WO1994007866A1 - Aromatase inhibitor - Google Patents

Abstract

A benzocycloalcane compound represented by general formula (I), wherein R represents hydrogen, C1-C4 lower alkoxy, nitro or C1-C4 lower alkoxycarbonyle; when X and Y represent each hydrogen or X and Y are combined together to represent oxygen, then Z represents hydrogen and the broken line represents an arbitrary bond; when X represents H, then Y and Z are combined together to represent a single bond; and n represents an integer of 0 or 1. This compound has a potent, selective aromatase-inhibiting effect and is useful as a remedy for estrogen-dependent cancers, such as breast, uterine or ovarian cancer, prostatomegaly, gynecomastia and endometriosis.

Description

 Description Aromatase inhibitor Technical field

 The present invention relates to benzocycloalkane compounds. More specifically, the present invention relates to a benzocycloalpine compound having an aromatase inhibitory action. Background art

 Aromatase is a cytochrome P-450 enzyme located at the end of a series of steroid hormone biosynthesis systems that begins with the cleavage of cholesterol side chains, and produces estrogens using androgens as substrates. Therefore, aromatase drugs inhibit estrogen biosynthesis and are used for the treatment of estrogen-dependent cancers such as breast cancer, uterine cancer or ovarian cancer, prostatic hypertrophy, feminization of males, and breast and endometriosis. can do.

 Aminoglutethimide (hereinafter referred to as “AG”) is known as an aromatase inhibitor and has already been used for the treatment of breast cancer. However, AG also inhibits desmolase (a cholesterol side-chain cleavage enzyme), which suppresses adrenal steroid production, and cannot be avoided in combination with corticosteroids.

 Therefore, an object of the present invention is to provide a compound which is potent and has a selective aromatase inhibitory action which does not have a desmolase inhibitory activity. Disclosure of the invention

According to the present invention, a benzocycloalkane compound represented by the following general formula (Hereinafter referred to as “the compound of the present invention”).

(In the formula, R represents a hydrogen atom, a lower alkoxyl group having 1 to 4 carbon atoms, a nitro group, or a lower alkoxycarbonyl group having 1 to 4 carbon atoms, and XY is a hydrogen atom or is a hydrogen atom together. When Z represents a hydrogen atom, the dashed line arbitrarily represents a bond, and when X represents a hydrogen atom, YZ together represents a single bond, and n represents an integer of 0 or 1.)

 Various isomers exist in the compound of the present invention. For example, the compound of the present invention has an asymmetric carbon at the 2-position and has optical isomers. Further, there are two kinds of isomers derived from the tautomerism of the imidazole ring in the compound of the present invention, that is, 4- and 5-substituted compounds related to the imidazole ring. When YZ together represent a single bond, there may be end- and exo-forms, and when the dashed line represents a bond, there may be E- and Z-isomers. The compounds of the present invention include all of these isomers and mixtures of these isomers. -The compound of the present invention can be converted into a physiologically acceptable salt by a conventional method. Examples of the salt include inorganic salts such as hydrochloride, hydrobromide and sulfate, methanesulfonate, acetate, oxalate, citrate, succinate, tartrate, and fumarate. Organic acid salts.

The compound of the present invention refers to compound B, compound C, Refers to compound D and compound E

 E D wherein R and n are as defined above.

 (First step)

 Benzocycloalkanones (compound A) and imidazole-4 (5) -force aldehyde (hereinafter referred to as “imidazo-l-41-carbaldehyde”. The imidazolyl group is also indicated as a 4-position substituent, but is also in the 5-position And an unsubstituted ketone (compound B) by an aldol condensation reaction.

The reaction is carried out by reacting benzocycloalkanonone with imidazo-l-4-carba: aldehyde in a suitable solvent in the presence of an acid or a base. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acids such as formic acid, acetic acid, oxalic acid, methanesulfonic acid, and tosylic acid. Examples of the base include metal hydroxides such as sodium hydroxide and hydroxylating power, metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, pyrrolidine, and pyridinium. Resin, morpholine, etc. Equipment. The solvent is not particularly limited as long as it does not inhibit the reaction, but water, alcohols such as methanol, ethanol and propanol, ethers such as dimethyl ether, tetrahydrofuran, dioxane and glyme, dichloromethane, and chloroform Halogenated hydrocarbons such as mouth form, and mixtures thereof.

 (2nd step)

 In this step, compound 化合物 is subjected to a catalytic reduction reaction to obtain a saturated ketone (compound C).

