[go: up one dir, main page]

MXPA00003167A - Novel dihydronaphthalene compounds and process for producing the same - Google Patents

Novel dihydronaphthalene compounds and process for producing the same

Info

Publication number
MXPA00003167A
MXPA00003167A MXPA/A/2000/003167A MXPA00003167A MXPA00003167A MX PA00003167 A MXPA00003167 A MX PA00003167A MX PA00003167 A MXPA00003167 A MX PA00003167A MX PA00003167 A MXPA00003167 A MX PA00003167A
Authority
MX
Mexico
Prior art keywords
production
compound
methyl
production example
methoxy
Prior art date
Application number
MXPA/A/2000/003167A
Other languages
Spanish (es)
Inventor
Rolf Wolfgang Hartmann
Bertil Wachall
Makoto Yoshihama
Masamichi Nakakoshi
Shin Nomoto
Yoshikazu Ikeda
Original Assignee
Yukijirushi Nyugyo Kabushiki Kaisha
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yukijirushi Nyugyo Kabushiki Kaisha filed Critical Yukijirushi Nyugyo Kabushiki Kaisha
Publication of MXPA00003167A publication Critical patent/MXPA00003167A/en

Links

Abstract

Dihydronaphthalene compounds represented by chemical formula (1), which have an excellent 17&agr;-hydroxylase/C17-20-lyase inhibitory activity, thromboxane A2 synthesis inhibitory activity, and aromatase inhibitory activity and are useful because of these activities as preventives or remedies for various male and female hormone-dependent diseases such as prostatic cancer, prostatic hypertrophy, masculinism, mammary cancer, and mastopathy, myocardial infarct, angina pectoris, and bronchial asthma.

Description

NOVEL COMPOUNDS OF DIHYDRO-CREAMINE AND PROCESSES TO PRODUCE THEMSELVES FIELD OF THE INVENTION The present invention relates to novel dihydronaphthalene compounds and to processes for their preparation. The compounds of the present invention have an excellent inhibitory activity of 17a-hydroxylase and / or C1720-lyase, inhibitory activity of thromboxane A2 synthesis and aromatase inhibitory activity, and thus are useful as preventive and / or therapeutic agents for various diseases dependent on male hormones and female hormones, such as prostate cancer, prostatomegaly, masculinization, breast cancer, mastopathy, endometrial cancer, endometriosis and ovarian cancer, as well as myocardial infarction, angina of chest and bronchial asthma.
PREVIOUS TECHNIQUE According to the biosynthesis of sex steroids, which express various actions in the body, it is known that C21 steroids, such as progesterone, are synthesized from cholesterol; likewise, male sex hormones, such as androstenedione and testosterone, which are C19 steroids, are synthesized by 17a-hydroxylase and / or C1.7"20-lyase, and using these steroids as substrates, female hormones, such as estrone and esradiol, which are C18 steroids, are synthesized. Therefore, the synthesis of male sex hormones and / or female sex hormones in the body, can be suppressed by the inhibition of these enzymes that synthesize sex steroids, that is, 17a-hydroxylase and / or C17_20- lyase or aromatases, which makes possible the prevention or treatment of diseases in which male sex hormones or female sex hormones act as aggravating factors, such as cancer of the prostate, pros atomegaliz, masculinization, breast cancer , mastopathy, endometrial cancer, endometriosis and ovarian cancer. Several findings have already shown that male hormone-dependent diseases, such as prostate cancer and prostatomegaly, can be treated by reducing levels of the male sex hormone in the blood. The therapeutic efficacy of reducing the level of male sex hormones by orchiectomy or adrenalectomy has been known for some time and, more recently, the effectiveness of reducing the level of male sex hormones derived from the gonads, by administering a agonist of an LH-RH (pituitary hormone), has been recognized. However, the aforementioned surgical removal of the organs is psychologically difficult to accept and also causes side effects and other disorders due to the reduction of mineral corticosteroids and glucocorticoids, derived from the adrenal gland. In the meantime, the administration of the LH-RH agonist will inhibit the synthesis of hormones derived from the gonads only, but not from other organs, such as the adrenal gland, and still cause a temporary increase in hormones, known as the phenomenon of broadening. , which is unique to agonists. On the other hand, an anti-male hormone agent, to antagonize the receptor of male hormones, has been developed, but recently, its effectiveness has been found to be diminished due to changes in the male sex hormone receptor. Against this background, a reducing agent of the male sex hormone is convenient. In this regard, the inhibition of 17a-hydroxylase and / or C17_20 lyase is known to reduce the levels of male sex hormones to a high degree and can be expected to be highly effective in treating diseases related to male sex hormones, such as prostate cancer, prostatomegaly and masculinization. In addition, the inhibition of 17a-hydroxylase and / or C17_20-lyase, also results in the suppression of the synthesis of female sex hormones. Heretofore, both steroid compounds and non-steroidal compounds have been proposed as inhibitors of 17a-hydrosylase / C1720-lyase. Examples of non-steroidal compounds include an imidazole derivative, disclosed in Japanese Patent, open to the public, No. 63-85907 (1988), and a condensed three-ring azole derivative, described in Japanese Patent Application No. 07 -510212 (1995). However, the efficacy of these compounds is not entirely satisfactory and the development of compounds with high activity has been desired.
DETAILED DESCRIPTION OF THE INVENTION As a result of an intensive study, in view of the aforementioned situation, the present inventors found that the novel dihydronaphthalene compounds have an excellent inhibitory activity of 17a-hydroxylase and / or C17_20-lyase, inhibitory activity of thromboxane A2 synthesis, and aromatase inhibitory activity. That is, an object of the present invention is to provide novel dihydronaphthalene compounds and processes to produce them. The present invention relates to novel dihydronaphthalene compounds and processes for producing them. The compounds according to the present invention have an excellent inhibitory activity of 17a-hydroxylase and / or C17_20-liasam inhibitory activity of thromboxane A2 synthesis and aromatase inhibitory activity, and thus are useful as preventive agents and / or Therapeutics for various diseases dependent on male sex hormones and female sex hormones, such as prostate cancer, prostatomegaly, masculinization, breast cancer, mastopathy, endometrial cancer, endometriosis and ovarian cancer, as well as myocardial infarction , angina pectoris and branchial asthma. The present invention relates to novel dihydronaphthalene compounds of the following general formula (I): wherein R 1 represents hydrogen, hydroxyl or alkyloxy, R 2 represents lower alkyl, aralkyl or phenyl, and R 3 represents alkyl, phenyl or imidazolyl. More specifically, examples of novel dihydronaphthalene compounds, according to the present invention, of the general formula (I) include: 1) 3- [(1-methyl-33,4-dihydro-2-naphthalenyl) methyl] -pyridine 2) 3- [(5-methoxy-1-methyl-3, 4-dihydro-2-naphthalenyl) methyl] -pyridine, 3) 3 - [(6-methoxy-1-methyl-3, 4-dihydro-2) -naphthalenyl) methyl] -pyridine, 4) 3- [(7-methoxy-1-methyl-3, 4-dihydro-2-naphthalenyl) methyl] -pyridine, 5) 5-methyl-6- (3-pyridylmethyl) .7, 8-dihydro-l-naphthalenol, 6) 5-methyl-6- (3-pyridylmethyl) .7,8-dihydro-2-naphthalenol, 7) 8-methyl-7- (3-pyridylmethyl). 5,6-dihydro-2-naphthalenol, 8) 4- [(1-methyl-3, 4-dihydro-2-naphthalenyl) methyl) pyridine, 9) 4- [(5-methoxy-1-methyl-3, 4-dihydro-2-naphthalenyl) methyl) -pyridine, 10) 4- [(6-methoxy-1-methyl-3, 4-dihydro-2 -naphthalene.il) methyl) -pyridine, 11) 4- [(7-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl) methyl) -pyridine, 12) 5-methyl-6- (4 - pyridylmethyl) -7,9-dihydro-1-naphthalenol, 13) 5-methyl-6- (4-pyridylmethyl) -7,9-dihydro-2-naphthalenol, 14) 8-methyl-7- (4-pyridylmethyl) -5,6-dihydro-2-naphthalenol, ) 4- [(1-ethyl-5-methoxy-3,4-dihydro-2-naphthalenyl) methyl] -pyridine, 16) 4- [(1-ethyl-6-methoxy-3, 4-dihydro-2 -naphthalenyl) methyl] -pyridine, 17) 4- [(1-ethyl-76-methoxy-3,4-dihydro-2-naphthalenyl) methyl] -pyridine, 18) 4- [(6-methoxy-1-methyl -3,4-dihydro-2-naphthalenyl) methyl] -1H-imidazole, 19) 4- [(5-methoxy-3,4-dihydro-2-naphthalenyl) methyl] -pyridine, 20) 4- [(6 -methoxy-3,4-dihydro-2-naphthalenyl) methyl] -pyridine, 21) 4- [(7-methoxy-3,4-dihydro-2-naphthalenyl) methyl] -pyridine, 22) 4- [(5-methoxy-1-propyl-3,4-dihydro-2-naphthalenyl) methyl] -pyridine 23) 6- (4-pidyrylmethyl) -7,8-dihydro-2-naphthalenol, 24) 2- (4-lH-imidazolylmethyl) -6-methoxy-3,4-dihydronaphthalene hydrochloride, 25) 4- [(7-methoxy-2-methyl-3,4-dihydro-2-naphthalenyl) methyl] -1H - imidazole, 26) 4- [(5-methoxy-2-methyl-3,4-dihydro-2-naphthalenyl) methyl] -1H-imidazole, 27) 4- [(1-ethyl-6-methoxy) -3 , 4-dihydro-2-naphthalenyl) methyl] -1H-imidazole, 28) 4- [(1-ethyl-7-methoxy) -3,4-dihydro-2-naphthalenyl) methyl] -1H-imidazole, 29) 4- [(1-ethyl-5-methoxy) -3,4-dihydro-2-naphthalenyl) methyl] -lH-imidazole hydrochloride, 30) 4- [(6-methoxy-1-propyl-3"4 - dihydro-2-naphthalenyl) methyl] -lH-imidazole, 31) 4- [(5-methoxy-1-propyl-3,4-dihydro-2-naphthalenyl) methyl] -lH-imidazole, 32) 4- [( 6-methoxy-1-phenyl-3, 4-dihydro-2-naphthalenyl) methyl] -1H-imidazole, 33) 4- [(7-methoxy-l-phenyl-3,4-dihydro-2-naphthalenyl) methyl] -1H-imidazole, 34) 4 - [(5-methoxy-l-phenyl-3,4-dihydro-2-naphthalenyl) methyl] -1H-imidazole, 35) 4- [(1-benzyl-6-methoxy-3, -dihydro-2-naphthalenyl ) methyl] -lH-imidazole, 36) 4- [(5-methoxy-3,4-dihydro-2-naphthalenyl) methyl] -lH-imidazole hydrochloride, 37) 4- [(75-methoxy -3,4 -dihydro-2-naphthalenyl) methyl] -1H-imidazole, 38) 4- [(5-ethoxy-1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -1H-imidazole, 39) 4- [ (6-ethoxy-l-methyl-3,4-dihydro-2-naphthalenyl) methyl] -1 H -i idazole, 40) 4- [(7-ethoxy-1-methyl-3, 4-dihydro-2-naph alenyl) methyl] -1H- imidazole, 41) 4- [(1-methyl-6-propoxy-3,4-dihydro-2-naphthalenyl) methyl] -lH-imidazole, 42) 4- [(1-methyl- 6-isobutoxy-3,4-dihydro-2-naphthalenyl) methyl] -lH-imidazole, The compounds of the present invention include, in addition to the aforementioned compounds, the stereoisomers and the salts of acids or of these compounds. Examples of acids for forming addition salts include inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids, such as formic acid, acetic acid, propionic acid , oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid and glutamic acid. Examples of bases for forming base salts include inorganic bases, such as sodium, potassium, magnesium, calcium and aluminum, organic bases, such as lower alkyl amines, lower alcohol amines, basic amino acids, such as lysine, arginine and ornithine, and ammonium. Also, hydrates and solvates with lower alcohols and other solvents, can also be formed. The compounds of the present invention can be produced by the following method. In brief, a 1-tetralone compound with a hydrogen or an alkoxy group is heated with the pyridylcarbaldehyde, which has a 3- or 4-pyridyl group, or the lH-imidazole-4-carbaldehyde, under acidic conditions . The resulting substituted 1-tetralone is reduced using an appropriate reducing agent, and the reduced compound is then treated with an appropriate Grignard reagent or reduced with hydride, followed by dehydration, to obtain the objective compound of the present invention, i.e. a dihydronaphthalene compound. In addition, a dihydronaphthalene compound, which has a hydroxyl group, can be obtained by purification with, for example, boron tribromide. The above reactions are shown in the following scheme: R1 Hydrogen or lower alkoxy R1: hydroxyl group The compounds of the present invention can be administered safely, orally or parenterally, as pharmaceutical preparations, to humans or other animals. Methods for parenteral administration include intravenous injection, intramuscular injection, cutaneous injection, intraperitoneal injection, transdermal administration, transpulmonary administration, nasal administration, transenteral administration, intraoral administration and transmucosal administration. Examples of parenteral preparations include injectable substances, suppositories, aerosols and percutaneous absorbent tapes. Examples of preparations for oral administration include tablets (comprising sugar coated tablets, coated tablets and oral tablets), dispersible powders, capsules (including soft capsules), granules (including coated granules), pills, troches , pharmaceutically acceptable slow release liquids and forms of the above. Examples of liquid compositions for oral administration include suspensions, emulsions, syrups (including dry syrups) and elixirs. These preparations are produced as medicinal compositions, together with pharmacologically acceptable carriers, excipients and disintegrants, lubricants, color agents and the like, according to known pharmaceutical production methods. Examples of carriers or excipients that are used for these preparations include lactose, glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose, licorice powder and powder of gentian. Examples of binding agents include starch, tragacanth gum, gelatin, syrup, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, hydroxypropylcellulose, methylcellulose, ethylcellulose and carboxymethylcellulose. Examples of disintegrating agents include starch, agar, gelatin powder, sodium carboxymethylcellulose, calcium carboxymethylcellulose, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate and sodium alginate. Examples of lubricating agents include magnesium stearate, talc, hydrogenated vegetable oils, and macrogol. Dyeing agents, pharmaceutically acceptable, can be used. Tablets and granules may be coated, if necessary, with sucrose, gelatin, hydroxypropylcellulose, purified lacquer, gelatin, glycerin, sorbitol, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylate of methyl, methacrylic acid polymers, or the like, or with a combination layer of two or more of these coating materials. Capsules made of ethylcellulose, gelatin or the like can also be used. Injectable agents can be prepared, if necessary, by adding pH control agents, regulating agents, stabilizers, solubilizing agents, or the like, according to customary methods.
