HU176105B - Process for producing new triphenyl-alkanol-derivatives - Google Patents

Description

The present invention relates to novel triphenylalkanol derivatives of formula I wherein X is hydrogen, fluoro, hydroxy or benzyloxy, Y is hydrogen, hydroxy or benzyloxy, with the proviso that X and Y can only have different meanings at the same time.

According to the present invention, a 1-ethyl-deoxybenzoin derivative of the Formula II wherein Y is hydrogen, hydroxy or benzyloxy is reacted with a phenylmagnesium bromide derivative of the Formula III where X is H, F or Benzyloxy. The compound thus obtained is optionally hydrogenated.

In a preferred embodiment of the process of the invention, the p-hydroxy-1-ethyldioxoxybenzoin is reacted with at least two moles of phenylmagnesium bromide derivative of formula III wherein X is hydrogen or fluorine in ether, hexamethylphospho-triamide (HMPT), or tetrahydrofuran (THF). In the compounds of formula I thus obtained, X is hydrogen or fluorine and Y is hydroxy.

In another preferred embodiment of the process of the invention, the 1-ethyldioxoxybenzoin is reacted with benzyloxyphenylmagnesium bromide in ether, HMPT, or preferably THF. The resulting product is hydrogenated to give a compound of formula I wherein X is hydroxy and Y is hydrogen.

derivatives

The preparation of the starting compounds of the process of the invention is described in U.S. Patent No. 1,013,907. British Patent Specification, and J. Org. Chem., 18, 96, 105 (1953); Z. Org. Male. 5, 1074-1077 (1969); J. Am. Chem. Soc., 42, 646-658 (1920).

The compounds of Formula I have significant antitumor activity in DMBA [7,12-dimethylbenz (a) -anthracene] -induced hormone-dependent experimental animal tumors. Surprisingly, the antitumor activity of these compounds is significantly greater than that of the stilbene derivatives which can be prepared from them by the action of water. To date, such stilbene derivatives have been produced in large numbers [E. C. Dodds, L. Golberg: Proc. roy, Soc. B. 5, 132. 83-101 (1944)] and examined in [D. J. Collins, J. J. Hobbs, C. W. Emmens, J. Med. Chem., 14, 952-957 (1971) and R. I. Nicholson, Η. P. Golder: Europ. J. Cancer II. 571-579 (1975)] for inhibiting the growth of hormonal and hormone-dependent tumors.

The new triphenylalkanol derivatives we produce are also novel in their type.

The pharmacological efficacy of the novel triphenylalkanol derivatives of general formula I according to the invention is represented by R, 2R + 1S, 2S-2-ethyl-1-phenyl-1- (4-hydroxyphenyl) phenylethanol (hereinafter A) and 1R, 2S + IS, 2R-2-diethyl-1-phenyl-1- (4-hydroxyphenyl) -phenyl ethanol (hereinafter B) is illustrated by the results (Table I).

Carrier tests

Studies were performed on female, virgin, CFY rats. At 50 days of age, the animals received twice a week oral administration of 10 mg of DMBA dissolved in 0.5 ml / animal of oral oleum. Breast tumors have 5-6 weeks after induction. week after week they started to develop. Animals having well-defined at least a bean (about 500 mm ³ ) tumors were considered tumorous. We started treatment on such animals. From the 3 months of the trial period to 2 months three times a week and 1 month the treatment-free observation period. The size and number of tumors were determined every 10-14 days. In untreated animals, tumors grew steadily, with tumors reaching 4-8. The local and general effects of the tumors led to the death of untreated animals within 3-4 months. The efficacy of the treatment can be measured in the absence of growth and the inhibition of new tumors.

No. The results are summarized in Table II, which are described by P. Griswold et al., "Induced Mammary Carcinoma in the Female Rat as a Drug Evaluation".

System ”(Cancer Research 26: 2169-2180 (1966)). Accordingly, mean tumor mass, mean tumor number, number of animals alive, objective effect, number of animals recovered, and side effects are determined at various times.

