• 专利附录
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    • 专利摘要:
    The invention provides novel compounds of the formula: and wherein m is 1 or 2, R6 and R7, which can be the same or different are H or an alkyl group of 1 to 4 carbon atoms, or wherein n is 0 to 4, R1 and R2, which can be the same or different are H, OH, alkoxy of 1 to 4 carbon atoms, benzyloxy or methoxymethoxy; R3 is H, OH, halogen, alkoxy of 1 to 4 carbon atoms, benzyloxy, methoxymethoxy, 2,3-dihydroxypropoxy or can form an N-containing three-, four-, five- or six-membered heterocyclic ring; R4 is OH, F, Cl, Br, I, mesyloxy, tosyloxy, formyloxy, alkylcarbonyloxy of 1 to 4 carbon atoms or CH2R4 is replaced by CHO; R5 is H or OH; or R4 and R5 together form an -0- bridge between the carbon atoms to which they are attached, and their non-toxic pharmaceutically acceptable salts and esters and mixtures thereof. Processes for the preparation of these compounds are described, and also novel pharmaceutical compositions containing them. These compounds exhibit valuable pharmacological properties as estrogenic, anti-estrogenic, and progestanic agents. They are also effective against oestrogen-dependent tumours. Certain compounds are useful as chemical intermediates for the preparation of pharmacologically active compounds of the invention.
    公开号:SU1508955A3
    申请号:SU833597902
    申请日:1983-05-26
    公开日:1989-09-15
    发明作者:Юхани Тоивола Реийо；Иоханнес Карьялайнен Арто；Ойва Антеро Куркела Кауоко；Седервалл Марья-Лииса；Вейкко Матти Кангас Лаури；Луис Бланко Гуиллермо；Каллерво Сундквист Ханну
    申请人:Фармос-Ихтюмя Ой (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the preparation of new compounds, namely alkene derivatives of the general formula
     / R, - (O) -
    (CHi nCIhRl
    where hydrogen is hydroxy;
     hydrogen, hydroxyl, methoxy, or 2- (N, H-dimethylamino) is a force of this;
     chlorine or bromine; n 1 or 2
    or their salts, which have estrogenic, anti-estrogenic, progesterone and antitumor activity and can be used in medicine.
    The purpose of the invention is the development, on the basis of a known method, of a method for the preparation of new compounds possessing valuable pharmacological properties.
    The invention is illustrated by the following examples.
    , and meper 1.a 4- (Tetrahydropyran-2-yl) oxy -1, 2-diphenylbutan-1-one,
    A mixture containing 19.6 g of deoxybenzoin, 20.9 g of tetrahydropyran-2-yl ether protected bromoethanol, 1.0 g of TEBAC and 50 ml of 48% sodium hydroxide solution is stirred for 2 hours at 75 ° C, Next water is added, the product is extracted in toluene. The toluene solution is washed with water and dried with sodium sulfate. Finally, the solvent is evaporated. A quantitative yield is obtained, but the oily product contains about 20% O-alkylated product,
    B. Preparation of A- (Tetrahydropyran-2-yl) oxy2-1,1,2-triphenylbutan-1-ol.
    A Grin's complex is prepared without aqueous formulations using 3.6 g of magnesium chips in 25 ml of anhydrous tetrahydrofuran, which pea is prepared from 23.6 g of bromobenzene in 50 ml of anhydrous tetrahydrofuran. Next, the residue obtained after evaporation in step a is added to 75 ml of anhydrous tetrahydrofuran. The reaction mixture is boiled. under reflux for 2 hours. The cooled mixture is poured into a saturated / ammonium chloride solution. After stirring by shaking, the organic layer is separated. The extraction process is repeated using ether. Next, the organic layers are combined and dried with sodium sulfate. Finally, the solvent is evaporated. with. 1, 1, 2-Triphenylbutan-1., - 4-diol. The residue obtained by evaporation in step b is subjected to
    five
    0
    five
    0
    five
    0
    five
    0
    five
    dissolving in a mixture containing 400 ml of absolute ethanol, 10 g of concentrated sulfuric acid and 75 ml of water. This mixture is stirred for 2-4 at room temperature, then the resulting solution is neutralized using 2 M sodium hydroxide solution. Next, the ethanol is evaporated, and water is added to the residue. Then the resulting product is extracted in ethyl acetate. The ethyl acetate solution is dried with sodium sulfate, and the solvent is evaporated. The resulting product is converted from toluene. The yield is 16.5 g (52% of deoxybenzoin), mp, 185-187 ° C,
    Spectrum PMR (s): 2.06 (2H, SK); 3.83 (2H, T); 3.92 (1H, T); 4.76 (2H, s); 6.85-7.45 (13H, M); 7.68 (2H, gg).
    Example2, and. 4- (Tetrapagidopropan-2-yl) 2-phenyl-l- (4-methoxyphenyl) -butan-1-one,
    The compound is prepared from 22.6 g of 4-methoxydesoxybenzoin and 20.9 g of tetrahydropyran-2-yl ether-protected bromoethanol in accordance with the procedure described in Example 1,
    b, 4- (Tetra agi dr o pyr en-2-yl) oxy - -1,2-diphenyl41- (4-methoxyphenyl) butane-1-op (RR, SS, and RS. SR).
    The isomers (RR, SS) are obtained from the residue after evaporation prepared in example la and 28.1 g of 4-bromanisol in accordance with the procedure described in example 1b
    The isomers (RS, SR) are obtained from the residue after evaporation prepared in Example 1b, and 23.6 g of bromobenzene in accordance with the same procedure as the above isomers (RR, SS),.,
    c, 1,2-Diphenyl-1- (4-methoxyphenyl) butane-1,4-diol (RR, SS and RS, SR),
    The isomers (RR, SS) are obtained from the residue after evaporation of the isomers (RR, SS) produced in step b according to the procedure described in Example 1c. The product is subjected to. Talization from toluene. The yield is 13.9 g (40% of deoxybenzoin). Mp, 124-2c,
    (RS, SR) -isomers are obtained by evaporation of the residue () of the isomers obtained in stage a in accordance with the same method as the (RS, SS) isomers, indicated above.
