text:
RussianPatents.com
New! → US patents search
Steroid 17-spermatocelectomy group and method thereof
C07J21 - Normal steroids containing carbon, hydrogen, halogen, or oxygen, having an oxygen-containing hetero ring spiro-condensed with the cyclopenta[a]hydrophenanthrene skeleton
C07J19 - Normal steroids containing carbon, hydrogen, halogen, or oxygen, substituted in position 17 by a lactone ring
A61K31/585 -
(57) Abstract:
The invention relates to new steroid, namely steroid with a 17-spermatocelectomy group having the General formula I, where R1is O, (H, H), (H, or), or NOR, and R is selected from H, (1-6C) alkyl and (1-6C) acyl; R2is H, (1-6C)akilam arbitrarily substituted with halogen, (2-6C)alkenyl arbitrarily substituted with halogen, (2-6C)quinil arbitrarily substituted with halogen, or halogen; R2is H; or R'2together with R2is (1-6C)alkylidene group or (2-6C)allenylidene group; or R'2together with R3are bond; R3is N, if R'2is not a bond; R4is (1-6C)alkyl; one of R5and R6is hydrogen and the other is hydrogen or (1-6C) alkyl; X is (CH2)nor (CnH2n-2), where n is 2 or 3, which is arbitrarily substituted with hydroxyl, halogen, (1-6C)alkyl, (1-6C)acyl, (7-9C)phenylalkyl, phenyl group which may be substituted (1-6C)alkyl, (1-6C)alkoxyl, hydroxyl or halogen; Y is O or (H, HE) and dashed lines show a random link, and at least one of the links 4-5, and 9-10 5-10 alacartoona and antiprogesterone activity. 2 c. and 4 C.p. f-crystals, 2 tab.
The invention relates to steroids with a 17-spermatocelectomy or lactophenol group, to receive them and to their use in obtaining contraceptives.
Steroids with a 17-spermatocelectomy group is known, i.e., such as described in EP-A-558416. These steroids can have a variety of hormonal activity, which can be identified by their ability to bind to various receptors. Studies have been conducted bind with receptors for 17-spermatocelectomy steroids according to EP-A-558416 to demonstrate their hormonal activity. These steroids show a significant antiglucocorticoid and antiprogesterone activity, and they may have androgenic or antiandrogenna, glucocorticoid and Progestogens properties. In addition, it was shown that these steroids have a higher affinity for binding with respect to the glucocorticoid receptor than to the progesterone receptor, and because of this disengagement, stated that they are selective antiglucocorticoid steroids.
Steroids according to EP-A-558416 have a 5-membered 17-spermatocelectomy group, a methylene group which is in the to, glucocorticoid activity is considered an unwanted side effect, and therefore there is a need for steroids, which are selective Progestogens compounds with weak or absent glucocorticoid activity.
New 17-spermatocelectomy or lactaline steroids, as detected at the present time, have affinity to the desired receptors, which are relatively higher to the progesterone receptor than to the glucocorticoid receptor. These new steroids, thus, exhibit a selective affinity for binding to the progesterone receptor. Their affinity for binding to the progesterone receptor, in addition, significantly higher than in the known close to the structure of steroids. In structure, they differ from the known 17-spermatocelectomy steroids in that they have 6 - or 7-membered spironolactonum or lactilol group, while the methylene group is separated from the carbonyl (or hydroxymethylene) groups of two or three methylene groups. Suddenly these steroids are very weak glucocorticoid or antiglucocorticoid activity.
Due to their selectivity, the steroids of this invention PTS and)glucocorticoid activity, will be substantially reduced.
Steroids according to the invention are steroids with a 17-spermatocelectomy or lactophenol group having the formula
< / BR>
where R1is O, (H, H), (H, or), or NOR, R is selected from H, (1-6C)alkyl and (1-6C)acyl;
R2is H, (1-6C)alkyl, optionally substituted with halogen, (2-6C)alkenyl, optionally substituted with halogen, (2-6C)quinil, optionally substituted with halogen, or halogen;
R'2is H;
R'2together with R2represents (1-6C)alkylidene group or (2-6C)allenylidene group; or
R'2together with R3are communication;
R3is H, if not is together with R'2communication;
R4is (1-6C)alkyl;
X is (CH2)nor (CnH2n-2), where n is 2 or 3, which is optionally substituted by hydroxy, halogen, (1-6C)alkyl, (1-6C)acyl, (7-9C)phenylalkyl, phenyl group which may be substituted (1-6C) alkyl, (1-6C)alkoxy, hydroxy or halogen;
one of R5and R6is hydrogen and the other is hydrogen or (1-6C)alkyl;
Y is O or (H, OH); and
dashed lines indicate optional connection, at least one of the e steroids of formula I, where R1is Oh, R4is stands, Y is O and n is 2.
More preferred are the steroids of formula I, where R1is O, R2is (1-6C)alkyl or (2 - 6C)quinil, R'2and R3are H, R4is stands, R5and R6are hydrogen; X represents (CH2)2, Y is O and the dotted line in ring D is not a bond and the other dashed line is the link 4-5.
The most preferred 17-spermatocelectomy steroids are - lactone (11, 17) -11-ethyl-17-hydroxy-3-oxo-19 - Nichola-4,20-Dien-24-OIC acid - lactone (11, 17) 17-hydroxy-3-oxo-11-(1-PROPYNYL)-19-Nichola-4, 20 - Dien-24-OIC acid.
The term "(1-6C)alkyl" means a branched or unbranched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. Preferred alkyl groups have 1-4 carbon atoms, and most preferred alkyl groups are ethyl and methyl.
The term "(2-6C)alkenyl" means a branched or unbranched alkenylphenol group having at least one double bond and 2 to 6 carbon atoms. Preferred is inil" means a branched or unbranched alkylamino, having at least one triple bond and 2 to 6 carbon atoms. Preferred alkyline groups have 2-4 carbon atoms. Examples are atenil and 1-PROPYNYL.
The term "(1-6C)alkylidene" means a branched or unbranched alkylidene group having 1-6 carbon atoms. Preferred alkylidene groups have 1-4 carbon atoms, and most preferred is methylene.
The term "(2-6C)allenylidene" means a branched or unbranched allenylidene group having 2-6 carbon atoms. Preferred allenylidene groups have 2-4 carbon atoms, such as attalides.
The term "(1-6C)acyl" means an acyl group derived from aliphatic carboxylic acids having 1-6 carbon atoms. Acetyl is the most preferred acyl group.
The term "halogen" means fluorine, chlorine, bromine or iodine. Chlorine is the preferred halogen.
Progesterone steroids of this invention can be used as contraceptives in mammals, more specifically in humans and animals. Compounds according to the invention, moreover, are conventional, well-known for POCs activity. The example is also used in hormone replacement therapy.
The steroids of formula I can be well-known methods described and used to obtain similar steroids.
A suitable way of getting some steroids according to the invention is characterized by the fact that the compound of formula II
where R'1is O, (H, H) or (H, OR), and R is selected from H, (1-6C)alkyl and (1-6C)acyl or its protected derivative;
R'2is H, or
R'2together with R3indicate the connection;
R3is H, if it is not together with R'2communication;
each Q is independently selected from H, (1-6C)alkyl and (7-9C)-phenylalkyl, phenyl group which may be
substituted (1-6C)alkyl, (1-6C)alkoxyl, hydroxyl or halogen;
n is 2 or 3;
the dashed lines show neoba the oxidation of the steroid with a 17-spermatocelectomy group and not necessarily to restore the connection, where Y is (H, OH), after which not necessarily available protective groups are removed with subsequent optional conversion of compounds of formula I, where R1is On, the corresponding compound where R1NOR is, R has the values listed previously.
The compounds of formula II can be obtained from the corresponding 17-ketosteroids. These 17-ketosteroids can be obtained in accordance with the method described in DE 2805490 or described y Van der Broex et al., Steroids Vol. 30, 481-510 (1977). When these 17-ketosteroids condense with 2-metilirovaniem-5-(protected hydroxy)-1-pentanol or 2-metilirovaniem-6-(protected hydroxy)-1-hexene, for example with 2-litio-5-trimethylsilyloxy-1-pentanol or 2-litio-6-trimethyl-silyloxy-1-hexene, followed by removal of the release (s) group (s), obtain the compounds of formula II.
Suitable protective groups are known in this field, for example, the monograph by T. W. Green: Protective Groups in Organic Synthesis (Wiley, NY, 1981).
The addition can also be carried out with a suitably protected derivative of carboxylic acid, for example, orthoevra, or suitably protected aldehyde, for example, 4,5 - dihydro-2-(3'-litio-but-3'-EN-1'-yl)-1,3-dioxolane the Finance can be used metals or methods, known in ORGANOMETALLIC chemistry (for example, lithium, zinc, magnesium, cerium), and an aromatic radical-anionic compounds such as lithium naphthalenide. The activating group in Allenova the radical may be a halogen, such as bromine or iodine, or a substituted metal, such as triamcinolone or trialkylamine group.
Intermediate compounds, thus obtained, can also be obtained by treating the protected appropriately derived 17-24-dihydroxy-21-norolean-20-ones reagents capable of converting the carbonyl group in alkylidene group, such as reagents Wittig, Horner, Peterson or similar reagents known in this field.
As a protective group for the 3-ketone function is particularly suitable cyclic acetals, such as 1,2-candirectly, 2,2-DIMETHYLPROPANE-1,3-vilareal, or acyclic acetals or thioacetals. Such groups known in the art, for example, can also be used enol ethers.
Conversion 17,24-digitoxigenin in - lactones according to the invention or 17,25-dihydroxy-26,27-generalstab in-lactones according to the invention can be performed using oxidizing agents known in this allowedit reaction, may vary, for example the oxidation 17,24-diol to the lactone may be performed before removing the protection of the carbonyl group at C-3. The lactones (Y is H, OH) can be obtained by partial oxidation of compounds of formula II by methods known in this field, for example by oxidation Swarna.
The expression "protected OH" means a hydroxyl group which is protected by way usual for the protection of hydroxyl groups, for example as described in T. W. Green.
Alternatively, steroids according to the invention can be obtained from compounds of formula III
where R1, R2, R'2, R3, R4, R5, R6, n, Q and the dotted line have the meanings given for compounds of formula II, L is a leaving group,
converted by base catalyzed shorting ring in the steroid with a 17-spermatocelectomy group, optionally followed by alkylation, phenylalkylamines, acylation, halogenoalkanes, with optional subsequent degidro-halogenoalkanes, and/or restored in a compound in which Y is (H, OH), after which not necessarily available protective group is removed with optional subsequent conversion of compounds of formula I, Catalyzed by base ring closure can be carried out using sodium or calibos(trimethylsilyl)amide or other volumetric basis, preferably in an ether, for example tetrahydrofuran, and the like.
The compounds of formula III can be obtained from the corresponding 17-ketosteroids. These 17-ketosteroids can be obtained by the method described in DE 2805490 or as described by Van der Broex et al., Steroids Vol. 30, 481-510 (1977). When these 17-ketosteroids condense with 2-metilirovaniem-3,3 - dialkoxy-1-propene or 2-metilirovaniem-4, 4-dialkoxy-1-butene, for example with 2-litio-3,3-diethoxy-1-propene or 2-litio-4,4 - diethoxy-1-butene, followed by selective hydrolysis dialkylanilines functional groups and recovering the resulting aldehyde can be obtained 17-hydroxy-20- (hydroxymethyl)pregn-20-ene or 17,23-dihydroxy-19,24-General-20 - ene derivative, 17-hydroxy-group tarifitsiruetsya in a suitable ester, such as acetate. Other hydroxy-group is converted into a leaving group, for example, by interacting with mozillateam obtaining tosilata.