The reaction is carried out by absorbing a calculated amount of hydrogen in a suitable solvent in the presence of a catalyst. As the catalyst, Noble metal catalysts such as radium, nickel, cobalt, ruthenium, rhodium and platinum are included. These noble metal catalysts can be used alone in particulate metal, supported on activated carbon, diatomaceous earth, silica or alumina, or used in tris (triphenylphosphine) rhodium chloride. Used as a homogeneous complex catalyst such as rhodium and hydride carbonyl tris (triphenylphosphine). The solvent is not particularly limited as long as it does not inhibit the reaction, but alcohols such as water, methanol, ethanol and propanol, ethers such as getyl ether, tetrahydrofuran, dioxane and lime, dichloromethane, Examples include halogenated hydrocarbons such as black form and the like, and mixtures thereof. For the purpose of accelerating the reaction, an acid such as hydrochloric acid or acetic acid or a base such as ammonia or triethylamine can be added. The hydrogen pressure is from 1 atm to 100 atm, preferably from 1 atm to 100 atm. The reaction conditions such as the reaction temperature and the reaction time vary depending on the used starting compounds and the solvent, but the reaction temperature is 0 to 200 ° C, preferably room temperature to 100 ° C, and 30 minutes to 30 minutes. Perform the reaction for several days. (3rd step)

 This is a step of subjecting compound C to a compound D by subjecting it to a perfluoro-kisna (Wo1ff-Kishner) reduction reaction.

 The reaction is carried out by reacting hydrazine on compound C in the presence of a base. Examples of the base include a metal hydroxide such as sodium hydroxide or hydroxylated hydrogen or a metal alkoxide such as sodium methoxide or potassium tert-butoxide. The solvent is not particularly limited as long as it does not inhibit the reaction. However, alcohols such as water, methanol, ethanol, propanol, butanol, tert-butyl alcohol, ethylene glycol, diethylene glycol and triethylene glycol, Examples include ethers such as trahydrofuran, dioxane, glyme, diglyme and triglyme, non-protonic dipolar solvents such as DMF, DMSO and HMPA, and mixtures thereof, and preferably alcohols, particularly preferably alcohols. Ethylene glycol. As the hydrazine, hydrazine hydroxide or anhydrous hydrazine can be used.Hydrazine hydrazine is preferable, and it is preferably from 1 to 100 equivalents, more preferably 5 equivalents to Compound C. Use up to 50 equivalents. The reaction conditions such as the reaction temperature and the reaction time vary depending on the starting compounds used and the solvent, but the reaction temperature is 0 to 300 ° C., preferably 100 to 250 ° C., and 1 hour. Perform the reaction for several days.

 Compound D is obtained by isolating a hydrazone compound, which is a condensate of compound C and hydrazine, and subjecting it to a base, or subjecting compound B to a catalytic reduction reaction or reduction reaction with a metal hydride. Can also be obtained.

[Fourth step]-A step of reacting compound B with hydrazine to obtain compound E. The reaction is carried out by reacting hydrazine with compound B in the presence of a base. Examples of the base include a metal hydroxide such as sodium hydroxide or hydroxylated water, and a metal alkoxide such as sodium methoxide or potassium tert-butoxide. The solvent is not particularly limited as long as it does not inhibit the reaction, but includes water, methanol, ethanol, propanol, butanol, tert-butyl alcohol, ethylene glycol, diethylene glycol, triethylene glycol, and the like. Alcohols, ethers such as tetrahydrofuran, dioxane, glyme, diglyme and triglyme, non-protonic dipolar solvents such as DMF, DMSO and HMPA, and mixtures thereof, and preferably alcohols. And particularly preferably ethylene glycol. As the hydrazine, hydrazine hydrate or anhydrous hydrazine can be used.Hydrazine hydrate is preferable, and 1 to 100 equivalents, preferably 5 to 5 equivalents to compound C is used. Use 0 equivalents. The reaction conditions such as the reaction temperature and the reaction time vary depending on the used starting compounds and the solvent, but the reaction temperature is 0 to 300 ° C, preferably 100 to 250 ° C, and 1 hour to several hours. Perform the reaction for a day.

 The benzocycloalkane compound of the present invention has potent and selective aromatase inhibitory activity. The pharmacological actions of representative compounds of the present invention are shown below.

 [Experimental example 1]

 [Inhibition of human placental aromatase in invitro]

Preparation of aromatase;

Aromatase was obtained from the microsomal fraction of postpartum fresh placental tissue according to the method of Thompson and Siteri (J. Biol. Chem., Vol. 249, 5364 (1974)). The separated microsomes were added to a minimal amount of phosphate buffer (0.05 M, pH 7.4). Suspended and stored at 30 ° C. No inactivation was observed within 4 months. Inhibition test;

