hexyl.

When R1- radical alkoxylalkyl, it is, for example, the radical of methoxyethoxymethyl.

When R1- radical aralkyl, it is, for example, the benzyl radical or the phenethyl.

When R1the aryl radical, it is, for example, a phenyl radical or a phenyl radical, substituted, in particular by one or more alkyl radicals.

When R1- the remainder of the ether, it can be Siciliana grouping, for example, grouping trialkylsilyl, such as trimethylsilyl, tertiary butyl, dimethylallyl or, for example, grouping triallelic, such as triphenylsilanol or diarylethylenes, such as defenestrate.Boticelli.

When R1- the remainder of ester, it can be any residue, known to specialists that can block position 3 in EB is imawesa group type the oxime or semicarbazone, it is, for example, a residue of the formula = N-OX, where X is a hydrogen atom, an alkyl radical with 1 to 6 carbon atoms, preferably methyl, acyl radical with 1 to 10 carbon atoms, preferably acetyl or benzoyl, or an aryl radical with 6 to 12 carbon atoms, or a residue =N-NH-CO-Y, where Y is the amino radical or group

< / BR>
Z1, Z2, Z3the alkyl radicals with 1 to 6 carbon atoms or form together with the atom of the pyridyl radical and Hal is a halogen atom, preferably chlorine or bromine.

In particular, the invention relates to compounds, such as defined above corresponding to the formula I1< / BR>
< / BR>
where

R has the meaning already defined above, and cycles A1and B1- rest

< / BR>
< / BR>
where

n and R1have already specified value and K1and K'1group protecting the oxo radical, such as they are already defined, and in particular of the compounds corresponding to the formula I'1< / BR>
< / BR>
where

R and n have the specified values.

The invention especially relates to compounds, such as defined above corresponding to the formula I2< / BR>
< / BR>
where

R has the specified value.

The subject invention is also what I formula II:

< / BR>
where the dashed line indicates the possible presence of the second communication

to obtain the compound of formula III

< / BR>
where

A1and B1have a certain value,

which process alkilany ether tsianuksusnogo acid of formula IV:

N C-CH2-CO2R2< / BR>
where

R2the alkyl radical with 1 to 6 carbon atoms,

to obtain the compound of formula V

< / BR>
where

R2, A1B1and the wavy lines are defined above,

which is treated by means of epoxidation, to obtain the compounds of formula VI

< / BR>
The function of ester restore to obtain the compounds of formula I1A< / BR>
< / BR>
The ketone function in position II which, if desired, to restore, to obtain a compound of the formula I1B< / BR>
< / BR>
in the compounds of formula (I1A) and (I1B) frees the ketone function in position 3, if desired, to obtain the compound of formula (I2), such as defined above.

Protection of the ketone function in position 3 is carried out by methods known in the art. Thus it is possible to use, in particular, diol, triol or mixed thiol of the formula HO-(CH2)n-OH, HS-(CH2< and concentrated HBR, in catalytic quantities, para-toluenesulfonic acid, or in the presence of a Lewis acid such as zinc chloride, titanium tetrachloride or boron TRIFLUORIDE, preferably in the form of the ether extracts. You can use methylethylketoxime in the presence of acid, for example one of those mentioned above.

You can also use the alkyl halide, alkoxylalkyl of aralkyl or aryl, in the presence of a base, forming intermediate enolate, for example, hydride, alcoholate or alkaline hydroxyl.

You can use the halide trialkyl, Triaryl or diarylethylene in alkaline medium, as indicated above.

You can still use a suitable acid chloride, acting in the presence of a base, which may be nitrogen base, such as triethylamine, pyridine, dimethylaminopyridine or mineral base, in particular hydride, alcoholate or alkali hydroxide.

You can still use a suitable hydroxylamine may be in the form of the hydrochloride or other salts, or the formation or a suitable derivative, also in the form of the hydrochloride or other salt.

Action Olkiluoto ether tsianuksusnogo acid preferably is carried out in anhydrous SREA, for example, a Lewis acid, an acidic resin, benzoic acid or paratoluenesulfonyl.