Suitable leaving groups are known in this field, for example from the monograph by A. L. Ternay: Centemporary Organic Chemistry (2 nd ed., W. R. Sounders Compary, 1979, 158 and 170-172). Suitable leaving groups are Halogens, such as chlorine, bromine and iodine, and especially tosyloxy group.
Alkylation of iliti - diisopropylamide (LDA) or potassium bis(trimethylsilyl)-amide, and the like.
To obtain 2-metallizovannyh dialkoxybenzene from alkenylsilanes can be used metals or methods known in ORGANOMETALLIC chemistry, such as alkylate those described above. As a protective group for the aldehyde functional group can be used the above-mentioned cyclic acetals or thioacetals or similar group known in this field. Again, the activating group on alkinoos part may be a halogen, such as bromine or iodine, or a substituted metal, such as triamcinolone or trialkyl-germanium group.
Synthesis of 17-hydroxy-20-(hydroxymethyl)pregn-20-ENES can also be achieved by attaching a suitably protected 2 - metal-2-propen-1-tins to estran-17-Onam with the subsequent removal of protecting the hydroxy group. The conversion of 17-hydroxy-20- (hydroxymethyl)pregn-20-ENES in the corresponding 17-monoacetate or 17-monopropionate can be accomplished using acidic catalysts, such as phosphoroxychloride or oxalic acid in trialkylamine or trialkylamine.
Some lactones according to this invention can also be obtained by selective reduction of lactones 17-hydroxide, for example, 21-, 22 - and 23-bromo derivatives of previous lactones or by similar removal of such deputies, recoverable, for example, [(4 - were)sulfonyl-hydroxy]groups. The same methods can be used to obtain lactones by restoring halogenated and/or unsaturated - lactones 17-hydroxyl - 20-ene-24-carboxylic acid.
The lactones according to the invention can also be obtained by lactonization 17-hydroxypoly-24-OIC acid or by lactonization ester of such an acid (for example, acetate, t-butyl or trialkylsilyl ether). They can also be obtained from 17-hydroxy-24-Nichola-23,23-dicarboxylic acid or mono - or diesters of such acids, or from 17-hydroxyamino-24 - NITRILES or 23-cyano-17-hydroxypoly-24-OIC acid or its esters. - lactones can also be obtained in this way from a 17-hydroxypoly-24-carboxylic acid or ester of such acid, or they can be obtained from the 17-hydroxypoly-24,24-dicarboxylic acid or mono - or diesters of such acids, or can be obtained from the 17-hydroxypoly-24-carbonitrile or 24-cyano-17-hydroxypoly-24-carboxylic acids or their esters.
The steroids of formula I, where n=2 and Y is Oh, mogu II, with 24-oxo - group.
Compounds according to the invention can be introduced interline or parenterally, and for a person's preferred daily dose of 0.0001 to 10 mg per kg of body weight. Mixed with pharmaceutically acceptable excipients, for example as described in the standard reference, Gennaro et al., Remington''s Pharmaceutical Sciences (18th ed. , Macx Pyblishing Company, 1990, especially part 8: Pharmaceutical preparations and their manufacture), these substances can be compressed into solid dosage forms such as pills, tablets, or capsules, or suppositories. Using a pharmaceutically suitable liquids the compounds may also be used in the form of an injection preparation in the form of solution, suspension, emulsion or aerosol products, such as aerosol for insertion into the nose.
For the manufacture of dosage unit forms such as tablets, the use of conventional additives such as fillers, colorants, polymeric binder, and the like. In General, may be any pharmaceutically acceptable additive, which does not interfere with the action of the active compounds.
Suitable carrier materials, which can be entered compositions the quantities.
Further, this invention is illustrated by the subsequent examples.
-lactone (17 )-17-hydroxy-3-oxo-19-Nichola-4,20 - Dien-24-OIC acid was obtained from 3-taxista-3,5 - Dien-17-it is as follows:
I) a Solution of 16.6 g of 2-bromo-5 - trimethylsilyloxy-1-pentene in 280 ml of anhydrous ether was cooled to -78oC and was added dropwise 88 ml solution of tert-utility (1.7 M in pentane). After 15 minutes, was added 14.9 g of the above-mentioned steroid; then the mixture was allowed to warm to 0oC over a period of time equal to 2 hours. Then the reaction mixture was poured into a saturated aqueous solution of ammonium chloride, which was extracted three times with ether. The combined extracts were washed with sodium hydrogen carbonate solution and a salt solution, dried with sodium sulfate and concentrated under reduced pressure to obtain 23 g of the desired (17)-3-ethoxy-24 trimethylsilyloxy-19-Nichola-3.5-inch, 20-trien-17-ol, which was used in the next stage without additional purification.
II) a Solution of 23 g of the above product in a mixture of 460 ml of acetone and 23 ml of 6N hydrochloric acid was stirred at room temperature for 1.5 hours. Then was added a saturated aqueous solution of sodium bicarbonate and acetone UDA is whether a salt solution was dried with sodium sulfate and concentrated under reduced pressure. The residue was chromatographically obtaining 9,07 g (17)-17,24-dihydroxy-19-Nichola-4,20-Dien-3-one.
III) To a cooled solution of 2.46 g of the diol obtained in the previous stage, in a mixture of 35 ml of acetone and 14 ml of water was added dropwise 6.8 ml 8N solution of chromium trioxide in sulfuric acid. The reaction mixture was stirred at room temperature for 1 hour; then it was poured into saturated aqueous sodium thiosulfate solution and the product was extracted into ethyl acetate. The extracts are successively washed with saturated aqueous sodium thiosulfate, saturated aqueous sodium hydrogen carbonate solution and a salt solution. The solution was dried with sodium sulfate and concentrated under reduced pressure. Column chromatography of the residue gave 0.66 g of the desired lactone (17)-17-hydroxy-3-oxo-19-Nichola-4,20-Dien-24-OIC acid. So pl. 207,8oC. [ ]D20= -25,5o(C=1, chloroform).
In the same manner as in example 1 were obtained:
a) lactone (17)-13-ethyl-17-hydroxy-3-oxo-18,19 - Generala-4,20-Dien-24-OIC acid, 13-atilgan-5-ene-3,17 - dione cyclic 3-(1,2-candirectly). So pl. >250oC. [ ]D20= -15,8o tilemaster-5-ene-3,17-dione cyclic 3-(1,2-candirectly). So pl. 239oC. [ ]D20= +81,2o(C=1, chloroform).
c) lactone (11,17) -17-hydroxy-11-methyl-3-oxo-19-Nichola- -4,20-Dien-24-OIC acid (11)-11-methylestr-5-ene-3,17 - dione cyclic 3-(1,2-candirectly).
So pl. 219oC. [ ]D20= +11,9o(C=1, chloroform).
d) lactone (17)-17-hydroxy-11-methylene-3-oxo - 19-Nichola-4,15,20-trien-24-OIC acid, 11-methylenethf-5,15-diene - 3,17-dione cyclic 3-(1,2-candirectly).
So pl. 168,5oC. [ ]D20= +50,2o(C=1, chloroform).
e) lactone (11,17) -17-hydroxy-11-methyl-19-Nichola-4,20 - Dien-24-OIC acid (11)-11-methylestr-4-EN-17-it.
f) lactone (11,17) -11-chloro-17-hydroxy-3-oxo-19-Nichola - 4,20-Dien-24-OIC acid (11)-11-character-5-ene-3,17 - dione cyclic 3-(1,2-candirectly).
So PL: 192,8oC. [ ]D20= +61,2o(C=1, chloroform).
g) lactone (11,17)-11-ethynyl-17-hydroxy-3-oxo-19 - Nichola-4,20-Dien-24-OIC acid (11)-11-etisilat-5-ene - 3,17-dione cyclic 3-(1,2-candirectly).
h) lactone (11,17) -11-ethynyl-17-hydroxy-3-oxo-19-Nichola - 4,20-Dien-24-SUB>20= +39,9o(C=1, dioxane).
i) lactone (11,17) -17-hydroxy-3-oxo-11-(1-PROPYNYL)-19 - Nichola-4,20-Dien-24-OIC acid (11) -11-(1-PROPYNYL)- variety-5-ene-3,17-dione cyclic 3-(1,2-candirectly).
So pl. of 147.7oC. [ ]D20= +71,5o(C=1, chloroform).
j) lactone (11,17) -17-hydroxy-3-oxo-11-(2-propenyl)-19 - Nichola-4,20-Dien-24-OIC acid (11)-11-(2-propenyl)- variety-5-ene-3,17-dione cyclic 3-(1,2-candirectly).
So pl. 214oC. [ ]D20= +9o(C=1, chloroform).
k) lactone (17)-11-attalides-17-hydroxy-3-oxo-19 - Nichola-4,20-Dien-24-OIC acid, 11-ateelement-5-ene-3,17 - dione cyclic 3-(1,2-candirectly).
So pl. 210oC. [ ]D20=+181,6o(C=1, chloroform).
l) lactone (17)-17-hydroxy-3-oxo-19-Nichola-4,11,20 - trien-24-OIC acid from östra-5,11-diene-3,17-dione cyclic 3- (1,2-candirectly).
So pl. 190oC. [ ]D20= +0,9o(s=0,53, chloroform).
m) lactone (6,17) -17-hydroxy-6-methyl-3-oxo-19-Nichola - 4,20-Dien-24-OIC acid from 6-methylestr-5-ene-3,17-dione cyclic 3-(1,2-candirectly).
So pl. 196oC. [ ]D20= -61,8o(C=0,5, chloroform).
n) lactone (11,17) -11-chloromethyl-17-hydroxy-3-ASS="ptx2">
So pl. 198oC.
o) lactone (11,17) -11-ethyl-17-hydroxy-3-oxo-19-Nichola - 4,20-Dien-24-OIC acid (11)-11-ethylester-5-ene-3,17-dione cyclic 3-(1,2-candirectly).
So pl. 224oC. [ ]D20= of-2.1o(C=1, chloroform).
p) lactone (11,17) -11-ethyl-17-hydroxy-19-Nichola-4,20 - Dien-24-OIC acid (11)-11-ethylester-4-EN-17-it.
So pl. 185oC. [ ]D20= -2,6o(with-0.1, chloroform).
(17)-17-hydroxy-11-methylene-3-oxo-19-Nichola-4,20 - Dien-24-OIC acid lactone (example 2) was also obtained from (17)-17,24-dihydroxy-11-methylene-19-Nichola-4,20-Dien-3-one by the stage of the oxidation process in the following way:
I) Dimethylsulfoxide (0,96 ml) was added at -60oC to a solution of 0,761 ml oxalicacid in 30 ml of anhydrous dichloromethane. After 15 minutes of stirring the solution was added dropwise a solution of 1.11 g (17)-17,24-dihydroxy-11-methylene-19-Nichola-4,20-Dien - 3-one in 25 ml of dichloromethane, and stirring was continued for 1 hour. Was added triethylamine (6 ml) and the reaction mixture was allowed to warm to 0oC for 30 minutes. Stirring was continued for another 30 minutes, and the mixture was poured into a saturated aqueous solution of sodium bicarbonate. The product was extracted with
oC.