    The product is recrystallized from tiluol. The yield is 16.0 g (46% of A-methoxybenzoin). M.p. 72-174 ° C.
    d. 1,2-Diphenyl-l- (4-methoxyphenyl) - -buten-A-ol (Z and E),
    A mixture of isomers (Z, E), The reaction is carried out under anhydrous conditions. First, 34.8 g of 1,2-diphenyl-1- (4-me-Q {Oxyphenyl) butane-I, 4-diol is dissolved in 200 ml of acetic anhydride. Next, 30 ml of acetyl chloride is added. The resulting mixture is evaporated for 2 hours at 1, after which the solvent is evaporated (the intermediate product is pure (g, E) -4-acetoxy-1,2-diphenyl-1- (4-methoxyphenyl) -1-butene). Next add at room temperature. The solvent is evaporated, and the residue obtained after evaporation is dissolved in 1% of petroleum ether. Insoluble matter was removed by filtration. The 1st solution solution is evaporated and the residue obtained after evaporation is recrystallized from methanol. The yield of the product is 26.7 g (68%). Mp 110-118 ° C.
    The range of the PNR (CDC1,): 3.01 (2H, t); 3.28 (2H, t); 3.67 (ЗН, s); 6.54 (2H, d); 6.8 (2H, d); 7.17 (5H, s); 7.32 (5H, s).
    Mass spectrum: m / e 392/394 (), 299 (65), 221 (79), 191 (94), 121 (100), 91 (50),
    Example 3. a. 4- (Tetrahydropyran-2-yl), 2-diphenyl-4- | 4 ml 200 ml of 94% ethanol, 20 ml of 20 (2- (N, N-dimethyl-a)) ethoxy phenyl by-water and 45 ml of a 20% aqueous solution of hydrant-1-ol (RR, SS and RS, SR)
    (R, R and SS) isomers are obtained from the evaporated precipitate obtained in Example 1a, and 36.6 g of the l-6poM-4- 2- (N, NT
    sodium oxide to the specified residue that formed after evaporation. The resulting mixture is boiled with reverse
    neutralized with 2 M hydrochloric acid, after which the ethanol is evaporated. Water is added to the residue, and the product is extracted with ethyl acetate.
    35
    40
    refrigerator, for 1 hour. Solution 25 dimethylamino) ethoxy | benzene according to the method of example I.
    (RS, SR) isomers are obtained in the following way.
    B. 1, 2-Diphenyl-1-4-2- (K, K-dime-An ethyl acetate solution is dried over sul-ZO tilamino) ethoxy-phenyl J6yTaH-1,4-diol sodium, and the solvent is evaporated (RR, SS and .RS SR wow. The yield of the pure mixture of isomers (Z: E in a ratio of 7: 3) is quantitative, m.p. 91-105 C,
    The residue obtained after evaporation of the mixture of isomers is recrystallized from a mixture consisting of hexane and ethanol in a ratio of 95: 5 ,. then get 14.5 g (44%) (E -) - isomer, t, pl.121-123, C.
    Spectrum,) | : 1.28 () .; 2.73 (2H, t); 3.57 (2H, t); 8.63 (ЗН, s); 6.53 (2H, d); 6.80 (2H, d); 7.15 (5H, m); 7.29 (5H, s). Thylamino) ethoxy1-phenyl -1-butene-4-ol Mass spectrum t / e: (), 299 (100), dd (Z and E). 221 (46), 191 (70), 121 (46) .91 (60). According to the procedure of Example 2d,
    (E) -isomer. M.p. 107-110 ° C.
    NMR (CDCl) S spectrum: 1.31 (lH, s), 2.80 (2H, t), 3.6 (2H, t); 3.81 (ЗН ,. с); 6.80-7.35 (14H, m).
    e. 4-Bromo-1,2-diphenyl-1- (4-methoxy syphenyl) 1-butene (Z).
    33.0 g of (Z) -l, 2-diphenyl-1- (4-methoxyphenyl) - -butene-4-ol is dissolved in 500 ml of anhydrous acetonitrile. Then, 39.3 g of triphenylphosphate and 49 , 8 g
    (RR, SS) -isomers are obtained from the evaporated precipitate (RR, SS) -isomers obtained in stage a, respectively, according to the method of Example 2c, except that 20 g of concentrated sulfuric acid are used. Yield 19.5 g (48% from desoxib nzion). T.pl. 165-167 with (from toluene).
    (FROM, 5K) -isomers were obtained in the same way. M.p. 139-14 ° C (from toluene).
    with. 1,2-Diphenyl-1 - 4-, N-dimetic mixture of Z and E isomers
    Isolation of (Z) -H3OMepa as free base.
    50
    55
    A mixture of isomers (Z: E in the ratio of 2: 1) is subjected to recrystallization from toluene, resulting in a gain of 15.9-g (41%) of (Z) -H30Mepa, with So pl. 110-112 ° C.
    NMR (CDCl) spectrum: 2.28 (6H, s); 2.60 (2H, t); 2.7 (2H, t); 3.53 (2H, t); 3.89: (2H, t); 6.53 (2H, d); 6.78 (2H, d); 7.12 (5H, s), 7.28 (5H, s).
    carbon tetrabromide. The mixing process is carried out for 1 h.
    at room temperature. The solvent is evaporated, and the residue obtained after evaporation is dissolved in 1% of petroleum ether. Insoluble matter was removed by filtration. The 1st solution solution is evaporated and the residue obtained after evaporation is recrystallized from methanol. The yield of the product is 26.7 g (68%). Mp 110-118 ° C.
    The range of the PNR (CDC1,): 3.01 (2H, t); 3.28 (2H, t); 3.67 (ЗН, s); 6.54 (2H, d) 6.8 (2H, d); 7.17 (5H, s); 7.32 (5H, s).
