• 专利附录
  • 专利说明
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    • 专利摘要:
    This invention relates to novel 17 alpha -esters of gestogens having an antitumour activity and to the preparation thereof. The invention is also concerned with pharmaceutical compositions containing the said compounds, and method of treatment therewith.
    公开号:SU797585A3
    申请号:SU772440653
    申请日:1977-01-21
    公开日:1981-01-15
    发明作者:Якоб Фекс Ганс；Вальдемар Гансен Бертил；Аксель Хольмберг Кристер；Бертил Хегберг Кнут；Кенивес Имре
    申请人:Актиеболагет Лео (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to new steroid derivatives, progestogen esters of the general formula St-R, where R is -o-eB-y-c- (A), FC) p about where R - / b - or; a halo-substituted alkyl group, with the halo being chl / pp or bromine; R- is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, and halo; A is a lineardepole hydrocarbon chain, saturated or containing one double bond, with at most 2 hydrogen atoms of radical A replaced by lower alkyl and at most one of the hydrogen atoms located on the carbon atom adjacent to the -Cg group is replaced by a group selected from amino or lower alkanoyl amino groups; B is a linear chain saturated carbon hydrogen chain, with at most 2 hydrogen atoms replaced by lower alkyl, X and Y are independently selected from the group consisting of -NH-and -S-; K and p are independently selected, from O and St is a steroid residue selected from the group consisting of pregnene carbon-4, pregna-4, 6-diene and 19-norpregnen-4, with the indicated steroid residue attached at its 17th position to R. Compounds of general formula St-R possess valuable pharmacological properties. The use of the known esterification reaction of alcohols with carboxylic acids or their reactive derivatives allows obtaining new esters of gestagens with valuable pharmacological properties. The purpose of the invention is to expand the range of steroid derivatives with valuable pharmacological properties. The goal is achieved by the method of obtaining new progestogen esters. Formula St-R, implying that a steroid of the formula St-OH, where St has the above values, or its reactive derivative, interacts with an acid of the general formula HOOCBR or its reactive derivative to produce an ester of the general formula S t - O - with B - where St and B have the above values; ..... R means a group which, together with an e-C COOH-group, can form a VO group in one or two stages and then the resulting ester is reacted with an acid of the general formula, where (), A, X, R , R, Kip have the above values, or with its reactive derivative, and the processes are carried out in the presence of an anhydride, such as trifluoroacetic anhydride, or in the presence of a catalyst — a strong acid, such as arylsulphonic acid or perchloric acid, or a base, such as pyridine, N, N-dimethylaniline or triethylamine, p and this reactive groups in the original St-OH is protected, followed by deprotection protection, whereupon the target pryudukty isolated by known methods if necessary. Example 1. A mixture of 20.0 g of 17t-oxypregnen-4-dione-3.20 and 145 g of chloroacetic anhydride is heated for 22 hours. After cooling, 200 mp of chloroform is added and the solution is washed with water and aqueous sodium bicarbonate, dried and evaporated to give an oil, to which 50 ml of diethyl ether is added. The fallen precipitate is filtered off and the filtrate is evaporated