II) Pyridinium dichromate (0.66 g) was added to a solution 0,050 g of the steroid obtained in the previous series, in 5 ml of anhydrous formamide. After stirring for 1 hour at room temperature the reaction mixture was poured into 100 ml of water. The product was extracted into ethyl acetate; the extracts were washed with water (3 times) and brine, dried with sodium sulfate and concentrated under reduced pressure. Column chromatography gave 0,030 g of the lactone (17 )-17-hydroxy-11-methylene-3-oxo-19-Nichola-4,20-Dien-24-OIC acid.
the lactone (17 )-17-hydroxy-11-methylene-3-oxo-19-Nichola - 4,20-Dien-24-OIC acid also received an alternative way of 11-methylenethf-5-ene-3,17-dione cyclic 3-(1,2-candirectly) as follows:
I) a Solution 78,38 g of 2-bromo-3,3-diethoxypropane (Ber. Dtsch. Chem. Ges. 1898, 31, 1015) in 750 ml of anhydrous THF was cooled to -60oC and was added dropwise 234 ml n-utility (1,61 N in hexane). After 15 minutes, was added dropwise a solution of 82,0 g of the above steroid in 1000 ml of THF. The temperature was allowed to rise to 0oC for 2 hours, after which the s was washed with saline, was dried with sodium sulfate and concentrated under reduced pressure. The crude material thus obtained was subjected to the processing described above, the second time. The resulting 137, 6mm g (17 )-3,3-[1,2-ethandiyl-bis (oxy)]-17-hydroxy-11-methylene-19-norpregna-5, 20-Dien-20 - carboxaldehydes used at a later stage without additional purification.
II) 130,7 g of the product obtained at the previous step, was dissolved in 1307 ml of anhydrous THF. Added p-toluensulfonate acid (7,86 ml of 1N aqueous solution) and the mixture was stirred at room temperature for 45 minutes. Then the reaction mixture was added dropwise to a cooled ice slurry 27 g Li-aluminiumhydride in 1000 ml of THF. After 1 hour at 0oC reaction extinguished saturated aqueous solution of sodium sulfate. Added ethyl acetate and the mixture filtered through celite. The filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by crystallization with getting 62,7 g of the desired (17 )-17-hydroxy-20-(hydroxymethyl)-11-methylene-19 - norpregna-5,20-Dien-3-one cyclic 1,2-candirectly.
III) a Solution of 38.6 g you eremetical at room temperature for 1 hour. Then the reaction mixture was diluted with 1000 ml of ethyl acetate; was added to 1000 ml of water and stirring continued for another 30 minutes. The mixture was poured into a saturated aqueous solution of sodium bicarbonate and the aqueous layer was extracted three times with ethyl acetate. The combined organic phases are washed with saline, dried with sodium sulfate and concentrated under reduced pressure to get 47,15 g (17 )-17-acetoxy-20- (hydroxymethyl)-11-methylene-19-norpregna-5,20-Dien-3-one cyclic 1,2-tendillas, which is used in the subsequent stage without further purification.
IV) Solution 47,15 g monoether obtained at the previous stage, in 80 ml of anhydrous pyridine was cooled in a water bath. Added p-toluensulfonate (40 g) and the mixture was stirred for 4 hours. The mixture was then poured into 2000 ml of water and the resulting suspension was stirred for 1 hour. The product was collected ethyl acetate and the aqueous phase was extracted with the same solvent. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried with sodium sulfate and concentrated under reduced pressure to get 55,0 g (17 )-17-acetoxy-11-methylene-20-[[[(4 - were)suusa stage without additional purification.
V) Solution of 60 g of potassium di(trimethylsilyl)amide in 1500 ml of anhydrous THF was cooled to -30oC. was Added a solution of 55 g of tosylate obtained in the previous phase, 400 ml of THF and the mixture was stirred at -30oC for 30 minutes. The reaction was suppressed by adding 500 ml of a saturated aqueous solution of ammonium chloride and the mixture was stirred at room temperature for 15 minutes. Then the product was extracted with ethyl acetate, the extracts washed with saline, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified column chromatography to obtain 24,52 g of the lactone (17 )-3,3-[1,2-atanderson (oxy)]-17-hydroxy-11-methylene-19-Nichola-5,20-Dien-24-OIC acid.
VI) According to the procedure similar to that from step II of example 1 of 5.00 g of the lactone obtained in the previous phase, was turned in to 3.34 g of the desired lactone (17 )-17-hydroxy-11-methylene-3-oxo - 19-Nichola-4,20-Dien-24-OIC acid.
In a manner analogous to the procedure of example 4, were obtained the following products:
a) lactone (17 )-17-hydroxy-19-Nichola-4,20-Dien-24-OIC acid of the variety-4-EN-17-she. So pl. 176oC.
b) lactone (11,17) -17-hydroxy-11-(1-PROPYNYL)-19-Nichola-4,20 - Dien-24-OIC acid (11 )-11-(1-propyne is n (7,17) -17-hydroxy-7-methyl-3-oxo-19-Nichola-4,20 - Dien-24-OIC acid (7 )-7-methylestr-5-(10)-ene-3,17-dione cyclic 3-(1,2-candirectly).
So pl. 197oC. [ ]D20= 0o(C=1, chloroform).
The lactone (17, 23S)-17-hydroxy-11-methylene-3-oxo-19 - Nichola-4,20-diene-23-carboxylic acid was obtained from (17 )- 3,3-[1,2-atanderson(oxy)]-17-hydroxy-11-methylene-19-Nichola - 5,20-Dien-24-OIC acid lactone (example 4, step V) as follows:
I) a Solution 0,506 ml Diisopropylamine in 15 ml anhydrous THF was cooled to -30oC and was added dropwise to 2.25 ml n-utility (a 1.6 N in hexane). The mixture was stirred for 10 minutes at -10oC and then cooled to -78oC. was Added dropwise a solution of 1.23 g of the above-mentioned steroid in 15 ml THF and stirring was continued for 15 minutes. Added itmean (0,93 ml) and gave the mixture to warm to 0oC for 2 hours. Was added a saturated aqueous solution of ammonium chloride and the product was extracted into ethyl acetate. The combined organic phases are washed with saline, dried with sodium sulfate and concentrated under reduced pressure to obtain 1.22 g of the lactone (17, 23S)-3,3-[1,2-atanderson (oxy)]-17-hydroxy-11-methylene-19-Nichola-5, 20-diene-23-carboxylic acid, which was used in the next stage without additional purification.
II) Following the procedure similar to the procedure of the ene-3-oxo-19 - Nichola-4,20-diene-23-carboxylic acid.
So pl. 187oC. [ ]D20= +92o(c=1, chloroform).
Following a procedure similar to that described in example 6, was obtained lactone (17, 23S)-17-hydroxy-11-methylene - 3-oxo-24-phenyl-19-Nichola-4,20-diene-23-carboxylic acid from (17 )-3,3-[1,2-atanderson(oxy)]-17-hydroxy-11-methylene-19 - Nichola-5,20-Dien-24-OIC acid lactone (example 4, step V). So pl. 177oC. [ ]D20= +58,8o(C=1, chloroform).
The lactone (17, 23S)-23-chloro-17-hydroxy-11-methylene-3 - oxo-19-Nichola-4,20-Dien-24-OIC acid was obtained from lactone (17 )-3,3-[1,2-atanderson(oxy)] -17-hydroxy-11-methylene - 19-Nichola-5,20-Dien-24-OIC acid (example 4, step V) as follows:
I) a Solution 5,04 ml Diisopropylamine in 75 ml anhydrous THF was cooled to -30oC and was added dropwise a solution of n-utility (a 1.6 N in hexane). The mixture was stirred for 10 minutes at -10oC and then cooled to -78oC. was Added dropwise a solution of 12.3 g of the above-mentioned steroid in 120 ml THF and stirring was continued for 15 minutes. The resulting solution was transferred for 5 minutes in a solution of 46.2 g tetrachloride carbon in 150 ml of THF, pre-cooled to -78oC. Stirring is continued the combined organic phases are washed with salt solution, was dried with sodium sulfate and concentrated under reduced pressure to get 6,12 g (17, 23S)-23,25,25,25-tetrachloro - 3,3-[1,2-atanderson(oxy)] -17-hydroxy-11-methylene-19,26,27 - trinorprosta-5,20-Dien-24-she, 0.24 g of lactone (17 )-23, 23-dichloro-3,3-[1,2-atanderson(oxy)] -17-hydroxy-11-methylene-19 - Nichola-5,20-Dien-24-OIC acid, of 0.43 g of the lactone (17, 23S)- 23-chloro-3,3-[1,2-atanderson(oxy)]-17-hydroxy-11-methylene-19-Nichola - 5,20-Dien-24-OIC acid and 0.45 g of lactone (17, 23R)-23-chloro - 3,3-[1,2-atanderson(oxy)] -17-hydroxy-11-methylene-19-Nichola-5, 20 - Dien-24-OIC acid.
II) the Solution 6,12 g (17, 23S)-23,25,25,25-tetrachloro-3,3- [1,2-atanderson(oxy)]-17-hydroxy-11-methylene-19,26,27-trinorprosta - 5,20-Dien-24-she's in 90 ml of toluene and 10 ml of diisopropylethylamine was heated in a flask under reflux for 1 hour. After cooling, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with saturated aqueous solution of sodium bicarbonate and saline. Drying with sodium sulfate and evaporation of the solvents gave of 4.57 g of the lactone (17, 23S)-23-chloro-3,3-[1,2-atanderson(oxy)] -17-hydroxy - 11-methylene-19-Nichola-5,20-Dien-24-OIC acid, which was used in the next stage without posleduyushe stage was turned in to 0.67 g of the lactone (17, 23S)-23-chloro-17-hydroxy-11-methylene - 3-oxo-19-Nichola-4,20-Dien-24-OIC acid.
The lactone (17, 23S)-23-chloro-17-hydroxy-11-methylene-3 - oxo-19-Nichola-4,20-Dien-24-OIC acid was obtained from a lactone (17, 23R)-23-chloro-3,3-[1,2-atanderson(oxy)]-17-hydroxy - 11-methylene-19-Nichola-5,20-Dien-24-OIC acid (example 8, step (I) using a procedure analogous to the procedure from step II of example 1. So pl. 219oC. [ ]D20= +112o(C=1, chloroform).
Example 10.
The lactone (17 )-23,23-dichloro-17-hydroxy-11-methylene-3-oxo - 19-Nichola-4,20-Dien-24-OIC acid was obtained from a lactone (17, 23S)-23-chloro-3,3-[1,2-atanderson(oxy)]-17-hydroxy-11 - methylene-19-Nichola-5,20-Dien-24-OIC acid (example 8, step (II) as follows:
I) a Solution of 1.17 ml Diisopropylamine in 70 ml anhydrous THF was cooled to -30oC and was added dropwise 5,16 ml n-utility (a 1.6 N in hexane). The mixture was stirred for 10 minutes at -10oC and then cooled to -78oC. was added dropwise a solution of 3.06 g of the above-mentioned steroid in 25 ml THF and stirring was continued for 15 minutes. Added carbon tetrachloride (22,32 g) for 5 minutes and the mixture gave Nagy solution of ammonium chloride and the product was extracted with ethyl acetate. The combined organic phases are washed with saline, dried with sodium sulfate and concentrated under reduced pressure. Column chromatography of the remaining product gave 1,71 g of the lactone (17 )-23,23-dichloro-3,3-[1,2-atanderson(oxy)] -17-hydroxy - 11-methylene-19-Nichola-5,20-Dien-24-OIC acid.