    Mass spectrum: m / e 392/394 (), 299 (65), 221 (79), 191 (94), 121 (100), 91 (50),
    Example 3. a. 4- (Tetrahydropyran-2-yl), 2-diphenyl-4- | 4 (2- (N, N-dimethyl-a shno) this phenyl by-1-ol phenyl (RR, SS and RS, SR)
    B. 1, 2-Diphenyl-1-4-2- (K, K-dimethylamino) ethoxy phenylJ6yTaH-1,4-diol (RR, SS and .RS, SR).
    tilamino) ethoxyphenyl -1-butene-4-ol (RR, SS) -isomers are obtained from the evaporated precipitate (RR, SS) -isomers obtained in stage a, respectively, according to the method of example 2c, except that 20 g of concentrated sulfuric acid. Yield 19.5 g (48% from desoxib nzion). T.pl. 165-167 with (from toluene).
    (FROM, 5K) -isomers were obtained in the same way. M.p. 139-14 ° C (from tow).
    with. 1,2-Diphenyl-1 - 4-, N-dimetic mixture of Z and E isomers
    Isolation of (Z) -H3OMepa as free base.
    A mixture of isomers (Z: E in the ratio of 2: 1) is subjected to recrystallization from toluene, resulting in a gain of 15.9-g (41%) of (Z) -H30Mepa, with So pl. 110-112 ° C.
    NMR (CDCl) spectrum: 2.28 (6H, s); 2.60 (2H, t); 2.7 (2H, t); 3.53 (2H, t); 3.89: (2H, t); 6.53 (2H, d); 6.78 (2H, d); 7.12 (5H, s), 7.28 (5H, s).
    7 15
    Isolation of the (d) isomer in the form of the hydrochloride salt. A mixture of isomers (Z: E in a ratio of 2 :) is dissolved in ethanol, and then excess concentrated hydrochloric acid is added. The solvent is evaporated, and further, the obtained residue is twice subjected to. - recrystallization from ethanol, resulting in a gain of 12.3 g (29%) (E) -isomer in the form of the hydrochloride salt, T, mp, 166-168 ° C (from acetone).


    The (Z) -isomer hydrochloride is also obtained from the (Z) isomeric base. (Z) -isomer is dissolved in ethanol. Next, hydrogen chloride gas is passed through the solution. Finally, the solvent is evaporated.
    Isolation of CHO)
    Uterine solutions obtained by isolation of the hydrochloride (Z) -isomer,
    The citric acid salt can be obtained as follows: 15First, 40.6 g of (Z) -isomepa-, as a free base, is dissolved in 175 ml of warm acetone and 24.5 g of citric acid in 100 ml of warm acetone. The solutions are then combined, 20 and the mixture is cooled. The citrate is collected by filtration, its melting point is 160-162 ° C,
    (E) -isomer, Compound. Is obtained from CE) -1,2-diphenyl-1-4- 2- (H, L combine and the solvent is evaporated, 25 dimeshthamino) ethoxy phenyl 1-butene. The evaporated residue is subjected to over-4 -ola, by the same technique as
    and the corresponding (Z) -isomer, Hydrochloride salt is crystallized from toluene. The yield is 35.8 g (81%), t, mp, 183- 85 ° C. This product can be separated from the salt form by the same method as the corresponding (Z) isomer. Melting point is 69-71 ° C (from hexane% NMR spectrum (with Clj): 2.34 (bH, s) 2.74 (2H, t); 2.97 (2H, t); 3.43 (2H, t) 4.08 ( 2H, t); 6.80-7.30 (14H, m).
    crystallization from acetone, resulting in a yield of 9.7 g (23%) (E) - isomer in the form of the hydrochloride salt, T, pl. 235-237 C, (E) -isomer can be separated from the salt in the same way as the mixture of isomers indicated above. The melting point of the (E) -isomer, as the free base, is 129-131 ° C (from toluene JJ
    la)
    Spectrum PIR; (CDC1,) S: 2.31 (2H, s); 2.71 (2H, t); 2.78 (2H, t) ;, 3.57 (2H, t); 4.05 (2H, T) j 6.87 (2H, t); 6.94 U5H / C); 7.10 (5H, s); 7.21 (2H, d) .40
    d. 4-Chloro-1, 2-difensh1-1 (N, N: dimethylamino) - ethoxy fensch -1-butene (Z and E).
    (Z) -isomer. The reaction is carried out under anhydrous conditions. Initially, 42.4 g of 45 (Z) -l, 2-diphenyl-1-4-C2- (K, H-dimethyl-amino) ethoxy fensch1 | -1-buten-4-ol was dissolved in 250 ml of chloroform. 23.8 g of thionyl chloride are then added dropwise. The resulting mixture is refluxed for 3 hours. The solvent is evaporated from the resulting product and the product is then recrystallized from ethyl acetate
    50
    eight
    0
    sodium carbonate solution, then the product is extracted into toluene and then the toluene solution is dried and the solvent is evaporated, m.p. 108-110 ° C (from acetone).
    Spectrum PMR CCDCI,): 2.27 (bN, s); 2.63 (2H, t) 1 2.91 (2H, t); 3.41 (2H, t); 3.92 (2H, t); 6.54 (2H, d); 6.79 (2H, s); 7.15 (5H, s); 7.31 (5H, s).
    Mass spectrum: vol. 405/407 (I, 7/3), 72 (20), 58 (100).
    The citric acid salt can be obtained as follows: 5First, 40.6 g of (Z) -isomepa-, in the form of free base, is dissolved in 175 ml of warm acetone and 24.5 g of citric acid in 100 ml of warm acetone. The solutions are then combined, 0 and the mixture is cooled. The citrate is collected by filtration, its melting point is 160-162 ° C,
    (E) -isomer, Compound. Is obtained from CE) -1,2-diphenyl-1-4- 2- (H, L5 dimeshthamino) ethoxy phenyl 1-butene-4-ol, according to the same procedure as
    dimeshtamino) ethoxy phenyl 1-butene-4-ol, according to the same procedure as

    and the corresponding (Z) -isomer, Hydrochloride salt is crystallized from toluene. The yield is 35.8 g (81%), t, mp, 183- 85 ° C. This product can be separated from the salt form by the same method as the corresponding (Z) isomer. Melting point is 69-71 ° C . (from hexane)% NMR spectrum (with Clj): 2.34 (bN, s); 2.74 (2H, t); 2.97 (2H, t); 3.43 (2H, t); 4.08 (2H, t); 6.80-7.30 (14H, m).
