NL8702897A - AZOLIC DERIVATIVES AND METHODS FOR PREPARING AND USING THESE DERIVATIVES. - Google Patents

Description

Az, Azole derivatives and methods for the preparation and use of these derivatives.

The invention relates to new azole derivatives and to methods of preparing these derivatives, pharmaceutical preparations containing them and to their use.

More particularly, the invention relates to azole derivatives of formula 1, wherein

R 1 and R 1, which may or may not be the same, each represent an unsubstituted or mono- or poly-substituted aryl group or heteroaryl group, an unsubstituted or mono- or poly-substituted alkyl group, cycloalkyl group, aryl group or heteroaryl group, or cycloal- kyl group, aryl group or heteroaryl group condensed with a benzene ring, or representing an alkoxy group and X - CH or N, where, when R 1 represents the methyl group and R 1 and R 1 represent a phenyl group, at least one of these phenyl groups is substituted must be.

In the aforementioned formula, R ^, R ^ and R ^ as aryl, in particular the phenyl or naphthyl group, in particular the phenyl group, containing as heteroaryl preferably 5 or 6 ring atoms and as hetero atoms one or more sulfur or nitrogen atoms. Non-20 condensed heteroaryl is, for example, thienyl or pyridyl. Examples of condensed groups are indolyl (e.g. indol-2-yl or indol-3-yl).

Suitable substituents on R 1 and R 1 are in particular halogen atoms, such as chlorine, bromine, iodine or fluorine, in particular fluorine or chlorine. Mono substitution is recommended, especially at the p position, when R 1 and R 1 represent phenyl.

Substituents on aryl or heteroaryl groups such as R 4 are, for example, halogen, nitro or cyano, or lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl.

Or lower alkoxy, each optionally substituted by halogen or phenyl, or optionally substituted phenyl or phenoxy. Particular examples of such substituents are alkyl of 1-4 carbon atoms, in particular methyl, halogen or phenyl.

Recommended substituents on R 2 are halogen atoms, such as, for example, fluorine or chlorine, or cyano.

R 4 as cycloalkyl condensed with benzene preferably contains 5 to 7 carbon atoms and is unsubstituted, for example inda-8702857-2-nyl, especially indan-2-yl.

R @ 1 as alkyl preferably contains 1-4 carbon atoms and may be substituted by cyano, alkoxy, benzyloxy or polyether (for example, alkoxy (mono-, di- or triethyleneoxy). · It is recommended that as alkoxy 1-4 carbon atoms.

Lower alkyl groups which exist as substituents or are present in substituents preferably contain 1-4 carbon atoms. Low alkenyl or alkynyl groups preferably have 2-4 carbon atoms.

The following meanings for the symbols in Formula 1 are recommended, both alone and in combination: and R 1 are p-F, especially p-Cl-phenyl.

X = CH.

15 R3 has the above-mentioned recommended meanings and in particular is p-F *. p-Cl »or p-CN-phenyl.

In a particular group of compounds of formula 1, R, R and X have the previously defined meanings and R as unsubstituted 1 6 -substituted or mono- or poly-substituted alkyl, aryl or hetero-20 aryl groups.

The compounds of formula 1 can exist both in free form and in the form of acid addition salts.

The compounds of formula 1, in free form or in the form of an acid addition salt, can be obtained according to the invention by acylating a compound of formula 2, in which R 1, R 2 and X have the previously defined meanings and thus recovered compound in free form or in the form of an acid addition salt.

The acylation is preferably carried out in a conventional manner using a carboxylic acid R 2 COOH or a reactive derivative thereof.

The process according to the invention can be carried out, for example, by reacting a compound of formula 2 in a solvent which is inert under the reaction conditions, for example in an organic or inorganic base, which simultaneously functions as an acid binding agent, such as pyridine. with a corresponding acid halide, optionally with the addition of an acylation accelerator, such as 4-dimethylaminopyridine. For acylation, one can use 8702897

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& - 3 - bond of formula 2 also react with an active ester, for example of the acid R 2 COOH. The reaction can be carried out, for example, with a pyridyl-2-thiol ester, in a solvent that is inert under the reaction conditions, for example in a lower alkyl-5-carboxylic acid amide, such as dimethylformamide, at room temperature. In addition, the compound of formula 2 in the presence of N-hydroxybenzotriazole and dicyclohexylcarbodiimide can react with R 1 COOH.