II) Following the procedure similar to that from step II of example 1, 0.85 grams of the product from the previous step was converted to the lactone (17 )-23,23-dichloro-17-hydroxy-11-methylene-3-oxo - 19-Nichola-4,20-Dien-24-OIC acid.
The lactone (17, 23R)-17-hydroxy-11-methylene-3-oxo-19 - Nichola-4,20-diene-23-carboxylic acid were obtained from cyclic 1,2-candirectly (17 )-17-hydroxy-20-(hydroxymethyl)- 11-methylene-19-norpregna-5,20-Dien-3-one (example 4, stage II), as follows:
I) a Solution 7,72 g of the above diol in a mixture of 20 ml of anhydrous THF, 20 ml trimethylolpropane and 0.18 ml of phosphoroxychloride was stirred at room temperature for 1 hour. The reaction mixture was then poured into 200 ml of water and the resulting suspension was stirred for 30 minutes. The product was collected ethyl acetate and the aqueous phase was extracted with the same RA is Aravali under reduced pressure. Column chromatography gave 6,79 g cyclic 1,2-candirectly (17 )-20-(hydroxymethyl)-11-methylene-17- (1-oxopropoxy)-19-norpregna-5,20-Dien-3-one.
II) Following the procedure similar to stage IV of example 4, 6,79 g of the steroid from the previous stage was transformed into 8.90 g of cyclic 1,2-candirectly (17 )-11-methylene-20- [[[(4-were)sulfonyl]oxy]methyl] -17-(1-oxopropoxy)-19 - norpregna-5,20-Dien-3-one which was used in the next stage without additional purification.
III) a Mixture of 300 ml of anhydrous dimethoxyethane and 32 ml of solution athribis(trimethylsilyl)amide (1N in THF) was cooled to -30oC. was added dropwise a solution of 4.77 g of tosylate obtained at the preceding stage in 20 ml of dimethoxyethane and the mixture was stirred at -30oC for 30 minutes. The reaction was suppressed by adding 100 ml of a saturated aqueous solution of ammonium chloride; the mixture was stirred at room temperature for 15 minutes and dimethoxyethane and THF was removed under reduced pressure. The residue was extracted with ethyl acetate; the extracts were washed with saline, dried with sodium sulfate and concentrated under reduced pressure to get 3,48 g of the lactone (17, 23R)-3,3-[1,2-atanderson(oxy)] -17-hydroxy - 11-methylene-19-Nichola-5,20-djeneba procedure, similar procedure from step II of example 1, of 1.36 g of the product from the previous stage was turned into a 0.84 g of the lactone (17 , 23R)-17-hydroxy-11-methylene-3-oxo-19 - Nichola-4,20-diene-23-carboxylic acid.
The lactone (17 )-17-hydroxy-23-methyl-11-methylene-3-oxo - 19-Nichola-4,20-diene-23-carboxylic acid were obtained from cyclic 1,2-candirectly (17 )-11-methylene-20-[[[(4-were)sulfonyl] oxy]methyl]-17-(1-oxopropoxy)-19-norpregna-5,20-Dien-3-one (example 11, stage II), as follows:
I) a Mixture of 110 ml of anhydrous dimethoxyethane and 12.8 ml of bis(trimethylsilyl)amide (1N in THF) was cooled to -30oC. was added dropwise a solution 1,91 g tosilata mentioned above, in 18 ml of dimethoxyethane and the mixture was stirred at -30oC for 30 minutes. Was added dropwise itmean (1,99 ml) and the reaction mixture was allowed to warm to 0oC for 2 hours. Was added a saturated aqueous solution of ammonium chloride and dimethoxyethane and THF was removed under reduced pressure. The residue was extracted with ethyl acetate; the extracts were washed with saline, dried with sodium sulfate and concentrated under reduced pressure to get 1,43 g (100%) of the lactone (17 )- 3,3-[1,2-e is the next stage without additional purification.
II) Following the procedure similar to that described in stage II of example 1, 1,43 g of the above-mentioned steroid turned 0.95 g of the lactone (17 )-17-hydroxy-23-methyl-11-methylene - 3-oxo-19-Nichola-4,20-diene-23-carboxylic acid.
The lactone (17 )-17-hydroxy-11-methylene-3-oxo-19-Nichola - 4,20,22-triene-23-carboxylic acid was obtained from a lactone (17 , 23R)-3,3-[1,2-atanderson(oxy)] -17-hydroxy-11-methylene - 19-Nichola-5,20-diene-23-carboxylic acid (example 11, stage III), as follows:
I) a Solution 0,672 ml Diisopropylamine in 20 ml of anhydrous THF was cooled to -30oC and was added dropwise a solution of 1.6 N in hexane) n-utility of 3.00 ml, and the Mixture was stirred for 10 minutes at -10oC and then cooled to -78oC. was added dropwise a solution of 1.70 g of the above-mentioned steroid in 20 ml of THF and stirring was continued for 15 minutes. Was added dropwise a solution of 1.59 g chetyrehpostovye carbon in 8 ml of THF and the mixture was allowed to warm to 0oC for 2 hours. Was added a saturated aqueous solution of ammonium chloride and the product was extracted into ethyl acetate. The combined organic phases are washed with saline, dried with sodium sulfate and con the C-11-methylene-19-Nichola-5,20-diene-23-carboxylic acid, which was used in the next stage without additional purification.
II) a Solution of 1.90 g prosteroid obtained at the previous stage, in a mixture of 38 ml of toluene and 3.8 ml of 1,5-diazabicyclo-[4,3,0]-non-5-ene was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The combined organic phases are washed with saline, dried with sodium sulfate and concentrated under reduced pressure to get to 1.38 g of the lactone (17 )-3,3-[1,2 - atanderson(oxy)]-17-hydroxy-11-methylene-19-Nichola-5,20,22-triene - 23-carboxylic acid, which was used in the next stage without additional purification.
III) Following the procedure similar to that from step II of example 1 to 1.38 g of the above-mentioned steroid turned 0.74 g of the lactone (17 )-17-hydroxy-11-methylene-3-oxo-19-Nichola - 4,20,22-triene-23-carboxylic acid.
The lactone (17 , 22R)-22-ethyl-17-hydroxy-11-methylene-3-oxo - 19-Nichola-4,20-Dien-24-OIC acid was obtained from diacetate (17 )-3,3-[1,2-atanderson(oxy)] -17-hydroxy-11-methylene-19 - norpregna-5,20-Dien-20-carboxaldehyde (example 4I p-toluensulfonate acid (0,414 ml of 0.1 N aqueous solution) and the mixture was stirred at room temperature for 45 minutes. Then the reaction mixture was added dropwise to a cooled on ice, a mixture of 40 ml of ethylmagnesium (3N in diethyl ether and 100 ml of THF. The reaction mixture was stirred for 2 hours, then the reaction is extinguished saturated aqueous ammonium chloride. The product was extracted into ethyl acetate; the extracts were washed with saline, dried with sodium sulfate and concentrated under reduced pressure. Column chromatography gave of 3.31 g of cyclic 1,2-candirectly (17 , 22R)-17,22-dihydroxy - 11-methylene-19-Nichola-5,20-Dien-3-one.
II) Following the procedure similar to stage III of example 4, equal to 4.97 g of the above-mentioned steroid turned in 5,72 g cyclic 1,2-candirectly (17, 22R)-17-acetoxy-22 - hydroxy-11-methylene-19-Nichola-5,20-Dien-3-one which was used in the next stage without additional purification.
III) a Solution of 2.28 g of monoether obtained at the previous stage, in 16 ml of anhydrous pyridine was cooled in a water bath. Added p-toluensulfonyl anhydride (3,27 g) and the mixture was stirred at room temperature for 3 hours. Then it was poured into 320 ml of water and the resulting suspension was stirred for 1 hour. The product was collected ethyl acetate and the aqueous layer exercebant sodium, saline solution, dried with sodium sulfate and concentrated under reduced pressure. The crude product (3.13 g), cyclic 1,2-candirectly (17, 22R)-17-acetoxy-11-methylene-22-[[(4-were)sulfonyl] oxy]-19-Nichola - 5,20-Dien-3-one used as such in the next stage.
IV) Following the procedure similar to stage V of example 4, 3.13 g tosilata with the previous stage was transformed in 0.72 g of the lactone (17, 22R)-22-ethyl-3,3-[1,2-atanderson(oxy)] -17 - hydroxy-11-methylene-19-Nichola-5, 20-Dien-24-OIC acid.
V) Following the procedure similar to that from step II of example 1, to 0.72 g of the steroid from the previous stage was turned in to 0.44 g of the lactone (17, 22R)-22-ethyl-17-hydroxy-11-methylene - 3-oxo-19-Nichola-4,20-Dien-24-OIC acid. So pl. 172oC. [ ]D20= +186o(C=1, chloroform).
The lactone (3,17) -3,17-dihydroxy-11-methylene-19-Nichola-4,20-Dien - 24-OIC acid was obtained from a lactone (17 )-17-hydroxy-11 - methylene-3-oxo-19-Nichola-4,20-Dien-24-OIC acid (from example 2) as follows:
Borohydride sodium (0,522 g) was added to a solution of 2.52 in town last steroid in 69 ml of anhydrous diglyme. The reaction mixture was stirred at room temperature for 1 hour. After cooling to 0oC the reaction was Outragiously in diethyl ether. The combined organic phases are washed with water, saturated aqueous sodium bicarbonate and brine, dried with sodium sulfate and concentrated under reduced pressure to get epimeres mixture of product recovery. Using column chromatography was selected 3V-hydroxyethane with the release of 0.40 g of the lactone (3,17) -3,17-dihydroxy-11-methylene-19-Nichola - 4,20-Dien-24-OIC acid.
The lactone (3,17) -17-hydroxy-3-methoxy-11-methylene-19-Nichola-4,20 - Dien-24-OIC acid (a) and the lactone (3,17) -17-hydroxy-3-methoxy-11 - methylene-19-Nichola-4,20-Dien-24-OIC acid (b) were obtained from cyclic 1,2 - candirectly (17 )-17-hydroxy-20- (hydroxymethyl)-11-methylene-19-norpregna-5,20-Dien-3-one (example 4, stage II), as follows:
I) a Solution of 4.59 g of the recent steroid in a mixture of 90 ml of methanol and 4.6 ml of 6N hydrochlorite acid was stirred at room temperature for 2 hours. Was added water (90 ml); the resulting suspension was filtered and the residue washed with water. Drying of the residue gave 3,86 g (17 )-17-hydroxy-20- (hydroxymethyl)-11-methylene-19-norpregna-4,20-Dien-3-one, which was used as such on the left of acid in 93 ml of acetone was stirred at room temperature for 48 hours. The reaction mixture is neutralized by adding a saturated solution of sodium bicarbonate and acetone was removed under reduced pressure. The residue was extracted with ethyl acetate; the extracts were washed with saline, dried with sodium sulfate and concentrated under reduced pressure obtaining of 2.51 g (17 )-2,2-dimethyl-5,11'- dimethylamino[1,3-dioxane-4,17'-variety[4] Yong] -3'-it is used as such in the next stage.