In the aromatic cyclizing. [1, 2 β - Η] monitoring the enzyme activity by measuring 3 Eta ₂ 0 produced from testosterone G ra V es及Hi S Alhanick method E ndocrinology, vol 1 0 5, 52 (19779)). Each Incubation tube contains 0.225 iCi of [lS, 2β- ^{3 3} ) testosterone, 2.5 // Μ unlabeled testosterone, and 2 mM Darcos-6-phosphate phosphate. — 6— phospnate), 1 EU glucose 16-phosphate dehydrogenase (glucose 16-phosphate dehydrogenase) and inhibitors dissolved in phosphate buffer (0.05 M, pH 7.4) 0.25 M). The test substance was previously dissolved in ethanol and diluted with a buffer. Final ethanol concentrations in control and inhibitor cultures were 2%. Each tube was pre-incubated for 5 minutes in a water bath at 30 ° C, and the reaction was started by adding microsome and evening protein (0.5 mg). Each culture solution had a total volume of 0.5 ml. Take a 100/1 partial sample at 0, 7, 14 and 21 minutes and pour the sample into a 1 mM mercuric chloride HgC12 solution 200 H1 The reaction was thereby terminated. To this was added a suspension of activated carbon (DCC) (2%) coated with 200 aqueous dextran, and the vial was shaken for 20 minutes and centrifuged at 1500 g for 5 minutes. Then, the steroids adsorbed on the activated carbon were separated. Aliquot of the supernatant was measured ³ H ₂ 0 by counting in scintillation one to down mixture in using B ec miles an, liquid scintillation spectrophotometer (LS 8000).

The results are shown in [Table 1]. table 1

 Human placental aromatase inhibitory activity

 a; Substrate testosterone concentration is 2.5 μM

b: AG equivalent value calculated from IC _B0 value [Experimental example 2]

 [Inhibition of P. adrenal desmolase in invitro]

Preparation of desmolase;

Tesmolase was obtained from the mitochondrial fraction of the pulmonary adrenal cortex according to the method of Hochberg et al. (Biochemistry, vol. 13, 63 (1974)). The separated mitochondria were resuspended in a buffer using sucrose as a minimum volume buffer, and then stored at 170 ° C. Within three months, desmolase activity was stable.

Inhibition test;

After thawing the mitochondrial suspension, it was sonicated three times at 0 ° C (one time every 10 seconds for 1 minute) using a microchip. The resulting suspension was centrifuged at 8000 g for 15 minutes to clarify. The following test was performed using the supernatant. With [26- ^{1 4} C] cholesterol as a substrate to measure the enzyme activity in ⁴ C] Lee Sokapuro phosphate (isocaproicacid) H 0 chberg et al method similar to measuring the emitted. Each fin particulate base Ishiyo down 'tube, [2 6- ^{1 4} C] cholesterol 0. 1 6 8 / C i, 1 0〃 g of Tw een 80, l mg of mitochondria. Protein and T ris—Inhibitor (0 or 25 // M) dissolved in HC1 buffer (0.1 M mercury chloride, 0.01 M, pH 7.4) was added. The test substance was previously dissolved in ethanol and diluted with a buffer. Final ethanol concentrations in control and inhibitor cultures were 1%. Each tube was pre-incubated for 3 minutes with shaking in a water bath at 30 ° C, and the NADP (1 mM) and NADP production system (1 OmM glucose-16-phosphate and 1 EU glucose-6 -Phosphate dehydrogenase) was added to start the reaction. Each culture solution had a total volume of 1 ml. At time 0, 3, 6, and 9 min, aliquots of 200 H1 were taken and the samples were pipetted with 1.5 ml of cold glycine monomercuric chloride buffer (0.05 M, 1 mM mercuric chloride). , PH 9.5) to stop the reaction. The diluted sample is then transferred to a Pasteur pipet with glass wool stoppered in 500 ± 100 mg of alumina (neutral, thin-layer grade, mesh 40 μm, Merck, Darma tadt, F RG) and filtered through an alumina microcolumn prepared. Filtration was completed by the next morning. A partial sample of the eluate was dispensed into a scintillation mixture, and counted. The results are shown in Table 2.

 Table 2

Inhibition of Pseudoparathyroid Desmolase in ViV0

 [Experimental example 3]

[Inhibition of glucocorticoid and mineral corticoid production (invitro; rat adrenal slice; measurement of aldosterone and corticosterone)] The method (J. Steroid Biochem. Vol. 34, 56 7 (1989)) was carried out with a partially modified method. The adrenal glands were removed from 14 male SD rats, cut into 8 pieces each, and 2 ml of culture medium [K rebs-riger-bicarbonatesalt solution was added to 8.4 mM gnorecose, and added to 0 ₂ / C 0 _The mixture was saturated (9, 55) with 2 and transferred to an incubation tube containing pH 7.6] (8 sections were inserted per tube). Pre After incubation (1 hour in a shaking water bath 37 ° C), adrenocorticotropic hormone _{(_ ACTH i, 4?;} 1 sm 1) to stimulate Koruchikoi de generate culture medium and fresh medium containing Aromataze inhibition And cultured for 2 hours under the conditions described above. Supernatant corticosterone and The aldosterone content was measured by radioimmunoassay without extraction (using a kit of DRGI nstruments, Marbur, Germany). IC _c0 values were calculated by interpolation with logarithmic ratios by comparison with ACTH stimulated controls.

The results are shown in [Table 3].