to dryness. The residue was diluted with a mixture of concentrated i (2 ml), 100 ml of methanol and 10 ml of tolu-ol. After over 3 hours, the solution is evaporated and the residue is dissolved in 200 ml of chloroform. After washing with sodium bicarbonate and water, drying and evaporating, an oily substance is obtained, from which, after treatment with 25 ml of ether, 177X-chloroacetoxy-pregene-4-dione-3,20 Cl precipitates, 13, l g). M.p. 216-217 0 after recrystallization from a mixture of acetone and water. The structure is exposed to NMR and IR data, as well as analysis for chlorine content. The main signals in the NMR spectrum are as follows: cP (ppm (0.70) singlet, 3N, H-18), 1, 20 (c.H3, H-19), 2.09 (C, 3N , -COS% 4.12 C, s, 2H, -CH.se}, 5.80 (broad s, 1H, H-4). Example 2. To a mixture of 80.8 g of 4-bromo acid and 68.0 ml of trifluoroacetic anhydride are added to 80.0 g of 17-o-oxypregnene-4-dione-3.20. After keeping at 4 ° C for 48 hours, the reaction mixture is poured into a mixture of ice and methylene chloride. The organic layer is washed water and aqueous sodium bicarbonate, dried, and evaporated to give an oil-bleach substance, which is dissolved in a mixture of B 4 ml concentrator ovane H2SO2, 200 ml of methanol and 200 ml of toluene.After keeping at 50 ° C for 3 hours, the solution is treated as described in Example 1 to obtain 99.0 g of 17-a: - {4-brombo-tanoyl-x) progen-4-diona-3, 20 1. T. pl. 134-135 C (from a mixture of acetone and water). In the same way, the following compounds were obtained from the corresponding starting materials; 17-tu: - {4-chloropaniloxyl) -19-npregene-4-dion-3,20; l7-oi {5-bromopentanoyloxy) -G-og-fluoropregnen-4-dione-3, 20; (4-bromobutyanoyl) -6-ct Methylpregene-4-dion-3, 201 il-oi- (4-bromobutanoyloxy) -b-chloro pro-4, b-diene-3,20-dione; 17-Q / - (4-bromobutanoyloxy) -6-methylpregna-4, b-diene-3, 20-dione and 17-tf - (4-bromobutanoyloxy) -b-chloro-1-ft, 2-l- methylenepregna-4, b-diene-3,20-dione. Per im 3. 22.1 g of 4- {jN, N-6Hc- (2-chloroethyl) -amino-phenylacetic acid is added to a solution of 27.2 g of tetrabutylammonium sulphate acid in 80.0 ml of a 2 molar solution of NaOH. The mixture is vigorously stirred for 3 minutes and then extracted three times with 150 ml of chloroform. 24.4 g of 17-c) -chloroacetoxypregnen-4-dione-3.20 prepared in Example 1 was added to the dried extract and the mixture was heated under reflux for 16 hours. The residue obtained after evaporation of the solvent was chromatographed on silica gel column using a mixture of toluene and ethyl acetate (2: 1) as eluent. An eluted fraction having R f 0.40 gives 33.4 g of 17-o; -4- (M, M-bis (2-chloroethyl) amino) phenylacetoxy-acetoxy-pregnen-4-dione-3, 20 one . Melting point 72-73 s after recrystallization from methanol. In essentially the same way, the following compounds are obtained from the corresponding halo esters of 17-α-oxysteroids obtained in Examples 1 h 2 and the corresponding acids (the structure of the compounds is confirmed as for the above-mentioned compound): 17-a-4- (4- (N , M-bis- (2-XJiopethyl) -ami o) -phenyl) -butanoyloxyacetoxy-pregnen-4-dione-3,20 17-0 4- (4- (N, N - 6HC-) 2-chloroethyl) -aminoCHJ phenyl) -butanoyloxy) -butanoyloxy-pregnen-14-dione-3, 20; 17-c (.