The dose of the compound of the present invention is not particularly restricted and will vary as a function of the severity of the condition to be treated, the age, health, and bodily weight of the patient and other factors. A proposed dose is from 1 to 1000, mg, preferably 50 to 200 mg, per day for an adult, and may be administered orally or parenterally once or several times a day.
EXAMPLES The present invention is explained in more detail by the following examples, which are for purposes of illustration only and are not intended to define the limits of the invention.
Example 1 Preparation of the compounds of the present invention The compounds of Production Examples 1 to 5 were synthesized as follows: To 90 ml of 54% sulfuric acid were added 7.5 g (60 mmoles) of pyridylcarbaldehyde and 50 mmoles of a compound of tetralona, and the mixture was heated at 80 ° C for 1 hour. The reaction solution was cooled in ice and the resulting precipitate of sulfate crystals was filtered, neutralized with 1 liter of a saturated aqueous sodium hydrogencarbonate solution, then washed with water by filtration. The yellow crystals, thus obtained, were dried on silica, then fractionated by column chromatography and / or recrystallized with an appropriate solvent to obtain the objective compound.
Example 2 Preparation of the compounds of the present invention The compounds of Production Examples 6 and 7 were synthesized as follows: To 105 ml of 89% phosphoric acid were added 11.0 g (103 mmoles) of pyridylcarbaldehyde and 70 mmoles of a compound of tetralone, and the mixture was heated at 80 ° C for 4 hours. The reaction solution was cooled in ice and the resulting crystal precipitate was filtered and then neutralized with a saturated aqueous sodium hydrogencarbonate solution (0.7 liter) and the resulting crystals were washed with water by filtration. The pale yellow crystals thus obtained were dried on silica and recrystallized from ethyl acetate to obtain the objective compound.
Example 3 Preparation of the compounds of the present invention The compounds of Production Examples 8 to 14 were synthesized as follows: 34 mmoles of an unsaturated ketone compound, obtained by the method of Example 1, were suspended in 250 ml of ethanol. 2 above (a compound of Production Examples 1 to 7). To this suspension were added 0.5 g of 10% Pd-C and 10 ml of 0.2 N hydrochloric acid, and the mixture was stirred under a flow of hydrogen, for 18 hours. After removing the catalyst by filtration, dehydration with anhydrous sodium sulfate and conration of the solvent obtained a residue containing the objective compound. The residue was subjected to silica gel column chromatography (elution with ethyl acetate or petroleum ether: acetone = 6: 4), to elute the objective compound or recrystallized with an appropriate solvent to obtain the objective compound as crystals.
Example 4 Preparation of the compounds of the present invention The compounds of Production Examples 15 to 22 were synthesized as follows: To a solution of methyl magnesium iodide, which was prepared by adding 1.56 g (64 mmoles) of magnesium pieces and 3.9 ml (63 mmoles) of methyl iodide in 50 ml of anhydrous ether, 70 ml of an anhydrous tetrahydrofuran (THF) solution, containing 25 mmoles of a saturated ketone compound, obtained by the method of Example 3 above (a compound of Production Examples 8 to 14) were added in drops. the mixture was refluxed for 18 hours, poured into 50 g of ice water and heated at 70 ° C for 2 hours, with 65 ml of 25% sulfuric acid. This reaction solution was basified with sodium hydroxide, while cooling. The resulting suspension was extracted several times with diethyl ether, then the organic layer was dehydrated with anhydrous sodium sulfate and conrated in vacuo. The conrate was purified by silica gel column chromatography (eluting with petroleum ether: acetone = 6: 4), and the resulting pale yellow oily substance was allowed to stand at 4CC, for "8 hours, to obtain the objective compound as crystals.
Example 5 Preparation of the compounds of the present invention The compounds of Production Examples 23 to 28 were synthesized as follows: A methylene chloride solution (90 ml), containing 3 mmoles of an alkyloxy compound (a compound of one) of Production Examples 15 to 22), obtained by the method of Example 4 above, was cooled to -78 ° C and 1 ml (10 mmol) of boron tribromide was added dropwise to this solution, under a flow of nitrogen. The solution was stirred at -78 ° C for about 30 minutes, then at room temperature for 4 hours, after which 3 ml of methanol was added dropwise. This reaction solution was conrated to a quarter of the original volume and the hydrobromic acid salt, thus obtained, was filtered. The resulting precipitate was dissolved in 1 N sulfuric acid and neutralized with a saturated solution of sodium hydrogencarbonate. In the case where no hydrobromic acid salt precipitated, the solution was conrated to dryness, the resulting oily substance was suspended in IN sulfuric acid, and this suspension of sulfuric acid was neutralized with a saturated solution of sodium hydrogencarbonate. The resulting precipitate was filtered and washed with an appropriate solvent to obtain the objective compound.
Example 6 Preparation of the compounds of the present invention The compounds of Production Examples 29m 30 and 32 were synthesized as follows: To 90 ml of a 50% sulfuric acid solution were added 60 mmoles of allylcarbaldehyde and 50 mmoles of a compound of tetralone, and the mixture was heated to 80 CC for 1 hour. This solution was cooled with ice and filtered and the resulting sulfate crystals were dissolved or suspended in 1 liter of water, after which the solution, or suspension, was neutralized with saturated sodium hydrogencarbonate. The yellow precipitate, thus produced, was filtered, washed with water, and then dried on silica. This precipitate was subjected to column chromatography (eluting with diethyl ether) and a fraction, containing the objective compound, was crystallized using an appropriate solvent, to obtain the objective compound as crystals.
Example 7 Preparation of the compounds of the present invention The compounds of Example 1 were synthesized.
Production 31 as follows: To 105 ml of an 89% phosphoric acid solution was added 11.0 g (103 mmoles) of pyridylcarbaldehyde and 70 mmoles of a tetralone compound, and the mixture was heated at 80 ° C for 4 hours. This solution was cooled with ice and the resulting precipitate of filtered phosphate crystals was dissolved in 0.7 liter of water, and then neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The precipitate, pale yellow, was filtered, washed with water and dried on silica. The resulting crude crystals were recrystallized with ethyl ether, to obtain the objective compound.
Example 8 Preparation of the compounds of the present invention The compounds of the Examples of Production 33 to 36 as follows: To 250 ml of ethanol was suspended 34 mmoles of an unsaturated ketone compound, obtained by the method of Example 6 or 7 (a compound of one of Production Examples 29 to 32). To this suspension were added 0.5 g of 10% Pd-C and 10 ml of 0.2 N hydrochloric acid, and the mixture was stirred under a flow of hydrogen, for 18 hours. After removing the catalyst by filtration, dehydrating with anhydrous sodium sulfate and concentrating under vacuum, the objective compound was obtained by fractionation by silica gel column chromatography or by crystallization with an appropriate solvent.
Example 9 Preparation of the compounds of the present invention The compounds of Production Examples 37 to 41, 43, 44 and 46 were synthesized as follows: To a solution of alkyl and magnesium halide, which was prepared by adding 1.56 g ( 64 mmoles) of magnesium and 63 mmoles of alkyl halide to 50 ml of anhydrous ether, 70 ml of an anhydrous tetrahydrofuran (THF) solution, containing 25 mmoles of a ketone-saturated compound (a compound), were added dropwise. from one of Production Examples 33 to 36), obtained by the method of Example 8. The mixture was refluxed for 18 hours, poured onto 50 g of ice, and heated at 70 ° C for 2 hours with 65 g. ml of 25% sulfuric acid. This reaction solution was alkalized with sodium hydroxide, while cooling. The resulting suspension was extracted several times with diethyl ether, for a pyridine derivative, or with dichloromethane: ethanol = 9: 1, for an imidazole derivative, then the organic layer was dehydrated with anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was fractionated by silica gel column chromatography, and the resulting pale colored oily substance was allowed to stand at 4 ° C for 8 days, to obtain the target compound as crystals. The compound of Production Example 44 was obtained as follows: One gram of an oily, pale-colored substance, obtained as above, was dissolved in 200 ml of ether: ketone. To this solution, 2 to 3 ml of a solution of hydrochloric acid / ether, prepared by adding 2 ml of a solution of hydrochloric acid (prepared first by adding 3 ml of concentrated hydrochloric acid to 50 ml of ether), was added to 20 ml of ether. . The mixture was stirred and then the precipitated hydrochloride was filtered. This hydrochloride was washed with a small amount of ether and then dried under vacuum to obtain the objective compound. further, the compounds of Production Examples 37 to 39 and 46, which refer to compounds more substituted in Production Examples 41 to 43, were isolated as by-products by column chromatography. The compounds to be used for the production of Production Examples 37 to 39 were obtained as follows: the 3,4-dihydronaphthalene-1-ethyl compounds and a related ethylene-tetrahydronaphthalene compound were mixed in a ratio of 1: 1 and the mixture was ted further for purification. To induce double bond isomerization, 0-4 g of the mixture was heated in a solution of 0.36 g of p-toluenesulfonic acid (2.1 mmoles) in 20 ml of acetic acid at 90 ° C, for 24 hours. This tion solution was basified with a saturated aqueous solution of sodium hydrogencarbonate and sodium carbonate, and extracted 3 times with ethyl ether. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was purified by column chromatography to obtain the objective compound.