 Table 3

 Inhibition of corticosterone and aldosterone production

本発明において、 テ トラヒ ドロナフラレン化合物は、 通常の製剤担体 を配合することにより、 錠剤、 ハー ド若しくはソフ トカプセル剤、 顆粒 剤、 散剤、 細粒剤若しくは坐剤等の固形製剤又は注射剤、 シロップ剤、 水剤、 懸濁剤若しくは乳剤等の液剤に調製することができる。 固形製剤 にあっては、 腸溶性製剤又は徐放性製剤等に調製してもよい。 配合する 製剤担体としては、 所望の剤型に応じ例えば、 賦形剤、 結合剤、 崩壊剤、 滑沢剤、 被覆剤、 溶解補助剤、 乳化剤、 懸濁化剤、 界面活性剤、 吸収助 剤、 安定化剤又は溶剤等が挙げられる。 発明を実施するための最良の形態

In the present invention, the tetrahydrodronafullerene compound can be used as a solid preparation such as tablets, hard or soft capsules, granules, powders, fine granules or suppositories, injections, syrups, etc. Solution, solution, suspension or emulsion can be prepared. Solid preparations may be prepared as enteric-coated preparations or sustained-release preparations. Depending on the desired dosage form, the formulation carrier to be mixed includes, for example, excipients, binders, disintegrants, lubricants, coating agents, dissolution aids, emulsifiers, suspending agents, surfactants, absorption aids And a stabilizer or a solvent. BEST MODE FOR CARRYING OUT THE INVENTION

 The compound of the present invention has a potent and selective aromatase inhibitory action, estrogen-dependent cancer such as breast cancer, uterine cancer or ovarian cancer, prostatic hypertrophy, gynecomastia of male and endometrium It is useful as a therapeutic agent for the disease.

Hereinafter, production examples of typical compounds of the present invention are shown.

Physical properties;

 Melting points were measured with a Kofler (Kof 1 er) melting point apparatus (uncorrected).

 The 1 H-NMR spectrum was measured with a Bruker AW-80 using TMS as an internal standard.

 The IR spectrum was measured by Perkin-Elma (Perkin-Elmer) 398.

 [Example 1]

 E-2- (4-imidazolylmethylene) -11-tetralone (compound-1); 1-tetralone (14.6 g, 0.10 mol) and imidazoluru-4-carbaldehyde (9.6 g, 0.10 mol) was heated in 40% sulfuric acid (75 ml) at 80-90 ° C for 20 hours. The reaction solution was poured into ice, and neutralized by adding concentrated ammonia water. The deposited yellow precipitate was collected by filtration, washed sufficiently with water, and dried over phosphorus pentoxide. The crude product was washed with petroleum ether, purified by silica gel column chromatography (acetone), and recrystallized from acetone-hexane to give yellow crystals with a melting point of 135-137 ° C. — 2.8 g (yield 57%) of 4- (1-imidazolylmethylene) -11-tetralone was obtained.

^A H-NMR (80 MHz; DMS O-dg): 2.75—3.15 (m, 2H), 3.15-3.60 (m, 2Η), 7.Ό5 -7.90 (m, 6Η), 7.95-8.20 (m, 1Η), 12.1 (s (br), 1 H).

 I R (KB r): 3 1 1 5, 3060, 2920, 2620, 1 668, 16 0 5, 1 5 9 5, 1 3 0 5, 6 2 5, 6 1 3, 4 9 0.

 [Example 2]

E-2- (4-imidazolylmethylene) -1-5-methoxy-1 1-tetralone (compound-1);

 Synthesized according to the method of Example 1 from 5-Methoxy 1-tetralone and imidazole-4. Yellow crystals, melting point 1 9 1 1 1 93

° C, yield 51%.

1 H-NMR (80 MHz: DMS 0-d ₆ ): 2.70-3.03

(m, 2H), 3.1 1—3.55 (m, 2Η), 3.84 (s, 1Η), 7.05-7.73 (m, 5Η), 7.85 ( s, 1st), 12.4 (s (br), 1st).

 IR (KB r): 311, 3005, 2955, 2840, 2665, 2610, 1668, 1610, 1585, 785, 620, 60.5. [Example 3]

 E—2— (4-Imidazolylmethylene) -16-methoxy-1-tetratolone (Compound-1);

 It was synthesized according to the method of Example 1 from 6-methoxy-1-tetralone and imidazole-41-carbaldehyde. Yellow crystals, melting point 1 57— 1 58

° C, yield 43%. .

 ^ -NMR (80 MHz; DMS O-dg): 2.77-3.08 (m, 2H), 3.21-3.62 (m, 2H), 3.84 (s, 3H) , 6.78-7.02 (m, 2H), 7.47-7.65 (m, 2H), 7.74-8.08 (m, 2H), 1 2.5 (s (br), 1 H).

IR (KB r): 3110, 3010, 2930, 2840, 2665, 2600, 1 665, 1 6 1 2, 1 593, 1 100, 625, 595.