Table I

Effect of Compounds A and B on Induced Rat Mammaadenocarcinoma

1 ^a 1 B control tamoxifen ARC Dose in mg / kg 1 20 20 i i 2 2 20 carrier 20 20 Treatment po. neither. po. neither. neither. neither. neither. neither. 0 days Dia. mg 855 524 598 483 515 820 653 500 Cv. 2.2 2.2 1.0 1.4 1.2 1.5 1.0 1.2 Ace. 5 5 5 5 5 6 6 5 Dia. mg 2162 334 2660 5243 880 24,965 2747 1 3000 30 days Cv. 1.8 0.8 2.0 2.2 1.0 3.5 1.0 1.2 Ace. 5 5 5 5 5 6 5 5 Dia. mg 1717 340 3894 8182 262 41 103 814 2750 60 days Cv. 1.0 0.4 3.0 3.3 1.7 3.5 0.5 1.0 Ace. 5 5 5 3 3 4 5 5 90 days Dia. mg 2734 2680 accompany finishes et time 856 39,297 1481 10,500 Cv. 1.8 1.6 1.7 4.0 1.8 1.0 Ace. 5 5 3 3 5 3 Prop. effect 5/5 5/5 3/5 3/5 5/5 0/6 5/6 3/5 * Healed 2/5 4/5 1/5 2/5 3/5 0/6 3/6 0/5 Side effects, body weight decrease 0 0 0 '0 0 Weight loss from the middle of the experiment 0 0

Avg: Mean tumor weight; Mean: mean tumor number; Ace: Number of live animals IV = 1,2-diphenyl-1- (p-hydroxyphenyl) -but-en * = The effect was manifested in the temporarily unchanged tumor state.

In vitro studies

The binding of the compounds to estrogen receptors was examined. The receptors were isolated according to the method of L. Terenius, European J. Cancer 9: 291-294 (1973).

In this method, it was combined with receptors isolated, soluble estrogen 10 ^-9 M ^and II ösztradioIlaI [2,4,6,7 (n> ³ H öeztradiol, spec active 93 Ci / mM;.. Amersham, England] 10 ^-7 and IQ ^-5 M respectively. By liquid scintillation measurements we calculated the% inhibition of labeled estradiol receptor binding by our compounds.

Results

10 ^-3 MA inhibited the binding of 10 ^-9 M ^s H-estradiol by 72.4%

ΙΟ ^-3 Μ B inhibited binding of 10 ^-9 M ³ H-estradiol to 87.9%.

10 “ ⁷ M-4 inhibited λ 10 ~ ⁹ M ³ H-estradiol binding by 40.7%

10 ⁷ Mfi inhibited the binding of 10 ' ⁹ M ^s H-estradiol by 71.5%

The in vitro and in vivo data presented demonstrate that Compounds A and B exert a high degree of inhibitory and curative activity in an otherwise highly resistant and poorly chemotherapeutic experiment. The compound type is also effective orally. The effect is always long-lasting and results in a definitive cure or 2-3 months of remission in the animals. The extremely important effect of the compounds is that in most cases they inhibit the development of new tumors. The compounds exert their action by binding to estrogen receptors.

Investigation of the effects of compounds A and B on estrogen (1) and antiestrogen (2).

1. The estrogen activity of the compounds was tested in a mouse and rat uterus assay (Edgren, R.A., et al., Steroids 2. 319 (1957)). Infantile animals receive the test substance in increasing doses, once daily. c., in 0.1 ml volume, in an aqueous suspension containing 1% Tween 80 for 3 days. On day 4 of the study, the animals were sacrificed and the weight of the uterus after purification was measured on a torsion balance. Doses of 2.5-fold uterine weight gain are listed in the table below:

Dose

test materials Mouse Rat | G / head / day neither. mg / kg / day SC. THE 2.5 0.5 B 10.0 1.1 estradiol 0.00043 0.0017

2. Anti-estrogenic activity of the compounds Harper, M.J.

K. et al., J. Reprod. Fit. 13. 101 (1967) in mice and rats.

Infantile animals were assayed for 3 days as described above. c. they got. Mice were treated with 0.03 µg / day and rats with 0.3 µg / day of estradiol benzoate.

Estradiol-induced uterine weight gain is reduced by the dose of the concomitant anti-estrogenic compound. The inhibition, i.e. the degree of anti-estrogen activity, is given in%.

test material Dose {Ag / animal / day neither. Inhibition% tamoxifen 0.3 22.5 (ICI) 1.0 23.5 3.0 39.2 10.0 46.2 MOUSE THE 1.0 24 3.0 26 10.0 42 B 3.0 14 10.0 21 30.0 30

Dose: mg / kg / day also. tamoxifen í ! 1.0 63.5 (ICI) 3.0 63.9 RAT 10.0 70.5 THE 1.0 0 10.0 20.0 B E0 0 10.0 34.6

Known from the literature (Harper, M. J. K. et al., J. Reprod. Fit. 13. 101 (1967)] that Tamoxifen [Z1,2-diphenyl] -1- (p-) 2- (dimethylaminoethoxy) phenyl (-1-butene) citrate] is a mild estrogen in mice and mild antiestrogen at higher doses, however, it exhibits strong anti-estrogenic activity in rats.

Compounds A and B show poor estrogen activity in both animal species compared to estradiol. Their antiestrogen activity in mice approximates that of Tamoxifen but is less in rats.