III) a Solution of 2.51 g of the steroid obtained at the previous step, in 50 ml of anhydrous THF was added dropwise to a cooled on ice, the suspension of 1.25 g of lithium aluminum hydride in 50 ml of THF. After 1 hour at 0oC reaction extinguished saturated aqueous solution of sodium sulfate. Added ethyl acetate and the mixture was filtered through brownmillerite. The filtrate was concentrated under reduced pressure to get 2,53 g of a mixture of (3'E, 17' )-2,2-dimethyl-5,11'-dimethylbenzene[1, 3-dioxane-4,17'-variety[4] Yong] -3'-ol and (3,17) -2,2-dimethyl-5, 11'-dimethylbenzene[1,3-dioxane-4,17'-variety[4] Yong] -3'-ol (85: 15), which was used as such in the next stage.
IV) a Solution of 2.53 g of the product from the previous stage, in a mixture of 26.4 ml of pyridine and 13.2 ml of acetic anhydride was stirred at room temperature for 6 hours. Then the reaction with whom and in ethyl acetate and the aqueous layer was extracted with the same solvent. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried with sodium sulfate and concentrated under reduced pressure to get 2,73 g of a mixture of 85:15 (3'E,17'B)-2,2-dimethyl-5,11'- dimethylarsino- [1,3-dioxane-4,17'-variety[4] Yong]-3'-Alzette and(3', 17')-2,2-dimethyl-5,11'-dimethylbenzene[1,3-dioxane-4,17'-variety[4] Yong] - 3'-Alzette, which was used as such in the next stage.
V) Following the procedure similar to stage I, 2,73 g of the product from the previous stage was transformed into 2,22 g of a mixture of 6:4 (3,17) -3-methoxy-11,20-dimethylene-19-norpregna-4-ene-17,21-diol and (3,17) -3-methoxy-11,20-dimethylene-19-norpregna-4-ene-17,21-diol, which was used as such in the next stage.
VI) Following a procedure similar to stage III of example 4, 2,22 g of the product from the previous stage has azetilirovanie 17-hydroxy-group, receiving 1.04 g (3,17) - 3-methoxy-11,20-dimethylene-19-norpregna-4-ene-16,21-diol-17-acetate and 0.75 g (3,17) -3-methoxy-11,20-dimethylene-19-norpregna-4-ene - 17,21-diol-17-acetate.
VIIa) Following a procedure similar to stage IV of example 4, 1.04 g (3,17) -3-methoxy-11,20-dimethylene-19-norpregna-4-ene - 17,21-diol-17-acetate was converted in 1.24 g (3,17) -3-methoxy-11, 20-dimethylene-19-norpregna-4,20-diene-17,21-dia) Following the procedure similar to the procedure described for stage V of example 4, 1.24 g of the product from the previous stage was turned in to 0.66 g of the lactone (3,17) -17-hydroxy-3-methoxy-11-methylene-19-Nichola - 4,20-Dien-24-OIC acid.
VII) Following a procedure similar to stage IV of example 4, 0.75 g (3,17) -3-methoxy-11,20-dimethylene-19 - norpregna-4-ene-17,21-diol-17-acetate was converted in 0.97 g (3,17) -3-methoxy-11,20-dimethylene-19-norpregna-4,20-diene-17,21-diol-17-acetate-21-(4-methylbenzenesulfonate), which was used as such in the next stage.
VIII) Following a procedure similar to stage V of example 4, 0.97 g of the product from the previous stage turned 0.53 g of the lactone (3,17) -17-hydroxy-3-methoxy-11-methylene-19-Nichola-4,20-Dien - 24-OIC acid.
The lactone (11B,17) -11-ethyl-17-hydroxy-3-oxo-19-Nichola - 4,9,20-trien-24-OIC acid were obtained from cyclic 3-(1,2 - candirectly)östra-5(10),9(11)-the diene-3,17-dione as follows:
I) Following a procedure similar to stage I of example 1, and 29.7 g of the recent steroid turned in 42,07 g of a mixture of starting material and ciklicheskoy such in the next stage.
II) a Mixture of 110 g of silica, 9.8 ml of a saturated aqueous solution of oxalic acid and 310 ml of dichloromethane was stirred for 10 minutes. Solution was added 42,07 g of the product from the previous stage in 130 ml of dichloromethane, and stirring was continued for another 20 minutes. Was added sodium bicarbonate (5 g) and the mixture was filtered through brownmillerite. The residue was washed with ethyl acetate and the filtrate was concentrated under reduced pressure to get to 6.22 g of cyclic 1,2-candirectly (17 )-17,24-dihydroxy-19 - Nichola-5(10),9(11),20-triene-3-one.
III) To a solution by 8.22 g of the product from the previous stage in 113 ml of dichloromethane was added 0.51 ml of pyridine, 1,92 ml of 2,2,2 - trifurcation and 27.7 ml of an aqueous solution of hydrogen peroxide (30%). After stirring at room temperature for 70 hours, the reaction mixture was poured into 300 ml of water. The aqueous layer was extracted with dichloromethane; the combined organic phase is again washed with saturated aqueous sodium thiosulfate and brine, dried with sodium sulfate and concentrated under reduced pressure. Column chromatography gave 3,26 g cyclic 1,2-candirectly (5,10,17) -5,10-epoxy-17,24-dihydroxy - 19-Nichola-9(11),20-Dien-3-one.
IV) To the mixture 3,26 g wisewomanC, was added dropwise 16 ml of ethylacetamide (3N in diethyl ether). After stirring at -20oC for 1 hour the reaction was suppressed saturated aqueous solution of ammonium chloride. The product was extracted with ethyl acetate; the extracts were washed with saline, dried with sodium sulfate and concentrated under reduced pressure to get 3,05 g cyclic 1,2-candirectly (5,11,17) -11-ethyl-5,17,24-trihydroxy-19 - Nichola-9,20-Dien-3-one, which used
as such in the next stage.
V) Following the procedure similar to that from step II of example 1, was 3.05 g of the steroid from the previous stage was transformed 1.38 g (11B,17 )-11-ethyl-17,24-dihydroxy-19-Nichola - 4,9,20-triens-3-one.
VI) To a solution of 23.1 g of pyridinediamine in 84 ml of anhydrous dimethylformamide was added a solution of 1.38 g of the product from the previous stage in 35 ml of the same solvent. The reaction mixture was stirred at room temperature for 45 minutes and then poured into 1200 ml of water. The product was extracted with ethyl acetate; the combined extracts were washed with water (3 times) and brine, dried with sodium sulfate and concentrated under reduced pressure. Column chromatography gave 0,78 g of the lactone (11,17) -11-ethyl-17 - galiform).
The lactone (17 )-17-hydroxy-3-oxo-19-Nichola-4,20,22 - trien-24-OIC acid obtained from diethylacetal (17 )-3,3-[1,2 - atanderson(oxy)]-17-hydroxy-19-norpregna-5,20-Dien-2-carboxaldehyde, in turn derived from a cyclic 3-(1,2-candirectly)variety - 5-ene-3,17-dione by the procedure similar to stage I of example 4, as follows:
I) 16,30 g diethylacetal (17 )-3,3-[1,2-atanderson(oxy)]- 17-hydroxy-19-norpregna-5,20-Dien-20-carboxaldehyde was dissolved in 180 ml of anhydrous THF. Added p-toluensulfonate acid (1,10 ml of 1N aqueous solution) and the mixture was stirred at room temperature for 4 hours. Was added a saturated aqueous solution of sodium bicarbonate and the product was extracted into ethyl acetate. The combined organic phases are washed with saline, dried with sodium sulfate and concentrated under reduced pressure to get 12,53 g (17 )-3,3-[1,2-atanderson(oxy)]-17-hydroxy - 19-norpregna-5,20-Dien-20-carboxaldehyde, which was used as such in the next stage.
II) To a cooled on ice to a solution of 2.0 g of the product from the previous stage, in a mixture of 30 ml of dichloromethane and 4.4 ml of pyridine was added chlorotrimethylsilane (3.4 ml). The reaction mixture was stirred at commct were extracted in dichloromethane; the extract was washed with saline, dried with sodium sulfate and concentrated under reduced pressure to get 2,59 g (17 )-3,3- [1,2-atanderson(oxy)]-17-trimethylsilyloxy-19-norpregna-5,20 - Dien-20-carboxaldehyde, which was used as such in the next stage.
III) a Solution of 1.32 ml Diisopropylamine in 45 ml of anhydrous THF was cooled to -30oC and was added dropwise 6,10 ml n-utility (a 1.6 N in hexane). The mixture was stirred for 10 minutes at -10oC and then cooled to -78oC. was added dropwise t-butyl acetate (1,28 ml) and stirring was continued for 30 minutes. Was added dropwise a solution 2,07 g of the product from the previous stage in 8 ml THF and the reaction mixture was stirred for another 2.5 hours. Was added a saturated aqueous solution of ammonium chloride and the product was extracted into ethyl acetate. The combined organic phases are washed with saline, dried with sodium sulfate and concentrated under reduced pressure. Column chromatography gave 0.52 g of 1,1-dimethylethyl-(17 , 22S)-3,3-[1,2-atanderson(oxy)] -22-hydroxy-17-trimethylsilyloxy - 19-Nichola-5,20-Dien-24-oate and 2.02 g of 1,1-dimethylethyl-(17 , 22R)-3,3-[1,2-atanderson(oxy)]-22-hydroxy-17-trimethylsilyloxy - 19-Nichola-5,20-Dien-24-oate.
obavljale powdered potassium hydroxide (0,546 g). After stirring for 3 hours at room temperature the reaction mixture was neutralized with an aqueous solution of acetic acid (50%) was poured into 150 ml of water and was extracted with dichloromethane. The combined organic phases are washed with saline, dried with sodium sulfate and concentrated under reduced pressure. Column chromatography gave 0,503 g of the lactone (17 )-3,3-[1,2-atanderson(oxy)]- 17-hydroxy-19-Nichola-5,20,22-trien-24-OIC acid and 0,255 g of the lactone (17 ,22R)-3,3-[1,2-atanderson(oxy)] -17,22 - dihydroxy-19-Nichola-5,20-Dien-24-OIC acid.
V) Following the procedure similar to that from step II of example 1, 0,453 g main product from the previous stage was transformed into 0,402 g of the lactone (17 )-17-hydroxy-3-oxo-19 - Nichola-4,20,22-trien-24-OIC acid.
So pl. 250oC. [ ]D20= -29,6o(c=0.5, chloroform).
Following a procedure similar to stage II of example 1, obtained lactone (17 ,22R)-17,22-dihydroxy-3-oxo-19 - Nichola-4,20-Dien-24-OIC acid from the lactone (17 ,22R) -3,3-[1,2-atanderson(oxy)]-17,22-dihydroxy-19-Nichola-5,20 - Dien-24-OIC acid (example 18, step IV). So pl. 235oC.