[Example 4]

 Ε-2- (4-imidazolylmethylene) -17-methoxy-1-tetratolone (compound-14);

 It was synthesized according to the method of Example 1 from 7-methoxy-1-tetralone and imidazo-l-41-carbaldehyde. Yellow crystals, mp 162-164 ° C, yield 53%.

¹ H-NMR (80 MHz; DMS 0-d ₆ ): 2.72-3.04 (m, 2H), 3.20-3.58 (m, 2H), 3.80 (s, 3H), 7.02-7.51 (m, 3H), 7.47-7.68 (m, 2H), 7.83 (s, 1H), 11.8 (s (br), 1 H).

 IR (KBr): 311 0, 30 1 5, 2925, 2845, 2 180, 2 120, 1 668, 1 602, 1 403, 1 030, 825, 6 1 5. [Example 5]

E-2-(41-midazolyl methylene) 1 7-Methoxycarbone 1

—Tetralone (Compound-1 5);

 It was synthesized according to the method of Example 1 from 7-methoxycarbonyl-1-tetrabutyl and imidazo-1-yl 4-aldehyde. Yellow crystals, melting point

190-193 ° C, yield 35%.

 ^ -NMR (80 MHz; DMS O- d ^): 2.89-3.

1 5 (m, 2 H), 3.3 1 — 3 · .59 (m, 2 Η). 3.89 (s,

3Η), 7.40-7.72 (m, 3Η), 8.07 (dd, J = 2.

8.50 (d, 3 = 2.1 Hz, 1 H), 8.50

5 0 (s, 1H).

 I R (KB r): 3475, 2955, 2850, 174-0, 1710,

1 6 6 8, 1 6 13, 1 4 4 5, 9 8 8, 7 5 7, 6 2 2, 4 1 2. [Example 6]

 E— 2— (4-imidazolyl methylene) — 7-nitro-1-tetralone (compound-1 6);

 It was synthesized according to the method of Example 1 from 7-two-row 1-tetrabutyl and imidazole-41-carbaldehyde. Yellow crystals, melting point 250 ° C or higher, yield 30%.

¹ H-NMR (80 MHz, DMS 0-d ₆ / TFA): 3.09 — 3.26 (m, 4H), 7.54 — 7.85 (m, 2H ), 8.14 (s, 1H), 8.14 (dd, J = 8.5, 2.5Hz, 1H), 8.60 (d, 3 = 2.5Hz) , 1 H), 9.15 (s, 1 H).

 IR (KB r): 3 1 45, 3 11 0, 29 90, 1 67 0, 1 6 1 3, 16 0 5, 1 5 2 0, 1 3 5 0, 1 3 4 0, 1 0 7 8, 8 5 3, 7 4 0, 6 2 5, 6 1 0.

 [Example 7]

E-2- (4-imidazolylmethylene) 111-indanone (Compound 17); synthesized from 1-indanone and imidazole-41-carbaldehyde according to the method of Example 1. Yellow crystals, mp 203-206 ° C, yield 65%.

! H- MR (8 0MH Z; DMS O- d 6): 4. 0 2 (s, 2 H), 7. 2 6 - 8. 1 0 (m, 7 H), 1 2. 6 (s ( br), 1 H).

I R (KB r): 3125, 2955, 2915, 2865, 1670, 1615, 16600, 1088, 7482, 625.

 [Example 8]

 E— 2— (4-Imidazoylmethylene) 1-4-methoxyl 1 indanone (Compound 1 8);

4-Methoxy 1 Indanone and imidazole 4 The compound was synthesized from a head according to the method of Example 1. Yellow crystals, mp 225-227. C, yield 71%.

¹ H-NMR (8 OMH z; DMS 0-d ₆ ): 3.78-4.06 (m, 5H), 7.15—7.61 (m, 4H), 7.71 (s , 1 H), 790 (s, 1 H), 12.5 (s (br), 1 H).

 I R (KB r): 3 1 30, 2970, 2920, 2840, 1695, 1645, 1 635, 1 490, 1 280, 1 270, 742, 660, 62 0, 5 7 0.

 [Example 9]

E—2— (4-Imidazoylmethylene) -1-5-Methoxy-11-Indanone (Compound-9);

 5-Methoxy-1-indanone and imidazo-l-41-carboaldehyde were synthesized according to the method of Example 1. Yellow crystals, mp 222-223. C, yield 64%.

 ^ -NMR (80 MHz; DMS O-dg): 3.88 (s,

3 H), 3.98 (s, 2 H), 6.98 (dd, J = 9 Hz, 1 H), 7.08-7.24 (m, 1 H), 7.40 (s, 1H), 7.55-7.76 (m, 2H), 7.86 (m, 1H), 12.1 (s (br), 1H).

 I R (KB r): 3 11 0, 2975, 2840, 1695, 1640,

1 6 0 0, 1 3 4 2, 7 7 0, 6 2 5.

