• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:

    公开号:SU942602A3
    申请号:SU802891743
    申请日:1980-02-29
    公开日:1982-07-07
    发明作者:Неделек Люсьен；Торелли Весперто；Фурне Робер；Турнемин Колетт
    申请人:Руссель-Юклаф (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new compounds of the formula
    where R is in the cC position or [y-alkyl or alkenyl with: 2-8 carbon atoms, cycloalkylalkyl with 4-8 carbon atoms or arylalkyl with 7-12 carbon atoms and / or X and Y are a group.
    or X is an oxy group and Y is a group
    ABOUT
    II * -CH 2 CH 2 (! -OM where M is a hydrogen atom, an alkali metal atom or an MND group.
    When R is saturated alkyl, the preferred radicals are ethyl, propyl, isopropyl, butyl, isobutip or tertiary butyl, pentyl, hexyl, 2-methylpentyl, 2,3-dimethylbutyl or H-heptyl; when R is alkenyl, then preferred the radicals are vinyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl when R is cycloalkylalkyl / the preferred radicals are cyclopropylalkyl, in particular cyclopropylmethyl or cyclopropylethyl, when R is arylalkyl, the preferred radical is benzyl.
    . When the M atom is an alkali metal, the preferred metals are sodium, potassium or lithium.
    Preferred compounds obtained by the proposed method are compounds of formula (1), where X and Y are a group
    as well as those where X is an oxy group and Y CJ ^ CHgCC ^ K. In this case, R is in position 7 s / and has the following meanings: ethyl, n-propyl, I-butyl, 2-methylpropyl, vinyl or allyl. In particular, the preferred compounds are potassium salt, 7 oL-propyl, -17 βoxy- 3-oxo-17 </ - pregn-4-en-21-carboxylic acid and dg-lactone 7d / -propyl-1 7-hydroxy-3-oxo-17cC-pregn-4-10 en-21- carboxylic acid.
    It is known that 7-mixed steroids of the pregnane series, in particular, d-lactone 7 оС-thioapetyl-17/3-hydroxy-3-oxo-17d-pregn-4-en-21-carboxylic acid 15 (spironolactone), have antialdosterone and reduced side anti-androgenic effect £ 1].
    A known method of producing 7-alkshg derivatives of androst-5-en-Z-one, which includes processing the original androst-4,
    6-dien-3-one dialkyl lithium cuprate in an organic solvent £ 2].
    The purpose of the invention is the expansion of means of influence on a living organism. 25
    This goal is achieved by a method of obtaining compounds of formula (1), namely, that the compound of the formula
    enter into interaction with the compound of the formula
    (III) where I has the above meanings and On C is an atom of chlorine or bromine, in the presence of a monovalent copper salt or with a compound of the formula (Ju2.Cu1i where R has the above meanings and then the reaction mixture is treated with an acid to obtain a compound of general formula 50
    where R has the above meanings, which are either isolated or treated with an alkali metal hydroxide or ammonium hydroxide to obtain a compound of the general formula
    where R has the above meaning,
    The M-atom of an alkali metal or group mn 4 , which, if necessary, is treated with acid to obtain a compound of formula (1β), where the M-atom of hydrogen with the release of the target products in the form of knocked down p> - isomers or mixtures thereof.
    In a preferred embodiment of the method, monochloride, monobromide or copper monoiodide is used as the salt of monovalent copper, the acid used is hydrochloric, nitric or sulfuric, the various isomers obtained are separated by chromatographic method or fractional crystallization, alkali metal hydroxide, to which the compound of formula (1e) is subjected is potassium hydroxide or caustic soda, the acid to which the compound of formula (Te) is treated is hydrochloric, nitric or acetic.
    PRI me R 1. 0G-lactone 7sb-ethyl 17 -oxy-Z-oxo-17 ob-pregn-4-en-21 carboxylic acid.
    To 2.86 g of copper monoiodide is added
    5.25 cm of N-butyl sulfide, and the resulting mixture was stirred at room temperature.
    Complete dissolution of the monovalent copper salt ends after about 10 minutes. To the resulting complex was added a solution of 10.2 g of canrenone (or 2G-lactone 17 β — hydroxy-3 — oxo — 17c _ pre-4,6-diene-21-carboxylic acid) in 150 cm ^ anhydrous tetrahydrofuran. The resulting solution was cooled to -30 ° C and 54 Ohm 5 0.9 M ether solution of ethyl magnesium bromide was slowly added over 75 minutes with vigorous stirring. diluted with 50 cm ^ of ethyl ether and 50 cm "3 of tetrahydrofuran. Stirring was continued at - 30 ° C for an additional 60 minutes and then the reaction mixture was acidified by adding 2N e 120 cm. hydrochloric acid solution. Stirred for 60 min at room temperature, decant the organic layer, washed with water, su
    W £ + 67 ± 1.5 (1%, 10 min and evaporated to dryness. The obtained crystalline residue was chromatographed on silica using a mixture of cyclohexane / ethyl ester of acetic acid (3: 2). The mixture was sequentially: 5
    6.3 g d. -isomer of the target product, melting at 167 ° C, the melting point does not change after recrystallization. product in methanol, chloroform),
    3.2 g of the β-isomer of the target product, melting at 150 ° C, and then at 170 ° C.