- t4- (4- (N, N-bis- (2-chloroethyl) amino) -phenyl acetoxy) -butanoyloxy-pregnen-4-dione-3; 20; 17-oi- 4- ( N, N-6Hd- (2-chloroethyl) -amino) -phenylthio-acetic-hydroxy-acetoxy-perfect-4-dione-3; 20; -4-dirn-3, 20; 17-ot-3-M, N-bic- (2-hlorobtil) -amino) -4-methylbenzoyloxyacetate-pregnen-4-dione-3, 20; B-chloro-17-o: - 2- (5-f4-N, H-bis- (2-chloroethyl} -amino) -phenyl) -pentanoyloxy) -propanoyloxy 3-pregna-4, 6-dien-3, 20 -dion; 17-oi- 2-C2E) -3- (2-N, N-bis- (2-chloroethyl) amino) -phenyl propenoyloxy) -propanoyloxy-6-methylpregna-4,6-diene-3, 20-dione1 17-O ((2-amino-3-C4- (N, N-bis- (2-chloroethyl amino) phenyl) propanoyloxy) -pentanoyloxy-6- (X-fluoropregnen-4-dione-3,20, b -chloro-17-cX- 4- (4- (M, M -bis- (2-chloroethyl) amino) -phenyl), butanoyloxyacetoxy C-1-C, 2 o-methyl pregna-4, b-diene, 3, 20-dione; 17 I (2S) -2-amino-3- (4- (Y, N-bis- (2-chloroethyl) -amino)) propanoyloxyacetoxy pregnen-4-dione-3, 20 (obtained from the corresponding N-benzyl-derivative), and its hydrochloride (obtained by treatment of free amiga with hydrochloric acid); (25) -2-amino-3- (4- (M, N-bis - (2-x.) -Amino) -phenyl) -propanoyloxy) -b.sutayloxyZpregnen-4-dione-3, 20 (obtained from the corresponding N-carbonyloxybenzyl derivative) and its hydrochloride (obtained by treatment of the free amine with hydrochloric acid) ; 17- (2S) -2-acetamido-3- (4- (N, N-bis- (2-chloroethyl) amino) phenyl) propanoyloxyacetoxy pregnen-4-dione-3, 20j 17-V34- ( 26) -2-acetamido-3- (4- (H, H-bis- (2-chloroethyl) -aminophenyl) -propanoyloxy) -butanoyloxy pregnen-4-dione-3, 20 (4- (N, N-bis - (2-chloroethyl) -amino) -phenyl) -butanoyloxyacetoxy3-6-c-methyl-pregnen-4-dione-3, 20; 17of - {, 4- (N, N-bis- (2-chloroethyl) -amoyl) -phenylacetoxy acetoxy-6-methylpregna-4, 6-diene-3, 20-dione; 6-hlop-17-Ot-tz- {N, M-bis- (2-chloroethyl) amino-4-methyl-benzoyloxyacetoxy-pregna-4, 6-diene-3, 20-dione 17- (2S) -2 α-amino-3- (3- (N, N-bis- (2-chloroethyl) amino) phenyl) propanoyloxyacetoxy-pregnen-4-dione-3, 20 (obtained from the corresponding N-carbonyloxybenzyl derivative) and its hydrochloride (obtained treatment of the free amine with hydrochloric acid); 17- (25) -2-aMHHO-3- (2- (N, H-bis- (2-chloroethyl) -amino) -phenyl) -propanoyloxyacetoxy-pregnen-4-dione-3 ,, 20 (obtained from the corresponding N-carbonyloxybenzyl-derivative) and its hydrochloride (obtained by treating the free amine with hydrochloric acid), 17-d-4- (4- (N, N-bis (2-chloroethyl) amino) phenyl) -butanoyloxy) - butanoyloxy-bo-met.ylpregnen-4-dione-3,20 b-chloro-17-oC-4- (4- (N, N-bis- (2-chloroethyl) amino) phenylacetoxy) butanoylOKCHJ-pregna -2, 4-dien-3, 20-dione; 17oi- 4- (3- (N, N-bis- (2-chloroethyl) -amino) -4-methyl-benzoyloxy) -butanyloxy-b-methyl-pregnene-4,6-diene-3, 20-dione; 6-chloro-15-o-C- (4- (N, N-bic- (2-chlorostil) amino) phenyl) -butanoyl; si) butanoyloxyZ-1-O, 2-o-methylene Gtregna- 4, b-diene-3,20-dione; 17 (: - 4-chloro-3- (N, N-bis- (2-chloroethyl) amino) benzoyloxyacetoxyZ-b-: - fluoropregene-4-dione-3, 20 and (4- (N, N- 6HC- (2-chloroethyl) -amino) -f-noxy) -propyl onyloxy-acetoxy-pregnen-4-dione-3, 20
    Example 4. A mixture of 40.7 g of 17 ° -chloroaceto-hydroxypregnen-4-dione-3.20 prepared in accordance with Example 1 and 32, P g of sodium azide in 500 ml of 60% acetone is boiled under reflux for 16 The acetone is evaporated off and the aqueous solution is extracted with a 1: 1 mixture of ether and ethyl acetate (3 x 100 ml). The combined extracts with water, dried and evaporated to obtain an oily substance, from which, after treatment with diethyl ether, crystals of the 17 precipitate out (v -azidoacetoxypregnene-4-dione-g-3.20 (32.0 g).