Example 10 Preparation of the compounds of the present invention The compound of Production Example 45 was synthesized as follows: An anhydrous methylene chloride solution (90 ml), containing 3 mmoles of the methoxy compound, obtained by the method of Example 9 , it was cooled to -78 ° C, and 1 ml of boron tribromide was added in drops to this solution under a flow of nitrogen. The solution was stirred at -78 ° C for 30 minutes, then at room temperature for 4 hours, after which 3 ml of methanol were added dropwise.
This reaction solution was concentrated to a quarter of its original volume, then the resulting hydrobromide was filtered and dissolved in 1 N sulfuric acid and the solution was neutralized with a saturated solution of sodium hydrogencarbonate. In the case where no hydrobromide was deposited, the solution was concentrated and the resulting oily substance was suspended in IN sulfuric acid. This suspension of sulfuric acid was neutralized with a saturated solution of sodium hydrogencarbonate. The resulting precipitate, containing the objective compound, was filtered and washed with an appropriate solvent to obtain the objective compound.
Example 11 Preparation of the compounds of the present invention The compounds of Production Examples 42 and 46 were synthesized as follows: To 10 mmol of the ketone saturated compound, obtained by the method of Example 8, dissolved in 65 ml of methanol, gradually added 378 mg (10 mmol) of sodium borohydride, while cooling on ice, to keep the temperature below 15 ° C. After stirring for 2.5 hours, the reaction solution was added to 100 ml of ice water, and heated at 70 ° C for 1 hour, with 50 ml of 25% sulfuric acid. This solution was made alkaline with sodium hydroxide, while cooling with ice.
The suspension, thus obtained, was extracted several times with diethyl ether for a pyridine derivative, or with dichloromethane: ethanol = 9: 1, for an imidazole derivative. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue, thus obtained, was fractionated by column chromatography on silica gel, to obtain a fraction containing the objective compound, from which an oily substance was obtained, after concentration in vacuum. The compound of Production Example 42 was obtained as crystals, allowing the oily substance to stand at 4 ° C for 8 days. To prepare the compound of Production Example 46, 1 g of the above-mentioned oily substance was dissolved in 200 ml of ether / acetone. To this solution was added 2 to 3 ml of a hydrochloric acid / ether solution, prepared by adding 2 ml of a hydrochloric acid solution (prepared first by adding 3 ml of concentrated hydrochloric acid to 50 ml of ether) to 20 ml of ether. After stirring, the deposited hydrochloride was filtered, washed with a small amount of ether, then dried under vacuum to obtain the objective compound.
Example 12 Preparation of the compounds of the present invention The compound of Production Example 47 was synthesized as follows: To 90 ml of 54% sulfuric acid were added 60 mmoles of 1H-imidazolyl-4-carbaldehyde and 50 mmoles of tetralone compound corresponding, and the mixture was heated at 80 ° C for 3 hours. This reaction solution was cooled with ice, and the precipitated sulfate was filtered, neutralized with 1 liter of a saturated aqueous sodium hydrogencarbonate solution, filtered again, washed with water, and then dried on silica. The residue, thus obtained, was recrystallized with an appropriate solvent to obtain the objective compound.
Example 13 Preparation of the compounds of the present invention The compound of Production Example 48 was synthesized as follows: To 250 ml of ethanol was suspended 34 mmoles of an unsaturated ketone compound, obtained in Example 12 above. To this suspension was added 0.5 g of 10% Pd-C and 10 ml of 0.2 N hydrochloric acid, and the mixture was stirred under a flow of hydrogen for 18 hours. After removing the catalyst by filtration, it was dehydrated with anhydrous sodium sulfate and the solvent was concentrated, and the resulting residue was recrystallized with an appropriate solvent to obtain the objective compound as crystals.
Example 14 Preparation of the compounds of the present invention The compound of Production Example 49 was synthesized as follows: To a solution of methyl magnesium iodide, which was prepared by adding 1.56 g (64 mmol) of magnesium and 3.9 ml (63 mmoles) of methyl iodide to 50 ml of anhydrous ether, 70 ml of anhydrous tetrahydrofuran (THF) solution or suspension, containing 25 mmoles of a saturated ketone compound, obtained by the method of Example 13, were added dropwise. The mixture was refluxed for 18 hours, emptied into 50 g of ice water and heated at 70 ° C for 2 hours with 65 ml of 25% sulfuric acid.This reaction mixture was made alkaline with sodium hydroxide. While cooling, the resulting suspension was extracted several times with dichloromethane: ethanol = 9: 1, and the organic layer was dehydrated with anhydrous calcium chloride and concentrated in vacuo.The concentrate was fractionated by column chromatography and the fraction The reaction containing the objective compound was recrystallized with an appropriate solvent to obtain the objective compound.
Example 15 Preparation of the compounds of the present invention The compounds of Production Examples 50, 64, 66, 68, 73 and 76 were synthesized as follows: To 90 ml of 50% sulfuric acid were added 60 mmoles of 1H-imidazolyl-4-carbaldehyde and 50 mmoles of the corresponding tetralone compound, and the mixture was heated to a 80 ° C for 2 hours, while stirring. This reaction solution was cooled with ice, and the precipitated sulfate was filtered, neutralized with 1 liter of a saturated aqueous solution of sodium hydrogencarbonate. The resulting crystals were filtered, washed with water and then dried to obtain the objective compound.
Example 16 Preparation of the compounds of the present invention The compounds of Production Examples 51, 65, 67, 69, 74 and 77 were synthesized as follows: To 250 ml of ethanol were suspended 34 mmoles of an unsaturated ketone compound, obtained in Example 15 above. To this suspension was added 0.5 g of 1.0% Pd-C and 10 ml of 0.2 N hydrochloric acid, and the mixture was stirred under a flow of hydrogen for 18 hours. After removing the catalyst by filtration and concentrating the solvent, the resulting residue was made alkaline with a saturated, aqueous solution of sodium hydrogencarbonate and extracted with the 2-butanone. The organic layer was washed with a saturated solution of sodium chloride and dehydrated with anhydrous magnesium sulfate. After concentration of the solvent in vacuo, the resulting residue was recrystallized with an appropriate solvent to obtain the objective compound as crystals.
Example 17 Preparation of the compounds of the present invention The compounds of Production Examples 52 to 57, 62, 63, 70 to 72, 75 and 77 were synthesized as follows: To a solution of alkyl and magnesium halide, which was prepared by adding 0.48 g (20 mmol) of magnesium and 20 mmol of alkyl halide to 17 ml of anhydrous ether, 50 ml of an anhydrous tetrahydrofuran (THF) solution containing 7.8 mmol of a saturated ketone compound were added dropwise. , obtained by the method of Example 8, 13 or 18. The mixture was refluxed for 18 hours, poured into 15 g of ice water and heated at 70 ° C for 2 hours with 24 ml of sulfuric acid at 25 ° C. %. This reaction mixture was basified with sodium hydroxide while cooling. The resulting suspension was extracted several times with ethyl acetate and the organic layer was washed with water and a saturated solution of sodium chloride, then dehydrated with anhydrous magnesium sulfate, after which the solvent was concentrated in vacuo. The residue, thus obtained, was fractionated by column chromatography, with NH silica gel (Fuji Silicia), and the fraction containing the objective compound was recrystallized with an appropriate solvent to obtain this objective compound.
The compounds of Production Examples 62 and 63 were isolated as by-products during the purification of the compounds in Production Examples 55 and 54. The compounds of Production Examples 55, 56 and 71 were obtained as hydrochloride crystals, dissolving the colorless oily substance to chestnut, mentioned above, isolated by column chromatography, in 2 ml of ethanol, adding diethyl ether (3 ml) saturated with hydrochloride, while cooling with ice, then filtering the crystals thus formed.
Example 18 Preparation of the compounds of. The present invention The compounds of Production Examples 58 to 60 were synthesized as follows: To a solution of phenylmagnesium bromide, which was prepared by adding 0.48 g (20 mmol) of magnesium and 2.1 ml 20 mmol of bromobenzene to 17 ml of anhydrous ether, 50 ml of an anhydrous tetrahydrofuran (THF) solution or suspension containing 7.8 mmoles of a saturated ketone compound, obtained by the method of Example 8, 13 or 16, was added dropwise. The mixture was subjected to at reflux for 18 hours, it was emptied into 15 g of ice water and heated at 70 C for 2 hours with 24 ml of 25% sulfuric acid. This reaction mixture was basified with sodium hydroxide while cooling. The resulting suspension was extracted several times with ethyl acetate and the organic layer was washed with water and a saturated solution of sodium chloride, then dehydrated with anhydrous magnesium sulfate, after which the solvent was concentrated in vacuo. The residue, thus obtained, was fractionated by column chromatography, with NH silica gel (Fuji Silicia), and the fraction containing the objective compound was recrystallized with an appropriate solvent to obtain this objective compound.
Example 19 Preparation of the compounds of the present invention The compound of Production Example 61 was synthesized as follows: A solution of benzylmagnesium bromide, which was prepared by adding 0.72 g (30 mmol) of magnesium pieces and 3.6 ml (30 mmoles) of benzyl bromide to 26 ml of anhydrous ether, 80 ml of an anhydrous tetrahydrofuran (THF) solution or suspension containing 12 mmole of a saturated ketone compound, obtained by the method of Example 8. The mixture was refluxed for 18 hours, emptied into 30 g of ice water and heated at 70 ° C for 2 hours with 35 ml of 25% sulfuric acid. This reaction mixture was basified with sodium hydroxide while cooling. The resulting suspension was extracted several times with ethyl acetate and the organic layer was washed with water and a saturated solution of sodium chloride, then dehydrated with anhydrous magnesium sulfate, after which the solvent was concentrated in vacuo. The residue, thus obtained, was fractionated by column chromatography, with NH silica gel (Fuji Silicia), and the fraction containing the objective compound was recrystallized with an appropriate solvent to obtain this objective compound. Production Example 1 Production of 2- [1- (3-pyridyl) methylidene] -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the 1-tetralone and pyridine-3-carbaldehyde, by the method of Example 1. Form: pale yellow crystals Yield: 80% Melting point: 76.5-77.5 ° C lH-NMR (80 MHz, CDC13) d (ppm): 2.73-3.28 (m, 4H); 7. 14-7.84 (m, 6H); 7.89-8.21 (m, 1H); 8.42-8.79 (m, 2H). IR (cm "1): 3045, 3015, 2930, 2880, 1660, 1600, 1590, 1410, 1290, 1020, 950, 740, 710.
Production Example 2 Production of 5-methoxy-2- [1- (3-pyridyl) methylidene] -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from 5-methoxy-l-tetralone and pyridine-3-carbaldehyde, by the method of Example 1. Form: yellow crystals Yield: 74% Melting point: 106-108 ° C * H-NMR (80 MHz, CDCl 3) d (ppm): 2.71-3.22 (m, 4H); 3. 85 (s, 3H); 6.91-7.47 (m, 3H); 7.60-7.88 (m, 3H); 8.47-8.76 (m, 2H) IR (cm "1): 3000, 2960, 2820, 1660, 1580, 1420, 1260, 1025, 740, 705.
Production Example 3 Production of 7-methoxy-2- [1- (3-pyridyl) ethylidene] -1,2,3,4-tetrahydro-1-naph alenone: The title compound was produced from the 7-methoxy-l-tetralone and pyridine-3-carbaldehyde, by the method of Example 1. Form: yellow crystals Yield: 88% Melting point: 102.4-104 ° C! H-NMR (400 MHz, CDC13) d (ppm): 2.90-2.94 (m, 2H); 3.08-3.11 (m, 2H); 3.88 (s, 3H); 7.09 (dd, 1H); 7.36 (dd, 1H); 7.79 (s, 1H); 8.57 (dd, 1H); 8.58 (s, 1H).