    An analytical sample is obtained by recrystallization from methanol. T. pl. 155 ° C, and then 172 ° C after hardening, (pD ^ + 62.5 + 1.5 ° (1%, chloroform).
    Example 2. - / (acton-7o / -propyl-17p> -oxy-3-oxo-17o6-pregn-4-en-20 21-carboxylic acid.
    To a complex of 382 mg of copper monoiodide and 0.7 cm of n-butyl sulfide obtained with stirring at room temperature, a solution of 5.1 175 canrenone (or lactone-17p> -oxy—) is added
    Z-oxo-17 (D-pregna-4,6-diene-21-carboxylic acid) in 75 cm of anhydrous tetrahydrofuran and 5 and 5O cm 3 of anhydrous ethyl ether. The mixture is cooled to -20 ° C 30 and with vigorous stirring, a 1.2 M ether solution of propyl magnesium bromide is added over 35 minutes. After an additional 10 minutes of stirring. , at –20 ° С the reaction mixture was acidified — 3J was added by adding 50 cm 3 3 5 n. hydrochloric acid solution, Stirred for 30 minutes at room temperature, and then extracted with ethyl acetate. The organic layer is washed with water, 4θ 0.2 N. sodium thiosulfate solution and water, dried with sodium sulfate and evaporated to dryness. The residue is chromatographed on silica using a mixture of benzene - ethyl ether (No: 4). Allocate 45 sequentially:
    3.3 g of crystalline fit -isomer of the target product,
    1.4 g of amorphous p> -isomer of the target product.
    An analytical sample of the target product (7 s / -propyl derivative) is obtained by recrystallization from methanol. 'T. pl. 205 ° C £ o (3 ^ 4-70 + 1.5 ° (1%, chloroform). 55
    Example 3. Potassium salt of 7o £ -propyl-17 ^ -oxy-3-oxo-17o1-pregn-4-n21-carboxylic acid,
    1J.5 g obtained in example 2 compounds, 5.4 cm 3 0.53 N. a solution of caustic potassium in ethanol and 5.4 cm 'of water is heated t * to a boil under reflux ! com for 15 min, and then evaporate +. melted to a small volume under reduced pressure to obtain a thick yellow syrup. After adding 50 cm 3 of acetone, the crystalline precipitate is filtered off, washed with acetone and dried. at 50 ° C, after which it is recrystallized from 1.3 cm of water. with the addition of s
    19.5 cm 3 of acetone. 1 g of the expected product is obtained in the form of a monohydrate. T. pl. about 29СРс, Е ^ Sv = + 48 + 1,5 ° (1%, water).
    Example 4. T-lactone 7o1- & y ~ til- ^ 17p-hydroxy-3-oxo-17 (£ -prev-4-ne21-carboxylic acid.
    To 191 mg of copper monoiodide, 0.35 cm 3 of c-butyl sulfide is poured with stirring, the resulting complex is dissolved in 35 cm ^ of anhydrous tetrahydrofuran and 1.7 g of canrenone (or 7G-lactone 17 β-hydroxy-Z-oxo1 7cL-pregna are added -4,6-diene-21-carboxylic acid). The resulting solution was stirred in an ice bath and added to it over 30 minutes. 7.5 cm 3 of a 1.2 M solution of butyl magnesium bromide in ethyl ether. . After 30 min, the reaction mixture was acidified using a large excess of 5 N. hydrochloric acid solution and treated in accordance with example 2. Chromatography on silica using a mixture of cyclohexane / ethyl acetate (3: 2), is isolated sequentially:
    crystalline q / -isomer, which is triturated in isopropyl ether, is filtered off and dried in air, 1.12 g of product are obtained, so pl. 147 ° C. The analytical sample after recrystallization from methanol melts at 149 ° C., (^ Jjj = + 54 + l ° (1%, chloroform),
    0.65 g of amorphous β-isomer.
    PRI me R 5. Potassium salt 74, ^ y — tyl-17 β-Oxy-3-oxo-17 оС-pregn-4-en21-carboxylic acid.
    1.19 g of the compound ^ obtained in Example 4 are heated to reflux for 15 minutes,
    5.4 cm 3 0.53 N. potassium hydroxide solution 'in ethanol and 5.4 cm and the water, and then the reaction mixture was concentrated in vacuo to give a pale yellow viscous syrup. After adding 50 cm of acetone, the potassium salt crystallizes in the form of fine needles. The crystals are filtered off, washed with acetone, dried at 50 ° C and then recrystallized by dissolving in 3 cm 3 of acetone containing 50% water and adding 28.5 cm ^ of acetone. 1.13 g of the expected product is obtained in the form of a dihydrate. T. pl. about 260 ° C £ </] = 36.5 + 1, ^ (1%. water). υ
    Example -J-lactone 7d / - (2-methylpropyl) —17 p> oo si-3-oxo-17 </ - pregn4-e n-21 — carboxylic acid. ‘
    The complex, obtained from 135 mg of copper monoiodide and 0.25 cm 3 of N-butyl sulfide, is dissolved in 15 cm 3 of anhydrous tetrahydrofuran and 680 mg of canrenone (or lactone 17βoxy-3-oxo-17cc —preg at –4.6– are added di e n-21 carboxylic acid). The solution is cooled to - 3O ^ C, with vigorous stirring, 4.3 cm 3 of a 0.7 M solution of isobutylmagnesium bromide in ethyl ether is added dropwise to it over 20 minutes. After complete addition, the reaction mixture was stirred for 15 minutes at -30 ° C.