    Mass spectrum: m / e 405/407 (),. 72 (19), 58 (100).
    PRI me R 4. a, 4-Benzyloxy- - 1,2-diphenylbutan-1-one.
    The compound is prepared from 19.5 g of deoxybenzoin and 21.5 g of benzyl phosphate protected bromoethanol, respectively; with the procedure specified in Example 1a, ..
    B. 4-Benviloxy-1,2-difensh1-1- (4-tetrahydropyran-2-yl-oxy-phenyl) butan-1-ol (RR, SS).
    The compound is obtained from the residue obtained by evaporation of evaporation, as indicated in Example 4a, and from 38.6 g of tetrahydropyran-2-yl ester protected 4-bromophenol in accordance with the method
    The yield of the hydrochloride salt described in Example 1b is 36.7 g (83%). The product has a temp-, s, 4-benzshshksi-1,2-diphenyl-l- (4 melting point melting point, equal to 194-196 ° C. This product can be separated from the salt form using 1 M
    hydroxyphenyl) -butan-1-ol (RR, SS),
    The compound is obtained from the residue obtained by evaporation from step a
    The one described in Example 1b, s, 4-Benzshksi-1,2-diphenyl-l- (4oxyphenyl) -butan-1-ol (RR, SS),
    The compound is obtained from the residue obtained by evaporation from step a.
    in accordance with the procedure described in example 1c,
    d, 1, 2-di4) enyl-1- (4-hydroxyphenyl) butane-1,4-diol.
    The residue obtained after evaporation in stage b is dissolved in 300 ml of 9A% ethanol. Next, add 2 g of catalyst - 5%
    Excretion (Z) isomer. A mixture of sodium hydroxide with a methylene chloride mother liquor is placed in a separatory funnel. The methylene chloride layer is removed and the aqueous layer is neutralized with concentrated hydrochloric acid, after which the extraction is carried out using palladium supported on activated Q-ethyl acetate, an ethyl acetate solution and coal. The reaction was obtained over sodium sulfate, the solution was stirred at room temperature and evaporated. (g) - The isomer is subjected to heating in a hydrogen atmosphere before technical recrystallization from a mixture of methanolpore, until I equivalent to 50:50 water is consumed. Output of hydrogen. The catalyst is filtered off. 15 mp 6.2 g (31%), the product has. Further, the solvent is evaporated, and the resulting product is crystallized from toluo. The yield is 12.7 g (38% of desoxybenzoin), m.p. 192-194 p.
    e. 1,2-Diphenyl-2- (4-hydroxyphensh1) -1-20 °) 1H, s).
    buten-A-ol (EE E). Mass spectrum: ta / e 315 (M, 35),
    According to the method of example 2d, the title compound is obtained. The yield of the pure mixture of isomers (Z: E in a 1: 1 ratio) was 22, .8 g (72%), mp. 1664-. .
    Branch (S) isomer. First, 20.0 g of the isomer mixture is subjected to dissolution in warm methylene chloride, and then added. 5 The exact amount of 2 M sodium hydroxide solution. After mixing or shaking, the mixture is filtered. The precipitate which is (E)
    isomer in the form of sodium salt suspension 6,42 (2H, d); 6.70 (2H, d); 7.15 (5H, s); doped in 2 M hydrochloric acid. Next, (E) -isomer is extracted in eipacetate as free phenol
    t, pl.169-171 C,
    The range of PNR (aneTOH-dg) &: 2.70 (2H, t); 3.52 (2H, t); 6.48 (2, d); 6.74 (2H, d); 7.15 (5H., S); 7.32
    285 (38), 207 (54); 191 (37); 107 (40), 91 (100).
    The sodium salt of the (g) isomer is prepared as described above for the (E) isomer. T, go1,205-217 with,
    f. 4-chloro-1,2-difenyl-l- (4-oxyphenyl) -l-butene (Z and E).
    Using the procedure of example 3d-, a quantitative yield is obtained, t, sh1, 85-87 C (from methanol).
    g
    PMR spectrum (CDjOD) 5: 2.67, (2H, t); 3.38 (2H, t); 4.76 (1, s);
    , -. .
    7.30 (5H, s).
    Mass spectrum: t / e: 334/336 (M 94/32), 285 (71), 207 (78), 191 (56), 183 (199) i 107 (55) ,. 91 (86).
     An ethyl acetate solution is dried with sulfate
    sodium, and the solvent is evaporated, 40 (E) -Isomer is recrystallized from a water-methanol mixture, 50/50. The yield is 7.2 g (36%)
    m.p. 165-167 ° C, -,. - PMR spectrum (CB, COC1,) Y 2.78 (2H, t); 45 yield, T, mp, 109-1,
    (E) -isomer, (E) -Isomer n according to the same procedure, but higher for the (2) -isomer. The product is washed: with petroleum gas. It was reached almost to
    3.54 (2H, t); 6.83 (2H, d); 6.90-7.35 (12H, m); 8.32 (W.s).
    Mass spectrum: ha / e 316 (M, 64), 285 (100), 207 (87), 191 (58); 107 (55), 91 (94).
