MXPA00008134A - E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical compositions thereof - Google Patents

Abstract

The present invention relates to E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol useful in lowering serum cholesterol and to pharmaceutical compositions thereof. A method of lowering serum cholesterol and a method for the prevention or treatment of atherosclerosis is also disclosed.

Description

E-2- [4- (4-CLORO- 1, 2-DIFENIL-BUT-1 -ENYL) PHENOXY] ETHANOL AND PHARMACEUTICAL COMPOSITIONS THEREOF FIELD OF THE INVENTION The present invention relates to E- 2- 4- (4-chloro-l, 2-diphenyl-but-l-enyl) phenoxy] ethane Pl (I) having properties that decrease serocide terol and pharmaceutical compositions thereof. Compound (I) is useful in reducing the levels of serocide terol in the treatment of atherosclerosis. It is also potentially useful in hormone replacement therapy (HRT).

BACKGROUND OF THE INVENTION It has been shown that the elevated levels of serocide terol associated with low density lipoproteins (LDL) are a major factor that contributes to the development of atherosclerosis progression. Therefore, it is desirable to provide a method for reducing serocolesterol levels in patients with hypercholesterolemia or at risk of developing hypercholesterolemia.

International Patent Application WO 97/32574 describes the use of Z-2- [4- (4-chloro-1,2-diphenyl-but-1-enyl) phenoxy] ethanol to decrease serocide terol. The compound has no significant estrogenic side effects in uterine tissue but is able to block the adverse effects of estrogen in the uterus. Therefore, this compound is especially useful in decreasing serocide terol. The corresponding isome is not described in this patent application. Z-2- [4- (4-chloro-l, 2-diphenyl-but-l-enyl) phenoxy] ethanol is a metabolite of the drug toremifene ant i is known t rógeno. Toremifene (Z-4-chloro- 1, 2-di-pheni 1 - 1 - [- [2 - (N, Nidimethylamino) ethoxy] -phenyl] - 1 -buten) is currently used clinically for the treatment of positive breast cancer, estrogen receptor. It has now been found that E-2- [4- (4-chloro-1,2-diphenyl-but-l-enyl) phenoxy] ethanol (I) is significantly more potent in total seroclock than total teol but about the same in Uterine effects when compared to the corresponding Z isomer. This was unexpected, since the E isomer of toremifene is purely estrogenic in the uterine tissue. Furthermore, it has been found that the E isomer of the invention is capable of inhibiting cholesterol biosynthesis directly, while the corresponding isomer Z has no such effect.

SUMMARY OF THE INVENTION In this manner, E-2 - [4 - (4-chloro-1, di-phenyl-1-but-1-yl) phenoxy] ethanol (I) is especially useful in decreasing serocide terol and in preventing or atherosclerosis treatment. Compound (I) is also potentially useful in hormone replacement therapy (HRT).

OBJECTS OF THE INVENTION According to the above, the invention provides a new compound useful in decreasing the levels of serocium terol, being said compound E-2 - [4 - (4-chloro-1,2-diphenyl-but-1 -eni 1) phenoxy] ethanol and having the structure Or a pharmaceutically acceptable ester of the same. Pharmaceutically acceptable esters include esters made with aliphatic carboxylic acids, preferably C 1-6 acids such as benzoic acid. The aliphatic and aromatic acids may, optionally, be substituted, for example, by one or more C? _4 to Iqui lo. The invention also provides a pharmaceutical composition comprising E-2- (4-chloro-l, 2-diphenyl-but-l-enyl) phenoxy] ethanol a pharmaceutically acceptable ester thereof as an active ingredient together with a pharmaceutically acceptable carrier. The invention also provides a method for decreasing the levels of serocole sterol, such method comprising administering to a patient in need of such treatment an effective amount of E-2 - [4 - (4-chloro-1,2-di-phenyl). 1-but- 1 -eni 1) phenoxy] ethanol or a pharmaceutically acceptable ester thereof. The invention also provides a method for the prevention or treatment of atherosclerosis, such method comprising administering to a patient in need of such treatment an effective amount of E-2- [4- (4-chloro-l 2-di-phen-1-but - 1 -eni 1) phenoxy] ethanol or a pharmaceutically acceptable ester thereof The invention also provides a method for hormone replacement therapy (HRT), such method comprises administering to a patient in need of such treatment an effective amount of E-2 - [4 - (-chloro-1,2-di-phenyl] -1-but-1-enyl) phenoxy] ethanol a pharmaceutically acceptable ester thereof.