Operate in the environment of an organic solvent, such as solvent aromatic compounds such as benzene, toluene or xylene, or cyclohexane.

By means of epoxidation is a tool that does not affect the grouping of the nitrile. Prefer hydrogen peroxide, used one, or in the presence of a transition metal, such as titanium, tungsten or molybdenum, for example in the form of a hydrated salt.

Apply preferably in an alkaline medium, in particular in the presence of carbonate, bicarbonate or alkali hydroxide or alkaline-earth hydroxide, in a solvent environment, which can be alkanol, preferably in a mixture with a co-solvent, in particular a halogenated solvent.

It is possible to use alkali hypochlorite, with a neutral pH or a pH close to neutrality.

This reaction epoxidase ,- ethylene nitrile shows original and unexpected nature, the fact that the nitrile saved that, a priori, not clear.

Restoration of function of ester is maintained by the action of alkaline borohydride in alcohol, environment, organic is igrid, for example double hydride of lithium and aluminium hydride Diethylenetriamine, hydride diisobutylaluminum or more dihydrobis(2-methoxy, ethoxy) sodium aluminate. Then act, for example, toluene or tetrahydrofurane.

Restoration of function of the ketone is carried out on one or the other above-mentioned reaction, under the conditions of these solvents.

It should be noted that both the recovery underway in the reverse order compared with that which occurs normally, i.e., the recovery of ester in 21 occurs before recovery of the ketone 11. It is also unexpected ways.

It is clear that without leaving the framework of the invention, it is possible to do both recover at the same time, without isolation of the intermediate compound (11-oxo. This example is in the experimental part.

The release of the ketone function in position 3 is means appropriate to the nature of the protective group. Use an acid medium in the presence of water or a mixture of water-alcohol, if Catala. For example, use a mineral or organic acid, such as hydrochloric acid, hydrogen bromide, sulfuric acid, perchloric acid, nitric, paratoluenesulfonyl, acetic acid, oxalic Calotte protection options 3-oxo is maintained by the action of iodine in the presence of a base, for example, alkali bicarbonate, or by the action of iodine in catalytic amounts in the presence of oxidizing agent, particularly hydrogen peroxide by the action of methyl iodide, Glyoxylic acid, or salts of metals, such as mercury or cadmium. You can usually act in a solvent such as lower alkanol, for example methanol or ethanol, mixed with halogenated solvent, for example methylene chloride, in the presence of water. In the case of a mixed Catala, unprotect is, for example, a mercury salt, such as chloride of mercury in the presence of buffer acetic acid/potassium acetate at about 100oC, the Nickel of Renee in the same conditions as above, or a mixture of hydrochloric acid - acetic acid hot.

In the case when R1- the remainder of the ester or ether complex, we also use a treatment with an acid, in particular, in the conditions described above for katala. The same applies to the release of the ketone function, protected in the form of oxime or semicarbazone.

The invention is also aimed at the use of compounds of formula (I) such as defined above, to obtain compounds of the formula A

< / BR>
where

R is defined above;

R3- grouping, protect the protect function hydroxy in position 21 of the compounds of formula (I), to obtain the compound of formula VII

< / BR>
where

R, R3A and B have already specified value,

function nitrile which hydratious to obtain the compounds of formula VIII

< / BR>
which is subjected to decomposition reaction Hofmann to obtain the compounds of formula IX

< / BR>
the function of the ketone which, if desired, release /position 3/, to obtain the target compound of the formula /A/.

Under the group protecting the hydroxy radical, means the grouping stable in terms of fashion and especially in the conditions of decomposition Hofmann, i.e., the residue of the ether and primarily alkyl radical with 1 to 6 carbon atoms, in particular methyl radical, ethyl, propyl.

Such esters are obtained, in particular, the action of the corresponding halide, in the presence of alkali, for example by the action of a suitable iodide or bromide, in the presence of a strong base such as a hydride, alkali metal amide or alkali alcoholate, operate in the environment of the solvent, which can be, in particular, ether such as tetrahydrofuran or dioxane, dimethylformamide, dimethylsulfoxide.

