HU198694B - Process for producing azol derivatives and pharmaceutical compositions containing them as active components - Google Patents

Description

The present invention relates to a process for the preparation and use of novel azole derivatives and pharmaceutical compositions containing them.

More particularly, the present invention relates to a process for the preparation of azole derivatives of formula I wherein

R ₁ and R 1 are phenyl or phenyl monosubstituted with halogen,

R 1 is C 1 -C 6 alkyl, C 1 -C 4 alkoxy, indolyl or indanyl, dano, benzyloxy or C 1 -C 4 alkoxy (C 1 -C 4 alkoxy) substituted with n = 1-5. C 4 -C 4 alkyl, phenyl monosubstituted with halo or dano, or biphenylyl monosubstituted with balogen atom, and

X is -CH = or -N and if

R ₃ is methyl, and R 1 and R 1 are phenyl, at least one of said phenyl groups being substituted.

Suitable substituents for the groups Rj, Rj are halogens, e.g. chlorine, bromine, iodine or fluorine, in particular fluorine or chlorine. When R 1 and R 1 are phenyl, monosubstitution is preferable at the p position.

ώ R _{3 is} C 1 -C 4 alkyl substituted with dano, benzyloxy or C 1 -C 4 alkoxy (C 1 -C 4 alkoxy) n - where n = 1-5.

Compounds of formula (I) in which the symbols, alone or in combination, have the following meanings are preferred:

Ri and _R2 ρ-fluoro, especially p-chlorophenyl group,

X is -CH =.

R ₃ is the preferred group listed above, in particular ρ-fluoro, ρ-chloro or p-danophenyl.

The compounds of formula (I) may be free compounds or acid addition salts thereof.

The free-form compounds of the present invention are prepared by acylation of compounds of formula (U). A. In the general formula (11), R ₁ , R 1 and X are as defined above. The compounds obtained after the addition are recovered in free form.

The addition is preferably carried out using compounds of the formula R ₃ COOH or a suitable reactive derivative thereof by a suitable method.

The process of the present invention may be carried out, for example, by reacting a compound of formula (11) with a suitable acid halide in a reaction inert solvent such as an organic or inorganic base. The basic solvent used, e.g. pyridine, at the same time serves as an antacid. Optionally, an adhesion accelerator, e.g. 4-Dimethylaminopyridine was added to the solution. For example, the compound of formula (II) may also be added to the active ester of an acid of formula R ₃ COOH. To facilitate the reaction, e.g. pyridyl-2-thiolester. The reaction is carried out in a solvent under reaction conditions, e.g. di-lower carboxylic acid amide, e.g. dimethylformamide at room temperature. In addition, the compound of formula (11) may be reacted with R ₃ COOH in the presence of N-hydroxybenzotnazole and didclohexylcarbodiimide.

The final product can be separated from the reaction mixture by known methods and purified if necessary.

Part of the starting compound of formula (II) is a novel compound and is prepared, e.g. according to the reaction scheme '[A].

The remainder of the starting compounds and the diluents are known compounds and can be prepared by known methods or by the methods described in the examples.

The following examples are intended to illustrate the present invention in more detail, but are not intended to limit the scope of the specification or the claims.

The temperatures in the examples in ° C are uncorrected. The yield is 85-95%.

Example 1

Preparation of 2,2-Bis (4-chlorophenyl) -2- (1H-imidazole-141) -1- (4-chlorobenzoylamino) ethane in 670 mg of 2,2-bis (4) in anhydrous pyridine -chlorophenyl) -2- (1H-imidazole-141) -1-aminoethane was treated dropwise with ice-cooling with 0.34 ml of 4-chlorobenzoyl chloride. After stirring at room temperature for 4 hours, the mixture was poured into cold saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium hydrogencarbonate solution and brine. It was then dried over magnesium sulfate and concentrated by evaporation. The resulting crystalline aphid was digested with ethyl acetate and diethyl ether. This gives a colorless crystalline solid, m.p. 241-244 ° C.

