JPS63145270A - Azole derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel azole derivative, a method for producing the same, a pharmaceutical preparation containing the same, or a use thereof.

[Description of the Invention] To be more specific, the present invention provides formula (1) [wherein R5
and R3 are the same or different, each unsubstituted or mono- or polysubstituted aryl or heteroaryl, R3 is unsubstituted or mono- or polysubstituted alkyl, cycloalkyl, aryl or heteroaryl,
or cycloalkyl, aryl or heteroaryl, or alkoxy fused to a benzene ring; X represents C)l or N;

However, when R3 is methyl and R1 and R3 are phenyl, at least one of the above phenyls is substituted.

In the above formula, R1, R7 and R3 may be present as aryl, in particular phenyl or naphthyl, especially phenyl; as heteroaryl, 5-6 ring atoms and one or more heteroatoms; sulfur or nitrogen atoms.

Non-fused heteroaryl is for example chenyl or pyridyl. Examples of fused groups are indolyl (e.g. indole-
2-yl or indol-3-yl).

Suitable substituents on R3 or R, specifically include chlorine,
It can be a halogen such as bromine, iodine or fluorine, especially fluorine or chlorine. Monosubstitution is preferred, especially the p-position when R1 and R2 are phenyl.

Substituents on the aryl or heteroaryl group as R1 are, for example, nitro or cyano, or lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl or lower alkoxy, each optionally containing halogen or Phenyl or phenoxy, which may be substituted with phenyl or optionally substituted. Examples of such substituents are Ct-4 alkyl, especially methyl, halogen or phenyl.

Preferred substituents on R3 are halogen atoms, such as fluorine or chlorine, or cyano.

Cycloalkyl fused with benzene, R3, preferably has 5-7 carbon atoms and can be unsubstituted, for example indanyl, especially indan-2-yl.

R3, which is alkyl, preferably has 1 to 4 carbon atoms and may be substituted with cyano, alkoxy, benzyloxy or polyether (eg alkoxy (mono, di or triethyleneoxy)).

R8, which is alkoxy, may have 1-4 carbon atoms.

Preferably, the lower alkyl moiety present as a substituent or contained in a substituent has 1 to 4 carbon atoms. Preferably, the lower alkenyl or alkynyl moiety has 2-4 carbon atoms.

In formula (I), the following symbol definitions are suitable as a single group or a combination.

R5 and R3 are pp- or especially p-Cρ-phenyl.

X is CH.

R3 has the preferred meanings given above, in particular p-F, p-C
l or poly-0N-phenyl.

Specific compounds of formula (1) include the above R1, R2 and
and R3 is unsubstituted or mono- or polysubstituted alkyl, aryl or heteroaryl.

The compound of formula (1) can exist both in free form and in acid addition salt form.

According to the invention, the free form or acid addition salt form of the compound of formula (1) can be obtained by acylating a compound of formula (II) The compound may be prepared by a process consisting of taking the compound in free form or in acid addition salt form.

Acylation is carried out using carboxylic acid R3-C0OH or a reactive derivative thereof in a conventional manner.

The process of the invention comprises, for example, combining the compound of (n) and the corresponding acid halide in a solvent that is inert under the reaction conditions, such as an organic or inorganic base such as pyridine, which at the same time also acts as an acid binding agent. ) in which an acylation accelerator such as 4-dimethylaminopyridine is optionally added. In the acylation, the compounds of formula (II) can be reacted, for example, with active esters of the acid R, COOH. The reaction is carried out, for example, with a pyridyl-2-thioester in a solvent that is inert under the reaction conditions, such as a di-lower alkylcarboxylic acid amide (eg dimethylformamide) at room temperature. Furthermore, the compound of formula (II) is R,C0
It can be reacted with OH to form N-hydroxybenzotriazole and dicyclohexanelupodiimide.

The final product is separated from the reaction mixture in a known manner,
Purified as needed.

Some of the starting materials of formula (II) are new and can be prepared, for example, according to the reaction scheme below.