Hydration of the nitrile function is maintained by the action of aqueous mineral bases and, in particular, the action of sorites, preferably polar, such as tetrahydrofuran, dioxane, dimethylformamide, diethylsulfoxide or acetonitrile.

The decomposition of the amide is carried out by the action of alkaline or alkaline-earth hypokalaemia, in particular hypochlorite or sodium hypobromite, if necessary, formed "on the spot". Operate in the environment of the solvent which can be preferably one of those mentioned above, and in the presence of water.

The invention extends to the use such as defined above, characterized in that the decomposition is carried out without intermediate allocation amide formula /VIII/.

The possible release of the ketone function is performed under the conditions listed above.

Finally, the invention aims as new industrial products:

the compounds of formula

< / BR>
where

A1B1, R2and the wavy lines are defined above;

R4and R5form together a bond of carbon-carbon or epoxy in position ,

the compounds of formula

< / BR>
where

A, B, R, R3and the wavy lines are defined above,

R6the cyano radical or a radical carbarnoyl,

the compounds of formula

< / BR>
where

A1B1R and R

The compound of formula (II) are described, for example, in patent US 2844600.

The following examples illustrate the invention but do not restrict it.

Example 1: Cyclic 3,3-/1,2-ethandiyl/-acetal 17,20-epoxy-20-cyano-21-hydroxypregn-5-ene-3,11-dione.

Stage A: Cyclic 3,3-/1,2-ethandiyl/-acetal androst-5-ene-3,11,17-trione.

In an inert gas mix 10 g of adrenosterone and 150 cm3methylethylidene, heated under reflux for 30 minutes, add 0,033 g of p-toluenesulfonic acid and continue heating under reflux for 6 hours 30 minutes. Cooled to about 50oC, add 0.5 cm3of triethylamine and concentrated to dryness under reduced pressure. The obtained product is recrystallized in ethanol, sucked off and washed with cold ethanol, and then with a mixture of ethanol-water and dried. Get 6,35 g of the target product.

So pl. = 196-198oC.

Range of IR /CHCl3/.

The absorption at 1740 cm-1/17 C=O/ and 1706 cm-1/11-O/.

NMR spectrum /CDCl3, 250 MHz, 'clock N. m/ 0,86: 18-CH3; 3,95: CH2Catala; 5,38: H 6.

Stage B: Ethyl ether 20-tzia is the first stage And the product, 100 cm3xylene, 6.2 cm3ethyl ester tsianuksusnogo acid, 3.1 cm3hexylamine and 0.31 g of benzoic acid.

Heated with reflux for 24 hours, removing the water formed during the reaction, and then cooled to about 15oC and add 5 cm310% aqueous sodium bicarbonate solution. Stirred for 1 hour, and then decanted, washed with water the organic layer and concentrate under reduced pressure. Receive a crystalline product, which is recrystallized in ethyl ether acetic acid. After washing the crystals in hexane and drying obtain 3.42 g of the target product. Chromatography mother solutions on silicon dioxide, and elwira with a mixture of cyclohexane-toluene-ethyl ester acetic acid, (2-2-1), gain of 2.75 g of the target product.

IR spectrum (CHCl3)

absorption at 2226 cm-1(-CN), 1725-1707 cm-1(C=O conjugated ester), 1611 cm-1(C=C).

The NMR spectrum (CdCl3, 300 MHz, ppm)

1,01: CH318; 1,23: CH319; of 1.34 (t); CH3complex ester; 3,94: CH2acetal, 4,27 (d); CH2complex ester; are 5.36: H 6.

Stage B: Ethyl ether 20-cyano-3,3-(1-,2-tenderbox) 11-oxo-17,20-epoxypropan-5-ene-21-acid.Lena and 4 cm3of ethanol. At 20oC is added to a solution of 0.2 cm350% hydrogen peroxide. Then add a saturated solution of potassium bicarbonate in 50% ethanol to pH 9, and then incubated with stirring at a constant pH of 3 hours minutes. Then add 0.5 cm310% acetic acid, and then concentrated to dryness under reduced pressure at 25oC. the Residue is absorbed in a mixture of water and methylene chloride, decanted and concentrated to dryness of the organic layer. The remainder chromatographic on silicon dioxide, elwira a mixture of methylene chloride-ethyl ester acetic acid /95-5/ and get 0,236 g of the target product.