The starting material 2,2-bis (4-chlorophenyl) -2- (1H-imidazol-1-yl) -1-aminoethane can be prepared as follows:

a) 2,2-Bis (4-chlorophenyl) aziridine

Grignard solution containing 200 ml of anhydrous ether, 8.45 g of magnesium and 36 ml of bromobenzene was combined with 340 ml of anhydrous toluene and the ether was distilled until the internal temperature reached 107 ° C. 28.8 g of p-chloroaceto-phenonoxime dissolved in 100 ml of anhydrous toluene were then added dropwise to the boiling solution and the mixture was heated under reflux for 1.5 hours. The cd date was then mixed with 300 ml of 20% ammonium chloride solution under ice-cooling. After phase separation, the aqueous phase was extracted with food. The combined organic layers were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The resulting oily residue was chromatographed on silica gel (0.040-0.063 mm) with petroleum ether 60-80 ° C and diethyl ether / petroleum ether (3: 2 by volume). The resulting brown oily product was identified by NMR spectrometry.

b) 2,2-Bis (4-chlorophenyl) -2-1H-imidazole-141) -1-aminoethane

3.96 g 2,2-di- (4-chlorophenyl) aziridine were heated to 95 ^e C (melted) for 20 hours and 5.1 g of imidazole. The melt was taken up in ethyl acetate / water and the aqueous layer was extracted several times with ethyl acetate.

198,694 were funded. The organic base was washed with 0.25% solution of tartaric acid and saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The resulting residue, which contained the desired product and the 1,1-bis (4-chlorophenyl) -2- (1H-imidazole-141) -1-aminoethane isomer, was separated on silica gel (0.040-0.063 mm). 20: 1: 5 by volume dichloromethane, methanol and petroleum ether. This gave a viscous, light brown oil.

The following starting materials were obtained similarly:

Example 2 2,2-Bis-phenyl-2- (1H-imidazole-141) 4-aminoethane was obtained in a viscous, yellow, oily form.

Example 3: 2,2-Bis (4-chlorophenyl) -2- (1H-1,2,4-triazole-141) 4-aminoethane was obtained in the form of a viscous yellow-brown oil.

By following the procedure described in Example 1, the appropriate starting materials were synthesized in the following table.

Example X ^R 1 ^R 2 ^R 3 M.p. Second CH «Λ «Λ She l 193-197 Third N SHE • '/ *** i '158-162 4th CH ·. · ·. · ! 178-182 5th 6th CH CH oo · 131-136 220-224 7th CH f 144-146 8th CH «1 amorphous 9th CH * '· ·· * «Λ - amorphous 10th CH ⁹ hfmorph (racemate 11th CH · *. · - · 253-25É 12th CH ·. · ·. · 233-235 13th CH ·. · ... Ola 14th CH ·. · 'Ί' 219-22C 15th CH 218-222 16th CH · · · ; 229-232 17th CH ... w, 181-183

The compounds of the present invention exhibit therapeutic activity and are useful as medicaments.

These compounds primarily exhibit aromatase inhibitory activity, which is exemplified by the following examples.

_t Example 1

Investigation of aromatase inhibitory activity

Human placental microsomes were used as enzyme splicing. To recover the microsomes, the entire human placenta was cooled immediately after harvesting, excess blood was removed by washing with 0.25 M sucrose solution, then cut and homogenized under cooling (1 g organ ♦ 1.5 g KO / Jtris buffer, pH = 7.4, ultraturrax 3 x 10 t / O ^v C). Cells, nuclei, and mitochondria were partially disrupted by centrifugation at 200, 700, and 11000 g for 10 minutes, and after settling, the necrosoma fractions were recovered by centrifugation of the surface-floating postnitochondrial material for 105 minutes. The resulting pellet was washed once and then suspended in isotonic KQ / Tris buffer to give a Cyt P-450 solution of 0.5 to 1 mol. Determination of the aromatase effect by a known modified procedure (Thompson EA, Siiteri PK

(1974), J. Bioi. Chem. 249, 5364-5372) using 10,203H-androstenedione as the IQ substrate in the presence of a NADHP regeneration system. The test compounds were added at concentrations of 0.01 to 1 mol. After incubation for 30 d at 37 ° C, the reaction was quenched with a large amount of chloroform and the aqueous phase separated. The enzyme activity was determined by measuring radioactive ³ H2 O in the aqueous phase. ³ H2O is produced by the aromatization of 10.20 ³ H-androstenedione.

Subsequently, the active compounds which exhibited aromatase inhibition under these _9n assay conditions were assayed over a broad concentration range and then determined to be 1C _JO .