    Then the resulting suspension is acidified with a large excess of 2 N. hydrochloric acid solution, stirred for 30 min at room temperature, and then extracted with ethyl acetate. The extracts are washed with water, dried and evaporated to dryness. The residue was chromatographed on silica using a benzene-ethyl ether (1: 9) mixture. Allocate sequentially:
    450 mg of the OC isomer, which is recrystallized from 1 cm 3 of methanol, gives 320 mg of solvated c. 0.5 mol of methanol crystals of the target product, melting at 190 ° C, after desolvation, so pl. about 100 ° C; [2] = + 63 + 1.5 ° (1%, chloroform).
    310 mg [3 — isomers, the product is recrystallized from a mixture of methylene chloride and isopropyl ether to obtain 230 mg of the product, mp. 218 ° C; [<2j = +79 + 1.5 ° (1%, chloroform). at. PRI me R 7.y-lactone 7-ethenyl-1-17 oxy-Z-oxo / 17s // - 4-pregnen ~ 21-carboxylic acid.
    At room temperature, 2.1 g of copper monoiodide and 5.6 cm 2 * of Ibutyl sulfide are mixed, and then the resulting complex is added to a solution of 10 g of canrenone * (or '£' -lactone-17 ^> - oxiZ-oxo-17c / - pregna-4,6-diene-21-carboxylic acid 35 new) in 200 cm 3 of anhydrous tetrahydrofuran. The resulting solution was cooled to -20 ° C and was added dropwise thereto over 80 minutes with vigorous stirring 44 cm 3 N. a solution of vinyl magnesium chloride in tetrahydrofuran. After the addition is complete, stirring is continued at −20 ° C. for another 60 minutes, and then the reaction mixture is acidified with 45 cm 3 N. hydrochloric acid solution. Stirred for 90 minutes. at room temperature and extracted with ethyl acetate. The organic layer was washed with water, a 0.2 M sodium thiosulfate solution, dried and evaporated to dryness. The remaining oil is chromatographed on silica 15 using a cyclohexane / ethyl acetate (1: 1) mixture.
    Allocate sequentially:
    2.9 g of the desired isomer, melting at 199 ° C after recrystallization of isobutyl ether of acetic acid, and then from ethanol at 75 ° C; [s /] = + 17.5 + + 1.5 ° (1%, chloroform), ®
    3.5 g of the P> -isomer having a triple melting point: about 100, then 25.142 and 161 ° С after recrystallization from a mixture of methylene chloride / isopropyl ether.
    PRI me R 8. J * -lactone 7c £ - (2propenyl) —17-oxy-Z-oxo-17οί-pregn, -
    4-en-21-carboxylic acid.
    a) Obtaining a soluble complex of bis- (n-butyl sulfide) copper monoiodide.
    At room temperature, 475 mg of copper monoiodide is mixed with 0.875 cm 3 of sulfide and-butyl. Slightly exothermic dissolution of monovalent—.
    Noah copper ends after 10 minutes. The resulting complex (yellow-orange liquid) is dissolved in 10 cm 3 of anhydrous ethyl ether.
    . b) Preparation of ’'lithium di-allyl cuprate.
    To a solution of 1.95 g of triphenylallylolose in 15 cm 3 of anhydrous ethyl ether, 2.85 cm 3 of a 1.75 M solution of phenyl lithium in a mixture are added with stirring. benzene ethyl ether (7: 3). An abundant white tetraphenilopov precipitate forms immediately. The reaction mixture was stirred for 15 minutes and then cooled to -30 ° C, the ether solution of the above complex was added to it for 10 minutes, and stirring was continued for another 15 minutes. A lithium diallyl cuprate solution containing tetraphenyl tin in the form of a suspension is obtained.
    c) Reaction with a steroid.
    To the mixture obtained above was added a solution of 680 mg of canrenone (or γ-lacquer 9 '942602 tones of '17 P - About xi-3-oxo-1 7 -preg on-4, 6-diene-21-carboxylic acid) in 25 cm ~ of anhydrous tetrahydrofuran. After stirring for .90 minutes at -30 ° C, the reaction mixture is acidified with 5 by adding 15 cm * 2 N. hydrochloric acid solution and stirring is continued at room temperature for 2 hours
    The tetrafenilopovo was separated by filtration, the organic layer was separated, washed with water, dried and evaporated to dryness. The residue is chromatographed on. silica using a mixture of chloroform / ethyl acetate (95: 5). 408 mg of the desired 15 compound are isolated, melting at 184 ° C, and then at 194 ° C after re-hardening. An analytical sample is obtained after recrystallization from .. methanol, so pl. 196 ° C, [c / J = + 113 + 3 ° 20 (0.7%, chloroform). B
    PRI me R 9. 0 · -lactone 7 l / -cyclopropylmethyl-17-hydroxy-3-oxo-17 <U_-pregn4-ene-21-carboxylic acid.
    25 25 cm * of ether is added to 3 g of magnesium chips, and then about 10 cm * of a solution of 9.05 g of chloromethylpiclopropane in 75 cm of ether are added with stirring. After starting the reaction at the boil under reflux, about 30 residues of the above solution are added over 40 minutes. Refluxing. continue with stirring for 30 minutes, and then leave’. left at room temperature.