The IR spectrum /CHCl3/.

The absorption at 1764 cm-1and 1740 cm-1: carbonyl; 1707 cm-1: 11-keto; 2243-2235 cm-1CN unpaired; 1672 cm-1: C=C

NMR spectrum /CDCl3, 300 MHz, ppm/

1,05 /s/ /3H/; 18-CH3; 1,22 /s/ /3H/: 19-CH3; 3,95 /m/ /4H/: ketal; and 5.30 /m/ /1H/ H 6; 1,37 /3H/; 4,35 /2H/: -CH2-CH3-.

Stage D: the Cyclic 3,3-/1,2-ethandiyl/-acetal 17,20-epoxy-20-cyano-21-hydroxypregn-5-ene-3,11-dione.

In an inert gas mixed 4,36 g of the product obtained as described in stage B, 44 cm3toluene and 44 cm3of ethanol. To a solution of probable ablaut 0,097 g of sodium borohydride and continue stirring 2 h at 0oC. Then add 5 cm320% ammonium chloride, stirred for 30 minutes at 10oC, and then concentrated to probjem. Add 50 cm3water and 50 cm3ethyl ester of acetic acid, stirred the mixture and decanted. Dry the organic layer and concentrate to dryness. The remainder chromatographic on silicon dioxide, elwira a mixture of methylene chloride - ethyl ester acetic acid /8-2/ receive 3,17 g of the target product.

IR spectrum: /CHCl3/.

Absorption at 3605 cm-1/-OH/, 2242 cm-1(-CN), 1705 cm-1/C=O/, 1670 cm-1/C=C/.

NMR spectrum /CDCl3, 200 MHz, ppm/

1,01: CH318; 1,22: CH319; 3,18: CH221; 3,95: CH2acetal; 5,35: H 6.

Example 2: Cyclic 3,3-/1,2-ethandiyl/acetal 11-, 21-dihydroxy-17,20-epoxy-20-CANopen-5-ene-3-one.

In an inert mixed gas of 5.9 g of the product obtained in stage b of example 1, 120 cm3ethanol and 1.2 g of sodium borohydride, and then stirred for 45 minutes at room temperature. The mixture is then heated to 45oC and add 0.6 g of sodium borohydride after 1 hour 30 minutes, and then again after 3 hours. After 4 hours and 30 minutes, cooled to 0-5oC, slowly add 200 cm3is then added to the mixture of water-ethyl ester acetic acid, dry the organic layer and concentrate to dryness. The residual product was then purified by chromatography on silica, elwira with a mixture of cyclohexane-ethyl ester acetic acid /1-1/ and get 3 g of the target product.

The IR spectrum /CHCl3/.

Absorption at 3614 cm-1/OH/, 2240 cm-1/C=/, the absence of C=O.

NMR spectrum /CDCl3, 200 MHz, ppm/

1,28 /s/: CH318; 1,32 /s/: CH319; 3,76 and a 3.87 /d - J = 12/: CH221; 3,95: CH2Catala; 4,5: H 11; the 5.25: H 6.

Example 3: 17 - hydroxy-21-methoxypropan-4-ene-3,11,20-Trion.

Stage A: Cyclic 3,3-/1,2-ethandiyl/-acetal 17,20-epoxy-20-cyano-21-methoxypropan-5-ene-3,11-dione.

In an inert gas mixed 20 cm3anhydrous tetrahydrofuran and 0,668 g of 50% sodium hydride in oil. Added over 5 minutes with stirring and 20-22oC the solution is 4.21 g of the product obtained in example 1 in 30 cm3tetrahydrofuran (THF). Stirred for 40 minutes at 20-22oC, and then add 3 cm3iodotope bromide and continue stirring for 1 hour. Thus the resulting solution was poured into a mixture of 50 cm320% aqueous solution of ammonium chloride and 50 g of ice. Extracted with ethyl ether, acetic acid, dried the organic layer and milovy ester of acetic acid. After drying receive a 4.03 g of the target product. So pl. # 256C.