R,-Co-CL+NH,0II-11cI!
->->R, -C-C11, + 2R, Mg1lal
-1 → l N0I (Other starting materials and untying agents are known or
Alternatively, it can be manufactured in the same manner as a known method, or in the same manner as in the methods described in Examples.

This invention will be explained in more detail with reference to the following examples, but these are not intended to limit the invention. Temperatures are uncorrected in degrees Celsius.

Example 1 2.2-bis-(4-chlorophenyl)-2-(II(
-imidazol-1-yl)-1-(4-chlorobenzoylamino)ethane.

4-chlorobenzoyl chloride 0.34rtt (l,
Under water cooling, 2.2-bis-(4-chlorophenyl)-2-
Add dropwise to 670 mg of (1H-imidazol-1-yl)-1-aminoethane and 4 mQ of dry pyridine.

The mixture is stirred at room temperature for 4 hours. Pour into cold saturated sodium bicarbonate solution and extract with ethyl acetate.

Combine the a-bars, wash with saturated sodium bicarbonate solution and sodium chloride solution, dry over magnesium sulfate, and concentrate. The residue crystallizes upon digestion with ethyl acetate and diethyl ether. Colorless crystal (mp241-2
44°C) is obtained.

2.2-bis-(4-chlorophenyl)-2-(1)
-imidazol-1-yl)-1-aminoethane (starting material) is obtained as follows.

a) 2,2-bis-(4-chlorophenyl)aziridine.

Magnesium 8.459, Bromobenzene 361111
A Grignard reagent solution consisting of 2 and 200M12 of anhydrous ether is mixed with 300M12 of dry toluene and the ether is distilled off until the internal temperature reaches 107°C. 28.8y of p-chloroacetophenone oxime and 10y of dry toluene
0xf2 is added dropwise to the boiling solution and the mixture is refluxed for 1.5 hours, then mixed with 20% ammonium chloride 300 sigma under water cooling. After phase separation, the aqueous layer is extracted with ether. The organic layers are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The oily residue was purified on silica gel (0,040-0,063yx) with petroleum ether (6
0-80°C) and diethyl ether/petroleum ether (3/2). The obtained brown oil is confirmed by NMR spectrum.

'HNMR(CDC(!3):2.36(21-I,s
, Broad, cHJ, 7.20-7.5'5
(8H.

m, aromatic) b) 2,2-bis-(4-chlorophenyl)-2-
(IFl-imidazol-1-yl)-1-aminoethane.

2.2-di(4-chlorophenyl)aziridine 3.9
69 is heated (melted) to 95° C. with 5.1 g of imidazole for 20 hours. The melt is treated with ethyl acetate/water and the aqueous layer is extracted several times with ethyl acetate. The organic layer is washed with 0.25% tartaric acid solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is a positional isomer 1 along with the target substance.

Since it contains l-bis-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-1-aminoethane,
Silica gel (0,040-0,063 order) and dichloromethane/methanol/petroleum ether (2G/I/
5) to chromatography. A viscous yellow-brown oil is obtained.

'H-NMR (CDC(!+): 1.04 (2H, broad.

-NHy), 3.90(2I(,s, CHt), 6
゜9-7.5 (6H, m, aromatic, imidazole), 7
．． 68 (1H, imidazole) The following starting materials are obtained in the same manner.

2.2-bis-phenyl-2(1summer)-imidazole-
■-yl)-1-aminoethane (raw material of Example 2). Viscous yellow oil.

2.2-bis-(4-chlorophenyl)-2-(+rt
-imidazol-1-yl)-1-aminoethane (raw material of Example 3). Viscous yellow-brown oil.

'H-NMR (CDC123): 1.75 (2H,s,
Broad, NHz), 3.93 (2I-(,s,-
CHJ, 6.9-7.5 (8H, m, aromatic), 7.8
8(1H,s,)riazole), 8.10(th(,triazole)) Compounds represented by the following formula (1) can be obtained in the same manner as in Example 1 from appropriate starting materials.

The compound of formula (1) has pharmacological activity and is therefore useful as a medicine.