    A complex of 135 mg of copper monochloride and 85 mg of lithium chloride c is obtained. . 35 cm * tetrahydrofuran.
    1.7 g of canrenone is added to the solution of this complex, and then cooled, 40 is given after the steroid has been dissolved to -30 ° C, for 30 minutes with stirring, 14.2 cm * of the above-obtained organomagnesium solution are added, stirring is continued for 15 minutes * 5 at - 30 ° C, and then the reaction mixture 15 cm * 5 N. hydrochloric acid solution. Allow the temperature of the mixture to rise to room temperature and extract it with ethyl acetate. The organic 5 ° layer was washed with water, a saturated aqueous solution of sodium chloride, dried and evaporated to dryness. The residue was chromatographed on silica eluting with ether / benzene (75:25). You- 55 share:
    1.25 g of the desired οι -isomer, which is recrystallized from isopropanol or ethyl acetate, so pl. 180 ° C, [clJ ^ = + - 58 + 1.5 ° (1%, chloroform).
    Calculated%: C 78.74; H 9.15 (396.57)
    Found,%: C 78.9, H 9.0
    0.5 g of the β-isomer, which is recrystallized from isopropanol, so pl. 132 ° C.
    ΓοΙίΙρ = + 64 + 1.5 ° (1%, chloroform).
    Calculated,%: С 78.74, Н 9.15 С ^ L О 3 (396.57)
    Found,%: C 78.5, H 9.0. Example 10. Potassium salt 7 cL cyclopropylmethyl-17p-hydroxy-3-oxo-17 <£ “pregn-4-en-21 carboxylic acid.
    7 cm * of water and 3.5 cm of 1.38 N are added to 2 g of the 7 "t isomer obtained in Example 9. potassium ethanol solution. It is heated under reflux for 30 minutes and then evaporated to dryness.
    Acetone is added to the residue, suctioned off, washed with acetone and the resulting product is dried. Obtain 2.2 g of the target t of product, [oljp = + 39-1 ° (1%, water)
    Calculated%: С 65.72, Н 8.38 <У1з 7 О 4 К. 1.25 IdO
    Found,%: C 65.7, H 8.3 Example 11. '{p-lactone 7o (-phenyl methyl — 17 β-hydroxy-3-oxo-17o1-pregn-4e ”-21-carboxylic acid.
    135 ml of copper dichloride and 84 mg of lithium chloride are stirred in 5 cm * of tetrahydrofuran, a solution of 1.7 g of canrenone in 30 cm * of tetrahydrofuran is added, the reaction mixture is cooled to 0 ° C and 14.3 cm are added to it over 40 minutes * 0.7 M solution of benzylmagnesium bromide in ether. Then the reaction mixture is acidified with 10 cm "* 5 N. hydrochloric acid solution, stirred for 1 h at room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried and evaporated to dryness. The residue is chromatographed on silica, eluting with a mixture of nonisol / ethyl acetate (70:30), yielding:
    1.2 g of the target at -isomer, which is recrystallized from 11 tones of methyl ethyl ethyl acetate, m.p. 258 ° С, Г <] + 2.5 ± 1 in (1%, chloroform). υ
    0.15 g of the β> -isomer, which is recrystallized from ethanol, so pl. 220 ° C. - 5
    A pharmacological study is carried out. the lactone 17 β-hydroxy-3-oxo-7-propyl-1 7 s / -pregn-4-en-21-carboxylic acid (product A), potassium salt 17β hydroxy-3-oxo-7 </ -propyl- 17 <X-pregn-4- , 0 en-21-carboxylic acid (product B) and their famous homologue, lactone 1 7 p -oxy-3-oxo-7 <X-methyl-17е <-pregn4-en2121-carboxylic acid acid (product C).
    To study antialdosterone 15 activity in male rats, the adrenal glands are removed seven days before diuresis, and the animals are left on an empty stomach for 17 hours before diuresis. The test products are administered orally one hour before diuresis. At the 20th moment of diuresis, animals are injected intraperitoneally with a 9% physiological wax. 5 ml sodium chloride solution (per 1 rat) and subcutaneously μg / kg of a 2.5% alcohol solution of 25% aldosterone monoanethate. 4 hours after forced diuresis, the content of sodium and potassium in the urine is established on a plasma photometer of an automatic analyzer. thirty
    The results, expressed as a percent inhibition of antialdosterone activity of 1 μg of aldosterone monoacetate injected under the skin per kg of weight (per logarithm of the ratio: sodium concentration /, 33 potassium concentration) are given in the table.
    Product The dose of the product administered orally, mg / kg Inhibition of activity,% A 2 47 IN 0.4 58 FROM 2 27
    As can be seen from the table, at a dose in mg / kg administered orally, product A is more active than product C, product B at a dose of 0.4 mg / kg gives 58% inhibition of antialdosterone activity, significantly exceeding the similar Compound C.
    To study the androgenic activity, the prostate, taken from male rats castrated 55 to 24 hours earlier, is homogenized in a buffer solution of the following composition: trimethamine 10 ml mol, sa charose 0.25 M, HCL pH 7.4, and then centrifuged at 105 000 () - within one hour.