DETAILED DESCRIPTION OF THE INVENTION The compound of the invention can be administered in a variety of ways including orally, parenterally transdermally, using conventional forms of preparation, such as capsules, tablets, granules, powders, suppositories, injections, patches, suspensions and syrups. The term "effective amount" means an amount of the compound of the invention that is capable of lowering total levels of serocholesterol or capable of blocking the adverse effects of estrogen particularly in the uterus or inhibiting menopausal symptoms. The compound of the invention can be administered according to the method of the invention on a monthly, weekly or daily basis or several times a day, depending on the needs of the patient. A typical daily oral dose is within the range of from about 0.5 mg to about 1000 mg, preferably from about 10 mg to about 800 mg, of the active compound. However, the dose can be varied appropriately depending on the age, body weight and conditions of the patient as well as the method of administration. The compound of the invention can be administered alone or together with other active compounds. The compositions according to the invention can be prepared by methods commonly employed in the art. In addition to the active compound, the compositions can < In containing pharmaceutically accepted additives is commonly used in the art, such as vehicles, binders, excipients, lubricants, suspending agents and diluents. The amount of the active compound in the compositions of the invention is sufficient to produce the desired therapeutic effect, for example about 0.5 to 1000 mg, preferably about 10 mg to £ 00 mg, in single dose for both oral and parenteral administration. The following examples illustrate the synthesis of the compound of the invention EXAMPLES Example 1. Preparation of E-2 - [- (4-chloro-1, diphenyl-but-1-enyl) phenoxy] ethanol a) E-4 - [4- (2-benzyloxyethoxy) phenyl] -3,4-diphenyl-but-3-en-l-ol The alkylation of the initial phenol with benz 1 - (2-bromoet i 1) ether was carried out as described in Example 1 of the Request for International Patent WO 96/07402 with the exception that now the starting compound was the other geometric isomer, E-4 - (-hydroxy-1, di-phenyl-1-but-1-enyl) -phenol, which was prepared by the method described in U.S. Patent 4,996,225. The product was extracted toluene. The toluene phases were combined, rinsed with water, dried and evaporated until dry. The residue was recrystallized from a minor amount of toluene and the precipitated product was used in the next step in further purification. XH NMR (300 MHz, CDC13) 2H t, CH2-C = 3.6 2H, dt CH2OH) 2H t, C_H2OBn), 4.2 (2H, t, CH2OPh), 4.6 2H OC1 Ph), 6.8-7.4 (19H, m). b) E- 1 - [4- (2-benzyloxyethoxy) phenyl] -4-chloro-1,2-diphenyl-but-l-ene The halogenation of E-4- [4- (2-benzyloxyethoxy) phenyl] -3 , 4-diphenyl-but-3-en-l-ol was carried out as described in Example 2 of International Patent Application WO 96/07402 but using E-4- [4- 2-benzyloxyethoxy) -phenyl ] -3,4-diphenyl-but-3-en-l-Ql as the starting compound. XH NMR (300 MHz, CDC13): 3.0 (2H, t 3.4 (2H, t), 3.8 (2H, t), 4.2 2H, t), 4 .6 (2H, s), 6.9-7.4 (19H, m ). c) E-2- [4- (4-chloro-l, 2-diphenyl-butyl-enyl) phenoxy] ethanol 6.9 g of El- [4- 2-benzyloxyethoxy) phenyl] -4-chloro-l, 2 -diphenyl-but-ene were dissolved in the mixture of ethyl acetate (60 ml) and ethanol 60 (ml). Palladium was added to carbon (5%, 0.7 g) and the solution was stirred vigorously under a nitrogen atmosphere at room temperature until none of the starting compound was left behind (thin layer chromatography). The palladium on carbon was filtered through diatomite and the filtrate was evaporated to dryness. The residue was crystallized several times from the ethanol water mixture. XH NMR (300 MHz, CDC13): 3.0 (2H, t 3.4 (2H, t), 4.0 (2H, m), 4.1 (2H, t), 6.8-7 (14H, m) MS spectrum (+ EI, 70 eV, direct input) : 378 (100%), 342 (8%), 329 (43%), 2 (23%), 284 (28%), 207 (32%), 191 (30 EXPERIMENTS Methods Activity is t ogenic / anties t rogeni ca of the study drug was tested by measuring the effect on uterine weight in immature female Sprag í-Dawley rats (18 days of age) The compound was given po in an EG solution for 3 days (n = 5 / group At the same time, the ability of the study drug to inhibit an estrogen-induced increase in uterine weight was studied in rats given estradiol 50 μg / kg sc The comparison was made with the corresponding Z-isomer. In the biosynthesis of cholesterol, the Hep G2 cell cultures were studied in vitro using 14 C-acet to cholesterol precursor.The test compound was added to the cell culture medium in concentrations from 0.01 to 10 micromolar After 2 hours the culture was stopped and the newly synthesized cholesterol was quantified by thin layer chromatography The comparison was made with the Z-isomer. Effects on uterine weight and serocide terol levels were studied in female Sprague-Dawley rats , ovariectomized adults intact. In the intact rats, the study drug was given p.o. in a daily dose of 3.17 mg / kg for two weeks and the comparison was made with the equimolar doses of the Z isomer, E isomer of toremifene, raloxifene estradiol. In the study of ovar iect omí a, he study drug was given p.o. in a daily dose of 0.1, 1 or 10 mg / kg for 4 weeks and comparison was made with the corresponding Z-isomer and estradiol (100 μg / kg). X Serocole sterol content was determined by an enzymatic method In the ovariectomy study the content of the cholesterol precursor molecule and serocide terol was measured by gas-liquid chromatography. Results In the uterine weight test of the immature rat, the E isomer of the invention showed approximately equal estrogenic and antistrogenic effect when compared to the corresponding Z isomer. The results are shown in Table 1, wherein 1271b means the E isomer of the invention, 127 (Z) means the corresponding Z isomer and E2 means estradiol. TABLE 1 serocole s terol with approximately equal efficacy (by 50-60%). The molecule 1271a (Z) f Me less effective. The results are shown in the Table 3. TABLE 3 Relative uterine weight molecule and serocholesterol drug content (control level was taken as 1.00, medium + SD, n = 3) Uterus Cholesterol 1271b (E) 0.85 + 0.07 0 43 + 0 05 1271a (Z ) 0.75 + 0.06 0 65 + 0 10 Toremi feno (E 1.09 + 0.10 0 40 + 0 18 Raloxifene 0.77 + 0.21 0 48 + 0 09 Estradiol 1.29 + 0.06 0 48 + 0 09 In the ovariectomy study 1271b ( it increased slightly (1.5 times) the relative uterine weight, just the corresponding Z-isomer. Estradiol increased the weight 3.3 times. The 1271b (E) reduced the level of serocholesterol very effectively (up to 77), 1271a (Z) was clearly less effective (the reduction was up to 34%) The results are shown in Table 4 TABLE 4 Relative Uterine Weight Dose and content of serocholesterol (control level has been taken as 1.00) (mg / kg) 1271b (E; Cholesterol 1271a (Z) Colesterd Uterus Uterus 0.1 1.54 0 92 1 2 2 0.5 0.90 1 1.50 0 62 1 7 8 0.96 5 0.89 10 1.53 0 2 3 2 0 4 0.66 In addition, in the study of ovariectomy it was observed that 1271b (E) but not 1271a (Z slightly increased the level of the serocholesterol precursor molecule suggesting a direct inhibition of cholesterol biosynthesis by 1271b (E Di scus ion The above data indicated that both 1271a (Z) and 1271b (E) are equivalent in anti-streptogenicity in the uterus of the rat, Eto differs from toremifene, since the E isomer of toremifene is clearly estrogenic in the uterus of the rat and the Z-isomer is anti- rogenic 1271b (E) ) is more effective as an iphemic hypol agent than the corresponding Z-isomer.This is at least partially explained by the ability of 1271b (E) to directly inhibit cholesterol biosynthesis In summary, test compound 1271b (E) is an anti-estrogenic drug that also has potent potent hypolipic properties.