In particular, these compounds have aromatase inhibitory activity in the tests described below.

l, in vivo aromatase inhibition Human placental microsomes were used as the enzyme source.

For the production of microsomes, whole human placentas were collected in the laboratory under cooling immediately after expulsion. Excess blood was removed by thorough washing with 0.25M sucrose solution. Then, the placenta was sectioned and immediately homogenized under cooling (organ!9+KCl1
, 59/Tris buffer, pH 7.

4゜Ultraflux 3X10 seconds 10°C). After sedimentation of partially disrupted underlying cells, cell nuclei and mitochondria for 10 minutes at 200.7000 and 11.0009, respectively, microsomal fractionation was carried out at 10500.
The supernatant was obtained by centrifugation after mitochondria at 0 g/60 min.

The pellet was then washed once and suspended in isotonic KCl/Tris buffer with Cyt-P-45 (once added to 0.5-1 μM Ninal, 1:1).

Aromatase activity was measured using a modified known method [Totus, Seeteri (1974), Journal of Biological Chemistry (J, Biol.

Chem, Vol. 249, pp. 5364-5372], using 1β,2β-3H-androstenedione as a substrate in the presence of an NADPH regeneration system.

The test compound was 0. Added at a concentration of OI and lμM. 3
After incubation at 7°C for 30 minutes, the reaction was terminated with a large excess of chloroform, and the aqueous and organic layers were separated. The radioactivity in the aqueous layer was attributed to 3H,O produced by aromatization of lβ, 2β-3H-androstenedione to estrone, and was therefore used as a measure of enzyme activity. Compounds that strongly inhibit aromatization under the test conditions were tested over a wide range of concentrations for IC5o determination.

2. Ovulation suppression: 6 normal cycles for female rats, 16 days on the day of ovulation.
The test substance was administered at 00:00 and at 11:00 on the day of ovulation. Ovulation was measured by counting eggs in vaginal smears.

3. Effects on ovarian aromatase and in vivo E2 production Adult female rats were pretreated with PMSG (pregnant hen serum gonadotropin) subcutaneously at 251'U/day for 12 days, and on day 133 the test substance was administered at 0.032-l Oxg/day. k
It was administered orally at a concentration of g. 8. After 24 and 48 hours the rats were sacrificed and blood and ovaries were taken. 1 per animal
Microsomes were made from individual ovaries and aromatizing activity was measured as described above.

Estradiol was extracted from the second ovary and quantified by RIA. Estradiol was also measured from blood.

4. In vivo subchronic effect The test substance was administered to young 23-day-old female rats once a day for 7 days. On days 4 and 7, additional subcutaneous injections of testosterone propionate were given.

On the 8th day, the animals were sacrificed, blood was collected, and the uterus was removed, washed, and weighed. Administration of testosterone significantly increased uterine weight, which was due to aromatization of testosterone to estradiol. Thus, the inhibition of metro (uterine hypertrophy) by the test substance is an accurate measure of the inhibition of estrogen production by aromatization during the 7-day treatment.

5. Chronic effect Estrogen-dependent breast tumors were induced in rats by the same oral administration of 7,12-dimethylbenz[a]anthracene (DMBA). 1 Iffi tumor has an average size of 1500
Administration of test substance was started when mm3 was reached and continued for 6 weeks.

The compound of formula (1) is about 11/kg to about 10I19/k
It showed this activity when administered orally once or twice a day.

Aromatase plays an important role in the synthesis of estrogen production in mammals.

Blocking this enzyme action by specific inhibitors results in a dramatic reduction in normal steroid concentrations. This non-invasive chemical reduction in steroid levels, unlike surgical removal of hormone-producing organs (prostate, ovaries, adrenal glands), can be used to treat steroid-dependent tumors, such as prostate tumors, polycystic ovarian syndrome, breast cancer, etc. It is a promising alternative or adjunct therapy for ovarian cancer, endometrial cancer, and Cushing syndrome.

The compounds of formula (1) are therefore indicated as specific inhibitors of steroid synthesis in the treatment of tumors as described above.