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

Starting materials of the formula II are partly new and can be obtained, for example, according to the reaction scheme A shown on the formula sheet.

The other starting materials, as well as acylating agents, are known or can be obtained analogous to known methods or analogous to the methods described in the examples.

The temperatures given in degrees Celsius in the following examples are uncorrected.

Example I; 2,2-Bis- (4-chlorophenyl) -2- (1H-imidazol-1-yl) -1- (4-chlorobenzoylamino) etphane.

0.34 ml of 4-chlorobenzoyl chloride was added dropwise to 670 mg of 2,2-bis- (4-chlorophenyl) -2- (1H-imidazol-1-yl) -1-aminoethane in 4 ml while cooling with ice. dry pyridine. This mixture was stirred at room temperature for 4 hours. It was then poured onto a cold, saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium hydrogen carbonate solution and sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The residue crystallizes out by treatment with ethyl acetate and diethyl ether. Colorless crystals with a melting point of 241-244 ° C were obtained.

The 2,2-bis- (4-chlorophenyl) -2- (1H-imidazol-1-yl) -1-aminoethane used as starting material can be obtained as follows: a) 2,2-Bis- (4-chlorophenyl) aziridine.

A Grignard solution, consisting of 8.45 g of magnesium and 36 ml of bromobenzene in 200 ml of absolute ether, was mixed with 300 ml of dry toluene and the ether was distilled off until the internal temperature was 8702897.

- 4 - * temperature had risen to 107 ° C. Thereafter, 28.8 g of p-chloroacetofe-nonoxime in 100 ml of dry benzene was added dropwise to the boiling solution, the mixture was refluxed for 1.5 hours and then mixed with 300 ml of a 20% strength under ice-cooling. ammonium chloride solution. After phase separation, the aqueous phase was extracted with ether.

The combined organic phases were washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The oily residue was chromatographed on silica gel (0.040 - 0.06 3 mm) with petroleum ether 60-80 ° and a mixture of diethyl ether and petroleum ether (3/2). The brown oil thus obtained was characterized by the NMR spectrum.

1 H-NMR (CDCl 3): 2.36 (2H, s, broad, -CH 2); 7.20-7.55 (8H, m, aromatics).

b) 2,2-bis- (4-chlorophenyl) -2-1H-imidazol-1-yl) -1-aminoethane.

3.96 g of 2,2-di- (4-chlorophenyl) aziridine were heated with 5.1 g of imidazole at 95 ° C (melt) for 20 hours. The melt was taken up in a mixture of ethyl acetate and water and the aqueous phase was extracted several times with ethyl acetate. The organic phases were washed with a 0.25% tartaric acid solution and a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue, which also contained as the desired product, also the delivery isomer 1,1-bis- (4-chlorophenyl) -2- (1H-imidazol-1-yl) -1-aminoethane, was passed over silica gel (0.040- 0.063 mm) separated with a mixture of dichloromethane, methanol and petroleum ether (20: 1: 5). A viscous, yellow-brown oil was thus obtained.

1 H NMR (CDCl 3): 1.40 (2H, broad, -NH 2); 3.90 (2H, s, -CH2); 6.9-7.5 (6H, m, aromatic, imidazole); 7.68 (1H, imidazole).

The following starting materials can be obtained in an analogous manner: 2,2-bis-phenyl-2 (1H-imidazol-1-yl) -1-aminoethane (for example II), obtained as a viscous, yellowish oil, and 2 2-bis- (4-chlorophenyl) -2- (1H-1,2,4-triazol-1-yl) -1-35 aminoethane (for example III) obtained as a viscous yellow-brown oil.

H-NMR (CDCl 3); 1.75 (2H, s, broad, -NH2); 3.93 (2H, s, 8702897 y - 5 - CH2; 6.9-7.5 (8H, m, aromatics); 7.88 (1H, s, triazole); 8.10 (1H, s, triazole).

The following compounds of formula 1 can be obtained analogously to example I from suitable starting materials.