 [Example 10]

 E-2- (4-imidazoylmethylene) -16-methoxy-11-indanone (compound-10);

It was synthesized according to the method of Example 1 from 6-methoxy-11-indanone and imidazole-4 carbaldehyde. Yellow crystals, melting point 1 98-20 1 ° C, yield 84%.

 ^ -NMR (80 MHz; DMS O-d g): 3.82 (s,

3 H), 3.92 (s, 2 H), 7.12-7.34 (m, 2 H), 7.

40-7.75 (m, 3 H), 7.88 (s, 1 H), 12.2 (s (br), 1 H).

 I R (KB r): 3 1 40, 2970, 2880, 1695, 1 630,

1 4 9 5, 1 0 3 5, 6 2 5.

 [Example 11]

 2- (4-Imidazolylmethyl) -1-tetralone (compound-11); compound-1 (11.2 g, 50 mmol) and Pd-carbon (0.5 g) were converted to methanol (20 0 ml) and stirred at 1 atm until the calculated amount of hydrogen was absorbed. The catalyst was removed, the solvent was distilled off, and the crude product obtained was purified by silica gel gel chromatography and then recrystallized from acetone-hexane to give a melting point of 158-160 ° C. As a result, 7.00 g (yield: 62%) of 2- (4-imidazolylmethyl) -11-tetralone was obtained as colorless crystals of.

 ^ -NMR (80 MHz; DMS O-dg): 1.26-3.32 (m, 7H), 6.80 (s, 1H), 7.17-7.69 (m, 4H), 7.78-8.03 (m, 1H), 11.6 (s (br), 1H). IR (KB r): 3 1 1 5, 3060, 2950, 2925 , 2835,

1 6 9 0, 1 6 0 0, 1 2 2 0, 9 5 0, 6 6 0.

 [Example 12]

 2- (4-imidazolylmethyl) -1-5-methoxy-1-tetralone (compound-12);

It was synthesized from compound-2 according to the method of Example 11. Colorless crystal, melting point 150-153 ° C, yield 64% _n ^ -NMR (80 MHz; DMS O-dg): 1.32-3.31 (m, 7H), 3.81 (s, 3H), 6.81 (s, 1H) ), 7.06-7.63 (m, 4H), 11.7 (s (br), 1H).

 I R (KB r): 3100, 3045, 2835, 2585, 1685, 16500, 1585, 1265, 945, 665.

 [Example 13]

 2— (4-imidazolylmethyl) -1-6-methoxy-1—tetralone (13-13);

 The compound was synthesized from compound-3 according to the method of Example 11. Colorless crystals, melting point 148-150 ° C, yield 67%.

 ^ -NMR (80 MHz; DMS O-dg): 1.36-3.33 (m, 7H), 3.81 (s, 3H), 6.68-7.04 (m, 4H), 7.50 (s, 1H), 7.85 (d, J = 10Hz, 1H), 11.8 (s (br), 1H).

 I R (KB r): 3290, 3110, 2995, 2940, 2840,

2590, 1678, 1660, 1160, 66 5.

 [Example 14]

 2— (4-imidazolylmethyl) -17-methoxy-1-tetralone (compound-14);

 The compound was synthesized from compound-4 according to the method of Example 11. Colorless crystals, mp 161-162 ° C, 86% yield. .

¹ H-NMR (80 MHz; CDC 1 o): 1.73-2.41 (m, 3 H), 2.57-3.15 (m, 4 H), 3.82 ( s, 3H), 4.8 (s (br), 1H), 6.83 (s, 1H), 6.90-7.30 (m, 2H), 7.42- 7.6 1 (m, 2 H).-

IR (KB r): 311 0, 2995, 2950, 2930, 2835, 1 6 8 0, 1 6 1 5, 1 5 0 0, 1 3 0 0, 1 0 4 0, 6 3 5.

 [Example 15]

 2- (4-imidazolylmethyl) -111-indanone (Compound-15); synthesized from compound-5 according to the method of Example 11. Colorless crystals, mp 160-163. C, yield 67%.

 ^ -NMR (80 MHz; DMS O-d ^): 2.29-3.50 (m, 5H), 6.78 (s, 1Η), 7.20-7.86 ( m,

5 Η), 11.5 (s (br), 1 Η).

 I R (KB r): 3060, 3000, 2840, 2630, 1 7 1 5, 1 6 0 5, 1 5 9 5, 7 6 0, 6 2 5.

 [Example 16]

 2— (4-imidazolylmethyl) —4-methoxy—1-indanone (compound-16);

 The compound was synthesized from compound-6 according to the method of Example 11. Colorless crystals, mp 160-162 ° C, yield 73%.

 ^ -NMR (80 MHz; DMS O-d ^): 2.36-3.31 (m, 5H), 3.84 (s, 3Η), 6.77 (s, 1Η) , 7.00-770 (m, 3 words), 10.5 (s (br), 1 word).