The IR spectrum /CHCl3/.

The absorption at 2248 cm-1(-CN) ; 1706 cm-1/C=O/, 1670-1637 cm-1/C=C/ OH no.

NMR spectrum /CDCl3, 300 MHz, ppm/

1,00 /s/: CH318; 1,22 /s/: CH319; 3,47 /s/: O-CH3; 3,57: -CH221; 3,95: CH2Catala; 5,35: H 6.

Stage B : Cyclic 3,3-/1,2-ethandiyl/acetal 17,20-epoxy-20-carbarnoyl-21-methoxypropan-5-ene-3,11-dione.

0.36 g of the product obtained in stage A, and 0,049 g of lithium hydroxide dissolved in 7.5 cm3dioxane and 2.5 cm3water. Heated under reflux for 2 hours. Cooled to room temperature, and then diluted to 0.2 N.-Oh hydrochloric acid. Extracted with methylene chloride, dried the organic layer and concentrate to dryness. Get 0,378 g of the target product, which is used in this form may be processed by the method of decomposition Hofmann, as indicated in the next stage.

NMR spectrum /CDCl3, 200 MHz, CHN.m./

0,88 /s/: CH318; 1,17 /s/: CH319; 3,24 /1H, d, J = 11 Hz/ 4,18 and /1H, d, J = 11 Hz/: CH221; 3,39 /3H, s/ O-CH3; lower than the 5.37 /1H, dd, J = 2.5 Hz and J = 7.5 Hz/ H 6; 5,67 /1H, d, J = 4 Hz/ and to 6.19 /1H, d, J = 4 Hz/: -NH2-.

Stage b: Cyclic 3,3-/1,2-ethandiyl/-the adiya's And product and 0,049 g of lithium hydroxide. Add 5 cm3dioxane and 1 cm3water, and then heated to reflux for 3 hours. The solution is cooled with ice bath and add 0.5 cm315% sodium hypochlorite and stirred for 3 hours at 0 - 20oC, adding two times 1 cm3sodium hypochlorite /15%/. Diluted with water, extracted with ether, dried and concentrated to dryness of the organic layer. The remainder chromatographic on silicon dioxide, elwira a mixture of ethyl ester of acetic acid - cyclohexane /15-85, and then 50-50/ and get 0,073 g of the target product, which is recrystallized optionally in a mixture of methylene chloride-hexane.

So pl. = 236oC.

The IR spectrum /CHCl3/.

Absorption at 3610 cm-1: OH, 1703 cm-1and 1670 cm-1: CO= and C=C.

NMR spectrum: /CDCl3, 200 MHz, ppm/

0,63 /s, 3H/: CH318; 1,21 /s, 3H/: CH319; 3,45 /s, 3H/: O-CH3; 3,95 /4H/: -CH2acetal, 4,17 /d, J = 18 Hz, 1H/ 4,36 and /d, J = 18 Hz, 1H/: CH221, are 5.36 /m 1H/ H 6.

Stage D: 17-hydroxy-21-methoxypropan-4-ene-3,11,20-Trion.

In an inert gas mixed 0.036 g of the product obtained in stage B, with 1 cm3methanol and 0.2 cm32 N. hydrochloric acid. Stand by stirring for 4 hours, the precipitate is sucked off and dried it. Get 0,012 g a the 3
/.

Absorption at 3610-3480 cm-1: 17-OH, 1706 cm-111 C=0 and 20 C=0; 1667 cm-1: 3-C-O conjugate; 1617 cm-14,5.

NMR spectrum /CDCl3, 200 MHz, ppm/

0,67 /s/: CH318; 1,41 /s/: CH319; 3,44 /s/: O-CH3; 3,47 /s/: OH 17; 4,19 /d/ and or 4.31 /d/: CH221, 5,74: H 4.

Example 4: 17 - hydroxy-21-methoxypropan-4-ene-3,11,20-Trion.

Stage A: 17,20-epoxy-20-cyano-21-hydroxypregn-4-ene-3,11-dione.