.8702897 4 * / - 6 -

X Rj R2 R3 mp ° C

II CH C6H5 C6H5 -Q-C1 193-197 «III N -O -Ö Cl 158-162 ° IV CH -CH3 178-182 ° I v CH -iC (CH3) 3 131-136 ° I vi CH - £ ^ -Cl-Cl 220-224 ° I VII CH 144-146 ° 1 CH 1Tn19) amorphous

H

IX CH 0C2H5 amorphous X CH CH (CH3) -0-CH2 - ^^ amorphous (racemate) XI CH Λν jö] 253-256 ° Η xii CH © CN 233-235 ° XIII CH CH2 (0-CH2-CH2) 30CH3 oil XIV 'CH CH2-CN 219-220 ° XV CH l · ® * l · ® * l · ® * 218-220 ° xvi CH - ^^ - Cl 229-232 ° XVII CH CH3 181-183 ° _______. 8702897 * * - 7 -

The compounds of formula 1 exhibit a pharmacological action and are therefore indicated for use as pharmaceuticals.

In particular, the compounds show an aromatase inhibitory activity in the following experiments.

5 1 * In vitro aromatase inhibition.

Human placenta microsomes were used as an enzyme source. To prepare these microsomes, whole human placenta were brought to the laboratory immediately after removal under cooling, excess blood was removed by intensive rinsing with 0.25 M 10 sucrose, the placenta were shredded and immediately homogenized under cooling (1 g organ + 1.5 g KCl / tris buffer, pH 7.4; ultraturrax 3 x 10 s / 0 ° C). After sedimentation of the partially degraded cells, nuclei and mitochondria at 200, 7000 and 11000 g, each for 10 minutes, the microsome fraction was obtained by centrifugation of the postmitochondrial supernatant at 105,000 g / 60 min. Each sample washed once was then suspended in an isotonic KCl / tris buffer to a Cyt P-450 concentration of 0.5-1 µm.

The aromatase activity assay was performed according to a modified known method (Thompson E.A., Siiteri P.K.

/ 1974 /, J. Biol. Chem. 249, 5364-5372) using 1p, 3-26 H androstenedione as the substrate in the presence of a NADPH regenerating system. The compounds to be tested were added in concentrations of 0.01 and 1 µM. After incubation at 37 ° C for 30 minutes, the reaction was terminated by mixing a large excess of chloroform and the aqueous and organic phases were separated. The radioactivity of the water phase is attributable to HO, which is formed in the aromatization of 16, 26 H-androstenedione to estrone and is used as a measure of the enzymatic activity.

Compounds that significantly inhibit aromatase under these test conditions were then tested over a wide range of concentrations to determine the ICg values.

2. Inhibition of ovulation.

Female rats with regular cycles received the compound to be tested at 1600 hours the day before ovulation and 1100 hours the day of ovulation. Ovulation was assessed by counting the eggs in a vagina smear.

, 8702397 - 8 - 3. Influence on ovarian aromatase and E2 production in vivo.

Adult female rats were pretreated with 25 IU / day s.c. for 12 days. PMSG (pregnant mare serum gonadotrophin),

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after which, on the 13th day, the compound to be tested was administered orally at a concentration of 0.032-10 mg / kg. The rats were then sacrificed 8, 24 and 48 hours later and the blood and ovaries were removed. Microsomes were prepared from one ovary per animal and the aromatase activity was determined as described above. Estradiol was extracted from the second ovary, the amount of which was determined by RIA, similarly the estradiol from the blood.

4. Sub-chronic effects in vivo.

The test compound was administered to juvenile 23-day-old female rats once daily for 7 days. In addition, subcutaneous testosterone propionate was injected on the 4 to 7 days. On the 8th day, animals were sacrificed, blood was collected and the uteri were removed, cleaned and weighed. The administration of testosterone leads to a significant increase in the weight of the uterus caused by the change of testosterone by aromatase to estradiol. Thus, the inhibition of metrauxe (uterine hypertrophy) by a test compound is an accurate measure of the inhibition of estrogen production by aromatase during the seven day treatment.

5. Chronic effects.

Estrogen dependent breast tumors were induced in rats by a single oral administration of 7,12-dimethylbenz / a-anthrazene (DMBA). Treatment of the compounds to be tested was started when the tumors reached a mean size of about 1500 mm and this treatment was continued for up to six weeks.

The compounds of formula 1 exert this activity at p.o. concentrations from about 1 mg / kg to about 10 mg / kg, once or twice daily.

Aromatase plays an important role in the biosynthesis of mammalian estrogens.

Blocking this enzyme by specific inhibitors can produce a drastic reduction in normal steroid levels.

Such a non-invasive chemical reduction in steroid levels, in contrast to the surgical removal of hormone-producing organs (prostate, ovary, adrenal glands), appears to be a desirable alternative and adjunct in the treatment of steroid-dependent tumors, for example, of the prostate , polykystic ovarian syndrome, breast carcinomas, ovaries, endometrium, as well as Cushing's syndrome.