IR (cm "1): 3010, 2930, 2830, 1665, 1490, 1395, 1020, 910, 735, 710 Production Example 4 Production of 5-methoxy-2 - [1- (4-pyridyl) methylidene] -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from methoxy-l-tetralone and pyridine43 -carbaldehyde, by the method of Example 1. Form: brown-colored crystals Yield: 60% Melting point: 144-145 ° C - -NMR (80 MHz, CDC13) d (ppm) : 2.78-3.20 (m, 4H); 3. 88 (s, 3H); 6.97-7.47 (m, 4H); 7.58-7.86 (m, 2H), 8.62 (dd, 2H) IR (cm "1): 3000, 2950, 2820, 1660, 1600, 1590, 1475, 1265, 1025, 970, 750, 535.
Production Example 5 Production of 7-methoxy-2 - [1- (4-pyridyl) ethylidene] -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the 7-methoxy-l-tetralone and pyridine-4-carbaldehyde, by the method of Example 1. Form: pale yellow crystals Yield: 84% Melting point: 134.5-135 ° C -? - NMR (400 MHz, CDC13) d (ppm): 2.90-3.00 (m, 2H); 3.07-3.09 (m, 2H); 3.88 (s, 3H); 7.09-7.11 (m, 1H); 7.18-7.20 (m, 1H); 7.28 (2H); 7.61 (d, 1H); 7.72 (s, 1H); 8.67 (dd, 2H) IR (cm "1): 3060, 30.20, 2960, 2830, 1660, 1590, 1490, 1320, 1030, 830, 750, 539.
Production Example 6 Production of 6-methoxy-2 - [1- (3-pyridyl) methylidene] -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from 6-methoxy-l-tetralone and pyridine-3-carbaldehyde, by the method of Example 2. Form: white crystals Yield: 84% Melting point: 106.5-107 ° C? -NMR (400 MHz, CDCI3) d (ppm): 2.93-2.96 (m, 2H); 3.08-3.11 (m, 2H); 3.88 (s, 3H); 6.72 (d, 1H); 6.89 (dd, 1H); 7.35 (dd, 1H); 7.72 (d, 1H); 7.76 (s, 1H); 8.12 (d, 1H); 8.57 (dd, 1H); 8.68 (s, 1H) IR (cm "1): 3000, 2930, 2820, 1660, 1610, 1590, 1480, 1335, 1265, 1025, 950, 850.
Production Example 7 Production of 6-methoxy-2- [1- (4-pyridyl) methylidene] - 1,2,3, 4- tetrahydro-l-na-talenone: The title compound was produced from 6-methoxy-l-tetralone and pyridine-4-carbaldehyde, by the method of Example 2. Form: pale yellow crystals Yield: 78% Melting point: 127.5-128.5 ° C * H-NMR (400 MHz, CDCl 3) d (ppm): 2.93-2.96 (m, 2H); 3.05-3.09 (m, 2H); 3.88 (s, 3H); 6.71 (d, 1H); 6.89 (dd, 1H); 7.27 (d, 2H); 7.70 (s, 1H); 8.12 (d, 1H); 8.66 (d, 2H) IR (cm "1): 3020, 2970, 2840, 1665, 1600, 1690, 1490, 1325, 1275, 1140, 950.
Production Example 8 Production of 2- (3-pyridylmethyl) -1, 2, 3, 4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 1, by the method of Example 3. Form : white crystals Yield: 83% Melting point: 45-46.5 ° C? -NMR (80 MHz, CDC13) d (ppm): 1.41-2.40 (m, 4H); 2. 45-3.13 (m, 4H); 3.17-3.66 (m, 1H); 6.80-7.70 (m, 5H); 7.93-8.21 (m, 1H); 8.34-8.63 (m, "2H) IR (cm" 1): 3020, 2920, 2860, 1670, 1600, 1575, 1440, 1225, 1025, 750, 720 Production Example 9 Production of 5-methoxy-2- (3-pyridylmethyl) -1, 2, 3, 4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 2 by the method of Example 3. Shape: pale red crystals Yield: 88% Melting point: 76.5-78 ° C? -NMR (400 MHz, CDCl3) d (ppm): 1.73-1.79, 2.10- 2.15 (, 2H), 2.61-2.7 6, 3.06-3.12 (m, 4H); 3.38-3.42 / m, 1H); 3.86 (s, 3H); 7.01-7.03, 7.57-7.60 (m, 2H); 7.21-7.31 (m, 2H); 7.66 (d, 1H); 8.46-8.50 (m, 2H) IR (cm1): 3060, 3010, 2910, 2820, 1680, 1595, 1580, 1420, 1260, 1040, 950, 745, 710.
Production Example 10 Production of 6-methoxy-2- (3-pyridylmethyl) -1, 2, 3, 4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 6 by the method of Example 3. Form: brown-colored crystals Yield: 73% Melting point: 61.5-62 ° C -NMR (400 MHz, CDC13) d (ppm): 1.75-1.81, 2.05-2.10 (m, 2H); 2.68-2.73 (m, 2H); 2.90-2.93 (m, 2H); 3.43-3.45 (m, 1H); 3.84 (s, 3H); 6.67 (d, 1H); 6.83 (dd); 7.21-7.25 (m, 1H); 7.58 (d, 1H); 8.03 (d, 1H); 8.46-8.50 (m, 2H) IR (cm "1): 3040, 3020, 2940, 2910, 2820, 1660, 1600, 1420, 1260, 1250, 1020, 920, 855, 710.
Production Example 11 Production of 7-methoxy-2- (3-pyridylmethyl) -1, 2, 3, 4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 3 by the method of Example 3. * • Shape: brown crystals Yield: 77% Melting point: 69.5-70 ° C? -NMR (400 MHz, CDC13) d (ppm): 1.76-1.84 (each M, 2H), 2.71-2.78 (m, 2H); 2.88-2.91 (m, 2H); 3.39-3.46 (m, 1H); 3.84 (s, 3H); 7.06 (dd, 1H); 7.14 (d, 1H); 7.22-7.26 (m, 1H); 7.53 (d, 1H); 7.57-7.60 (m, 1 H) '; 8.47-8.50 (m, 2H) IR (cm "1): 3100, 3080, 3060, 2970, 2880, 2850, 1685, 1620, 1510, 1435, 1260, 1040, 745, 730, 560 Production Example 12 Production of 5-methoxy-2- (4-pyridylmethyl) -1, 2, 3, 4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 4 by the method of Example 3. Form: dark yellow crystals Yield: 70% Melting point: 103.5-105 ° C? -NMR (80 MHz, CDC13) d (ppm): 1.58-3.58 (m, 7H); 3.86 (s, 3H); 6.84-7.39 (m, 4H); 7.54-7.72 (d, 1H); 8.50 (d, 2H) IR (crrT1): 3020, 2940, 2840, 1675, 1600, 1590, 1470, 1260, 1045, 970, 740, 510 Production Example 13 Production of 6-methoxy-2- (4-pyridylmethyl) -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 7 by the method of Example 3. Form: colorless crystals Yield: 83% Melting point: 84-85 ° C -NMR (400 MHz, CDC13) d ( ppm): 1.76-1.82, 2.03-2.00 (m, 2H); 2.66-2.77 (m, 2H); 3.44-3.48 (m, 1H); 3.85 (s, 3H); 6.67 (d, 1H); 6.83 (dd, 1H); 7.20 (d, 2H); 8.03 (d, 1H); 8.51 (d, 2H) IR (cm "1): 3060, 3010, 2940, 2840, 1670, 1605, 1495, 1255, 1135, 1030, 930, 845, 525 Production Example 14 Production of 7-methoxy-2- (4-pyridylmethyl) -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 5 by the method of Example 3. Form: colorless crystals Yield: 79% Melting point: 90-91.5 ° C? -NMR (80 MHz, CDC13) d (ppm): 1.35-2.32 (m, 2H); 2. 63-2.97 (m, 4H); 3.22-3.58 (m, 1H); 2.82 (s, 3H); 7.09-7.25 (m, 4H); 7.54-7.58 (m, 1H); 8.52 (d, 2H) IR (cpf1): 3060, 3010, 2980, 2920, 2820, 1670, 1605, 1490, 1415, 1245, 1030, 830, 510.
Production Example 15 Production of 3- [(1-methyl-3, 4-dihydro-2-naph-alenyl) -methyl] pyridine: The title compound was produced from the compound of Production Example 8 by the method of Example 4. Shape: pale yellow oily substance Yield: 64%? -NMR (400 MHz, CDC13) d (ppm): 2.16-2.17 (m, 2H); 2.68-2.72 (m, 2H); 3.63 (s, 2H); 7.11.7.33 (m, 5H); 7.51 (d, 1H); 8.45-8.51 (m, 2H) IR (cm1): 3010, 2980, 2910, 2870, 2820, 1570, 1470, 1420, 1020, 760, 720 Production Example 16 Production of 3- [(5-methoxy-1-methyl-3, 4-dihydro-2-naphthalenyl) -yl] pyridine: The title compound was produced from the compound of Production Example 9 by the method of Example 4. Form: yellow oily substance Yield: 63% -NMR (400 MHz, CDC13) d (ppm): 2.11-2.17 (m, 5H); 2.68-2.72 (m, 2H); 3.63 (s, 2H); 3.82 (s, 3H); 6.78, 6.98 (d, 2H); 7.17-7.21 (m, 2H); 7.51 (d, 1H); 8.44.8.51 (m, 2H), IR (cm "1): 3010, 2980, 2920, 2820, 1570, 1465, 1635, 1260, 1045, 780, 710 Production Example 17 Production of 3- [(6-methoxy-l-methyl-3, 4-dihydro-2-naphthaleniDmethyl] pyridine: The title compound was produced from the compound of Production Example 10 by the method of Example 4. Form: orange oily substance Yield: 48%? -NMR (400 MHz, CDC13) d (ppm): 2.14-2.16 (m, 5H); 2.65-2.69 (m, 2H); 3.61 (s, 2H); 3.80 (s, 3H); 6.68 (d, 1H); 6.75 (dd, 1H); 7.18-7.26 (m, 2H); 7.51 (d, 1H); 8.44-8.50 (m, 2H) IR (cm "1): 3010, 2980, 2920, 2820, 1605, 1570, 1495, 1420, 1250, 1030, 710 Production Example 18 Production of 3- [(7-methoxy-l-methyl-3, -dihydro-2-naphthaleniDmethyl] pyridine: The title compound was produced from the compound of Production Example 11 by the method of Example 4. Form: oily brown substance Yield: 65% -NMR (400 MHz, CDC13) d (ppm): 2.13-2.15 (m, 5H); 2.61-2.65 (m, 2H); 3.63 (s, 2H); 3.82 (s, 3H); 6.68 (dd, 1H); 6.89 (d, 1H); 7.01-7.03 (m, 1H); 7.18-7.21 (m, 1H); 7.51 (d, 1H); 8.46-8.50 (m, 2H) IR (cm "1): 3020, 2990, 2930, 2830, 1615, 1575, 1490, 1420, 1310, 1210, 1045, 720 Production Example 19 Production of 4- [(1-methyl-3, 4-dihydro-2-naphthalenyl) -methyl] pyridine: The title compound was synthesized from the material compound, 2- (4-pyridylmethylene) .1, 2, 3, 4-tetrahydro-1-naphthalenone and purified by crystallization with petroleum ether, according to the method of Sam J. et al. (J. Pharm, Sci., 56, 644-47, 1967). Form: colorless crystals Yield: 76% Melting Point: 67-69 ° C? -NMR (300 MHz, CDC13) d (ppm): 2.13-2.18 (m, 5H); 2.68-2.79 (m, 2H); 3.63 (s, 2H); 7.06-7.24 (m, 5H); 7.33 (d, 1H); 8.49 (d, 2H) IR (cm "1): 3060, 301 * 5, 2995, 2980, 2920, 2880, 2815, 1598, 1413, 995, 765, 473.