    A solution of 25.2 g of triphenylphosphine in 100 ml of benzene is added dropwise to a solution of 32.0 g of the indicated azide in 200 ml of benzene. After boiling under reflux for 4 hours, the solution is cooled to room temperature and a current of dry HC C is passed through the solution until a precipitate begins to form. Ether is added to complete precipitation and the resulting crystals are collected. The product is dissolved in methylene chloride and the solution, after washing with aqueous sodium bicarbonate and water, drying and evaporating, gives 9.40 g of 1-oxa-4-azacyclohex-3-en-b-one (A) formed by spontaneous intramolecular condensation of 17 ° α-aminoacetoxy regnen-4-dione-3, 20. The structure of compound A is confirmed by the I | 1P spectrum: (G (ppm) 0.97 (s, 3N, H-18) 1.19, (c, EH, H-19), 2.27 (s, ZN, SNZ-S N-), 4,14 and 4,48 (doublets, each 1H, AV system with I 22 Hz, -N), 5.75 (broad with s, 1H, H-4)
    Compound A (9.40 g) was dissolved in a mixture of 240 ml of acetone and 120 ml of a 0.15 molar aqueous CSE solution / the pH of the solution was kept constant at 4.2 by continuously adding 5 molar HC 6 solution. When HC consumption ceased a solution of 22.0 g of (N, H-bis- (2-chloroethyl) -amino) -phenyl3-butyric anhydride in 200 ml of acetone is added and the pH of the mixture is maintained by 4.2 by continuous addition of S molar solution of NaOH.
    When the absorption of NaOH ceases, acetone is removed by evaporation, and the mixture is extracted with aqueous solution; ether and ethyl acetate (1: 1.3 x 100 ml). The extract is washed with 1M aqueous sodium carbonate and water, dried and evaporated. The residue is triturated in boiling diisopropyl ether, and read recrystallized from a mixture of ethyl acetate and diisopropyl ether to obtain 8.85 g (4- (N, N-6Hc- (2-chloroethyl-amino) -phenyl) -butanoylaminoacetoxy pregnen-4 -dione-3, 20, (decomposed by heating
    Example 5. To a solution of 27.2 g of acid tetrabutylammonium sulfate in 80 ml of 2 M NaOH was added 13.4 g of 4-nitrobenzoic acid. The mixture is vigorously stirred for
    15min and then extracted thrice
    150 ml of chloroform. To the dried extract was added 27.2 g of β-broacetoxypregnen-4-dione-3, 20, prepared as in Example 1. After boiling for 24 hours under reflux, the solution is rinsed with water, 2.5 M NZO, water, aqueous sodium bicarbonate, and water, dried and evaporated. When adding 1.00 ml of a mixture of toluene and ethyl acetate in a ratio of 1: 1 to the residue from evaporation, 29.1 g of crystals of 17a precipitate; - (4-nitrobenzoyloxyacetoxy) -pregnen-4-dione-3, 20..
    The 4-nitrobenzoic acid ester obtained above (29.1 g) is suspended in a mixture of 4,300 ml of tert-butanol and 700 ml of water, and then 58 ml of 1 M KOH are added dropwise with stirring. After at room temperature for
    16 hours water was added and the solution was extracted with chloroform (5 x 1000 ml). The combined extracts are dried and evaporated and the residue is added
    1: 1 mixture of toluene and ethyl acetate
    (120 ml). After exposure to whom
    natal temperature for 16 h
    11.0 g of crystals are filtered off
    17cx-oxyacetoxypregnen-4-dione-3, 2
    (mp. 220-22lOc).
    An additional amount of 17 y-oxyacetoxypregnen-4-dmon-3,20 (2.6 g) is obtained from the filtrate by chromatography on a silica gel column using a mixture of toluene and ethyl acetate (1: 2) as eluent (Rf 0.25).
    The above alcohol was acetylated with acetic anhydride in pyridine to give 17.-c-acetoxyacetoxypregnene-4-dione-3, 20, which exhibits the following main signals in NMR spectrum: (I (ppm) 0.69 ( s, ZN, N-18); 1.19 (s, ZN, H-19 /, 2.17 and 2.17 (singlets, each on ZN, 2-COCH), 4.65 (s, 2H, - ОССН-), 5.76 (broad C, 1H, H-4) °
    A solution of 13.6 g of the above spit in 200 ml of absolute benzene is treated with phosgene at. After keeping at room temperature for 16 hours, the solution is evaporated to give a crystalline residue, from which, after treatment with ether, 14.2 g of 170-chlorocarbnyloxy-acetoxypregnene-4-dione-3, 20, are obtained.