Suitable indicated daily doses range from about 10+y to about 100iy of a compound of formula (I), given in divided doses, eg, up to 4 times a day.

The compound of formula (1) can be administered in the form of tablets or capsules by any known route, in particular by the enteral, preferably oral route.
Or it can be administered parenterally, for example in the form of an injectable solution or suspension.

The compound of Example 1 is a preferred compound for aromatase inhibition. For example, this compound showed an ID5° value of <0.032 H/kg in Test 3 above, whereas aminoglutethimide was >56y+9/kg. Therefore, for aromatase inhibition, the compound of Example 1 should be administered to large mammals, e.g. humans, at lower frequencies (e.g. lO - 100
x9/day) and can be used using the same administration method.

Compounds of formula (1) can be administered in free base form or in pharmaceutically acceptable acid addition salt form. Such salts are prepared by conventional methods and exhibit activity on the same order of magnitude as the free base. This invention also provides pharmaceutical compositions comprising a free base form or a pharmaceutically acceptable acid addition salt form of a compound of formula (I) in admixture with one or more pharmaceutical carriers or diluents.

Such compositions are manufactured by conventional methods. A unit dosage form contains, for example, about 2.5 to about 50 mg of a compound of formula (I) in free base form or in pharmaceutically acceptable acid addition salt form.

The invention also features the use of the free base form or pharmaceutically acceptable acid addition salt form of a compound of formula (1) in the manufacture of a medicament, in particular an aromatase inhibitor, and their use in the manufacture of a medicament for the inhibition of aromatase. to be

Claims (11)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 and R_2 are the same or different,
each unsubstituted or mono- or polysubstituted aryl or heteroaryl, R_3 is unsubstituted or mono- or polysubstituted alkyl, cycloalkyl, aryl or heteroaryl, or cycloalkyl, aryl or heteroaryl fused to a benzene ring; or alkoxy; X represents CH or N; However, when R_3 is methyl and R_1 and R_2 are phenyl, at least one of the above phenyls shall be substituted.] A free form or acid addition salt form of an azole derivative represented by the following. (2) R_1 and R_2 are the same or different and optionally monosubstituted phenyl, and R_3 is optionally cyano, C_1_-_4 alkoxy, benzyloxy or C_1_-_4 alkoxy (
C_1_-_4 alkyl optionally substituted with mono-, di- or tri)ethyleneoxy, C_1_-_4 alkyl, optionally substituted phenyl, C_5_-_7 optionally fused with a benzene ring
Compounds according to claim 1, which are cycloalkyl or 5- or 6-membered heterocycles having one or more sulfur or nitrogen atoms as heteroatoms and optionally fused with a benzene ring. (3) R_1 and R_2 are p-Cl- or p-F-
3. The compound according to claim 1 or 2, which is phenyl. (4) R_3 is p-Cl-, p-F- or p-CN-
Any one of claims 1 to 3, which is phenyl
Compounds described in Section. (5) 2,2-bis-(4-chlorophenyl)-2-(
1H-imidazol-1-yl)-1-(4-chlorobenzoylamino)ethane. (6) The compound according to claim 1, wherein R_3 is unsubstituted or mono- or polysubstituted alkyl, aryl or heteroaryl. (7) Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) Acylation of the compound represented by [in the formula, R_1, R_2 and A process for producing a compound according to claim 1, which comprises harvesting it in acid addition salt form. (8) A free form or a pharmaceutically acceptable acid addition salt form of the compound of formula (I) according to claim 1, which is used as a medicine. (9) It is used as an aromatase inhibitor,
A compound of formula (I) according to claim 1 in free form or in pharmaceutically acceptable acid addition salt form. (10) Free form or pharmaceutically acceptable acid addition salt form of the compound of formula (I) according to claim 1 in the manufacture of a medicament for inhibiting aromatase. (11) A pharmaceutical composition comprising a compound of formula (I) according to claim 1 in free form or in a pharmaceutically acceptable acid addition salt form together with a pharmaceutically acceptable diluent or carrier. .