    The supernatant in a certain concentration, containing a third T, 17 ^ -oxy17c0-methylestra-4,9,11-triene 3-one (hereinafter referred to as R) with tretium T, is incubated at 0 ° C for 2 hours in the presence of or in the absence of an increasing concentration of R not containing a third T, testosterone or the product being studied.
    After two hours, determine the radioactivity containing the radioactive labeled third T associated with the acceptor.
    The relative means of the studied product or ARL is determined by the formula ( ARL-1θθχ -CTICX, (V)>
    where CT is the concentration of cold testosterone (without a third T), which inhibits the binding of R to a third T by 50%;
    CX - concentration of the studied product, which inhibits 50% binding
    R with third T.The following results were obtained: Product Arl Testosterone 100 Product A 0.4. Product B. 0.2 Product C 28 Product A has almost no affinity towards prostatic acceptor testosterone, whereas the product is C obl / L
    gives in relation to it a rather significant affinity. Product B gives an ARI value of 0.2, t. e. exhibits an even lower affinity for the prostatic testosterone acceptor.
    权利要求:
    Claims (2)
    [1]
    shat and evaporated to dryness. The resulting crystalline residue is chromatographed on silica using a mixture of cyclohexane / ethypone acetic acid (3: 2). After the sample: 6.3 g of the d-isomer of the target product, melting at, the melting point does not change after recrystallization of the product in methanol, + 67 + 1, chloroform), 3.2 g and the isomer of the target product, melting at 150 ° C and then at .170 ° С. An analytical sample is obtained by recrystallization from methanol. T. pl. 155 ° С, and then 172С after hardening, 5 + 1.5 ° (1%, chloroform). Example 2. G- / acon-7sk-propyl-17) -oxy-3-oxo-176-pregv-4-en21-carboxylic acid. To a complex of 382 mg of copper mono-iodide and 0.7 cm of sulfide and-butyl, obtained with stirring at room temperature, was added a solution of 5.1. Of canrenone (or 3: - lactoni-17 (% oxy-3-oxo-17o. -4.6, -diene-21-carboxylic acid) in 75 cm of anhydrous tetrahydrofuran and 5O cm of anhydrous ethyl ether. The mixture is cooled before - and with vigorous stirring it is added with 1.2 M ethereal solution of methyl magnesium bromide. After the expiration of additional 1O minutes of agitation., At - the reaction mixture is acidified by adding 5O cm of a 5N solution of hydrochloric acid, The mixture is stirred at room temperature for 30 minutes and then extracted with ethyl acetate. The organic layer is concentrated & 0.2 g of sodium thiosulfate in Doi, dried with sodium sulfate and evaporated to dryness. The residue is chromatographed on silica, using a mixture of Beschol - ethyl ether (No: 4). Isolation 5a sequentially: 3.3 g of crystalline cC-isomer of the target product, 1.4 g of amorphous ft-isomer of the target product. An analytical sample of the target product (7c propyl derivative) is obtained by recrystallization from methanol, m.p. 20SPcC rf3i5M-70 + l, 5 ° (1%, xporo .. forms) .3 frost. The potassium salt of pvl-17 ox-3-oxo-17oL-progn-4-en21-carboxylic acid, 1, .5 G obtained in example 2, 5.4 cm, 0.53 n. a solution of caustic potash in ethanol and 5.4 cm of water is heated to a boil with a reverse fridge for 15 minutes and then an ice cream. to a low volume under reduced pressure to obtain a thick yellow syrup. After addition of 5 O cm of acetone, the crystalline precipitate is filtered off, sprinkled with acetone and dried. at, after which the recrystallization is made of 1.3 cm of water with the addition of 19, 5 cm of acetone. Obtain 1 g of the target. th product in the form of monohydrate. T. pl. about 29CPC, WJ3, + 48 ± 1.5 (1%, water). Example 4. T-lactone 7af.-6ytil 17p-hydroxy-3-oxo-17-preg-4-e 21-carboxylic acid. To 191 mg of copper mono-iodide is poured on with stirring O, 35 cm of c-butyl sulphide, the resulting complex is dissolved in 35 cm of anhydrous tetrahydrofuran and 1.7 g of canrenone (or J-lactone of 17-oxy-3-oxo- pregna-4,6-diene-21 -carboxylic acid). The resulting solution was stirred in an ice bath and added to it over 30 minutes. 7.5 cm1.2 M solution of butyl magnesium bromide in ethyl ether. After 30 minutes, the reaction mixture is acidified using a large excess of 5N. hydrochloric acid solution and treated in accordance with Example 2. Chromatography on silica using 3: 2 mixture of Br-clohexane / ethyl acetate (ethyl acetate) was isolated successively: crystalline Q /, is an isomer which was triturated in isoprotic ether (| 1 , filtered off in air, dried to give 1.12 g of chopped product, ie, 147 ° C. The analytical sample after recrystallization from methanol melts at 149 ° C, + 1 (1%, chloroform), 0.65 g of amorphous. p n M e r 5. Kalveva salt 7 til-17 ft -ox1 Zczyuks-17 o6 .- "regn-4-e # 21-carbs &amp; spot". 