 I R (KB r): 3 1 30, 3065, 2970, 2940, 2905, 2840, 1712, 1 602, 1 596, 1 487, 1 258, 780,

6 6 2.

 [Example 17]

 2- (4-imidazolylmethyl) -5-methoxy-1-indanone (compound-17);

The compound was synthesized from compound-7 according to the method of Example 11. Colorless crystals, mp 166-167 ° C, 80% yield. ^ -NMR (80 MHz; DMSO-dg): 2.34-3.38 (m, 5H), 3.83 (s, 3H), 6.69-7.1 2 (m, 4 H), 7.44-7.73 (m, 2 H), 10.6 (s (br), 1 H). IR (KBr): 3 0 7,5,3 0 1 0, 2 7 7 0, 2 8 9 0, 2 8 4 0, 2 6 3 5, 1 6 9 5, 16 1 0, 1 5 9 5, 1 2 6 2, 8 1 8, 6 2 2. [Example 18]

 2— (4-imidazolylmethyl) -16-methoxy-11-indanonone (compound—18);

 The compound was synthesized from compound-8 according to the method of Example 11. Colorless crystals, melting point 150-153 ° C, yield 68%.

¹ H-NMR (80 MHz, DM S 0 -d ₆ ): 2.45-3.31 (m, 5 H), 3.79 (s, 3 H), 6.77 ( s, 1Η), 7.

0 4-7.47 (m, 3Η), 7.50 (s, 1Η), 10.5 (s (br), 1).

 I R (KB r): 3 0 7 0, 2 9 4 0, 2 8 4 5, 1 7 1 2, 1 6 2 0,

1 4 9 3, 1 16 3, 10 2 8, 8 5 5, 6 2 9.

 [Example 19]

 2 — (41-imidazolylmethyl) 1, 1, 2, 3, 4-tetradronaftalene (compound 1 2 1);

Compound 11 (3.40 g, 15 mimol), potassium hydroxide (13.1 g, 2334 mimol) and hydra and jinhydra (12.4 g, 24 mol) (7 mmol) was heated to reflux in diethylene glycol (200 ml) for 1.5 hours. The generated water and the remaining hydrazine hydrate were distilled off, and the temperature was raised to 195 to 200 ° C. The reaction was stopped when the generation of nitrogen stopped. The reaction solution was poured into 600 g of crushed ice, and extracted with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate. solvent The crude product obtained by distilling off the residue under reduced pressure was subjected to silica gel column chromatography, and recrystallized from acetone-hexane to give 2- (4-imidazolylmethyl) with a melting point of 1117-119 ° C. 1.1.6 g (yield 50%) of 1,1,2,3,4-tetratetradronaphthalene was obtained.

 ^ -NMR (80 MHz; CDClg) 1.12-2.90

(m, 9H), 3.5 (s, (br), 1H), 674 (s, 1H), 6.92-7.11 (m, 4H), 7.49 (s, 1 H).

 I R (KB r): 3200, 3060, 2920, 2900, 2840, 2600, 1 595, 1 582, 1 497, 1 483, 1 11 0, 950, 8 18 and 6 63.

 [Example 20]

 2- (4-imidazolylmethyl) -1-5-methoxy-1,2,3,4-tetrahydrodronaphthalene (compound-122);

 The compound was synthesized from compound-12 according to the method of Example 19. Colorless crystal, melting point 157-159. C, yield 56%.

 ^ -NMR (80 MHz-. DMS O-d): 1.00-2.87 (m, 9H), 3.72 (s, 3H), 6.42-7.17 (m, 4H), 7.51 (s, 1H), 11.8 (s (br), 1H).

 IR (KB r): 3180, 3055, 2935, 2840, 2590, 1590, 1470, 1266, 1100, 945, 772, 665. [Example 21].

 2- (4-imidazolylmethyl) -16-methoxy-1,2,3,4-tetrahydrodronaphthalene (compound-13);

 The compound was synthesized from compound-13 according to the method of Example 19. Colorless crystals, melting point 100-102 ° C, yield 48%.

^ -NMR (80 MHz; CDC 1): 1.14-2.93 (m, 9 H), 3.73 (s, 3 H), 5.19 (s (br), 1 H), 6.59 (s, 1 H), 6.52-7.00 (m , 3 H), 7.52 (s, 1 H).

 I R (KB r): 3200, 3 1 20, 2925, 2835, 16 1, 4, 150, 1, 27, 0, 1, 2, 3, 5, 0 3, 8, 8, 26, 66 2.

 [Example 22]

 2- (4-imidazolylmethyl) -17-methoxy-1,2,3,4-tetratetradronaphthalene (compound-24);

 The compound was synthesized from compound-14 according to the method of Example 19. Colorless crystals, melting point 113-114 ° C, yield 42%.