In an inert gas 4.1 g of the product obtained as described in example 1, is mixed with 80 cm3methanol and 7 cm3chloride methylene. Add 20 cm32n. hydrochloric acid and stirred at room temperature for 4 hours. Suck-formed crystals, wash them with a mixture of methanol-water /8-2/ and then water. Concentration of the mother solutions produce an extension product. After drying purify the product by chromatography on silica, elwira a mixture of chloroform - isopropanol /95-5/, and get a 3.3 g of the target product. So pl. = 256oC.

IR spectrum: /CHCl3/.

Absorption at 3310 cm-1: OH, 1703 and 1654 cm-1: With=O; 1612 cm-1: C=C

NMR spectrum /CDCl3, 300 MHz, ppm/

1,04 /s/: CH318; 1,42 /s/: CH319; 3,84 /Syst AB/: -CH2OH; 5,74 /s/ a: H 4.

An CLASS="ptx2">

Stage B: 17,20-epoxy-20-cyano-21-methoxypropan-4-ene-3,11-dione.

Broadcast in 21 prepared by the method described in stage a of example 5 starting from the product obtained above in stage A.

Stage b: 17 - hydroxy-21-methoxypropan-4-ene-3,11,20-Trion.

At the end of use of the compound obtained above in stage B, or, as indicated in stage B of example 3, separating the intermediate product 17,20-epoxy-20-carbarnoyl-21-methoxypropan-4-3,11-dione, and then treating this compound with a solution of sodium hypochlorite on the principle of decomposition Hofmann, or, as indicated in stage b of example 3, i.e., producing this decomposition without intermediate highlight the connection 20-carbamoyl. Get the target product, the same as obtained in stage G of example 3.

Example 5: 11,17 - dihydroxy-21-methoxypropan-4-one-3,20-dione.

Stage A: Cyclic 3,3-/1,2-ethandiyl/acetal 11 - hydroxy-17,20-epoxy-20-cyano-21-methoxypropan-5-ene-3-one.

Act as in stage a of example 3, on the basis of the product obtained in example 2, and obtain the target product.

Stage B: Cyclic 3,3-/1,2-ethandiyl/-acetal 11,17 - dihydroxy-21-methoxypropan-5-ene-3,20-dione.

Act, on the basis of the product obtained above in stage A, is-epoxy-20 - carbarnoyl-21-methoxypropan-5-ene-3-one, and then treating this compound with a solution of sodium hypochlorite, on the principle of decomposition Hofmann, or, as indicated in stage b of example 3, i.e., making this decomposition without releasing connection 20-carbamoyl.

Stage: 11-,17 - dihydroxy-21-methoxypropan-4-ene-3,20-dione.

Act as described in stage G of example 3 from the compound obtained above in stage B. Obtain the target product.

Example 6: 11,17 - dihydroxy-21-methoxypropan-4-ene-3,20-dione.

Stage A: 11,21 - dihydroxy-17,20-epoxy-20-CANopen-4-EN-3-one.

In an inert gas mixed 3 g of the product obtained in example 2, 66 cm3methanol and 10 cm3chloride methylene. Add 15 cm32n. hydrochloric acid and stirred at room temperature for 2 hours. Sucked off the crystals, wash them with a mixture of methanol - water /75-25/ and then the water is sucked off saducees crystals, washed with water and finally concentrating the mother liquor solutions, sucked off the newly formed crystals and wash them with water. All dried crystals and recrystallized them in methanol. Receive 1 g of the target product.

IR spectrum: /CHCl3/.

Absorption at 3485 cm-1: region OH/NH, 2240 cm-1CN, 1628 and 3 19; 3,81 /d/: OH 11; 3,76 and 3,88 /-Syst AB/: CH221; 4,45: H 11; 5,69 /s/ a: H 4; 7,18: mobile H.

Analysis: C22H29O4N /371,52/.

Calculated: C% 71,12; H% 7,86; N% Of 3.77.

Found: C% 71,00; H% Of 7.90; N% 3,70.

Stage B: 11 - hydroxy-17,20-epoxy-20-cyano-21-methoxypropan-4-EN-3-one.

Prepare the ester in 21 according to the method described in stage a of example 3, on the basis of the product obtained in the previous stage A.