    The sodium salt can be obtained as described above. Another method consists in the solution} of pure (E) -isomer in ethanol, adding an equivalent amount (sodium hydroxide in ethanol and evaporating the solvent. The sodium salt is washed with acetone. The salt obtained has t, bm, 215-226 ° C,
    PMR spectrum (): 2 3.42 (2H, t); 4.79 (1H, s); 6 6.93 (5H, s); 7.12 (2H, d); 7
    Example 5, 4-p (Tetra 50-ran-2-yl), 2-bis 4- (ropyran-2-yl) oxy1 phenylbut
    a, The compound is obtained and 4,4-bis (tetrahydropnran-2-sh of deoxybenzoin and 20.9 g of those
    55 Pyran-2-yl-ether-protected nol according to the method. sledge in example 1a
    b.4- (Tetrahydropyran-21-phenyl-1, 2-bis 4- (tetrahydrin
     water in the ratio of 50:50. The yield is 6.2 g (31%), the product has
    t, pl.169-171 C,
    The range of PNR (aneTOH-dg) &: 2.70 (2H, t); 3.52 (2H, t); 6.48 (2, d); 6.74 (2H, d); 7.15 (5H., S); 7.32
    Mass spectrum: ta / e 315 (M, 35),
    285 (38), 207 (54); 191 (37); 107 (40), 91 (100).
    The sodium salt of the (g) isomer is prepared as described above for the (E) isomer. T, go1,205-217 with,
    f. 4-chloro-1,2-difenyl-l- (4-oxyphenyl) -l-butene (Z and E).
    Using the procedure of example 3d-, 30 are each quantitative yield, t, sh1, 85-87 C (from methanol).
    g
    PMR spectrum (CDjOD) 5: 2.67, (2H, t); 3.38 (2H, t); 4.76 (1, s);
    6.42 (2H, d); 6.70 (2H, d); 7.15 (5H, s);
    , -. .
    -, -,. - 7, 30 (5H, s).
    Mass spectrum: t / e: 334/336 (M 94/32), 285 (71), 207 (78), 191 (56), 183 (199) i 107 (55) ,. 91 (86).
    (E) -isomer, (E) -Isomer is prepared by the same procedure as above for the (2) -isomer. The product obtained is washed with: petroleum ether. Almost quantitative yield was achieved, T, pl, 109-1,
    PMR spectrum (): 2.96 (2H, t); 3.42 (2H, t); 4.79 (1H, s); 6.79 (2H, d); 6.93 (5H, s); 7.12 (2H, d); 7.12 (5H, s),
    Example 5, 4-p (Tetrahydropyran-2-yl), 2-bis 4- (tetrahydropyran-2-yl) oxy1 phenyl butan-1-one,
    a, The compound is obtained from 39.6 g of 4,4-bis (tetrahydropnran-2-pc) oxy-deoxybenzoin and 20.9 g of tetrahydropyran-2-yl-ether-protected bromoethanol according to the procedure described in example 1a,
    b.4- (Tetrahydropyran-2yl) oKCHj - 1-phenyl-1,2-bis 4- (tetrahydropyl
    ran-2-yl) oxy phenyl butan-1-ol (RS, SR).
    The compound was obtained from the residue obtained by evaporation in Example 5a, and 23.6 g of bromobenzene according to the procedure described in Example 1b.
    c, 1-Phenyl-1,2-bis (4-oxyphenyl) - butan-l, A-diol (RS, SR).
    The compound is obtained from the residue obtained after evaporation in step b according to the procedure described in example 1c. The product obtained is recrystallized from tol. The yield is 8.4 g (24% of 4,4-bis | (tetrahydropyran-2-yl-oxo deoxybenzoin), the product has a value of 1.213-215 ° C.
    d, 1-Phenyl-1,2-bis (4-hydroxyphenyl) -1-butan-4-ol (Z, E).
    35.0 g of 1-phenyl-1, 2-bic (4-oxyphenyl) butan-1, 4-diol are refluxed for 1.5 hours in a mixture containing 250 ml of ethanol and 10 ml of concentrated hydrochloric acid. The solution is treated with charcoal. After filtration, the solvent is evaporated, and the residue after evaporation is recrystallized from toluene. The yield of the mixture of isomers (Z; E 1: 1) was 19.2 g (58%), and so pl. 182-1964.
    PMR (CD, 00): 2.64 (1H, t) 2.74 (1H, t); 3.50 (2H, t) 4.77 (ЗН, с 6.38-7.33 (13Н, m).
    Primerb,
    a-, 5- (Tetrahydropyran-2-yl) ox1 1,2-diphenylpentan-1-one.
    The compound is obtained from 19.6 g of deoxybenzoin and 22.3 g of tetrahydropyran-2-yl ether-protected 3-bromopropanol in accordance with the procedure described in example 1a,
    B .. 5- (Tetrahydropyran-2-yl) oxy 1,2-diphenyl-1 - | 4- (tetrahydropyran-2-yl) oxy | phenyl pentan-1-ol (RR, SS),
    The compound is obtained from the evaporation residue obtained in Example 6a, and 38.6 g of tetrahydropyran-2-yl ether-protected 4-bromo phenol according to the procedure described in Example 1b.
    with. 1, .2-Diphenyl-1- (4-hydroxyphenyl) pe-1,5-diol (RR, SS).
    The compound is obtained by evaporation of the residue produced in step b using the same method as 1,1,2-triphenylb-
    0
    0
    five
    five
    ,
    tan-1,4-diol in example 1c, the resulting product is recrystallized from toluene. The yield is 11.1 g (32% of benzoxybenzoin), the product has mp, 182-184 s,
    d. 1,2-Diphenyl-1- (4-hydroxyphenyl) -1-pentene-5-ol (Z and E).
    Using the procedure of Example 2d, the result is a mixture of pentenol derivatives (Z: E in a 1: 1 ratio). The yield is 5.6 g (17%) t, mp, 157-163 ° C,
    The isomers are separated according to the procedure described in Example 5e for their homologs.
    (E) -Isomer is subjected to recrystallization from methanol: water in a ratio of 2: 3, t, sh1, 167-169 C,
    Spectrum of PNR () S: 1.36-1.74 (2H, m); 2.44-2.67 (2H, m); 3.42 (2H, t); 4.75 (2H, s); 7.76 (2H, m); 6.91 (5H, ms); 7.05 (ЗН, d); 7, 9 (5H, s).
    Mass spectrum: m / e 330 (M, 100), 265 (39), 207 (73), 183 (89), 107 (57), 91 (90).