15 mvv is heated to reflux with coldness of 1.19 g of 4 compounds obtained in shchmer, 5.4 cm of ohm, 53 in. Of caustic in ethanol and 5.4 cm of vrda, and then the reaction mixture is covied in vacuum to obtain light yellow thick orphan. After adding 5 O cm of potassium acetone, the salt crystallizes as fine needles. The crystals are filtered. 794 is washed with acetone, dried at 50 ° C and then recrystallized, a solution in 3 cm of acetone containing 5 O% Bd, and added 28.5 cm acetone. 1.13 g of the expected product is obtained in the pH of the dihydrate. T. pl. about 36.5 +1, (1%, water). P and m 8 p b. 3g-lactone 7a / - (2-methylpropyl) - / -oxy-3-oxo-17a-pregn4-ene 21-carboxylic acid, the complex obtained from 135 mg of mono-iodide copper and 0.25 cm of sulfide II-butyl is dissolved 15 cm of anhydrous tetrahydrofuran and 680 mg of KBHpeHotia are added (or –l who on i7p hydroxy is 3-. x-co-17os-pregna-4,6-diene-21carbonic acid). The solution is cooled to -, with vigorous stirring, a 4.3, 7 M solution of isobutyl magnesium bromide in ethyl ether is added dropwise to it over 2 minutes. After the addition is complete, the reaction mixture is stirred for 15 minutes at -30 ° C. Then the resulting suspension is acidified with a large excess of 2N. solution of hydrochloric acid, stirred for 30 minutes at room temperature, and then extracted with ethyl acetate. The extracts are washed with water, dried and evaporated to dryness. The residue is chromatographed on silica using a mixture of benzene-ethyl ether (1: 9). The following is isolated: 450 mg of the isomer, which is recrystallized from 1 cm of methanol, to give 320 mg of solvated salts. . 0.5 mol of methanol of crystals of the target product, melted at, after desolvation, mp, about 10O ° C; {piJ + 63 + 1.5 ° (1%, chloroform). 310 mg of the 5-isomer, the product is recrystallized from a mixture of methylene chloride and isopropyl ether and obtain 230 mg of product, t, mp, 218 ° C-, o6j 4-79 +1.5 (1%, chloroform),, P p and M e, p 7.-lactone 7-ethenyl-1 -17 hydroxy-3-oxo / 17c / -4-pregnen-21-carboxylic acid ,. , At room temperature, stirring 2, 1 g of copper mono-iodide and 5.6 cm of sulfide and butyl, and then the complex formed is added to a solution of 10 g of canrenone (or-lactone-17 / -oxy 3-ox-17o-pregna-4,6 —die —21-carboxylic acid) in 200 cm of anhydrous tera fraudrophylacine w. The resulting solution is cooled to -20 ° C and 2 .8 drops are added to it over 80 minutes with intensive stirring at 44 cmH. a solution of vinyl magnesium chloride in tetrahydrofuran. After the addition was terminated, stirring was continued for another 60 minutes, and then the reaction mixture was acidified with 45 cm n. hydrochloric acid solution. Stir for 90 minutes. at room temperature and extracted with ethyl acetate, the organic layer is washed with water, 0.2 M sodium thiosulfate solution, dried, evaporated to dryness. The remaining oil is chromate plated on silica using a mixture of cyclohexane / ethyl acetate (1: 1). The following are separated: 2.9 g of the desired isomer, melting at 199 ° C after recrystallization of acetic acid isobutyl ester, and then from ethanol at 75 ° C; 1O1 +17.5 + + 1.5 ° (1%, chloroform ), 3.5 g of P-isomer, possessing a triple melting point: about 100, then 142 and 161 ° C after recrystallization from a mixture of methylene chloride / isopropyl ether, For example, J-lactone 7a, - (2propenyl ) -17 | L-oxy-3-oco-17o6-preg4-en-21-carboxylic acid, a) Preparation of a soluble complex of bis- (butyl sulfide H-butyl) -monoiodide copper, 475 mg of mono-iodine is stirred at room temperature and copper with 0.875 cm of n-butyl sulfide. Slightly exothermic monovalent dissolution. after 10 minutes, the resulting complex (yellow-orange liquid) is dissolved in 10 cm-anhydrous ethyl ether, b) Preparation of diallyllylcuprate, To add a solution to 1.95 g of triphenyllyl-lolose in 15 cm of anhydrous ethyl ether 2.85 cm 1.75 M solution of phenyl lithium in the mixture. benzene ethyl ester (7: 3). An abundant white precipitate of tetraphenyl is formed immediately. The reaction mixture is stirred and then cooled until the complex obtained above is added to it within 10 minutes and stirring is continued. A solution of lithium diallyl cure is obtained containing tetrafeJ OBO in suspension, the reaction with the steroid. A solution of 680 mg of canrenone added to the mixture obtained above (or - β-lactone i 7 i -.oxy-3-oxo-l 7d-pregna-4,6 diene-21-carboxylic acid) in 25 ol of anhydrous tetrahydrofuran. After stirring for 90 minutes. when the reaction mixture is acidified by the addition of 15 cm 2 n. hydrochloric acid solution and continue stirring at room temperature for 2 Tetrafescholovo is separated by filtration, the organic layer is separated, washed with water, dried and evaporated to dryness. The residue is chromatographed on. dvuok 1si silicon using a mixture of chloroform / ethyl acetate (95: 5). 