The compounds of formula 1 are therefore indicated for use as specific inhibitors of steroid synthesis, for the treatment of tumors, as mentioned above.

An indicated, suitable, daily dose is between about 10 mg to about 100 mg of a compound of formula 1, for example, suitably administered in divided doses up to four times daily.

The compounds of formula 1 can be administered by any suitable route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.

The compounds of formula 1 can be administered both in free base form and in the form of a pharmaceutically acceptable acid addition salt. Such salts can be prepared in a conventional manner and exhibit the same degree of activity as the free bases.

The present invention also provides pharmaceutical compositions containing one or more compounds of formula 1, in free base form and / or in the form of a pharmaceutically acceptable acid addition salt, optionally together with at least one pharmaceutical carrier or diluent. Such preparations can be prepared or manufactured in a conventional manner. Unit dosage forms contain, for example, about 2.5 mg to about 50 mg of a compound of formula 1, in the form of the free base or a pharmaceutically acceptable acid addition salt.

The invention also relates to compounds of formula 1 in free form or in the form of a pharmaceutically acceptable acid addition salt for use as pharmaceuticals, in particular as aromatase inhibitors and to the use of compounds of formula 1 in free form or in the form of a pharmaceutically acceptable acid addition salt for the preparation or manufacture of a medicament, 8702887 - 10 - for inhibiting aromatase.

". 87 02 887

Claims (13)

Azole derivatives of formula 1, wherein R 1 and R 2 which may or may not be the same, each represent an unsubstituted or mono- or poly-substituted aryl group or heteroaryl group, R 1 represents an unsubstituted or mono- or poly-substituted alkyl group, cycloalkyl group, aryl group or heteroaryl group, or cycloalkyl group, aryl group or heteroaryl group condensed with a benzene ring, or alkoxy group, and where X = CH or N, where, if R represents the methyl group and represents R 1 and R 1 phenyl, at least one of these phenyl groups must be substituted, in free form or in the form of an acid addition salt. 2. Compounds according to claim 1, wherein R 1 and which may or may not be the same, each represents an optionally monosubstituted phenyl group, R 1 optionally by cyano, alkoxy of 1-4 carbon atoms, benzyloxy or C 1-4 alkoxy - (mono-, di- or tri-) ethyleneoxy substituted alkyl group of 1-4 carbon atoms, alkyl group of 1-4 carbon atoms, an optionally substituted phenyl group, a cycloalkyl group of 5-7 carbon atoms, optionally with a benzyl ring or a heterocyclic ring with 5 or 6 atoms in the ring, with one or more sulfur or nitrogen atoms as hetero atoms and optionally condensed with a benzene ring, represents 3. A compound according to claim 1 or 2, characterized in that R 1 and R 2 represents a P-c - ~ f p-F-phenyl group. A compound according to any one of claims 1 to 3, characterized in that R 1 represents p-Cl, p-F or p-CN phenyl. 5.2-Bis-(4-chlorophenyl) -2- (1H-imidazol-1-yl) -1- (4-chlorobenzoylamino) ethane. A compound according to claim 1, characterized in that R 1 represents an unsubstituted or mono- or poly-substituted alkyl group, aryl group or heteroaryl group. Process for preparing a heterocyclic compound, characterized in that a compound of formula 1 as defined in claim 1 is prepared by a compound of formula 2, wherein R 1, R 1 and X have the previously defined meanings 870289) - 12 - s * acylation and recovering the compound thus obtained in free form or in the form of an acid addition salt. A compound according to claim 1 as defined in claim 1, in free form or in the form of a pharmaceutically acceptable acid addition salt, for use as a pharmaceutical. A compound according to claim 1 as defined in claim 1 in free form or in the form of a pharmaceutically acceptable acid addition salt, for use as an aromatase inhibitor. 10. A method of using a compound of Formula 1 as defined in claim 1, in free form or in a pharmaceutically acceptable acid addition salt form, for the preparation or manufacture of a medicament for aromatase inhibition. 11. A pharmaceutical composition comprising one or more compounds of formula 1, as defined in claim 1, in free form and / or in the form of a pharmaceutically acceptable acid addition salt, optionally with a pharmaceutically acceptable diluent and / or carrier, contains. 12. Compounds and methods as described in the description and / or examples. Molded therapeutic preparations according to any one of the preceding claims. 9 8 8 /