    (Z) -Isomer is recrystallized from a mixture: water-methanol in a ratio of 1: 2, the product has t, sh1. 164-167 ° C
    Spectrum of Poland (SVZOV) S: 1.35-1.72 (2H, m); 2.77-2.5 (2H, m) .; 3.39 (2H, t); 4.74 (2H, s); 6.40 (2H, d); 6.68 (2H, d);
    7.12 (5H, s); 7.26 (5H, ms). . Mass spectrum: ha / e 330 (, 100).
    285 (19), 207 (70), 183 (97), 115 (76), 91 (81).
    e, 5-Chloro-1,2-diphenyl-1- (4-hydroxy-phenyl) -pentene (Z, E).
     Using the “method of example 3d”, a mixture consisting of (Z) - and (E) -isomers is obtained. The isomeric mixture is subjected to recrystallization from petroleum ether to obtain as a result of 7.7 g (22%) of the (Z) -isomer, the product has t, mp, 116-118 C,
    Spectrum of Poland () S: 1.56-1.94 (m); 2.74-2.66 (2H, m); 3.35 (2H, t); 4.74 (1H, s); 6.41 (2H, d); 6.49 (2H, d);
    7.13. (5H, s); 7.22-2.41 (5H, m). Example 7, 4-Bromo-1,2-diphenyl- (N, N-dimethylamino) coupling - phenyl-l-butene (Z).
    A mixture containing 38.7 g of (Z) -l, 2-gc diphenyl-1-4- (N, N-dimethyl amino) ethoxy | phenyl-butene-4-ol, 52.4 g of triphenylphosphine, 66, 4 g of carbon tetrabromide and 400 ml of dry acetonitrile are shaken for 2 hours at 22 ° C,
    thirty
    40
    45
    50
    after which the o6pa3OBaBiirHiicfl product as a precipitate is separated by filtration.
    Yield 21.) g (A7%), mp, PA-116 C (recrystallized from methanol) .5
    NMR (CDC1,) S spectrum: 2.27 (bN, s), 2.63 (2H, t); 2.88-3.09 (2H, m); 3.19 Proxy progesterone or molecules, under Jerge research. Combinations such as the molecule + estradiol and the molecule + medroxyprogesterone were also studied. The number of living cells after 4 hours, 24 hours and 48 hours of incubation is determined by the method of biolomi.
    3.40 (211, m); 3.92 (2H, t); 6.54 (2H, d); centions (intracellular definition6, 79 (2H, d); 7.15 (2H, s); 7.31
    (5H, s).
    Mp pl. 165-167 C.
    Compounds I exhibit estrogenic, antiestrogenic, progestan and antitumor activity.
    The estrogen receptor agent is determined on the basis of the ability of molecules to compete with ZN-labeled and
    10 of ATP). The antitumor effect is investigated in live orx anisma in relation to DMVA-induced adenocarcinoma of the mammary gland of a rat capable of transplantation of mammary jelly.
    5 and adenocarcinoma of the ovary, and pr-residic scaly cell carcinoma capable of transplantation, according to the following methods: Breast adenocarcinoma
    5 and adenocarcinoma of the ovary, and pr-residual scaly cell carcinoma capable of transplantation, in accordance with the following methods. Breast adenocarcinoma
    17-betaestradiol in rat uteri cytosol. After incubation, 20 was induced by DMVA in female ganda, unrelated to the receptor, and spawned at the age of 35-40 days. Treatment of glands bound to the receptor is subjected to separation using a known method using dextran.
    As the molecules under study were started, after it was possible to palpate tumors. The size of the tumor and the number of tumors were evaluated twice a week. The sizes of tumors in the control group treated with solvent alone were compared with tumors in groups of activated charcoal.
    The estrogen-antiestrogenic (progesteronic) effect in a living organism was determined as follows.
    Estrogenic properties of molecules
    determined by subcutaneous injected in the study.
    yes molecules suspended in sesame oil, undeveloped mice aged 21 days, for three consecutive days. On the fourth day
    The activity of molecules against other tumors was investigated by introducing molecules with the help of the gastric tube to animals that were impaired.
    mice were sacrificed and the implantation
    uterus Estradnol (positive control) increased the weight of the uterus. All uterus correlate with estrogenic effect of molecules.
    The anti-estrogenic effects of the molecules were determined in a similar way on neuvivshis mice,:. In this case, the ability of molecules to inhibit uterine weight gain caused by estrogen was also investigated.
    Progestan effects have been studied in a similar way as estrogen. Medroxyprogesterone Acetate, which leads to an increase in ve- The uterus was used for cpafe.
    Pr ivoobumolevy effect was studied outside the body as follows.
    35
    transplantation of mouse uterine sarcoma
    or prostatic rat adenosarcoma.
    Daily or twice a week
    40 produced the drug. In this case, MNRI mice (females weighing about 20 g) and rats of the Fischer-344 breed (males weighing approximately 200 g) were used. Estram ustinphosat- used as
    45 positive controls. Edepocarcinoma of the mammary gland transplanted to rats was developed through the inoculation of elements caused by DMVA carcinoma, subcutaneously healthy adults
    50 female rats. The tumor that gave
    substantial growth, used for further transplantation. Other transplantable tumors
    were inoculated subcutaneously as
    The growth of the MCF-7 cell line (ad-washed cell suspension (human Yukinocarcinoma).
     cells / animals).
    known as estrogen dependent) is evaluated in the presence or absence of estradiol, medroxyprogesterone acetate or molecules to be studied. Combinations such as the molecule + estradiol and the molecule + medroxyprogesterone were also studied. The number of living cells after 4 h, 24 h, and 48 h of incubation was determined by the method of biolinescence ATP). The antitumor effect is investigated in the live orx anisma in relation to DMTA-induced adenocarcinoma of the mammary gland of a rat capable of transplantation of the mammary gland,
    and adenocarcinoma of the ovary, and pr-residual scaly cell carcinoma capable of transplantation, in accordance with the following methods. Breast adenocarcinoma
    was induced by DMVA in female rats aged 35–40 days. Treatment with the molecules under study was started-after it was possible to palpate tumors. The size of the tumor and the number of tumors were evaluated twice a week. The sizes of the tumors in the control group treated with solvent alone were compared with the tumors in the groups; the subactivity of the molecules against other tumors was investigated by introducing the molecules with the help of the gastric tube into animals that had been implanted
    - Implantation capable of
    35
    transplantation of mouse uterine sarcoma
    or prostatic rat adenosarcoma.