408 mg of the title compound are isolated, melting at, and then at 194 ° C after re-solidification. An analytical sample is obtained after recrystallization from. methanol, so pl. 196 ° С, с + 113 + 3 ° (О, 7%, chloroform). PRI me R 9. 3-lactone of the 7th "-cyclopropylmethyl-17 p -oxy-3-oxo-17aL -pre 4-ene-21-carboxylic acid. 25 cm of ether are added to 3 g of magnesium shavings, and then about 10 cm of a solution of 9.05 g of chloromethyl diclopropane and 75 cm of ether are added with stirring. After the start of the reaction at reflux, add the precipitate of the above solution for 4 minutes. Refluxing. Continue with stirring for 30 minutes and then leave at room temperature. Obtained complexis 135 mg of copper monochloride .i 85 mg of lithium chloride. 35 cm of tetrahydrofuran. 1.7 g of canrenone was added to the solution of this complex, and then cooled after dissolving the steroid, 14.2 cm of the above obtained organomagnesium solution was added during 30 minutes with stirring, and stirring was continued for 15 minutes. a mixture of 15 cm 5 n hydrochloric acid solution. The temperature of the mixture is allowed to rise to K (liquid and extracted with ethyl acetate. The organic layer is washed with water, saturated sodium chloride solution, dried and evaporated to dryness. The residue is chromatographed on silica with an ether / benzene mixture (75:25) A yield of: 1.25 g of the desired oi-isomer, which is recrystallized from isopropanol or acetic acid ethyl ester, mp 180 ° C, CotJjj H-5e + l, 5 (l%, chloroform).%: C 78.74; H 9.15 (396.57) Found: C 78.9, H 9.0 0.5 g of the p-isomer, which is recrystallized from isopropane anola, mp P. 132 C. + 64 + 1.5 (1%, chloroform). Calculated,%: C 78.74, H 9.15 C (396.57) Found,%: C 78.5, H 9.0 .., Example 1 O. Kaliev salt of 7cf-cycloproper methyl-7p-hydroxy-3-oxo-17ai pregn-4-en-21carboxylic acid. To 7 g of isomer obtained in Example 9 7 is added 7 cm of water. and 3.5 cm of 1.38 N ethanolic solution of potassium hydroxide, heated under reflux for 30 minutes and then evaporated to dryness. Acetone is added to the residue, sucked off, washed with acetone and the resulting product is dried. Obtain 2.2 g of the target POflyKTa, Co (.J j) + 39-l ° (l%, water) Calculated. %: C 65.72, H 8.38. ) Ki, 25 nr Found,%: C 65.7, H 8.3 eno,%: C 65.7, H 8 PRI me R 11. gf-lactone 7c-phenylmethyl-17 / -oxy-3 -oxo-1 7O1-Pregn-4ene-21-carboxylic acid. 135 ml of copper dichlorvord and 84 mg of lithium chloride are mixed in 5 cm of tetrahydrofuran, a solution of 1.7 g of canrenone in 30 cm of tetrahydrofuran is added, the reaction mixture is cooled to 0 ° C and 14.3 cm0.7 are added to it M solution of benzyl magnesium bromide in E (Fe). Then the reaction mixture was acidified with 1 O cm of a 5N solution of hydrochloric acid, stirred for 1 h at room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried and pack The residue is chromatographed on silica, eluting with benzene / ethyl acetate (7O: 30), to give; 1.2 g of the desired at-isomer, which is recrystallized from methyl ethyl acetate, mp 258 ° C, and + 2.5 ± 1 (1%, chloroform). One 5 g of the i -isomer, which is recrystallized from ethanol, mp 220 ° C. A pharmacological study of the lactone aT / -oxy-3-ox-Tsb is carried out propyl-7oil-nperH-4-enn21 - carboxylic acid (product A), potassium salt 17/5 OKC f -oKco-7ot-npomoi-17oL-nperH-4ene-21-carboxylic acid (product B) and their known homolog - lactone 1 7 p C-3 oxo-7 oi-methyl-17 Cs-preg. 4-e-21- "arboxylic acid (product C To study the antialdosterone activity in male rats, the adrenal glands were removed seven days before diuresis, and the animals were left on fasting 17 h before diuresis. The test products are administered orally one hour before diuresis. At the time of diuresis, animals are injected intraperitoneally with physiological water. a solution of sodium chloride in the amount of 5 ml (va 1 rat) and subcutaneously 1 µg / kg of a 2.5% alcoholic solution of aldosterone mono-apetate. Four hours after the forced diuresis, the content of sodium and potassium in the urine is determined on a plasma photometer of an automatic analyzer. The results, expressed as percent inhibition of anti-aldosterone activity of 1 µg of aldoster monoacetate, injected under the skin per kg of body weight (per logarithm: sodium concentration of potassium concentrate) are given in the table. As stated in the table, at a dose of 2 mg / kg, administered orally, product A appears to be more active than product C, product B at a dose of 0 mg / kg gives 58% inhibition of the anti-aldosterone activity, significantly higher than a similar indicator of compound C. To study androgenic activity, the prostate taken from male rats castrated for 24 hours was homogenized &amp; in a buffer solution of the following composition: trimethamine 