The lactone (17 , 22S)-17,22-dihydroxy-3-oxo-19-Nichola - 4,20-Dien-24-ovo is 5,20-Dien-24-oate (example 18, stage III) as follows:
I) To a solution of 2.15 g of the recent steroid in 1.5 ml of anhydrous methanol and 13 ml of anhydrous THF was added powdered potassium hydroxide (0,580 g). After stirring for 75 minutes at room temperature the reaction mixture was poured into 150 ml of water and was extracted with ethyl acetate. The organic phase was discarded; the aqueous phase was acidified (to pH 3) aqueous solution of acetic acid (50%) and then was extracted with dichloromethane. The combined dichloromethane extracts were dried with sodium sulfate and concentrated under reduced pressure to obtain 1.20 g (17 ,22S)-3,3-[1,2-atanderson(oxy)] - 17,22-dihydroxy-19 - Nichola-5,20-Dien-24-OIC acid, which was used as such in the next stage.
II) Following the procedure similar to that from step II of example 1, using as solvent THF, 1.20 g of the product from the previous stage was transformed into 0,455 g of the lactone (17 ,22S)-17,22-dihydroxy-3-oxo-19-Nichola-4,20-Dien-24 - OIC acid.
So pl. 229oC. [ ]D20= +58,4o(C=0,5, chloroform).
The lactone (17 )-23-bromo-17-hydroxy-3-oxo-19-Nichola - 4,20,22-trien-24-OIC acid was obtained from a lactone (17 ) -3,3-[1,2-atanderson(oxy)]-17-hydroxy-19-Nichola-5,20 - Dien-24-avocatura, similar procedure from step I of example 13, of 10.05 g of the above-mentioned lactone was converted to 4.17 g of the lactone (17 )-23,23-dibromo-3,3-[1,2-atanderson(oxy)] -17-hydroxy-19 - Nichola-5,20-Dien-24-OIC acid.
II) Following the procedure similar to stage II of example 13, to 4.17 g of the steroid from the previous stage turned 1.30 g of the lactone (17 )-23-bromo-3,3-[1,2-atanderson(oxy)] -17 - hydroxy-19-Nichola-5,20,22-trien-24-OIC acid.
III) Following the procedure similar to that from step II of example 1 to 1.38 g of the product from the previous stage was transformed into 1.17 g of the lactone (17 )-23-bromo-17-hydroxy-3-oxo-19-Nichola - 4,20,22-trien-24-OIC acid.
The lactone (17 )-17-hydroxy-3-oxo-19-Nichola-4,6,20 - trien-24-OIC acid was obtained from (17 )-3-ethoxy-24-trimethyl - silyloxy-19-Nichola-3,5,20-trien-17-ol (example 1, step I) as follows:
I) a Solution of 11.4 g of the above-mentioned steroid in 20 ml dichloromethane was added under vigorous stirring to a mixture of 8.2 g of tetrachloro-1,4-benzoquinone, 18 ml of methanol, 43 ml of dichloromethane, 1.0 ml of water, 1.7 ml of acetic acid and 0.18 ml of pyridine. After 75 minutes stirring solution was added 3.25 g of sodium hydroxide and 3.25 g of hydrosulfite on the nnye the organic phase was washed with an aqueous solution of sodium hydroxide (2N), water and saline, dried with sodium sulfate and concentrated under reduced pressure. Column chromatography gave 2,39 g (17 )-17,24-dihydroxy-19-Nichola-4,6,20-triene-3-one.
II) Following the procedure similar to that from step VI of example 17, 2,39 g of the steroid from the previous stage was turned into a 1.70 g of the lactone (17 )-17-hydroxy-3-oxo-19-Nichola-4,6,20 - trien-24-OIC acid.
So pl. 230oC. [ ]D20= -94,8o(C=1, chloroform).
The lactone (7,17) -17-hydroxy-7-methyl-3-oxo-19-Nichola - 5(10),20-Dien-24-OIC acid was obtained from 3-(dimethylacetal) (7 )-7-methylestr-5(10)-ene-3,17-dione as follows:
I) Following a procedure similar to stage I of example 1, 30.0 g of the recent steroid was turned in by 45.1 g of a mixture of starting material and dimethylacetal (7,17)-17-hydroxy-7-methyl-24 - trimethylsilyloxy-19-Nichola-5(10),20-Dien-3-one, which was used as such in the next stage.
II) 256 ml of a solution of tetrabutylammonium fluoride (1N in THF) was added to a cooled on ice to a solution of 45.1 g of the steroid from the previous stage in 128 ml of anhydrous THF. The reaction mixture was stirred at 0oC for 45 minutes and then poured into 2 l of water. The product was extracted with ethyl acetate; the volume of the thief, was dried with sodium sulfate and concentrated under reduced pressure. Column chromatography gave 15,55 g dimethylacetal (7,17) -17,24-dihydroxy-7-methyl-19-Nichola-5(10),20 - Dien-3-one.
III) a Mixture of 200 ml of dichloromethane and 40 ml of pyridine was cooled in a water bath. Was carefully added oxide of chromium (VI) and the mixture was stirred for 10 minutes. A solution of 7.0 g of the product from the previous stage, in a mixture of 1 ml of pyridine and 250 ml of dichloromethane was added to the reaction mixture and stirring continued at room temperature for 1 hour. Then it was poured into water Hydrosulphite solution of sodium (10%) and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried with sodium sulfate and concentrated under reduced pressure. Column chromatography gave 5,47 g of the lactone (7,17) -17-hydroxy-3,3-dimethoxy-7-methyl-19 - Nichola-5(10),20-Dien-24-OIC acid.
IV) To a solution of 1.36 g of the product from the previous stage in 27 ml of ethanol was added to the solution 0,070 g of dihydrate of oxalic acid 7.0 ml of water. The reaction mixture was stirred at 30oC for 30 minutes. Was added triethylamine (1 ml) and the mixture was poured into saturated aqueous bicarbonate Nai sodium sulfate and concentrated under reduced pressure. Column chromatography gave of 1.03 g of the lactone (7,17) -17-hydroxy-7-methyl-3-oxo-19-Nichola-5(10),20-Dien-24-OIC acid.
So pl. 77oC. [ ]D20= +53o(C=1, chloroform).
The lactone (11,17) -17-hydroxy-3-(hydroxyimino)-11-(1-PROPYNYL)-19 - Nichola-4,20-Dien-24-OIC acid was obtained from a lactone (11,17) -17 - hydroxy-3-oxo-11-(1-PROPYNYL)-19-Nichola-4,20-Dien-24-OIC acid (see example 2) as follows:
To a solution of 1.95 g of the above lactone 8.5 ml of pyridine was added 3.80 g of hydroxylamine hydrochloride. The reaction mixture was stirred at room temperature for 1 hour and then poured into 150 ml of water. The product was extracted with dichloromethane; the combined organic phases are washed with water, dried with sodium sulfate and concentrated under reduced pressure. Column chromatography gave of 1.94 g of the lactone (11,17) -17-hydroxy-3- (hydroxyimino)-11- (1-PROPYNYL)-19-Nichola-4,20-Dien-24-OIC acid as a mixture of E/z epimeres 45:55.
So pl. 250oC. [ ]D20= +173,6o(C=0,5, chloroform).
The lactone (3E,11,17 )-3-(acetoacetamide)-17-hydroxy-11 - methyl-19-Nichola-4,20-Dien-24-OIC acid (a) and the lactone (3Z,11 ,17 )-3-(acetoacetamide)-17-hydroxy-11-methyl-19 - Nichola-4,20-Dien is EP 2) as follows:
To a solution of 2.4 g of the above lactone in 12 ml of pyridine was added 5,04 g of hydroxylamine hydrochloride. The reaction mixture was then stirred at 80oC for 4 hours. After cooling the mixture was poured into 150 ml ice water and stirred for 30 minutes. The resulting suspension was filtered; the residue is thoroughly washed with water and dried under reduced pressure at 50oC. the Product was collected with a mixture of 24 ml of pyridine and 12 ml of acetic anhydride. The reaction mixture was stirred at room temperature for 2 hours and then poured into 800 ml of ice water. The resulting precipitate was collected and dried under
reduced pressure. Column chromatography of the solid substance thus obtained, gave 0.85 grams of the lactone (3E, (11,17) -3-(acetoacetamide)-17-hydroxy-11-methyl-19-Nichola-4,20 - Dien-24-OIC acid.
So pl. 194oC. [ ]D20= +63,6o(C=1, chloroform);
and 0.29 grams of lactone (3Z, 11, 17 )-3-(acetoacetamide)-17 - hydroxy-11-methyl-19-Nichola-4,20-Dien-24-OIC acid.
So pl. 182oC. [ ]D20= +122,3o(C=1, chloroform).
The lactone (17 , 23Z)-17,24-dihydroxy-11-methylene-3-oxo - 19-Nichola-4,20,23-triene-23-carboxylic acid was obtained from lactodorum:
I) a Solution 1,68 ml Diisopropylamine in 24 ml of anhydrous THF was cooled to -30oC and was added dropwise to 7.5 ml of a solution of n-utility (a 1.6 N in hexane). The mixture was stirred for 10 minutes at -10oC and then cooled to -78oC. was added dropwise a solution of 1.64 g of the above-mentioned steroid in 20 ml of THF and stirring was continued for 15 minutes. Was added ethyl formate (2,24 ml) and the mixture was allowed to warm to 0oC for 2 hours. Was added a saturated aqueous solution of ammonium chloride and the product was extracted with ethyl acetate. The combined organic phases are washed with saline, dried with sodium sulfate and concentrated under reduced pressure to get 2,09 g of the lactone (17 , 23Z)-3,3-[1,2-atanderson(oxy)]-17,24-dihydroxy-11-methylene-19-Nichola-5,20,23-triene-23-carboxylic acid, which was used in the next stage without additional purification.
II) Following the procedure similar to that from step II of example 1, of 2.09 g of the product from the previous stage turned 0.39 g of the lactone (17 , 23Z)-17,24-dihydroxy-11-methylene - 3-oxo-19-Nichola-4,20,23-triene-23-carboxylic acid.
So pl. >105oC, decomp.
The lactone (17 , 23Xi)-17-hydroxy-11-methylene-3,24-dioxo - 19,26,27-trinorprosta-4,20-Dien-23-Oh acid (example 4, stage V) as follows:
I) a Solution of 1.26 ml Diisopropylamine in 18 ml of anhydrous THF was cooled to -30oC and was added dropwise a solution of n-utility (a 1.6 N in hexane). The mixture was stirred for 10 minutes at -10oC and then cooled to -78oC. was added dropwise a solution of 1.23 g of the above-mentioned steroid in 16 ml THF and stirring was continued for 15 minutes. Added acetylchloride (0,852 ml) and the mixture was allowed to warm to 0oC for 2 hours. Was added a saturated aqueous solution of ammonium chloride and the product was extracted with ethyl acetate. The combined organic phases are washed with saline, dried with sodium sulfate and concentrated under reduced pressure to obtain 2.10 g of the lactone (17 , 23Xi) -3,3-[1,2-atanderson(oxy)]-17-hydroxy-11-methylene-24-oxo - 19,26,27-trinorprosta-5,20-diene-23-carboxylic acid, which was used in the next stage without additional purification.