Stage: 11,17 - dihydroxy-21-methoxypropan-4-ene-3,20-dione.

Come from the product obtained in the preceding stage B, or, as indicated in stage B of example 3, highlighting the intermediate 11 - hydroxy-17,20-epoxy-20-carbarnoyl-21-methoxypropan-4-EN-3-one, and then treating this compound with a solution of sodium hypochlorite on the principle of decomposition Hofmann, or, as indicated in stage b of example 3, i.e., making this decomposition without isolating the intermediate compound 20-carbamoyl. Get the target product, the same as the one that is obtained in stage b of example 5.

1. Derivatives 17,20-epoxides Pregnana General formula I

< / BR>
where R is oxo or hydroxy-group, and the cycles a and b is the remainder of

< / BR>
where-To - oxoprop or group, protecting her, formulas

< / BR>
where n = 2 or 3;

R1I< / BR>
< / BR>
where R has the above significance, and R is oxo, protected, andIand BIhave the meanings specified in paragraph 1 for a and B.

3. Connection under item 1 or 2 of General formula II< / BR>
< / BR>
where R and n have the above values.

4. Connection on p. 1 of General formula I2< / BR>
< / BR>
where R has the above significance.

5. The method of obtaining 17,20-epoxides Pregnana General formula I, as specified in paragraph 2, characterized in that the compound of General formula II

< / BR>
where - - - means possible second bond carbon-carbon

protect the ketone function in position 3, to obtain the compound of General formula III

< / BR>
where AIand BIhave the above values,

which is further processed alkilany ether tsianuksusnogo acid of General formula IV

NC-CH2-CO2R2< / BR>
where R2- C1-C6alkyl,

to obtain the compound of General formula V

< / BR>
where R2, AIBIand the wavy lines are defined above,

which is treated with hydrogen peroxide, possibly in the presence of transition metal to obtain compounds of General formula VI

< / BR>
the function of ester which restores when manual is poured to obtain compounds of General formula IIB< / BR>
< / BR>
in the compounds of the formula IIaand IIBthe ketone function in position 3 by request free, to obtain the compound of the formula I2.

6. The method of obtaining compounds of General formula

< / BR>
where R has the above meanings;

R3- C1-C6alkyl;

the dotted line is a possible second bond carbon-carbon

characterized in that the compound of formula I protect the hydroxy-group in position 21 to obtain compounds of General formula VII

< / BR>
where R, R3, A and b have the above values,

function nitrile which hydratious, to obtain the compound of General formula VIII

< / BR>
which is subjected to decomposition reaction Hoffmann, to obtain the compound of General formula IX

< / BR>
in which optionally free function of the ketone at the 3 position to obtain the target compounds of formula A.

7. The method according to p. 6, characterized in that the conduct of the decomposition without intermediate allocation amide of formula VIII.

8. The method according to PP.6 and 7, characterized in that the hydration functions nitrile lead by the action of aqueous mineral Foundation in medium polar solvent.

9. Compounds of General formula

< / BR>
form together apachegroup in position , or together form a second bond carbon-carbon intermediates in the synthesis of compounds of formula I.

10. Compounds of General formula

< / BR>
where a, b, R and the wavy lines are defined in paragraph 1;

R3is defined in paragraph 6;

R6is cyano or carbarnoyl,

as intermediates in the synthesis of compounds of formula A.

11. Compounds of General formula

< / BR>
where AIBIand R are defined as in point 2;

R3defined as in point 6 with the exception of compounds in which AIBImean residue

< / BR>
which means a protective group

< / BR>
where n = 2 or 3, and R - coradical, as intermediates in the synthesis of products of formula I.