The compounds of the present invention can be used in the preparation of pharmaceutical compositions by converting the triphenylalkanol derivative of the Formula I together with non-toxic pharmaceutically acceptable inert diluents and / or carriers.

In order to carry out the process of the invention, the following embodiments are provided:

Example 1

IR, 2R4-1S, 2S-2-ethyl-1-phenyl-1- (4-hydroxyphenyl) phenylethanol (X = H, Y = OH)

7.78 g of magnesium turnings in 120 ml of anhydrous THF are reacted with 31.6 ml (300 mM) of bromobenzene to form a solution of phenylmagnesium bromide in the usual manner. While stirring, while maintaining the temperature between 35-40 ° C, a solution of 24.03 g (100 mM) of 1- (4-hydroxyphenyl) -2-phenyl-1-butanone in 40 ml of anhydrous THF was added over 30 minutes, the resulting solution was refluxed for 1 hour, and the resulting solution was combined with 400 ml of 10% ammonium chloride solution while maintaining the temperature at 20-25 ° C. The resulting mixture was extracted with chloroform (3 x 100 mL). The combined chloroform phases are washed with 50 ml of 10% ammonium chloride solution and dried over magnesium sulfate. The solution was concentrated in vacuo and the distillation was continued after addition of 100 ml of benzene. The resulting oily residue was stirred well with 200 mL of hexane and the oil crystallized. After standing for one hour, the crystals are filtered and washed with 50 ml of hexane. This gave 28.8 g (90.5%) of the title product (m.p. 117-123 ° C) which was recrystallized from ether / hexane. Yield: 21.42 g (67.5%), m.p. 119-121 ° C.

Analysis (. Ms 318.42) C ₂₂ H ₂₂ O _2: Calcd: C, 83.00%; H, 6.95%; Found: C, 83.17; H, 6.78%.

The starting material 1- (4-hydroxyphenyl) -2-phenyl-1-butanone is disclosed in U.S. Patent No. 1,013,907. according to British Patent Specification No. 3, it can be prepared as follows:

25.43 g (100 mM) of 1- (4-methoxyphenyl) -2-phenyl-1-butanone [J. W. Wilson et al., J. Org. Chem., 18, 96, 105 (1953)] with 63.5 g (550 mM) of pyridine hydrochloride is refluxed for 30 minutes. The resulting solution was poured into a mixture of 150 ml of water and 150 g of ice. The resulting gum slowly crystallizes. The crystalline product was filtered and washed with water (100 mL). The filtered product was dissolved in chloroform (250 mL), the chloroform layer was dried over magnesium sulfate and the solution was evaporated. The distillation was continued after the addition of 100 ml of benzene, and the residue was dissolved in 60 ml of hot benzene. After cooling to 10 ° C, the product crystallizes. The precipitated crystals are filtered off and washed with 30 ml of hexane. Yield: 21.60 g (90.0%), m.p. 131-132 ° C. (British Patent No. 122-124 ° C).

Example 2

IR, 2R + 1S, 2S-2-Ethyl-1- (4-fluorophenyl) -1- (4-hydroxyphenyl) phenylethanol (X = F, Y = OH)

All of the procedures described in Example 1 were followed except that 33.0 mL (300 mM) of 4-fluorobromobenzene was prepared in place of bromobenzene. Yield: 30.02 g (89.5%), m.p. 128-138 ° C. The crude product was recrystallized from ether / hexane to give 25.86 g of the title compound. Yield: 77.0%, m.p. 139-140 ° C.

Analysis results for C ₂₂ H _{2 J} 10 O (ms.

336.42):

Calculated: C, 78.55; H, 6.29%; F = 5.65%; Found: C, 78.6%; H, 6.48%; F = 5,8O%.

Example 3

IR, 2R + 1S, 2S-2-Ethyl-1-phenyl-1- (4-phenylmethoxyphenyl) phenylethanol (in formula I X = H, Y = Bn 2 O)

31.84 g (100 mM) of 2-ethyl-1-phenyl-1- (4-hydroxyphenyl) phenylethanol (Ia) prepared as described in Example 1 are dissolved in 200 ml of 2-butanone. To the solution was added 50 g of anhydrous potassium carbonate and 23 ml (200 mM) of benzyl chloride. The suspension was refluxed for 8 hours, then filtered and the resulting solution was evaporated. To the residue was added 180 ml of isopropanol. After 1 hour, the precipitated crystals are filtered off and washed with 50 ml of isopropanol and 100 ml of hexane. 26.40 g of the expected product are obtained. Yield: 64.6%, m.p. 138-140 ° C.