^X H -NMR (80 MHz; CDC 1): 1.0 -2.92 (m, 9 H), 3.73 (s, 3 H), 6.58 (s, 1 H), 6 65 — 7.06 (m, 3 H), 7.4 (s (br), 1 H), 7.55 (s, 1 H).

 I R (KB r): 3 1 1 0, 3055, 2990, 2835, 2585,

1 6 1 3, 1 5 0 3, 1 2 6 0, 1 0 4 3, 9 4 8, 6 6 2.

 [Example 23]

Exo-1 1- (4-imidazolyl) 1-1a, 2,3,7b-tetrahydro1H-cyclopropa [a] naphthalene (compound 31);

Compound 1 was reacted with hydrazine according to Example 19 to give exo 1- (4-imidazolyl) -1a ,, 2,3,7b-tetrahydro 1H-cyclopropa [ _a Naphthalene was synthesized. Colorless glass, melting point 60-65 ° C, yield 82%.

^ -NMR (80 MHz; DMS O-dg): 1.41-2.80 (m, 7H), 6.75 (s, 1Η), 6.85-7.40 ( m, 4), 7.45 (s, 1H), 8.8 (s (br), 1H). IR (KBr): 3020, 2925, 2855, 1605, 1580, 1493, 1460, 750, 628.

 [Example 24]

Exo-11 (41-imidazolyl) 1-4-Methoxy 1a, 2,3,7b-Tetrahydro 1H-cyclopropa [a] naphthalene (Compound-1 32); Compound -2 to Example 23 The compound was synthesized according to the method described above. Colorless crystals, mp 186-187 ° C, yield 30%.

¹ H-NMR (80 MHz; DM S 0-d ₆ ): 1.01-3.11 (m, 7H), 3.73 (s, 3H), 6.59-7 . 2 1 (m, 4H), 7.46 (s, 1H), 11.7 (s (br), 1H).

 I R (KB r): 3080, 2940, 2910, 2855, 1603,

1 5 9 8, 1 4 7 5, 1 2 6 8, 1 1 1 5, 1 07 6, 6 3 0.

 [Example 25]

Exo-1-1 (4-imidazolyl) -1-5-methoxy 1a, 2,3,7b-tetrahydro 1H-cycloprono [a] naphthalene (Compound-33); From Compound 13 to Example 23 Synthesized according to the method. Colorless crystals, mp 155-157 ° C, yield 67%.

^{1 H - NMR (80 MH z} ; CDC 1 3): 1. 5 8 - 2. 4 2 (. M 5 H), 2. 43 - 2. 79 (m, 2 H), 3. 74 (s, 3 H), 6.55-6.85 (m, 3 H), 7.14 (d, J = 8 Hz, 1 H), 7.48 (s, 1 H), 7.9 ( s (br), 1H).

 I R (KB r): 3 1 1 5, 3080, 3025, 3000, 2935,

2850, 1615, 1583, 1505, 1248, 1040, 760, 6300.

 [Example 26]

Exo-1-1 (4-I-midazolyl) -1-6-Methoxy-1a, 2, 3, 7b —Tetrahydro-1H-cycloprono, “[a] naphthalene (compound 34); synthesized from compound 14 according to the method of Example 23. Purified by chromatography to give the title compound as a colorless oil. Was obtained (yield 85%).

1 H - NMR (8 0 MH z; CDC 1 3): 1. 4 7 - 2. 7 9 (m, 7 H), 3. 73 (s, 3 H), 6. 50 - 7. 06 (m , 5 H), 7.4 (s (br), 1 H), 7.47 (s, 1 H).

 This free base was dissolved in acetone and treated with an excess of 10% oxalic acid-aceton solution. The precipitated salt was recrystallized twice from acetone to give a colorless powder having a melting point of 199 ° -203 ° C. (the yield from compound 14 was 37%, which was 7%).

¹ H-NMR (8 OMH z; DMS 0-d ₆ ZTFA): 1.40-2.71 (m, 7 H), 3.71 (s, 3 H), 6.5 4-7. 1 1 (m, 3 Η), 7.47 (s, 1 Η), 8.93 (s, 1 Η). Industrial applicability

 As described above, Compound 1 exhibited potent and selective aromatase inhibitory activity. Therefore, the benzocycloalkane compound I can be used as a therapeutic agent for estrogen-dependent cancer such as breast cancer, uterine cancer or ovarian cancer, prostatic hypertrophy, gynecomastia of males, and endometriosis.

Claims

The scope of the claims  The following formula

(In the formula, R represents a hydrogen atom, a lower alkoxyl group having 1 to 4 carbon atoms, a nitrogen atom or a lower alkoxycarbonyl group having 1 to 4 carbon atoms, and both XY are a hydrogen atom or an oxygen When representing an atom, Z represents a hydrogen atom, a broken line represents an arbitrary bond, and when X represents a hydrogen atom, YZ together represent a single bond, and n represents an integer of 0 or 1.) And a salt thereof.