    Daily or twice a week
    40 produced the drug. In addition, MNRI mice (females weighing about 20 g) and rats of the Fischer-344 breed (males weighing about 200 g) were used. Estrum-usteenphosate- used as
    45 positive controls. Breast edepocarcinoma transplanted to rats was developed by inoculation of elements caused by DMVA carcinoma, subcutaneously healthy adults.
    50 female rats. The tumor that gave
    substantial growth, used for further transplantation. Other transplantable tumors
     washed cell suspension (Yu
     cells / animals).
    Compound1 I have shown good estrogen receptor agents that
    15
    The beating is measured using a method using dextran-activated coal.
    The results are shown in Table. one .
    The estrogenic effect of compounds I, measured on the basis of their ability to increase the weight of the uterus of undeveloped mice, was always significantly less than the estrogenic effect of estradiol, which was used by the dp positive control,
    The estrogenic effect of compounds 1 and 2 can only be detected at higher concentrations. At a dosage of 5 mg / kg live weight, the effect of the first was 50% less than that of estradiol at a dosage of 0.05 mg / kg live weight.
    Compounds 1-3 (Table 1) have anti-estrogenic effects, which was measured by ito their ability to inhibit uterine weight gain is undeveloped: our mice induced by estradiol.
    Compound 1 at a dose of 0.5 mg / kg live weight, and compounds 2 and 3 at a dosage of 5 mg / kg live weight, respectively, 27, 25, 20% inhibition of the effect of increasing the weight of the uterus in young caused by i, estradiol.
    l / v. , /
    Progestan effects of Compound I; were defined as previously described. Medroxyprogesterone acetate used as a positive control causes inhibition of uterine weight in undeveloped mice to 40%.
    Compound I also has anti-estrogenic and estrogenic properties, and it has been shown that it also has progestan properties7
    50
    mi, - and causes a slight inhibition of the mammary gland of rats caused by DMVA.
    The antitumor effect of compound 1 was found in the dose range from 1.0 to 30 mg / kg of live weight. At the highest dose, it was found that tumor growth ceased completely (see, Table 4). b
    The size refers to the product (width) X (height) of the tumor. The growth rate is determined by the difference in size compared with the size that was found on the first day of treatment. The antitumor effect is smaller than that which Compound 1 shows against cancer iroirovanie medroxyprogesterone at the lowest dose studied,
    Tables 2 and 3 present the summarized data of estrogenic (anti-estrogenic and progestan effects). Percentage data refers to an increase (weight loss of the mice uterus).
    The antitumor effects of compounds I have been tested outside the body in relation to the MCF-7 line of human cellular adhenoracene; lezas, and in vivo against rat mammary adenocarcinoma, I-induced DAVA ovarian carcinoma
    55
    1508955
    rats, carpine simplicity of rats and sarcoma of the uterus,
    Table 3 shows data on the antitumor effects of certain compounds of formula I. The presented results show the following:
    Effect Yu, -. concentration of compound j
    failure to ensure 50% cell growth inhibition +++ X ++ 5 X 5 + 5 X 10 M
    5 X 10- The reported data on the estrogenic / antigenic and progestan effects of compounds I are given below. 0 Experience Compound 1 (table 1) Estrogenic
    Progestan
    Antiestrogen, 27%
    decline
    five
    0
    Without additives
    With estradiol 0.05 X 0.05 mg / kg of live
    weight-. . .
    With medroxy-weak inhibition, a prostate-14% decrease compared with the control
    0.06 mg / kg
    live vet .:
    sa
    Compounds tested were found to be very effective outside the body in relation to MCF-7 breast cells and, by increasing the concentration, the death of the cell 0 line was achieved using each of the compounds.
    Antitumor effects of compound, - II
    five
    I
    “II
    Ki I in vivo determined in tests against adenocarcinoma
    50
    55
    17
    The gland called DMVA was observed for compound 2.
    The effect of Compound 1 against ovarian carcinoma in rats and uterine sarcoma in mice was tested on tumor transplant methods using the methods described above. After two weeks of treatment at a dose of 100 mg / kg of live weight, the size of uterine sarcoma was 30% less than the corresponding parameter in control specimens, and after 10 days of treatment at a dose of 5 mg / kg of live weight, the size of ovarian cancer was 20%. less compared to control specimens.
    The acute toxicity of LDjg in mice varies from 1000 to 3200 mg / kg of live weight for the compounds under study. The clinical dosage of an adult person when administered orally varies from 10 to 200 mg per day.
    A comparison was made of the biological activity of compound I (toremifene) with diethylstilbestrol and hexestrol,
    Growth Methods for MCF-7 Cell Line



    and
    estrogen-antiestrophic Bnn (prog. es-zo of compound I, possessing high
    The teronic effect based on uterus weighting is described above,
    Bish obtained the following results
    The difference between compound 1 and hexestrol as well as between compound 1 and diethylstilbestrol was studied by uterotrophic analysis in mice and the human estrogen receptor positive cell line of the human mammary gland.
    Uterotrophic analysis describing the estrogenic properties of molecules and cell cultures, shows the activity of molecules that inhibit the growth of a cancer.
    In uterotrophic analysis; hexestrol and diethylstilbestrol 6bUIH
    administered subcutaneously to mice in doses of 5 and 50 (KG / KG. T oremifen was administered in the amount of 50, 500 and 5000 / ig / kg. The size of the uterus (weight, in mg) is divided by the weight of the animal (expressed in g) in each group, data are presented in; tab., 5.