    A solution of 14.2 g of the above mentioned chloroformate in 100 ml of dry chloroform is added dropwise with stirring with a mixture of 11.4 g of N, N-6H- (2-chloroethyl) -4-phenylenediamine hydrochloride and 7.95 g of triethylamine in 100 ml of dry chloroform. After keeping at room temperature for 16 hours, the solution is washed with water, 2 M HCS and water. Drying and evaporation gave an oily substance that chromatographed on a silica gel column using a mixture of toluene and ethyl acetate (2: 1) as eluent. having an Rf value of 0.28 gives 7.35 g of 17aH, N-bis- (2-chloroethyl) -amino) -phenylcarbamoyloxyacetoxy) -pregnen-C -4-dione-3.20 (1, m.p. 104-105 ° C).
    Basically in the same way, the following compounds are obtained from the corresponding halo esters of the 17 o-oxysteroids obtained in Example 1 and the corresponding 4-phenylenediamine and 4-aminophenol, respectively: 6-chloro-17-cc-G4- (N, N-bis- (2-Chloroethyl) -amino) 2-methoxyphenylcarbamoyloxyacetoxyZ-16-methylenepregna-4, 6-dene-3, 20-dione; 6-hlop-17-rt-t4- (N, N-bic- {a-chloroethyl) amino-phenoxycarbonyloxyacetoxyZ-16s1g. - methylpregna-4, 6-diene-3, 20-dione and 17ot-L4- (N, M-bis- (2-chloroethyl) -amino) phenoxycarbonyl-hydroxyacetoxy-pregnen-4-dione-3, 20
    Example 6. To a solution of 17.0 g of acidic tetrabutylammonium sulfate in 10.0 ml of a 5 M solution of NaOH, was added 3.25 g of sodium azide. The solution was extracted with 100 ml of methylene chloride and 100 ml of toluene was added to the dried extract. Methylene chloride is removed by evaporation and 17.2 g of 17ci-f4-bromo-butanoyloxy) -pregnen-4-dione-3, 20, prepared according to example 2, are added to the toluene solution obtained in Example 2. After keeping at room temperature for 20 hours, the solution washed with water, dried and evaporated. The residue, after treatment with ether, gives 17ct- (4-azidobutanoyloxy) -pregnen-4-dione-3, 20 (14.2 g).
    A mixture of 5.8 g of trimethyl phosphite, 14.2 of the above azide and 130 ml of toluene is heated at 3 hours. The solution is evaporated and 250 ml of methanol and 250 ml of 1 M solution of HC p are added to the residue. After at 45 s for 3 h, the methanol is evaporated, the aqueous solution is washed with ethyl acetate, and the aqueous phase is extracted with methylene chloride. After drying and evaporation of the extract, 29.1 g of 17-Oi- (4-aminobutanoyloxy) -pregnen-4-dione-3,20 hydrochloride are obtained. The above amine hydrochloride is acetylated with acetyl chloride to give (4-acelaminobutanoyl oxy) -pregnen-4-dione-3, 20. To a mixture of 1200 ml of acetone and 400 ML | 0.14 M KS was added 42.8 g of 4-0 N, M-bis- (2-chloroethyl) -amino: phenylacetic acid anhydride. The pH of the solution was adjusted to 6.0, and a solution of 29.1 g of the above-mentioned amine hydrochloride in a mixture of 1200 ml of acetone and 400 ml of 0.15 M CS was added. The pH is maintained at 6.0-6.5 by the continuous addition of 5 M NaOH. When the absorption of NaOH ceases, acetone is removed by evaporation and the aqueous solution is extracted with 2400 ml of ethyl acetate. The organic phase is washed with 1 M sodium carbonate solution and water, dried and evaporated to give 41.0 g of 17 °: -. 