Example 2

2g Ovulation inhibition

Assay material was taken from normal monthly cycling females at 11 o'clock on the day before ovulation and at 16 o'clock on the day of ovulation. Ovulation was determined by counting the number of eggs in the smear ·

Example 3

Ovarian aromatase effect and in vivo test _for formation

Adult female rats were previously treated with 25 IU / day for 12 days. PMSG serum (pregnant horse gonadotropin serum), followed by

On day 13, the test compound was administered orally at a concentration of 0.032-10 mg / kg. The rats were then sacrificed at 8, 24, and 48 hours, and the blood vessels and ovaries were removed. Microsomes were obtained from one of the ovaries of each animal and the aromatase activity was determined as described above. Estradipl was recovered from the other chair of the chair and quantified by RIA, similar to blood estradiol determination.

Example 4

Chronic Side Effect Test Messenger

The test substance was administered once daily for 7 days to young 23-day-old female rats. 4-7. days, no injectable terone propionate was administered. On day 8, the animals were sacrificed, their blood and uterus removed, cleaned and weighed. Testosterone treatment resulted in a significant increase in ά uterine mass caused by the conversion of testosterone aromatase to estradiol II. This means that hpgr, the metraux inhibitory activity of the test substance (bee-31)

198,694 enlargements) accurately reflect the inhibition of estrogen production by aromatase after 7 days of treatment.

Example 5

Chronic effect study

Estrogen-dependent breast cancer was induced in rats by a single oral administration of 7,12-dimethylbenz / a / anthrazene (DMBA). Treatment with the test drug was started when the average tumor size reached about 1500 ml and continued for six weeks.

The active compounds of formula (1) were effective when administered once or twice daily in a concentration range of 1-10 mg / kg.

Aromatase plays an important role in mammalian estrogen synthesis.

Inhibition of this enzyme by specific inhibitors drastically reduces normal steroid levels. Such non-invasive chemical reduction of steroid levels seems to be more desirable compared to surgical removal of hormone-forming organs (prostate, uterus, adrenal glands) and steroid-dependent tumors, e.g. a good complementary treatment of prostate, polydastic uterine syndrome, breast cancer, ovary, uterine mucosa, and Cushing's syndrome.

Accordingly, the active compounds of formula (I) can be used spedically as steroid synthesis inhibitors in the treatment of the tumors listed above.

As described above, an amount of 10-100 mg of the active ingredient of the formula I should be administered daily, e.g. can be done in four installments per day.

The administration of the active compounds of formula (I) may be carried out by any conventional method, in particular by the intestine, preferably orally, e.g. in tablet or capsule form; in the form of a solution or suspension for injection.

The active compounds of formula (I) may be used in the form of the free base or of a pharmaceutically acceptable acid addition salt thereof, which may be prepared by any conventional method and having the same activity as the free base active ingredient. The present invention also relates to the preparation of pharmaceutical compositions containing the active compounds of formula (I). The composition comprises at least one pharmaceutically acceptable carrier or diluent. These composites can be prepared in any conventional manner. The unit dose contains 2.5-50 mg of the active ingredient of the formula (1).

The present invention further relates to the preparation of the compounds of formula (I) as an aromatase.

Claims (3)

PATENT CLAIMS A process for the preparation of a compound of formula (I): wherein: R, and R ₂ is phenyl or phenyl monosubstituted with halo, R ₃ is substituted with C 1-6 alkyl, C 1-4 alkoxy, indolyl or indanyl, cyano, benzyloxy or C 1-4 alkoxy (C 1-4) n - n 1-5 - C 1-4 alkyl, phenyl monosubstituted with halo or dano, or biphenylyl monosubstituted with halogen, and X is = CH- or N, and when R 1 is methyl, and R 1 and R ₂ are phenyl, at least one of said phenyl groups is replaced by a compound of formula 11 wherein R ₁ , R ₂ and X are the same as defined above with a compound of the formula R ₃ COOH - R ₃ as above - or a reactive derivative thereof, and the resulting compound is recovered. Process for the preparation of a compound of formula (I) according to claim 1, wherein X = CH-, R 1, R ₂ and R ₃ 4 -chlorophenyl, characterized in that 2,2-bis (4- chlorophenyl) -2- (1H-imidazole-141) -1-aminoethane is acylated with 4-chlorobenzoyl chloride and the resulting compound is isolated. 3. A process for the preparation of a pharmaceutical composition comprising an active ingredient of the formula I, R ₁ , R ₂ , R _3, and X, characterized in that the active ingredient obtained by the process according to claim 1 or 2 is processed into a pharmaceutical composition with a pharmaceutically acceptable diluent or carrier. pc drawing