Production Example 20 Production of 4- [(5-methoxy-l-methyl-3,4-dihydro-2-naphthalenyl) methyl] pyridine: The title compound was produced from the compound of Production Example 12 by the Method of Example 4. Form: colorless crystals Yield: 52% Melting Point: 87-89IC-NMR (80 MHz, CDC13) d (ppm): 1.62-2.32 (m, 5H); 2. 48-2.93 (m, 2H); 3.60 (s, 2H); 3.79 (s, 3H); 6.62-7.34 (m, 4H); 7.49 (d, 1H); 8.45 (d, 2H) IR (cm "1): 3070, 2995, 2920, 1600, 1580, 1570, 1465, 1260, 1050, 795 Production Example 21 Production of 4- [(6-methoxy-1-methyl-3, 4-dihydro-2-naphthalysyl) methyl] pyridine: The title compound was produced from the compound of Production Example 13 by the method of Example 4. Form: pale green crystals Yield: 64% Melting Point: 51-51.5 ° C? -NMR (80 MHz, CDC13 ) d (ppm): 1.96-2.32 (m, 5H); 2. 49-2.94 (m, 2H); 3.59 (s, 2H); 3.79 (s, 3H); 6.64-6.85 (m, 2H); 7.04-7.35 (m, 3H); 7.49 (d, -1H); 8.48 (d, 2H) IR (cm "1): 3020, 2930, 2840, 1610, 1505, 1420, 1255, 1040, 820 Production Example 22 Production of 4- [(7-methoxy-l-methyl-3, 4-dihydro-2-naphthaleniDmethyl] pyridine: The title compound was produced from the compound of Production Example 14 by the method of Example 4. Form : colorless crystals Yield: 65% Melting point: 57.5-58.5 ° C -NMR (80 MHz, CDC13) d (ppm): 1.92-2.29 (m, 5H); 2. 43-2.84 (m, 2H); 3.60 (s, 2H); 3.79 (s, 3H); 6.63 (dd, 1H); 6.82-7.32 (m, 4H); 8.47 (d, 2H) IR (cm1): 3000, 2920, 2820, 1610, 1590, 1485, 1420, 1200, 1035, 810, 510.
Production Example 23 Production of 5-methyl-6- (3-pyridylmethyl) -7,8-dihydro-1-naphthalenol: The title compound was produced from the compound of Production Example 16 by the method of Example 5. Form: white solid Yield: 71% Melting point: 171-173 ° C? -NMR (400 MHz, d6-DMSO) d (ppm): 2.05-2.09 (m, 2H); 2.51-2.59 (m, 2H); 3.75 (s, 2H); 6.70, 6.80 (d, 1H); 6.98-7.02 (m, 1H); 7.71 (dd, 1H); 8.07 (d, 1H); 8.64-8.67 (m, 2H); 9.20 (s, 1H) IR (cm1): 3020 (long), 2900, 2740, 2700, 1570, 1550, 1460, 1300, 1285, 1165, 940, 785 Production Example 24 Production of 5-methyl-6- (3-pyridylmethyl) -7,8-dihydro-2-naphthalenol: The title compound was produced from the compound of Production Example 17 by the method of Example 5.
Form: white crystals Yield: 57% Melting point: 180-182 ° C? -NMR (400 MHz, d6-DMSO) d (ppm): 2.03-2.09 (m, 5H); 2.50-2.55 (m, 2H); 3.59 (s, 2H); 6.52 (d, 1H); 6.58 (dd, 1H); 7.10 (d, 1H); 7.25-7.29 (m, 1H); 8.07 (d, 1H); 8.40-8.45 (m, 2H); 9.25 (s, 1H) IR (cm "1): 2980 (wide), 2900, 2820, 2680, 2600, 1610, 1600, 1595, 1425, 1290, 1255, 1160, 815, 710 Production Example 25 Production of 8-methyl-7- (3-pyridylmethyl) -5,6-dihydro-2-naphthalenol: The title compound was produced from the compound of Production Example 18 by the method of Example 5. Form: brown colored solid Yield: 53% Melting point: 145-147.5 ° C -NMR (400 MHz, d6-DMSO ) d (ppm): 1.96-2.13 (m, 5H); 2.45-2.56 (m, 2H); 3.62 (s, 2H); 6.51-6.52 (m, 1H); 6.72-6.73 (m, 1H); 6.87-6.89 (m, 1H); 7.25-7.31 (m, 1H); 7.70-7.72 (m, 1H); 8.41-8.46 (m, 2H); 9.08 (s, 1H) IR (cm "1): 3000 (wide), 2900, 2810, 2650, 1610, 1570, 1475, 1420, 1300, 1040, 805, 710 Production Example 26 Production of 5-methyl- 6- (4-pyridylmethyl) -7,8-dihydro-2-naphthalenol: The title compound was produced from the compound of Production Example 20 by the method of Example 4. Form: white solid Yield: 43% Dot of fusion: 158-160.5 ° C? -NMR (400 MHz, d6-DMSO) d (ppm): 2.03-2.09 (m, 5H); 2.50-2.585 (m, 2H); 3.62 (s, 2H); 6.68-6.70, 6.78-6.80, 7.00-7.01 (m, 3H); 7.23 (d, 2H); -8.45 (d, 2H); 9.18 (s, 1H) IR (cm "1): 3040 (wide), 2910, 2820, 2650, 1600, 1570, 1460, 1300, 1280, 1000, 785 Production Example 27 Production of 5-methyl-6- (4-pyridylmethyl) -7,8-dihydro-2-naphthalenol: The title compound was produced from the compound of Production Example 21 by the method of Example 4. Form: white solid Yield: 88% Melting point: 197.5-200 ° C? -NMR (400 MHz, d6-DMSO) d (ppm): 2.03-2.09 (m, 5H); 2.47-2.55 (m, 2H); 3.59 (s, 2H); 6.53-6.60 (m, 2H); 7.09-7.23 (m, 3H); 8.45 (d, 2H); 9.18 (s, 1H) IR (cm1): 2980 (wide), 2910, 2870, 2810, 2670, 2650, 1600, 1450, 1255, 1005, 810, 780 Production Example 28 Production of 8-methyl-7- (4-pyridylmethyl) -5,6-dihydro-2-naphthalenol: The title compound was produced from the compound of Production Example 22 by the method of Example 4. Form: solid white Yield: 93% Melting point: 146.5-147 ° C? -NMR (400 MHz, d6-DMSO) d (ppm): 1.99-2.08 (m, 5H9; 2.50-2.54 (m, 2H); 3.62 (s, 2H); 6.51-6.54, 6.72-6.73, 6.88-6.90 (m, 3H9, 7.23 (d, 2H), 8.46 (d, 2H), 9.10 (s, 1H) IR (cm1): 3000 (wide), 2900, 2810, 2640, 1600, 1570, 1420, 1340, 1305, 1190, 1005, 810, 620 Production Example 29 Production of 5-methoxy-2- [1- (4-pyridyl) methylidene] -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the compound 5-methoxy-l-tetralone and pyridine-4-carbaldehyde, by the method of Example 6 Form: brown colored crystals Yield: 60% Melting point: 144-145 ° C? -NMR (80 MHz, CDC13) d (ppm): 2.78-3.20 (m, 4H); 3. 86 (s, 3H); 6.97-7.47 (m, 4H); 7.58-7.86 (m, 2H); 8.62 (dd, 2H) IR (cm "1): 3000, 2950, 2820, 2660, 1600, 1590, 1475, 1265, 1025, 970, 750, 535 Production Example 30 Production of 7-methoxy-2- [1- (4-pyridyl) methylidene] - 1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of 7-methoxy-l-tetralone and pyridine-4-carbaldehyde, by the method of Example 6 Form: pale yellow crystals Yield: 84% Melting point: 134.5- 135 ° C -NMR (400 MHz, CDC13) d (ppm): 2.90-3.06 (m, 2H); 3.07-3.09 (m, 2H); 3.88 (s, 3H); 7.09-7.11 (m, 1H); 7.18-7.20 (m, 1H); 7.28 (2H); 7.61 (d, 1H); 7.72 (s, 1H); 8.67 (dd, 2H) IR (cm "1): 3060, 3020, 2960, 2900, 2830, 1660, 1590, 1490, 1320, 1255, 1030, 830, 750, 530 Production Example 31 Production of 6-methoxy-2- [1- (4-pyridyl) methylidene] -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the 6-methoxy compound. l-tetralone and pyridine-4-carbaldehyde, by the method of Example 7 Form: pale yellow crystals Yield: 78% Melting point: 127.5-128.5 ° C? -NMR (400 MHz, CDC13) d (ppm) : 2.93-2.96 (m, 2H); 3.05-3.09 (m, 2H); 3.88 (s, 3H); 6.71 (d, 1H); 6.89 (dd, 1H); 7.27 (d, 2H); 7.70 (s, 1H, -CH =); 8.12 (d, 1H); 8.66 (d, 2H) IR (cm "1): 3020, 2970, 2840, 1665, 1600, 1590, 1490, 1325, 1275, 1140, 950 Production Example 32 Production of 2- [1- (lH-4-imidazolyDmethylidene] -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the 6-methoxy compound. l-tetralone and lH-imidazolyl-4-carbaldehyde, by the method of Example 6 Form: pale yellow crystals Yield: 84% Melting point: 154-155 ° C? -NMR (80 MHz, d6-DMSO) d (ppm): 2.86 (t, 2H), 3.37 (t, 2H), 3.83 (s, 3H), 6.79-7.05 (m, 2H), 7.58 (s, 2H), 7.85-8.05 (m, 2H) IR (cm1): 3100, 2900, 2820, 2590, 1660, 1610, 1585, 1440, 1330, 1305, 1255, 1130, 1095, 830, 620, 590 Production Example 33 Production of 5-methoxy-2- (4-pyridylmethyl) -1, 2, 3, 4-tetrahydro-1-naphthalene: The title compound was produced from the compound of Production Example 29, by the method of Example 8 Form: dark yellow amorphous powder Yield: 70% Melting point: 103.5-105 ° C -NMR (80 MHz, CDC13) d (ppm): 1.58-3.58 (m, 7H); 3. 86 (s, 3H); 6.84-7.39 (m, 4H); 7.54-7.72 (d, 1H); 8.50 (d, 2H) IR (cm "1): 3020, 2940, 2840, 1675, 1600, 1590, 1580, 1470, 1260, 1045, 970, 740, 510 Production Example 34 Production of 6-methoxy-2- (4-pyridylmethyl) -1,2,4,4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 31, by the method of Example 8 Form: colorless crystals Yield: 83% Melting point: 84-85 ° C -NMR (400 MHz, CDC13) d (ppm): 1.76-1.82, 2.03-2.09 (m, 2H); 2.66-2.77 (m, 2H); 3.44-3.48 (m, 1H); 3.85 (s, 3H); 6.67 (d, 1H); 6.83 (dd, 1H);; 7.20 (d, 2H); 8.03 (d, 1H); 8.51 (d, 2H) IR (cm "1): 3060, 3010, 2940, 2840, 1670, 1605, 1495, 1255, 1135, 1030, 930, 845, 525. Production Example 35 Production of 7-methoxy 2- (4-pyridylmethyl) -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 30, by the method of Example 8 Form: colorless crystals Yield: 79% Melting point: 90-91.5 ° C? -NMR (80 MHz, CDC13) d (ppm): 1.35-2.32 (m, 2H); 2.63.2.97 (m, 4H); 3.22-3.58 (m, 1H ), 3.82 (s, 3H), 7.09-7.25 (m, 4H), 7.54-7.58 (m, 1H), 8.52 (d, 2H) IR (cm "1): 3060, 3010, 2980, 2920, 1670, 1605, 1490, 1415, 1245, 1030, 830, 510.