4- (4- (N, N-bic- (2-chloroethyl) amino) -phenyladethyl amino) -butanoyloxy -pregnen-4-dione-3, 20 (decomposed by heating) In general, the following compounds are also prepared from the corresponding layered oxy ether halides prepared according to example 2 and the corresponding acid acids: 17cv; –4- (2- (4- (N, N-6Hc (2-chloroethyl) amino) -phenyl) -2-methyl propanoyl-amino) -butanoyloxy-19-nor-pregnen-4-dione-3, 20; (N, M-bis- (2-bromoethyl) -amino) -4-methylbenzoylamino) -pentanoyloxy1-6 pregnen-4-dione-3,20 and 17rt -4-C3- {N, N-bys- (2- chloroethyl) -amino-4-methylbenzoylamino) -butanoyloxy 5-pregnen-4-dione-3, 20. Example 7. A mixture of g 3-f N, N-bis- (2-chloroethyl) -amino | -4-methylbenzoic acid and 21.0 g of acetic anhydride trifles are heated with stirring for 15 minutes. To the mixture was added 16.5 g of 17 0 -oxypregnen-4-DIO-3.20, and the mixture was heated with stirring at BO for 5. h., 150 ml of toluene was added, the solution was filtered and 20 ml were added to the filtrate chloroform. After washing with water and aqueous sodium bicarbonate, drying and evaporation, an oily substance is obtained, to which a mixture of 300 ml of methanol and 3 ml of concentrated HC 6 is added. After holding at room temperature for 16, the solution is evaporated and the residue is chromatographed on a silica gel column using as eluent a mixture of tolu la and ethyl acetate (2: 1). An eluted fraction having Rf 0.40 gives 6.8 g of 17c-- 3- (N, N-bis - (2-chloroethyl) amino) -4-methylbenzoyl oxy-pernen-4-diona-3, 20 ( 1, mp 170-1710C). basically, the following compounds are also prepared from the corresponding source materials (the structure of the compounds is confirmed, as above): (N, H-bis- (2-chloroethyl) amino) phenylacetoxy3-pregnen-4-dione-3, 20; (m, M-bis- (2-chloroethyl) -amino) -phenyl) -butanoyloxy-pregnen-4-dione-3, 20; 17-O; -4- (3- (N, N-bis- (2-chloroethyl) amino) -4-methyl-benzoyloxy) -butanoyl-1-pregnen-4-dione-3, 20 and 17- (25) -2 -acetamido-3-and- (N, M-bis- (2-chloroethyl) -amino) -phenyl) -propanoyloxy pregn-4-dione-3,20. Example 8. Kc 1seu and 125 ml of 1,2-dimethoxyethane and 6: 5 g of 70% HCCO add 10.8 g of NdO. The mixture is heated with stirring at 4555s for 25 minutes and then cooled to room temperature. 24.0 g of 17CX- (4-bromobutanoyloxy) -pregnen-4-dione-3, 20, prepared as described in Example 2, and 10 ml of water are added and the reaction mixture is stirred at room temperature for 5 hours. ml of chloroform, the mixture is filtered and the filtrate is washed with water, aqueous sodium bicarbonate and water. The residue obtained after drying and evaporation is chromatographed on a silica gel column using a mixture of toluene and ethyl acetate (1: 4) as eluent. From the eluted fraction having Rf 0.20, 13.6 g (4-p-x-tanoyl) -predhen-4-dione-3, 20 (m.p. 1611 & 2 ° C) are obtained. Alcohol is acetylated with acetic anhydride in pyridine to produce - (4-acetoxybutanoyloxy) -pregnen-4-dione-3, 20. Example 9. Illustrates the action of compounds of the general formula (I) in suppressing the growth of tumors. LD 50 is the dose that causes 50% mortality in animals, and ED 50 is the dose that causes a 50% decrease in the size of the tumors. It is evident from the below enny that the compounds have a very low toxicity and that thermal indicators (TP), i.e. the ratio LD 50 / AU 50 is very high. The calculation and interpretation of experimental data is in agreement with the standards set by the National Cancer Chemotherapy Service Center. Some of the results obtained are presented in the tables below. Compounds are designated by code number, a: b, where a means an example in which the compound in question is described, and b refers to the serial number of the compounds obtained in this example. Thus, the 4: 2 compound represents the second compound obtained in Example 4. The systematic names of the compounds are presented in the examples. This example shows that new compounds are useful in combating tumor growth and suppressing the growth of tumors and in some cases even cause a complete reduction of tumors and can be used to treat a large number of animals suffering from disorders that react easily. treatment of anti-cancer substances and immunosuppressive substances. A. Carciosarcoma Walker 256. Experimental animals: Spraque-Dawlaque rats. Implanted pieces of tumor tissue with a diameter of 2-4 mm, subcutaneously. The hedgehog is orally administered daily for 5 days, starting from the day after implantation. Animals are killed on the ninth day. The weight of the tumors of the test animals is compared with the weight of the tumors of the control animals. The results are shown in Table. 