Analysis for C ₂₉ H ₂₈ O ₂ (ms 408.54): Calculated: C, 85.26; H, 6.90%; Found: C, 85.41; H, 6.70%.

Example 4

IR, 2S + 1S, 2R - "- 2-Ethyl-1" phenyl-1- (4-phenylmethoxyphenyl) phenylethanol (in formula I X = Bn 2 O, Y 2 = H)

3.89 g (160 mg) of magnesium turnings in 100 ml of anhydrous THF with 39.40 g (150 mM) of 4-phenylmethoxy-bromobenzene [T. E. Zalesska, O. A. Neckeck:

Z. Org. Male. 5, 1074-1077 (1969)] in a conventional manner to prepare a Grignard reagent. 22.43 g (100 mM) of 1,2-diphenyl-1-butanone [S. G, Potvell, R. Adams, J. Am. Chem. Soc., 42, 648-658 (1920)], is added to Grignard reagent in 50 mL of anhydrous THF at 25 C for 5 minutes. The solution is refluxed for 2 hours and then 200 ml of 10% ammonium chloride solution are added under cooling. The product was extracted once with 300 ml and then with three times 100 ml of chloroform. The combined chloroform layers were washed with 50 mL of 10% ammonium chloride solution and dried over anhydrous potassium carbonate. The solution was evaporated and distillation was continued after addition of 100 ml of benzene. Methanol (100 mL) was added to the residue and the resulting solution was kept at 0 ° C overnight. The precipitated crystals were filtered and washed with methanol (50 mL) and hexane (100 mL). Yield: 25.54 g (62.5%), m.p. 61-67 ° C. The crude product was recrystallized from isopropanol to give 18.05 g of the title compound. Yield: 44.1%, m.p. 110-112 ° C.

Analysis (. Ms 408.54) C H _{2Hpyrrol 29} O _2: Calcd: C, 85.26%; H, 6.90%; Found: C, 85.21; == H, 6.91%.

Example 5

IR, 2S + 1S, 2R-2-Ethyl-1-phenyl-1- (4-hydroxyphenyl) phenylethanol (X = OH, Y = H)

40.85 g (100 mM) of 2-ethyl-1-phenyl-1- (4-phenylmethoxyphenyl) phenylethanol (le) prepared as described in Example 4 are dissolved in 50 ml of THF and 100 ml of methanol. The solution was hydrogenated in the presence of 4 g of 10% palladium on charcoal (1 mole of hydrogen in 8 hours). The catalyst was filtered off and the resulting solution was evaporated. The resulting oil was dissolved in a mixture of ether (10 mL) and hexane (30 mL), cooled to 0 ° C and kept at this temperature overnight. The precipitated crystals are filtered off and washed with 100 ml of hexane. Yield: 24.15 g (75.9%), m.p. 92-96 ° C. The crude product was recrystallized from ether-hexane to give 18.21 g of the title compound. Yield: 57.1%, m.p. 96-98 ° C.

Analysis (. Ms 318.42) C ₂₂ H ₂₂ O _2: Calcd: C, 83.00%; H, 6.95%; Found: C, 83.22; H, 7.01%.

Example 6

Preparation of the Pharmaceutical Preparation Tablets containing the active ingredient for oral use for pharmaceutical purposes are prepared as follows:

IR, 2R + 1S, 2S-2-ethyl-1-phenyl-1- (4-hydroxyphenyl) -phenylethanol 50.0 mg corn starch 30.0 mg lactose 85.2 mg polyvinylpyrrolidone 5.4 mg microcrystalline cellulose 8.4 mg magnesium stearate 1.0 mg mean weight: 180.0 mg The tablets are film coated.

Claims (3)

Patent claims A process for the preparation of a novel triphenylalkanol derivative of the Formula I wherein X is hydrogen, fluoro, hydroxy or benzyloxy, Y is hydrogen, hydroxy or benzyloxy, provided that X and Y can have only different meanings, wherein reacting a 1-ethyl-deoxybenzoin derivative of formula II wherein Y is hydrogen, hydroxy or benzyloxy with a phenylmagnesium bromide derivative of formula III wherein X is hydrogen, fluoro or benzyloxy but not Y; the resulting compound is optionally hydrogenated. Process according to claim 1, characterized in that the solvent is ether, hexamethylphosphoric triamide, preferably tetrahydrofuran. 3. A process for the preparation of a method according to claim 1, wherein the active ingredient is one or more compounds of formula I having an antitumor effect, wherein X and Y are as defined in claim 1, characterized in that the active ingredient is mixed with injectable excipients in the form of a solution, tablet, capsule, emulsion, suspension, ointment or other pharmaceutical form. 1 figure