Production Example 36 Production of 2- (1H-imidazolylmethyl) -6-methoxy-1,2,3,4-tetrahydro-1-naph alenone: The title compound was produced from the compound of Production Example 32, by the method of Example 8 Form: colorless crystals Yield: 70% Melting point: 148-150 ° C -NMR (80 MHz, d6-DMS0) d (ppm): 1.46-3.30 (m, 7H); 3.81 (s, 3H); 6.67-7.24 (m, '3H); 7.50 (s, 1H); 7.91 (d, 1H) IR (cm "1): 3100, 2920, 2840, 2820, 2560, 1655, 1595, 1350, 1250, 1100, 1020, 930, 825, 660, 580, 440.
Production Example 37 Production of 4- [(1-ethyl-5-methoxy-3,4-dihydro-2-naphthalene D-methyl] -pyridine: The title compound was produced from the compound of Production Example 33, by the method of Example 9 Form: yellow solid Yield: 5% Melting point: 59-62 ° C? -NMR (400 MHz, CDC13) d ( ppm): 1.13 (t, 3H); 2.08 (t, 2H); 2.56-2.68 (m, 4H); 3.63 (m, 2H); 3.82 (s, 3H); 6.79 (d, 1H); 7.02 (d, 1H); 7.16-7.24 (m, 3H); 8.50 (s, 2H) IR (cm1): 3060, 2980, 2930, 2830, 1600, 1570, 1470, 1410, 1310, 1260, 1160, 1060, 1050, 990, 940, 790, 730.
Production Example 38 Production of 4- [(1-ethyl-6-methoxy-3, 4-dihydro-2-naphthalenyl-methyl] -pyridine: The title compound was produced from the compound of Production Example 34, by the method of Example 9 Form: colorless crystals Yield: 41% Melting point: 134-137 ° C -NMR (400 MHz, d6-DMSO) d (ppm): 1.02 (t, 3H); 2. 08 (t, 2H); 2.57 (q, 2H); 2.65 (t, 2H); 3.74 (s, 3H); 3.91 (s, 2H); 6.72-6.81 (m, 2H); 7.27 (d, 1H); 7.89 (d, 2H); 8.81 (d, 2H) IR (cm1): 3060, 3020, 2960, 2935, 2880, 1610, 1570, 1415, 1265, 1160, 1125, 1080, 1040, 990, 820, 620.
Production Example 39 Production of 4- [(L-ethyl-7-methoxy-3,4-dihydro-2-naphthaleniDmethyl] -pyridine: The title compound was produced from the compound of Production Example 35, by the method of Example 9 Form: pale yellow oily substance Yield: 13%? -NMR (400 MHz, CDC13) d (ppm): 1.15 (t, 3H); 2. 10 (t, 2H); 2.56-2.68 (m, 4H); 3.63 (s, 2H); 3.82 (s, 3H); 6. 69 (d, 1H); 6.93 (s, 1H); 7.04 (d, 2H); 7.89 (s, 2H); 8.50 (s, 2H). IR (cm "1): 3030, 3010, 2960, 2930, 2880, 2830, 1600, 1570, 1490, 1410, 1310, 1276, 1215, 1045, 870, 900.
Production Example 40 Production of 4- [(6-methoxy-l-methyl-3,4-dihydro-2-naphthaleniDmethyl] -lH-imidazole: The title compound was produced from the compound of Production Example 34, by the method of Example 9 Form: white solid Yield: 29% Melting point: 171-173 ° C? -NMR (400 MHz, d6-DMSO) d (ppm): 2.02 (s, 3H); 2.15 (t, 2H), 2.61 (t, 2H), 3.44 (s, 2H), 3.72 (s, 2H), 6.65-6.79 (m, 3H), 7.16 (d, 1H), 7.51 (s, 1H) IR (cm " 1): 3100, 3060, 2960, 2920, 2880, 1605, 1500, 1460, 1310, 1255, 1170, 1030, 830.
Production Example 41 Production of 4- [(5-methoxy-3,4-dihydro-2-naphthalysyl) -methyl] -pyridine: The title compound was produced from the compound of Production Example 33, by the method of Example 9 Form: pale yellow solid Yield: 8% Melting point: 75-77 ° C? -NMR (400 MHz, CDC13) d (ppm): 2.16 (t, 2H); 2.79 (t, 2H); 3.49 (s, 2H); 3.81 (s, 3H); 6.24 (s, 1H); 6. 66-6.73 (each d, each 1H); 7.11 (t, 1H); 7.18 (d, 2H); 8.52 (s, 2H) IR (cm "1): 3000. 2960, 2920, 2880, 2830, 1600, 1590, 1470, 1440, 1270, 1095, 885, 895, 725.
Production Example 42 Production of 4- [(6-methoxy-3,4-dihydro-2-naphthalenyl) -methyl] -pyridine: The title compound was produced from the compound of Production Example 34, by the method of Example 11 Form : orange crystals Yield: 77% Melting point: 63-64 ° C? -NMR (400 MHz, CDC13) d (ppm): 2.15 (t, 2H); 2.77 (t, 2H); 3.47 (s, 2H); 3.79 (s, 3H); 6.23 (s, 1H); 6.58 (d, 1H); 6.66 (dd, 1H); 6.99 (d, 1H); 7.18 (d, 2H); 8.51 (d, 2H) IR (cm "1): 3060, 3040, 3000, 2980, 2940, 2920, 2830, 1615, 1600, 1570, 1400, 1250, 1150, 1110, 1060, 800, 790, 590, 475 .
Production Example 43 Production of 4- [(7-methoxy-3,4-dihydro-2-naphthalenyl) -methyl] -pyridine: The title compound was produced from the compound of Production Example 35, by the method of Example 8 Form: pale yellow oily substance Yield: 11% -NMR (400 MHz, CDC13) d (ppm): 2.16 (t 2H); 2. 72 (t, 2H); 3.49 (s, 2H); 3.78 (s, 3H); 6.23 (s, 1H); 6.58 (d, 1H); 6.66 (dd, 1H); 6.99 (d, 1H); 7.18 (d, 2H); 8.51 (d, 2H) IR (cm1): 3060, 3020, .3000, 2930, 2830, 1605, 1580, 1500, 1420, 1270, 1220, 1140, 1040, 815.
Production Example 44 Production of 4- [(5-methoxy-1-propyl-3,4-dihydro-2-naphthalenyl) -methyl] -pyridine hydrochloride: The title compound was produced from the compound of Example Production 34, by the method of Example 9 Form: colorless crystals Yield: 19% Melting point: 145-147 ° C? -NMR (400 MHz, dg-DMSO) d (ppm): 0.91 (t, 3H); 1.36-1.45 (m, 2H); 2.07 (t, 2H); 2.53 (t, 2H); 2.65 (t, 2H); 3.74 (s, 3H); 3.92 (s, 2H); 6.74-6.80 (m, 2H); 7.25 (d, 1H); 7.89 (d, 2H); 8.8. (d, 2H) IR (cm "1): 3040, 2940, 2870, 2830, 2460, 2105, 2005, 1635, 1615, 1605, 1500, 1310, 1255, 1035, 1005, 850, 820, 790 Production Example 45 Production of 6- (4-pyridylmethyl) -7,8-dihydro-2-naphthalenol: The title compound was produced from the compound of Production Example 42, by the method of Example 10 Form: yellow amorphous powder Yield: 8 % Melting point: > 300 ° C -NMR (400 MHz, CDC13) d (ppm): 2.05 (t, 2H); 2.62 (t, 2H); 3.46 (s, 2H); 6.21 (s, 1H); 6.44-6.55 (m, 2H); 6.82 (d, 1H); 7.26 (d, 2H); 8.47 (d, 2H); 9.25 (s, 1H) IR (cm "1): 3120 (long), 3020, 2920, 1610, 1500, 1420, 1285, 1150, 1010, 820, 790 Production Example 46 Production of 2- (lH-4-imidazolylmethyl) -6-methoxy-3,4-dihydronaphthalene hydrochloride: The title compound was produced from the compound of Production Example 36, by the method of Example 11 Form: colorless crystals Yield: 58% Melting point: 184-186 ° C? -NMR (400 MHz, d6-DMSO) d (ppm): 2.17 (t, 2H) 2. 73 (t, 2H); 3.56 (s, 2H); 3.72 (s, 3H); 6.22 (s, 1H) 6.63-6.74 (m, 2H); 6.95 (d, 1H); 7.50 (s, 1H); 9.00 (s, 1H) 14.58 (s, 1H) IR (cm "1): 3080, 3000, 2820, 2600, 1620, 1580, 1260, 1160, 1115, 1040, 860, 810, 635 Production Example 47 Production of 2- [1- (1H-4-imidazolyl) methylidene] -7-methoxy-1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from 7-methoxy-1-tetralone and imidazolyl-4-carbaldehyde, by the method of Example 12 Form: pale yellow crystals Yield: 94% Melting point: 162-164 ° C? -NMR (80 MHz, ds-DMSO) d (ppm): 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, 1H) IR (cm "1): 3110, 3015, 2925, 2845, 2180, 2120, 1670, 1600, 1400, 1030, 830, 610 Production Example 48 Production of 2- (1H-4-imidazolylmethyl) -7-methoxy-1,2,3-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 47, by the method of Example 13 Form: colorless crystals Yield: 44% Melting point: 158-160 ° C? -NMR (80 MHz, d6-DMSO) d (ppm): 1.73-2.41 (m, 3H); 2.57-3.15 (m, 4H); 3.82 (s, 3H); 6.83 (s, 1H); 6.95-7.22 (m, 2H); 7.24-7.55 (m, 2H) 'IR (cm "1): 3110, 2990, 2950, 2930, 2840, 1680, 1615, 1500, 1300, 1040, 625 Production Example 49 Production of 4- [(7-methoxy-l-methyl-3,4-dihydro-2-naphthaleniDmethyl] -lH-imidazole: The title compound was produced from the compound of Production Example 48 by the method of Example 14 Form: chestnut solid Yield: 15% Melting point: 133-135 ° C? -NMR (400 MHz, d6-DMSO ) d (ppm): 2.09 (s, 3H); 2. 22 (t, 2H); 2.64 (t, 2H); 3.59 (s, 2H); 3.81 (s, 3H); 6.67 (dd, 1H); 6.79 (s, 1H); 6.86 (d, 1H); 7.01 (d, 1H); 7.57 (s, 1H) IR (cm1): 3070, 3000, 2830, 2830, 2620, 1610, 1570, 1490, 1275, 1205, 1045, 990, 870, 840, 815, 735, 630.
Production Example 50 Production of 2- [1- (1H-4-imidazolyl) methylidene] -5-methoxy-1,2,3,4-tetrahydro-1-naph alenone: The title compound was produced from 5-methoxy -l-tetralone, by the method of Example 15 Form: yellow crystals Yield: 87% Melting point: 194.0-195.0 ° C? -NMR (80 MHz, d6-DMS0) d (ppm): 2.86 (t, 2H), J = 6.5Hz); 3.36 (t, 2H, J = 6.5Hz), 3.83 (s, 3H); 7.18 (d, 1H, J = 7.9Hz); 7.32 (t, 1H, J = 7.9Hz); 7.55 (d, 1H, J = 7.9Hz); 7.55 (s, 1H); 7.62 (s, 1H); 7.85 (s, 1H) IR (KB cm "1): 3450, 3100, 2850, 1660, 1580, 1310, 1260, 1140, 1080, 1020 FAB-MS: 255 (M + l) Elemental isis: C15H14N202 ^ H20 = 263.30 Calculated: C 68.43, H 5.74, N 10.64 Found: C 68.80, H 5.59, N 10.89 Production Example 51 Production of 2- (lH-4-imidazolylmethyl) -5-methoxy-1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 50 , by the method of Example 16 Form: colorless crystals Yield: 83% Melting point: 145.5-148.0 ° C? -NMR (500 MHz, CDCI d (ppm): 1.59 (m, 1H); 2. 04 (ddd, 1H, J = 4.3, 8.9, 13.5 Hz); 2.51 (dd, 1H, J = 9.1, . 0 Hz); 2.56 (m, 1H); 2.73 (m, 1H); 2.90 (dt, 1H, J = 4.3, 17.7 Hz); 3.08 (dd, 1H, J = 4.0, 14.6 Hz); 6.78 (s, 1H), 7.11 (dd, 1H, J = 0.9, 7.9 Hz); 7.23 (t, 1H, J = 7.9 Hz); 7.42 (dd, J = 0.9, 7.9 Hz); 7.57 (d, 1H, J = 0.9 Hz) IR (cm "1): 3450, 3050, 2820, 1680, 1580, 1460, 1250, 1100, 1040, 940 FAB-MS: 257 (M + l) Elemental Analysis: C15H16N202 = 256.30 Calculated: C 70.29, H 6.29, N 10.93 Found: C 69.97, H 5.83, N 10.98.