II) Following the procedure similar to that from step II of example 1, 2,10 g of the product from the previous stage was turned into a 0.33 g of the lactone (17, 23Xi)-17-hydroxy-11-methylene-3, 24 dioxo-19,26,27-trinorprosta-4,20-diene-23-carboxylic acid.
The lactone (11,17) -17-hydroxy-11-methyl-3-ox-dione and 2-bromo-6-trimethylsilyloxy-1 - hexene, as described in example 1.
So pl. 230,1oC.
Example 29. The ability of compounds according to the invention to bind to receptors
The affinity of the compounds according to the invention in relation to progesterone receptors were identified in the cytoplasmic progesterone receptors present in the tumor cells of breast cancer in human (MCF-7 cells, the incubation time of 16 hours, the temperature of the 4oC) and compared with the affinity (16 )- 16-ethyl-21 - hydroxy-19-norpregna-4-ene-3,20-dione in accordance with the method described by E. W. K Bergin et al., T. Steroid Biochem., Vol. 19, 1563-1570 (1983).
The affinity of the compounds according to the invention in relation to glucocorticoid receptors was determined on glucocorticoid receptors present in intact cells of multiple myeloma man (IM-9 cells, the incubation time is 1 hour, the temperature of the 37oC) and compared with the affinity of dexamethasone in accordance with the method described. H. J. Kloosterboer et al., J. Steroid Biochem., Vol. 31, 567-571 (1988).
Table 1 shows the ability of the compounds according to the invention to bind to receptors: from progesterone receptors (PR), glucocorticoid receptor (GR), and their ratio (PR/GR).
Compounds of the present invention compared with investt a much larger ratio PR/GR, than known compounds having a ratio of typically >1, in contrast to the known compounds, for which the values of the ratio PR/G <1. This means that the known compounds exhibit relatively higher affinity for binding to the glucocorticoid receptor than with progesterone receptor, whereas the compounds according to the invention have a relatively high affinity with respect to the progesterone receptor and a relatively low affinity towards unwanted glucocorticoid receptor. Compounds having a relatively low affinity to the progesterone receptor, can be suitable Pro-drugs.
1. Steroid 17-spermatocelectomy group having the formula I
where R1is 0, (H,H), (H,or), or NOR; R is selected from H, (1-6C) alkyl or (1-6C)acyl;
R'2is H, or R'2together with R2is (1-6C)alkylidene group or (2-6C)allenylidene group; or R'2together with R3form a connection;
is, and the other is hydrogen or (1-6C)alkyl;
X is a group (CH2)nor (Cn-H2n-2), where n is 2 or 3, and which is optionally substituted by hydroxyl, halogen, (1-6C)alkyl, (1-6C)acyl, phenyl(1-6C)alkyl, phenyl group which may be substituted with halogen;
Y is O or (H,HE);
dotted lines indicate optional connection, at least one of the ties 4 - 5, 5 - 10 and 9 - 10 is a double bond.
2. Steroid under item 1, wherein R1is O; R4is stands; Y is O and n is 2.
3. Steroid under item 2, wherein R1is O; R2is (1-6C)alkyl or (2-6C)quinil; R'2and R3is H; R4is stands; R5and R6is hydrogen; X is (CH2)2; Y is O and the dashed line in D-ring is not a bond and the other dashed line is 4 - 5 connection.
4. Steroid under item 1, characterized in that it is-lactone (11, 17) -11-ethyl-17-hydroxy-3-oxo-19-Nichola-4,20-Dien-24-OIC acid or-lactone(11, 17) -17-hydroxy-3-oxo-11-(1-PROPYNYL)-19-Nichola-4,20-Dien-24-OIC acid.
5. The method of producing steroid under item 1, having the formula I, Otley is, (1-6C)alkyl or (1-6C) acyl or its protected derivative;
R2, R2', R3, R4, R5and R6specified in paragraph 1;
each Q is independently selected from H, (1-6C)alkyl and phenyl(1-6C) alkyl, phenyl group which may be substituted (1-6C)alkyl, (1-6C)alkoxy, hydroxyl or halogen;
L is a removable group, such as Casilina group;
dotted lines indicate optional connection, at least one of the relations 4 - 5, 5 - 6, 5 - 10 and 9 - 10, is a double bond,
transform by base catalyzed ring closure in the steroid with a 17-spermatocelectomy group, optionally followed by alkylation, phenylalkylamines, acylation, halogenoalkanes optional subsequent dehydrohalogenation and/or restoring to a compound where Y is (H,HE), then remove the optional available protective group, and then optionally convert the compound of formula I, where R1is On, the corresponding compound where R1is the above group NR.
6. Steroid according to any one of paragraphs.1 to 4, having affinity to the progesterone and glucocorticoid receptors.
Same patents:
-lactone 3(7 -acetylthio-17 -hydroxy-3 - oxoandrosta-4-en-17 -yl)propionic acid" target="_blank">
The method of obtaining -lactone 3(7 -acetylthio-17 -hydroxy-3 - oxoandrosta-4-en-17 -yl)propionic acid // 2163606
The invention relates to pharmaceutical chemistry, and in particular to an improved method for producing a potassium-sparing diuretic such as spironolactone (verospiron, aldactone) of the available raw materials - Starinov of plant and animal origin
Antiandrogenna connection predecessor antiandrogenna compounds, pharmaceutical compositions // 2141966
Derivatives 17,20-epoxides pregnana, methods for their preparation, connection // 2125060
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
where R-=0, -OH, and In the remains of
and K=O, or group
where n=2,3;
R1-the remainder of the ether or of ester,
wavy lines indicate the mixture of isomers
The method of obtaining hydrocortisone, compounds as intermediates in the synthesis of hydrocortisone // 2060257
Tigogenin beta-cellobioside // 2042688
Derivatives of condensed polycyclic heterocyclic compounds and method of production thereof // 2167877
The invention relates to novel condensed polycyclic heterocyclic compounds of the formula I and the way they are received
Combination containing receptor antagonist of angiotensin ii and apositional receptor antagonist of aldosterone // 2166330
Pharmaceutical combined preparation for hormonal contraception // 2165259
The invention relates to the field of medicine and relates to a pharmaceutical combination preparation for hormonal contraception
-glycyrrhizic acid with phenylboronic acid, exhibiting anti-inflammatory and antiulcer activity" target="_blank">
Amide -glycyrrhizic acid with phenylboronic acid, exhibiting anti-inflammatory and antiulcer activity // 2032694
Drospyrenon for replacement hormonotherapy // 2275198
FIELD: pharmaceutical industry, medicine.
SUBSTANCE: method relates to composition containing estrogen as the first active ingredient in amount sufficient to treatment of diseases, disorders, and symptoms associated with deficit of endogen estrogen levels in women; and drospyrenon as the second ingredient in amount sufficient to endometrium protection from unfavorable estrogen effects. Methods for treatment also are disclosed. Preparations of present invention are useful in combination therapy for continuous, subsequent or intermittent administration.
EFFECT: method for replacement hormonotherapy in women of improved efficiency.
46 cl, 7 ex
Derivatives of sapogenin, their synthesis, using and method based on their using // 2311423
FIELD: organic chemistry, steroids.
SUBSTANCE: invention discloses derivatives of steroid sapogenins of the general formula (I): wherein R means alkylcarbonyl, alkoxycarbonyl substituted possibly with amino-group and others under condition that R is not acetyl and R is not ethoxycarbonyl if C3 is in S and C25 in R-configurations simultaneously; R is nor succinyl if C3 and C25 are in S-configuration simultaneously, or C3 R(α) or S(β), and C25 in R-configuration. Also, invention discloses using these compounds in treatment of cognitive dysfunction, noncognitive neurodegeneration, noncognitive neuromuscular degeneration and loss of receptors in absence of cognitive, nervous and neuromuscular insufficiency. Also, invention discloses methods for synthesis of these compounds, treatment and pharmaceutical composition containing thereof.
EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical compositions.
30 cl, 2 tbl, 5 dwg, 16 ex
Combination and method for prophylaxis of breast cancer // 2322981
FIELD: medicine, oncology, organic chemistry, antibiotics.
SUBSTANCE: invention proposes a combination and corresponding method for treatment of tumors that are positive with respect hormone receptors. Combination comprises rapamycin or 40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin, or ABT578, or compound of the formula (1): or an aromatase inhibitor: atamestan, exemestan, formestan, aminoglutetinide, rogletimide, pyridoglutemife, trilostan, testolactone, ketocona-zol, vorozol, fandrozol, anastrozol or letrozol. In the formula (1) R1 means -CH3 or (C3-C6)-alkynyl; R2 means hydrogen atom (H) or -CH3-CH3-OH; X means oxygen atom (O), (H, H) or (H, -OH) under condition that R2 doesn't mean H if X means O, and R1 means -CH3. Proposed composition shows synergism in suppression of breast cancer proliferation.
EFFECT: valuable medicinal properties of combination.
Topical formulation, containing spironolactone nanoparticles // 2331424
FIELD: medicine.
SUBSTANCE: invention relates to topical formulation with: spironolactone nanoparticles, containing medium-diameter nanoparticles measured by photonic correlation spectroscopy technique, in the range approximately 300 nm to 900 nm, and dispersion of solid polar lipids crystals in polar liquid, with additional stabiliser. The nanoparticles are included in crystal structure formed by solid polar lipids crystals; the lipids mentioned being directed their hydrophilic ends outside, and hydrophobic ends inside, relative to spironolactone nanoparticles. Items of the patent application are also as follows: method of producing the formulation, the crystal lattice arrangement of solid polar lipids crystals with spironolactone nanoparticles included, and use of the nanosuspension with structure mentioned for medication producing, intended for therapy in anti-androgen responding conditions.
EFFECT: achieving of high stability formulation and increased bioavailability of spironolactone.
17 cl, 4 ex, 8 tbl, 11 dwg
Way of prevention and treatment of cardiovascular complications at patients with chronic disease of kidneys being on hemodialysis, having anuria // 2363472
SUBSTANCE: invention concerns medicine, namely to nephrology, and can be used for prevention and treatment of cardiovascular complications at patients with chronic disease of kidneys which are on hemodialysis HD. Essence of the way: angiotensin converting enzyme and-or blockers of hypertensinogen receptors and-or antagonists of calcium are administered to the patients with anuria. Spironolactone is additiobally administered in a dose of 25 mg a day throughout 6 months. The developed doses and the regimen of spironolactone introduction raise efficiency of the way at the given category of patients at the expense of reliable depression of aldosterone level in blood, correction of endothelial dysfunction and a fibrinolitic link of the hemostasis system.
EFFECT: efficiency of the way at the given category of patients at the expense of reliable depression of aldosterone level in blood, correction of endothelial dysfunction and a fibrinolitic link of the hemostasis system.
1 tbl, 2 ex
Hypertension treatment in women underwent hormon replacement therapy // 2373940
SUBSTANCE: invention refers to medicine, namely to therapy and endocrinology, and concerns hypertension treatments in women in combination with hormone replacement therapy. That is ensured by introduction of Drospirenone (DRSP) in amount 0.5-3 mg/day and 17β-estradiol in amount 1-3 mg/day.
EFFECT: invention provides maximally effective arterial pressure reduction with minimum by-effects in given category of patients.