1. Table Continued table. 2 The following additional compounds exhibit antitumor activity in the above test: 3: 6, 3: 8, 3: 9, 3:10, 3:13, 3:15, 3:17, 3: .19, 3:20, 3:22, 3:23, 3:24, 3:25, 3:26, 4: 2, 5: 2, 5: 3, 6: 2, 6: 3, 6: 4, and 7: 1. C. Ehrlich Ascites Tumor, Hyperdiploid U (46 chromosomes). Experimented animals: mice of the species SPF NMRI. 2 x 10 tumor cells are intraperitoneally implanted. One intraperitoneal injection per day after implantation. Animals are killed on the eighth day. The weight of the tumors of the test animals is compared with the weight of the tumors of the control animals. ; The results are shown in Table. 3. Table 3
    The following additional compounds exhibit antitumor activity in the above test: 3: 5,3: 6, 3:11, 3:12, 3:14, 3:16, 3:18, 3:21, 4: 1, 5: 1, 6: 1 and 7: 4.
    V. Hepatoma AN 130,
    Experimenting animals: rats.
    Implanted 5 x 10 tumor cells intraperitoneally. One intraperitoneal injection per day after implantation. Animals are killed on the eighth day.
    The weight of the tumors of the test animals is compared with the weight of the tumors of the control animals.
    The results are shown in table 2.
    Table 2
    The following additional compounds exhibit antitumor activity in the above test: 3: 3, 3: 4, 3: 5, 3: 6, 3: 8, 3: 9, 3:11, 3:12, 3:14, 3: 16, 4: 1, 5: 1, 5: 4, 6: 1, 6: 4, 7: 4 and 7: 5.
    0. Lymphocytic leukemia L 1210.
    Experimented animals: mice of the species CDF {C3HXDBA / J) Hz.
    10 tumor cells are implanted intraperitoneally. One intraperitoneal injection per day after implantation
    权利要求:
    Claims (1)
    [1]
    Claim
    A method of producing progestogen esters of the general formula St-R, where R is ft. 9 where R * is a jb or% gal-substituted 45 alkyl group C ^ -Cd, wherein the halogen is chlorine or bromine;
    R 4 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy group and halogen, jq
    A is a linear chain hydrocarbon chain Cj-Cd, saturated or containing one double bond, with at most 2 hydrogen atoms of radical A replaced by lower alkyl and at most one of the hydrogen atoms located on the carbon atom adjacent to where A, X, R 1 , R 9 ·, Kip have the above meanings, either with its reactive derivative, the process being carried out in the presence of an anhydride such as trifluoroacetic anhydride or in the presence of a strong acid catalyst such as arylsulfonic acid or perchloric acid, or a substance such as pyridine, N, N-dimethylaniline or triethylamine, while the reactive groups in the starting St-OH are, if necessary, protected, followed by deprotection, after which the desired products are isolated.
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    同族专利:
    公开号 | 公开日
    ATA37877A|1980-05-15|
    AT360183B|1980-12-29|
    FI770191A|1977-07-23|
    FR2338951B1|1979-08-24|
    DE2702509A1|1977-07-28|
    AU2142677A|1978-07-27|
    SE7614264L|1977-07-23|
    BE850668A|1977-07-22|
    NL7700637A|1977-07-26|
    NO770190L|1977-07-25|
    HU174941B|1980-04-28|
    GB1558472A|1980-01-03|
    FR2338951A1|1977-08-19|
    ES455133A1|1978-05-01|
    US4177269A|1979-12-04|
    DK25277A|1977-07-23|
    LU76629A1|1978-09-13|
    JPS52111553A|1977-09-19|
    CA1087168A|1980-10-07|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB2419/76A|GB1558472A|1976-01-22|1976-01-22|17-esters of 17- hydroxy gestogens|
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