    Cell cultures use an estrogen receptor positive human breast cancer cell line, a cultured MCF-7 cell. : dried in the presence of hexestrol, diethyl
    0
    five
    0
    five
    stilbestrol and toremifell. The concentrations of each compound were 10-10, 10-9, 10-8, 10-7, 10-6, and 10-5 mol / L. The number of living cells was recorded at each concentration and calculated as a percentage of the control (without adding hormones).
    From the data of Table 5 it is clear that the maximum estrogenic effect of toremife - even at high levels is weaker than. : hexestrol and diethylstilbestorol; toremifene is capable of antagonizing the estrogenic effects of hexestrol and diethylstilbestrol.
    All three compounds can inhibit the growth of MCP-7 cell tumors in vitro according to the method, depending on. Concentrations: Toremifene is a more effective growth inhibitor of a compact tumor than hexestrol and diethylstil- / bestrol. So the concentration of toremifene, which increases the number of surviving cells in half when compared with the control, is 10 times lower than the concentration of hexestrol and diethylcryth-. bestrol.
    Thus, the proposed method. allows you to synthesize new
    estrogenic, antiestrogenic prot. gestan and antitumor activity.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of producing alkene derivatives of the general formula
    about with
     about
    fcH2) nCH2R / t
    Where
    R.
    R.0
    R
    P
    one
    hydrogen or hydroxyl;
    -hydrogen, hydroxyl, me -: - toxyl or 2- (N, N-dimethyl.- amino) ethoxyl;
    chlorine or bromine, or 2,
    or their salts, characterized in that the compound of the general formMyjlbf
    -sn-s (CH2)
    191508955
     tetrahydropyran-2-yloxy or benzyloxy; hydrogen or tetrahydropyran-2-yloxy;
    F, R - hydrogen, markoxin or tetra1 idropyran-2-yloxy j p - has the indicated values,
    impose interaction with the compound of the General formula
    where K „is hydrogen, methoxyl, 2-dime Ilamino) ethoxyl
    (N, Nr
    or
    tetrahydropyran-2-yloxy5 forms a compound of the general formula
    He is with:
    (CH2) nCH iR5
    where rj rg r and
    RS tetrahydropyran-2-yloxy or benzyl carbon;
    P has the indicated meanings, is subjected to acidic hydrolysis, which forms the compound of the general formula.
    Coefq - Neni
    Test compound
     4-XIIOp-le2-diphenyl-l / 4- 2- (N, N-Dimethylamino) ethoxyJ phenyl 1 butene (Z) -isomer
    4-Bromo-, 2-diphenyl-1 - G4-G2- (K, K-dimethyl amino) ethoxyphenyl:} -1 -buthene, (E) -isomer
    4-Xpor-1,2-diphenyl - (4-oxyphenyl) -l-buten (Z) -isomer
     4-Chloro-1,2-difsnyl-1-4-2- (K, N-dimethyl amino) -ethoxy phenyl -1-buten, (E) -isomer
    The concentration of the compound at which there was a 50% substitution (inhibition) of estradiol (inhibition) - 10 M (weak affinity) g 10 (inhibition) - 10 M (weak affinity) Yu M inhibition) —YM (weak affinity) inhibition
    (
    Where
    R, R and R have the indicated signs.
    cheni
    dehydrated followed by substitution in the compound of the general formula
    , ®
      five/
    (CH2lnCH..OH
    where R, R have the indicated values, hydroxyl group for chlorine or bromine and isolate the desired product in free form or as a salt. Priority; by featured
    27.05.82 with R. and R,., Is hydrogen; (N, N-dimethyl-amino) ztoxyl; ., - chlorine or bromine; n 1,
    25.06.82 with E, and R - hydroxyl; R} is hydrogen5 hydroxyl or methoxy; n 2.,. .
    T.a b l and c a 1 j
    Affinity
    +++
    +++ ++
    +++ ++
    +, +
    21150895522
    Table
    Summary of estrogen / antiestrogen and progestan effect of compounds T
    about
    Estrogenic, 2% increase
    Antiestrg gene, 25% reduction
    Table3
    Antitumor Effect of Compounds I Against MCF-7 Cellular
    The compound (table, I)
    1 2 4 3
    Table
    The size and growth of tumors caused by DMVA, during treatment with compound 1, compared with the control group
    3,914
    4,716
    8,509
    11, 622
    16,176
    17.473
    22,695
    29.542
    35,115
    32,803
    Estrogenic, 20% increase in Antiestrogen, decrease less than 10%
    No effect
    Antitumor effect
    +++ +++ +++ ++
    1.5188
    1.6739
    1.3070
    1.0474
    0,1179
    0.820
    0.0721
    -0.0891
    0.09316
    0.1193
    ABOUT
    0.1551 -0.2118 -0.4714 -O, .5 39 2 -0.5762 -0.5851 -0.5682 -0.5640 -0.5379
    Table
    j The effect of hexestrol; diethylstilbestrol i
    and toremifene in the volume of the uterus (18 days) of the undeveloped uterus. The number of animals in each group 5
    Group
    Dose, / ug / kg day
    -
    + +
    No hormones 5 50
    50 50 500
    5000
    50 + 500
    50 + 500
    Uterine weight (mg) Animal weight (g)
    7.1 ± 0.4
    17.9 + 3.2
    28.1 ± 1.8
    27.9 ± 3.0
    32.6 ± 3.1 10.5 + 1.3 2-1.6 + 1.5 24.1 + 2.7
    21.4 + 2.4 21.1 + 0.7
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FI821879A|FI67538C|1982-05-27|1982-05-27|PROCEDURE FOR FRAMSTATION OF AV-1,2-DIPHENYL-1-ETHOXY) PHENYL) -1-BUTEN|
    GB08218414A|GB2126576B|1982-06-25|1982-06-25|Alkane and alkene derivatives|LV920318A| LV5066A3|1982-05-27|1992-12-17|The method of acquiring alkenades or their islands|
    LTRP766A| LT2243B|1982-05-27|1993-07-07|ALKEN DAILY AND SUSTAINABLE BUDGET|
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