 

Same patents:

The invention relates to new anti-inflammatory and antiallergic active compounds and methods for their preparation

The invention relates to compounds of General formula I in the form 22R and 22S-ephemerol, where X1and X2are the same or different and each represents a hydrogen atom or a fluorine atom, provided that X1and X2at the same time are not hydrogen atoms; methods for their preparation; pharmaceutical preparations containing them; and the use of these compounds in the treatment of inflammatory and allergic diseases

The invention relates to a new method of obtaining 11-ketosteroid derivatives of General formula I, where R is H, acyl, C1- C8, R1- CH3CH2OR11, R11- H, acyl, C1- C8, 3-oxoprop protected in the form of atlanticocean consists in the fact that the compound of formula II is converted into gelegenheden formula III in the presence of alcohol, and the resulting product is treated with acid

The invention relates to a new method of obtaining 11-ketosteroid derivatives of General formula I, where R is H, acyl, C1- C8, R1- CH3CH2OR11, R11- H, acyl, C1- C8, 3-oxoprop protected in the form of atlanticocean consists in the fact that the compound of formula II is converted into gelegenheden formula III in the presence of alcohol, and the resulting product is treated with acid

The invention relates to the field of synthesis of steroid compounds

The invention relates to covered bridge in position 1417thestratriene General formula I

< / BR>
where

if OR3is set tothen

R1, R2and R3independently from each other represent a hydrogen atom, acyl groupin which R4represents an organic residue with a number of carbon atoms up to 11, or a residue -/CH2/nCOOH carboxylic acid, with n=1-4, and, in addition, R1denotes benzyl, C1-C8-alkilany or C3-C5-cycloalkenyl balance, and

if OR3is in "beta", then

R1, R2and R3independently from each other represent a hydrogen atom, acyl group with 1-12 C-atoms, and R1additionally represents C1-C8is an alkyl residue, and in both cases A-B denote ateno or ethano-bridge,

the method of production thereof, pharmaceutical preparations that contain these compounds and to the use for the preparation of Lech

The invention relates to organic chemistry, specifically to a method for producing triterpene glycopeptides derived glycyrrhizic acid (GA) using unprotected glycoside (carboxy-component) and free amino acids or dipeptides (aminoquinones AK)

The invention relates to inhibitors of steroid alpha-reductase have the following formula:

< / BR>
where Y is oxygen or sulfur; R is the group: (a) OR4where R4is hydrogen or C1-C6alkyl group; b)where each of R5and R6independently hydrogen or C1-C6alkyl group;)where R7is hydrogen or C1-C6alkyl group, W is a group; (I)where R8- C1-C6alkyl group, a C5-C6cycloalkyl group, C6-C9cycloalkylation group, phenyl group or benzilla group; or (II)where R9- C1-C6alkyl group or a C5-C6cycloalkyl group, or (III)where R5and R6defined above; g)where each of R10and R11- independently hydrogen or C1-C6an alkyl group or both in the static ring, optionally comprising at least one additional heteroatom selected from oxygen and nitrogen; n is an integer from 2 to 4; R1is hydrogen, C1-C6alkyl group, a C5-C6cycloalkyl group, C6-C9cycloalkylation group or aryl group; each of R2and R6independently selected from the group consisting of hydrogen, C1-C6of alkyl, C5-C6cycloalkyl, C6-C9cycloalkenyl and aryl, or R2and R3together with the nitrogen atom to which they are bound, form pentatominae or hexatone rich heterophilically ring, optionally comprising at least one additional heteroatom selected from oxygen and nitrogen; the symboldenotes a single or double bond, provided that when is a double bond, the hydrogen in the 5-position is absent, and its pharmaceutically acceptable salts

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 have anti-tumor properties

The invention relates to new androstane derivative of formula I, where R1is a hydrogen atom or alkanoyl: R2- alkanoyl; W1and W2- same or differentor one of the symbols means a chemical bond, and the otheror W1-and W2-; one of R3and R4- the hydrogen atom and the other is - OR1or R3and R4together mean oxoprop or C2-5- alkylenedioxy; E, R5- alkyl or alkenyl; provided that derivatives containing a cyclic structure with two atoms of nitrogen, only the Deputy E means the above group, which is connected by a chemical bond with the nitrogen atom not directly related to steroid skeleton of the molecule, while the other alternate E mean free pair of electrons; X-anion, and n and m independently of each other - 2 or 4 provided that the sum of n and m in one cyclic structure is from 4 to 6, regardless of their values in a different cycle

The invention relates to pharmaceutical industry and relates to a combined pharmaceutical preparation for contraception

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