Claims (5)

1. CLAIMS Having described the invention as background, the claim contained in the following claims is claimed as property 1. E-2- [4- (4-chloro-l, 2-diphenyl-but ll eni 1) phenoxy] ethanol or an icamer pharmaceutical ester ) You're acceptable from it.
2. 2. A pharmaceutical composition comprising E-2 - [4- (4-chloro-l, 2-diphenyl-but-l-enyl) phenoxy] ethanol or an acceptable pharmaceutically acceptable ester thereof as an active ingredient. together with an acceptable vehicle arketing and camertte.
3. 3. A method for decreasing serum cholesterol levels, such method comprises administering to a patient in need of treatment an effective amount of E-2- [4-chloro-1,2-diphenyl-but-l-enyl) phenoxy ] ethanol or a pharmaceutically acceptable ester thereof,
4. 4. A method for the prevention of atherosclerosis treatment, such method comprises administering to a patient in need of such treatment an effective amount of: 2- [4- (4-chloro -l, 2-diphenyl-but-l-enyl) phenoxy] ethanol or a pharmaceutically acceptable ester of the same
5. 5. A method for hormone replacement therapy (HRT), such a method involves administering to a patient in need of such therapy an effective amount of E-2- [4 - (4-chloro-1,2-di-f-emyl-but-1-enyl) phenoxy] ethanol or a pharmaceutically acceptable ester thereof.