Production Example 52 Production of 4- [(5-methoxy-l-methyl-3, 4-dihydro-2-naphthaleniDmethyl] -lH-imidazole: The title compound was produced from the compound of Production Example 51, using magnesium iodide, by the method of Example 17 Form: white crystalline powder Yield: 66% Melting point: 132.5-135.0 ° C -NMR (500 MHz, d6-DMSO) d (ppm): 2.03 (s, 3H); 2.13 (t, 2H, J = 8.5Hz), 2.58 (t, 2H, J = 8.5Hz), 3.45 (s, 2H), 3.74 (s, 3H), 6.73 (s, 1H), 6.82 (d, 1H, J = 8.2Hz); 6.89 (d, 1H, J = 8.2Hz); 7.13 (t, 1H, J = 8.2Hz); 7.50 (s, 1H); 11.76 (width s 1H)); IR (KBr cm "1): 3400, 3100, 2830, 1680, 1590, 1570, 1510, 1480, 1400, 1260 FAB-MS: 255 (M + l) Elemental Analysis: C16H18N20 H20 = 263.4 Calculated: C 72.98, H 7.27, N 10.64 Found: C 73.19, H 7.01, N 11.11.
Production Example 53 Production of 4- [(1-ethyl-6-methoxy-3,4-dihydro-2-naphthalenyl-methyl] -lH-imidazole: The title compound was produced from the compound of Production Example 36, using magnesium bromide, by the method of Example 17 Form: brown colored crystalline powder Yield: 32% Melting point: 138.0-141.5 ° C? NMR (500 MHz, d6-DMSO) d (ppm): 1.02 (t, 3H, J = 7.3 Hz); 2.12 (t, 2H, J = 7.6Hz); 2.52 (dd, 2H; J = 7.3, 15.0 Hz); 2.58 (t, 2H; J = 7.6 Hz); 3.42 (s, 2H); 3.71 (s, 3H); 6.69-6.89 (m, 3H); 7.17 (d, 1H, J = 6.6 Hz); 7.48 (s, 1H); 11. 75 (width s, 1H) IR (KBr cm "1): 3450, 3 * 050, 2830, 1600, 1500, 1460, 1300, 1250, 1170, 1040 FAB-MS: 269 (M + l) Elemental Analysis: C17H20N2O = 268.36 Calculated: C 76.09, H 7.51, N 10.44 Found: C 75.11, H 7.26, N 10.30 Production Example 54 Production of 4- [(1-ethyl-6-methoxy-3,4-dihydro-2-naphthaleniDmethyl] -lH-imidazole: The title compound was produced from the compound of Production Example 48, using the bromide of magnesium, by the method of Example 17 Form: white crystalline powder Yield: 33% Melting point: 111.5-113.5 ° C? -NMR (500 MHz, d6-DMSO) d (ppm): 1.04 (t, 3H, J = 7.6 Hz); 2.13 (t, 2H, J = 7.6Hz); 2.51-2.57 (M, 4H); 3.45 (s, 2H); 3.72 (s, 3H); 6.70 (dd, 1H, J = 2.5, 8.2 Hz); 6.74 (width s, 1H); 6.79 (d, 1H, J = 2.5 Hz); 7.00 (d, 1H, J = 8.2 Hz); 7.49 (s, 1H); 11.76 (width s, 1H) IR (KBr, -cm "1): 3450, 3060, 2830, 1600, 1570, 1490, 1270, 1170, 1040, 980 FAB-MS: 269 (M + l) Elemental Analysis: C17H20N2O = 268.36 Calculated: C 76.09, H 7.51, N 10.44 Found: C 75.74, H 7.01, N 10.86 Production Example 55 Production of 4- [(1-ethyl-5-methoxy-3, 4-dihydro-2-naphthalenyl) methyl] -1H-imidazole hydrochloride: The title compound was produced from the compound of Production Example 51, using magnesium bromide, by the method of Example 17 Form: brown-colored crystals Yield: 14% Melting Point: 164.0-166.6 ° C? -NMR (500 MHz, d6-DMSO) d (ppm): 1.00 (t, 3H, J = 7.6Hz); 2.10 (t, 2H, J = 8.0 Hz); 2.55 (dd, 2H, J = 7.5, 15.1 Hz); 2.61 (t, 2H, J = 7.6Hz); 3.65 (s, 2H); 3.76 (s, 3H); 6.85 (d, 1H, J = 7.6Hz); 6.96 (d, 1H, J = 7.9Hz); 7.17 (dd, 1H, J = 7.6, 7. 9 Hz); 7.38 (d, 1H, J = 1.2 Hz); 9.02 (d, 1H, J = 1.2 Hz), 14.59 (width s, 2H) IR (KBr, -cm "1): 3390, 3080, 2950, 2820, 1610, 1570, 1460, 1250, 1040, 770 FAB-MS: 269 (M + l) Elemental Analysis: C17H20N2O HCl = 304.82 Calculated: C 66.99, H 6.94, N 9.19 Found: C 66.76, H 6.64, N 9.43.
Production Example 56 Production of 4- [(6-methoxy-1-propyl-3,4-dihydro-2-naphthaleniDmethyl] -lH-imidazole: The title compound was produced from the compound of Production Example 36, using magnesium bromide, by the method of Example 17 Form: colorless crystals Yield: 12% Melting point: 123.5-124.5 ° C? -NMR (500 MHz, d6-DMS0) d (ppm): 0.90 (t, 3H, J = 6.4Hz); 1.41 (m, 2H); 2.11 (dd, 2H, J = 7.6 7.9Hz); 2.49 (m, 2H); 2.58 (dd, 2H, J = 7.6 8.0 Hz); 3.44 (s, 2H); 3.71 (s, 3H); 6.69-6.72 (m, 3H); 7.126 (d, 1H, J = 8.5 Hz); 7.48 (s, 1H); 11.2 (width s, 1H) IR (KBr cm "1): 3430, 3070, 2950, 1600, 1490, 1460, 1300, 1240, 1030, 930, 820 Elemental Analysis: ClßH22N20 = 282.39 Calculated: C 76.55, H 7.85, N 9'.92 Found: C 76.43, H 8.04, N 10.20.
Production Example 57 Production of 4- [(5-methoxy-3,4-dihydro-2-naphthalenyl) -methyl] -lH-imidazole: The title compound was produced from the compound of Production Example 51, using magnesium bromide, by the method of Example 17 Form: white crystalline powder Yield: 47% Melting point: 174.5: 175.5 ° C? -NMR ( 500 MHz, d6-DMSO)) d (ppm): 0.91 (t, 3H, J = 7.5Hz); 1.54 (m, 1H); 1.78 (m, 1H); 2.02 (dt, 1H, J = 7.3, 14.9 Hz); 2.17 (dt, 1H, J = 7.3, 14.9 Hz); 2.36 (m, 2H); 2.44-6.67 (m, 3H), 3.19 (width s, 1H), 3.28 (width s, 1H); 3.76 (s, 3H); 5.92 (t, 1H, J = 7.32); 6.78 (d, 1H, J = 7.94); 7.08-7.15 (m, 2H); 7.49 (s, 1H); 11.73 (width s, 1H) IR (KBr; cm "1): 3430, 3050, 2900, 1560, 1460, 1430, 1250, 1100, 980, 820, 770 FAB-MS: 283 (M + l) Elemental Analysis: C18H22N20 = 282. 39 Calculated: C 76.55, H 7.85, N 9.92 Found: C 76.05, H 7.73, N 9.84.
Production Example 58 Production of 4- [(6-methoxy-l-phenyl-3,4-dihydro-2-naphthalenyl) -methyl] -1H-imidazole: The title compound was produced from the compound of Production Example 36, by The method of Example 18 Form: colorless crystals Yield: 31% Melting point: 201.5-202.5 ° C? -NMR (500 MHz, d6-DMSO) d (ppm): 2.25 (dd, 2H; J = 7.6, 8.2Hz); 2.76 (dd, 2H, J = 7.6, 8.2 Hz); 3.22 (s, 2H); 3. 69 (s, 3H); 6.38 (d, 1H, J = 8.5 Hz); 6.57 (dd, 1H, J = 2.7 8.5 Hz); 6.73 (width s, 1H); 6.75 (d, 1H, J = 2.7Hz); 7.23 (d, 2H, J = 7.0Hz); 7.32 (t, 1H; J = 7.3Hz); 7.40 (dd, 1H, J = 7.3 7.6 Hz); 7.37 (s, 1H); 11.73 (width s, 1H). IR (KBr, -cm "1): 3450, 3050, 2850, 1600, 1570, 1240, 1100, 1030, 810, 700 FAB-MS: 317 (M + l) Elemental Analysis: C21H20N2O = 316.40 Calculated: C 79.72, H 6.37, N 8.85 Found: C 79.25, H 6.46, N 8.94.
Production Example 59 Production of 4- [(7-methoxy-l-phenyl-3,4-dihydro-2-naphthalenyl) -methyl] -lH-imidazole: The title compound was produced from the compound of Example Production 48, by the method of Example 18 Form: colorless crystals Yield: 42% Melting Point: 198.5-199.5 ° C? -NMR (500 MHz, d6-DMSO) d (ppm): 2.25 (dd, 2H,, J = 7.6, 8.2 Hz); 2.71 (dd, 2H, J = 7.6, 8.2Hz); 3.22 (s, 2H); 3.63 (s, 3H); 5.99 (d, 1H, J = 2.7Hz); 6.66 (dd, 1H, J = 2.7 8.2 Hz); 6.73 (s, 1H); 7.07 (d, 1H, J = 8.2Hz); 7.25 (d, 2H, J = 8.2Hz); 7.34 (dd, 1H, J = 7.3 7.6Hz); 7.40 (dd, 2H, J = 7.0, 7.6Hz); 7.48 (d, 1H, J = 0.9 Hz); 11.75 (width s, 1H) IR (KBr, -cm1): 3430, 3050, 2920, 1600, 1480, 1460, 1300, 1200, 1040, 980, 700 FAB-MS: 3217 (M + l) Elemental Analysis: C21H20N2O = 316.40 Calculated: C 79.72, H 6.37, N 8.75 Found: C 79.58, H 6.40, N 8.99.