17 cl, 3 ex, 1 tbl, 8 dwg
Multiphase pharmaceutical preparation for ovulation inhibition in mammal // 2396082
SUBSTANCE: multiphase pharmaceutical preparation for ovulation inhibition in mammal contains a number of individually packed and individually removed daily units placed in a single package, and used for oral administration for at least 21 days running; specified daily units contain a combination of oestradiol and drospirenone. A daily unit contains 0.5 to 4 mg of oestradiol and 2 to 4 mg of drospirenone. At least 70% of specified drospirenone are released from specified unit within 30 minutes.
EFFECT: invention provides higher oral bioavailability of drospirenone.
6 cl, 5 dwg, 5 ex
Drospirenone for hormonal replacement therapy // 2402331
FIELD: medicine, pharmaceutics.
SUBSTANCE: as an active ingredient, a pharmaceutical composition contains 6β,7β; 15β; 16β-dimethylene-3-oxo-17α-preg-4-ene-21,17-carbolactone (drospirenone, DRSP) together with a pharmaceutically acceptable excipient or carrier. Said composition does not contain estrogen. Drospirenon is prepared in fast soluble dosage form. At least 70% of drospirenone are dissolved within 30 minutes. For ensuring said immediate release, drospirenone is either micronised, or in dosage form of surface area more than 10000 cm2/g, or is applied on the surface of particles of an inert carrier. The composition can be applied for endometriosis treatment and introduced in the form of a multiphase pharmaceutical preparation.
EFFECT: immediate-release drospirenone compositions under the invention exhibits high biological availability when administered orally.
Pharmaceutical composition containing tetrahydrofolic acid // 2479306
SUBSTANCE: group of inventions refers to medicine, namely pharmacy and may be used for creating an oral solid dosage form. The dosage form contains a pharmaceutically acceptable salt of an alkaline-earth metal of 5-methyk-(6S)-tetrahydrofolic acid and granules containing progestogen, oestrogen and microcrystalline cellulose. What is also presented is a pharmaceutical kit for females for providing the concentrations or treating the diseases, conditions or symptoms associated with endogenous oestrogen deficiency.
EFFECT: group of inventions provides the good storage stability of tetrahydrofolic acid, and at the same time provides rapid and reliable release of oestrogen and progestogen being parts of the composition.
13 cl, 3 dwg, 4 tbl, 6 ex
Pharmaceutical composition, method for preparing it and multiphase pharmaceutical preparation for ovulation inhibition in mammal // 2482853
SUBSTANCE: pharmaceutical composition contains as a first active agent, 6β, 7β; 15β, 16β-dimethylenene-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone) in an amount according to a daily dose after the administration of the composition and making approximately 2 to approximately 4 mg, and as a second active agent, 17a-ethinylestradiol (ethinylestradiol) in an amount according to a daily dose and making approximately 0.01 mg to approximately 0.05 mg together with one or more pharmaceutically acceptable carriers or additives. The composition contains drospirenone applied on inert carrier particles. A method for preparing a pharmaceutical composition involves spraying of the drospirenone and ethinylestradiol solution on the inert carrier particles. The pharmaceutical preparation according to the invention contains a number of separately packed and individually taken daily dosage units of the described compositions in a single package used for oral administration for at least 21 days running with said daily dosage units containing the combination of drospirenone and ethinylestradiol. The composition may additionally contain 7 and less daily dosage units containing no active agent, or containing ethinylestradiol only.
20 cl, 5 dwg, 5 ex
Anti-cancer steroid lactones unsaturated in position 7(8) // 2572595
SUBSTANCE: invention refers to a compound of general formula and its pharmaceutically acceptable salts and stereoisomers possessing anti-cancer activity, a based pharmaceutical composition, using them and a method of treating cancer with using them. In general formula I R1 and R2 are specified in hydrogen and halogen; R3, R5, R6, R7, R11, R12, R14 and R15 mean hydrogen; R4 means -OH; R8, R9 and R17 mean unsubstituted C1-C6 alkyl; R10 is specified in hydrogen, =O and ORb, wherein Rb means unsubstituted C1-C6 alkyl; R13 is specified in unsubstituted C1-C6 alkyl, OH-substituted C1-C6 alkyl and COH; R16 means -OH; and the line ----- represents either a bond, or an epoxy group.
EFFECT: producing pharmaceutically acceptable salts and stereoisomers possessing anti-cancer activity.
17 cl, 10 tbl, 5 ex
© Patent search, search for pacenow for inventions - russianpatents.com 2012-2019


text:
Innovations in Healthcare admits Vynamic into its network
24 July 2020 Consulting.us
Healthcare sector management consultancy Vynamic has joined Innovations in Healthcare, a Duke University-affiliated nonprofit which helps scale healthcare innovations worldwide.
Innovations in Healthcare was founded in 2011 by Duke Health, McKinsey & Company, and the World Economic Forum, and works with partners and innovators to expand and scale solutions that solve healthcare challenge across the globe.
At the core is a network of 90+ innovators working to expand access to affordable, quality healthcare – including ProMujer, ClickMEdix, BasicNeeds, and We Care Solar. IiH connects these innovators with opportunities, information, and partners who can help scale their work. The organization's network of partners includes Philips, Bill and Melinda Gate Foundation and Pfizer Foundation.
"Our partnership with Innovations in Healthcare provides a fantastic opportunity for Vynamic to help healthcare businesses across the globe achieve the three valuable outcomes that we are most passionate about: actionable strategy, operational intelligence, and healthy culture," said Jeff Dill, CEO of Vynamic, who will join the Innovations in Healthcare board of advisors as part of the alliance.
Dill added, "Vynamic's unique collaborative model and problem-solving approach will help Innovations in Healthcare innovators implement their solutions more effectively and efficiently in the places that need it most. We will support these innovators in articulating their value propositions, enabling operational models to help them grow, and cultivating a healthy culture within their organizations."
The partnership announcement follows the February launch of a new Vynamic office in Durham, North Carolina, where Duke University and Innovations in Healthcare are located. The new location is ideally situated to support healthcare clients in the Research Triangle Park.
"The support of Vynamic is a huge step for Innovations in Healthcare and we are excited to see how this unique partnership will help to accelerate scalability," said Lisa Bourget, Innovations in Healthcare's senior director of strategy, management, and partnerships.
"We are currently working with nearly 100 innovators who are improving access to healthcare for more than 39 million people. We look forward to fusing Vynamic's experience in rapidly solving complex problems with our ability to identify, grow, and scale promising global healthcare solutions."
Vynamic was founded in 2002 and supports healthcare sector clients with consulting services in strategy, operations, and culture. Headquartered in Philadelphia, the 165-person firm has further offices in Boston, Durham, and London. The company was acquired in 2017 by UDG Healthcare, an Ireland-based provider of advisory, clinical, commercial, communication, and packaging services to the healthcare sector.
More Healthcare
BerryDunn acquires healthcare consultancy VantagePoint BerryDunn, a national accounting and consulting firm, has acquired VantagePoint Healthcare Advisors, a Hamden, CT-based healthcare consulting firm. The transaction closed on January 1, 2021.
Ettain Group acquires healthcare-focused Centerline Partners Ettain Group, a national provider of recruitment and managed solutions, has acquired Centerline Partners, a Beverly, MA-based management consulting firm specializing in the life sciences industry.
Mazars USA adds Wayne Pryor as head of healthcare transaction services Mazars USA has added Wayne Pryor as a partner and head of the healthcare transaction services group. He remains based in Nashville.
Non Profit news
More Non Profit
Partnership for New York teams up with 14 consulting firms Non-profit organization Partnership for New York worked with 14 pro bono consultants to create a post-pandemic recovery strategy for the city.
Nonprofit-focused consultancy Graham-Pelton launches new service lines Graham-Pelton, a fundraising and management consulting firm for the non-profit sector, has launched two new service lines which address vulnerabilities in staff turnover and cybersecurity.
North Highland to offer pro-bono consulting service to nonprofits Global management consulting firm North Highland is taking a stand to reduce poverty with a new philanthropic program, which will select four non-profit organizations focused on economic empowerment
More Partnerships
EY-Parthenon partners with startup accelerator Plug and Play EY-Parthenon, the strategy consulting business of EY, has formed a global collaboration with Plug and Play, a Silicon Valley-headquartered startup ecosystem and venture fund.
EY announces dedicated Microsoft Services Group EY Global has created a dedicated Microsoft Services Group – the first of the Big Four accounting and consulting firms to do so. The move will expand EY's already strong relationship with Microsoft.
Grant Thornton partners with Anaplan on business performance offering Grant Thornton LLP (US) has joined the partner program of Anaplan, a cloud software-as-a-service (SaaS) provider focusing on enterprise performance management.

redpajama_set_name: RedPajamaCommonCrawl


My first little guy was a challenge. He was cute & chunky, but cried a lot. He ended up having severe reflux & gas issues for his entire first year…crying for hours and hours at night. We swaddled, patted, paced, swung, shushed…with no luck.
This past Sunday night we sat at the dinner table…my husband, eldest son & myself. I watched my son devouring yummy lasagna a friend brought us. After dinner he walked into the kitchen & returned with a pie for us to share. Then he suggested we play a game of Uno…just the three of us (I snagged this pic real quick on my phone).
I NEVER would have guessed 6 1/2 years ago that this would be the same son. I really thought he would be challenge forever. That he would need consoling for a lifetime.
Yet here he sits with my husband and I enjoying an adult meal & playing a fun game. Loving each others' company, laughing at jokes & talking strategy.
What the older moms tell you is true. They DO grow up.
So if you are in a hard season (talking to myself too!) remember this will pass. It WILL. Eventually. Pass.
If your baby is crying ALL. THE. TIME. That baby will stop crying eventually. He will grow up. He will laugh a lot more than he cries. You will have lots of fun with him. Some day.
I know that when days are long that perspective doesn't always help. So just take today. Be fully present and think of 3 things to be thankful for (join Ann in her Joy Dare). Perhaps that will change our hearts from frustration to gratitude to joy (again giving myself a pep-talk!).
Let's enjoy today because sadly they DO grow up.
Thanks Heather! Needed to hear this today with all the crying….
no problem. it's true in so many ways…I realized after I posted that 6 1/2 years from now he will be a teenager! That time will go by even more quickly. be blessed today ashley!


We're pleased to bring you the GoSquared CSS3 Cheat Sheet.
A one-page cheat sheet about HTML that you can stick on the wall for quick reference.
Introducing the VI Help Sheet for all you Linux loving developers out there.
Want to learn Node.js? Here's the cheat sheet that'll help, then.
PHP is one of the most commonly used languages. Keep up to date with this.
Get a weekly email with resources and goodies from GoSquared by entering your email address below.


We are leading manufacturer and supplier of Ceramic Cup in New Delhi, Delhi, India. This is widely used in the cafe for drinking coffee and tea. This mug is designed with rounded handle by which it is comfortably held by the user. It is made by using the excellent grade ceramic material that has supreme strength. Lightweight, easy to wash, flawless finish and attractive color are some of the greatest features of this mug that makes it an ideal choice for our customers. The provided Ceramic Cup is available in different sizes according to the demands of clients. We offer this product at market leading rates.
Established in 2011, Sai Creations has been a leading name in offering top notch Crockery. Located in New Delhi, Delhi, we offer the best quality Ceramic Cup to our customers at best prices in the industry.