10 ml, mol, sucrose 0.25 M, Nerph 7.4, after which is centrifuged at 105,000 for one hour. The superkatant in a certain conditra of shsh containing the third T, 17p-hydroxy17o6-ethyletra. -4,9,11-triene 3-one (hereinafter referred to as R) with the third T, is incubated for 2 hours in the presence or absence of an increasing concentration , not soda {third third T, testosterone or a studied product. After two hours, the radioactivity containing the radioactively labeled third T bound to the acceptor is determined. The relative means of the studied product or ARL is determined by the formula IARl.lOO) fCTJCX, U), where CT is the concentration of cold testosterone (without a third of T), which inhibits by 50% binding of R to the third T; CX is the concentration of the product studied, which inhibits by 5% R binding to the third T. 1 The following results were obtained: Product RL Testosterone100 AO product, 4Product B.0.2 Product C28 Product A is practically without affinity for the prostatic testosterone acceptor, whereas product C has, in relation to it, a rather significant affinity. Product B gives an A R C value of 0.2, i.e., it exhibits an even lower affinity for the prostate testosterone acceptor. Claims. The method of producing 7c-alkyl derivatives of steroids of the general formula (1) where R is in position c or .p is alkyl or alkenyl with 2-8 carbon atoms, cycloalkylalkyl with 4-8 carbon atoms or arylalkl with 7-12 atmsamp carbon and / or X and Y group .0. wra X-hydroxy group and Y-gruggar (1H2 (H2) (1-OM where M is a hydrogen atom or an alkali metal atom or a 1H4 nucleus in the form of (- isomers or a mixture of them, characterized in that they combine certain formulas (I) Q - is introduced into interaction with a compound of the general formula (III) RMgHae, where R. has the above values and Nab is a chlorine or bromine atom, (in the presence of choli odrrlent copper or a compound of the general formula 0) (WiCuLi, where R has the above then the reaction mixture is treated with an acid to obtain a compound of the general formula (1 A.) 94 2 where R. has the decree higher values, which are either introduced or treated with an alkali metal hydroxide or ammonium hydroxide to obtain a compound of the general formula (Ig) 1 xQH ". T T - iiH dHoCoM / ii 0 # 4sAsX R where R has the above value; M - an alkali metal atom or a NH4 group., which is optionally treated with an acid to obtain a compound of formula (Ig), where M is a hydrogen atom, with the selection of the target products as oi and PI-isomers or a mixture thereof. Sources of information taken into account during the examination 1. Mashkovsky M. D. Medicines. M., Medicine, t. 1, p. 392, 1972.
    [2]
    2.Ger. eu.2, ZO9, 328; cl. 12О 25 / О2, published 1975.
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    同族专利:
    公开号 | 公开日
    IL59479A|1983-05-15|
    FR2451923B1|1983-02-18|
    PT70980A|1980-04-01|
    HU181686B|1983-11-28|
    AT1151T|1982-06-15|
    DE3060488D1|1982-07-22|
    GR66633B|1981-04-03|
    DK122480A|1980-09-23|
    AU530162B2|1983-07-07|
    IE800592L|1980-09-22|
    ES489143A1|1980-08-16|
    MX6389E|1985-05-24|
    ZA801614B|1981-03-25|
    AU5669980A|1980-09-25|
    CA1125279A|1982-06-08|
    EP0018245B1|1982-06-02|
    IE49568B1|1985-10-30|
    IL59479D0|1980-05-30|
    PT70980B|1981-07-02|
    MA18780A1|1980-10-01|
    JPS6239160B2|1987-08-21|
    EP0018245A1|1980-10-29|
    JPS55129300A|1980-10-06|
    FR2451923A1|1980-10-17|
    US4258039A|1981-03-24|
    PH17103A|1984-05-29|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1270765A|1969-07-14|1972-04-12|Taisho Pharma Co Ltd|beta-1,3-LINKED POLYSACCHARIDES|
    US3787394A|1972-10-04|1974-01-22|Merck & Co Inc|19-nor-7alpha-methyl or 19-nor-20-spirox-4,14-dien-3-one and 18-methyl derivatives thereof|
    DE2452303A1|1974-11-05|1976-05-13|Bayer Ag|EXTRACTION PRODUCTS FROM YEAST CELL WALL COMPONENTS CONTAINING MATERIAL, A PROCESS FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT|
    FR2374042B1|1976-06-04|1980-04-30|Merieux Inst|FR2496669B1|1980-12-23|1983-10-28|Roussel Uclaf|
    DE3234972A1|1982-09-17|1984-03-22|Schering AG, 1000 Berlin und 4709 Bergkamen|7-ALKYL-17-PREGN-4-EN-21.17-CARBOLACTONE AND -21-CARBONIC ACID SALTS AND METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM|
    DE3612632A1|1986-04-11|1987-10-22|Schering Ag|METHOD FOR PRODUCING 7PROPYLSTEROIDS|
    IT1250410B|1991-02-14|1995-04-07|Simes|STEROID COMPOUNDS ACTIVE ON THE CARDIOVASCULAR SYSTEM|
    US5234506A|1991-07-17|1993-08-10|Church & Dwight Co., Inc.|Aqueous electronic circuit assembly cleaner and method|
    US20040010138A1|2002-03-21|2004-01-15|Schering Ag|Process for the production of 7alpha-methyl steroids|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR7907273A|FR2451923B1|1979-03-22|1979-03-22|
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