Production Example 60 Production of 4- [(5-methoxy-l-phenyl-3,4-dihydro-2-naphthalenyl) -methyl] -lH-imidazole: The title compound was produced from the compound of Production Example 51, by the method of Example 18 Form: colorless crystals Yield: 39% Melting point: 200.0-202.0 ° C? -NMR (500 MHz, d6-DMSO) d (ppm): 2.23 (dd, 2H; J = 7.9, 8.5 Hz); 2.73 (dd, 2H, J = 7.9, 8.5Hz); 3.20 (s, 2H); 3. 77 (s, 3H); 6.10 (d, 1H, J = 8, OHz); 6.73 (s, 1H); 6.80 (d, 1H, J = 8.2 Hz); 6.97 (d, 1H, J = 8, OHz); 7.23 (d, 2H, J = 7.3 Hz); 7.32 (dd, 1H, J = 7.0, 7.6 Hz); 7.40 (dd, 2H, J = 7.3 7. 9Hz); 7.48 (s, 1H); 11.74 (width s, 2H). IR (KBr; cm "1): 3450, 3050, 2850, 1580, 1460, 1250, 1210, 1070, 980, 940, 700 FAB-MS: 317 (M + l) Elemental Analysis: C21H20N2O = 316.40 Calculated: C 79.72, H 6.37m, N 8.85 Found: C 79.41, H 6.40, N 8.87.
Production Example 61 Production of 4- [(1-benzyl-6-methoxy-3,4-dihydro-2-naphthaleniDmethyl] -lH-imidazole: The title compound was produced from the compound of Production Example 36, by the method of Example 19 Form: colorless crystals Yield: 29% Melting point: 122.5-123.0 ° C? -NMR (400 MHz, d6-DMSO) d (ppm): 2.28 (dd, 2H, J = 7.6, 8.2Hz); 2.76 (dd, 2H, J = 7.3, 8.2 Hz); 3.67 (s, 2H); 3.93 (s, 3H); 6.58 (dd, 1H, J = 2.7 8.5 Hz); 6.68 (d, 1H, J = 2.4Hz); 6.74 (s, 1H); 7.01 (d, 1H; J = 8.5Hz); 7.11 (m, 1H); 7.21 (m, 4H); 7.51 (s, 1H); 11.83 (width s, 1H). IR (KBr; cm1): 3430, 2930, 2830, 1610, 1570, 1490, 1300, 1280, 1250, 1040 FAB-MS: 331 (M + l) Elemental Analysis: C21H20N2O = 330.43 Calculated: C 79.97, H 6.71, N 8.48 Found: C 79.65, H 6.65, N 8.24 Production Example 62 Production of 4- [(5-methoxy-3,4-dihydro-2-naphthalenyl-methyl] -lH-imidazole hydrochloride The title compound was produced from the compound of Production Example 51, by the method of Example 17 Form: colorless crystals Yield: 19% Melting point: 192.5-194.5 ° C? -NMR (500 MHz, d6-DMSO) d (ppm): 2.17 (dd, 2H, J = 8.2, 8.5Hz); 2.70 (dd, 2H, J = 8.2 8.5Hz); 3.57 (s, 2H); 6.22 (s, 1H); 6.64 (d, 1H, J = 7.3 Hz); 6.81 (d, 1H, J = 8.2Hz); 7.09 (t, 1H, J = 7.9Hz); 7.49 (s, 1H); 9.04 (s, 1H); 14.54 (width s, 2H). IR (KBr; cm "1): 3450, 3080, 2800, 1610, 1570, 1460, 1260, 1080, 840, 620 FAB-MS: 241 (M + l) Elemental Analysis: C15H16N20 HCl = 276.77 Calculated: C 65.10, H 5.19, N 10.121 Found: C 65.51, H 6.17, N 10.16.
Production Example 63 Production of 4- [(7-methoxy-3,4-dihydro-2-naph taleniDmethyl] -1H-imidazole The title compound was produced from the compound of Production Example 48, by the method of Example 17 Form: colorless crystals Yield: 5% Melting point: 155.5-156.5 ° C? -NMR (500 MHz, ds-DMSO) d (ppm): 2.16 (dd, 2H, J = 8.0, 8.3 Hz); 2.70 (dd, 2H, J = 8.0 8.3Hz); 3.38 (s, 2H); 3.68 (s, 3H); 6.18 (s, 1H); 6.56 (d, 1H, J = 2.4Hz); 6.61 (dd, 1H, J = 2.4, 8.2Hz); 6.79 (s, 1H); 6.97 (d, 1H, J = 8.2Hz); 7.51 (s, 1H); 11.80 (width s, 1H). IR (KBr; c 1): 3450, 3070, 3000, 1600, 1500, 1460, 1300, 1260, 1210, 1030 FAB-MS: 241 (M + l) Elemental Analysis: C15H16N20 = 240.31 Calculated: C 74.97, H 6.71 , N 11.66 Found: C 74.97, H 6.67, N 11.45.
Production Example 64 Production of 5-ethoxy-2- [1- (1H-4-imidazolyl) methylidene] -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced using 5-ethoxy-1-tetralone, by the method of Example 15. Form: brown-colored crystals Yield: 82% Melting point: 122.0-124.0 ° C? -NMR (500 MHz, dg. -DMSO) d (ppm): 1.37 (dd, 3H, J = 6.7, 7.0 Hz); 2.86 (dd, 2H, J = 6.4, 6.7 Hz); 3.42 (dd, 2H, J = 6.4, 6.7 Hz); 4.07 (dd, 2H; J = 7.0, 13.7 Hz); 7.18 (d, 1H; J = 7.9 Hz); 7.31 (t, 1H, J = 7.9 Hz); 7.52 (s, 1H); 7.53 (d, 1H, J = 7.9Hz); 7.64 (s, 1H); 7.82 (s, 1H); 12.44 (width S, 1H). IR (KBr; cm "1): 3450, 3100, 2870, 1660, 1570, 1460, 1320, 1260, 1060, 1020 FAB-MS: 269 (M + l) Elemental Analysis: C16H16N202 = 268.32 Calculated: C 71.62, H 6.01, N 10.44 Found: C 71.41, H 6.06, N 10.19.
Production Example 65 Production of 5-ethoxy-2- (1H-4-imidazolylmethyl) -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 64, by the method of Example 16 Form: brown crystalline powder Yield: 80% Melting point: 132.0-134.0 ° C -NMR (500 MHz, CDC13) d (ppm): 1.34 (dd, 3H, J = 6.7, 7.0 Hz); 1.65 (m, 1H); 2.10 (m, 1H); 2.54 (dd, 1H, J = 8.9, 14.7 Hz); 2.63 (m, 1H); 2.78 (m, 1H); 2.97 (dt, 1H, J = 4.3, 17.7 Hz); 3.11 (dd, 1H, J = 4.3, 14.7 Hz); 4.06 (m, 2H); 6.79 (s, 1H); 7.17 (d, 1H, J = 7.9Hz); 7.28 (t, 1H, J = 7.9Hz); 7.46 (d, 1H, J = 7.9Hz); 7.57 (d, 1H, J = 0.9Hz). IR (KBr; cm "1): 3430, 3050, 2850, 1680, 1580, 1460, 1250, 1100, 1040, 940 FAB-MS: 271 (M + l) Elemental Analysis: C16H18N202 = 270.33 Calculated: C 71.09, H 6.71, N 10.36 Found: C 70.62, H 6.66, N 10.22.
Production Example 66 Production of 6-ethoxy-2- [1- (1H-4-imidazolyl) methylidene] -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the 6-ethoxy-l-tetralone, by the method of Example 16 Form: brown crystalline powder Yield: 62% Melting point: 133.5- 134.5 ° C -NMR (500 MHz, CDC13) d (ppm): 1.32 (dd, 3H , J = 6.7, 7.0 Hz); 2.95 (dd, 2H, J = 6.4, 6.7 Hz); 3.34 (width s, 2H); 4.08 (q, 2H, J = 7.0 Hz); 6.69 (d, 1H, J = 2.4Hz); 6.83 (dd, 1H, J = 2.4, 8.5 Hz); 7.38 (s, 1H); 7.76 (s, 2H); 8.04 (d, 1H, J = 8.6Hz). IR (KBr; cm "1): 3450, 3100, 2900, 1610, 1330, 1270, 1130, 1040, 1000, 760 FAB-MS: 269 (M + l) Elemental Analysis: C1gHlsN202 = 268.32 Calculated: C 71.62, H 6.01, N 10.14 Found: C 71.71, H 6.09, N 10.36.
Production Example 67 Production of 6-ethoxy-2- (lH-4-imidazolylmethyl) -1, 2, 3, 4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 66, by the method of Example 16 Form: brown crystalline powder Yield: 92% Melting point: 143.5-144.5 ° C? -NMR (500 MHz, dg-DMSO ) d (ppm): 1.32 (dd, 3H, J = 6.7, 7.0 Hz); 1.66 (m, 1H); 2.04 (m, 1H); 2.53 (dd, 1H J = 9.1, 14.7 Hz); 2.72 (m, 1H); 2.88 (dd, 2H, J = 4.9 5.2Hz) 3.12 (dd, 1H, J = 4.0, 14.6Hz); 4.09 (dd, 2H, J = 7.0, 13.7 Hz) 6. 76 (s, 1H); 6.80 (d, 1H, J = 2.4Hz); 6.86 (dd, 1H, J = 2.4, 8. 5Hz); 7.49 (s, 1H); 7.83 (d, 1H, J = 8.8 Hz); 11.777 (width s, 1H). IR (KBr; cm "1): 3430, 3100, 2870, 1660, 1600, 1470, 1350, 1270, 1210, 1100 FAB-MS: 271 (M + l) Elemental Analysis: C16H18N202 = 270.33 Calculated: C 71.09, H 6.71, N 10.36 Found: C 71.52, H 6.72, N 10.27.
Production Example 68 Production of 6-ethoxy-2- (1H-4-imidazolylmethyl) -1, 2, 3, 4-t-tetrahydro-1-naphthalenone: The title compound was produced using 7-ethoxy-1-tetralone, by the method of Example 15 Shape: brown colored crystals Yield: 55% Melting point: 139.5-141.0 ° C? -NMR (500 MHz, d6-DMSO) d (ppm): 1.33 (t, 3H, J = 7.0Hz); 2.86 (dd, 2H, J = 6.4, 6.7Hz); 3.35 (width S, 2H); 4.05 (q, 2H, J = 7.0Hz); 7.10 (dd, 1H, J = 2.7, 8.2 Hz); 7.27 (d, 1H; J = 8.5Hz); 7.39 (d, 1H, J = 2.7 Hz); 7.56 (s, 1H); 7.63 (s, 1H); 7.85 (s, 1H); 12.54 (width s, 1H) IR (KBr; cm1): 3450, 3150, 2900, 1650, 1570, 1490, 1420, 1320, 1240, 1120 FAB-MS: 269 (M + l) Elemental Analysis: C ^ H ^ ^ O;, = 268.32 Calculated: C 71.62, H 6.01,? 10.44 Found: C 71.33, H 6.40,? 10.36.
Production Example 69 Production of 7-ethoxy-2- (1H-4-imidazolylmethyl) -1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 68, by the method of Example 16 Form: colorless crystals Yield: 59% Melting point: 176.5-178.5 ° C? -NMR (500 MHz, dg-DMSO) d (ppm): 1.31 (dd, 3H, J = 6.7, 7.0 Hz); 1.66 (m, 1H); 2.06 (m, 1H); 2.56 (dd, 1H, J = 9.1, 14.6 Hz); 2.77 (m, 1H); "2.85 (m, 1H), 3.13 (dd, 2H, J = 3.9, 14.6 Hz), 4.03 (dd, 2H, J = 6.7, 13.7 Hz), 6.78 (s, 1H), 7.10 (dd, 1H; = 2.7, 8.5 Hz), 7.22 (d, 1H, J = 2.7Hz), 7.52 (s, 1H), 11.79 (width s, 1H), IR (KBr, cm1): 3450, 3130, 2950, 1660, 1610 , 1500, 1270, 1240, 1050, 920. FAB-MS: 271 (M + l) Elemental Analysis: C16H18N202 = 270.33 Calculated: C 71.09, H 6.71, N 10.36 Found: C 71.01, H 7.10, N 10.37.
Production Example 70 Production of 4- [(5-ethoxy-l-methyl-3,4-dihydro-2-naphthaleniDmethyl] -lH-imidazole: The title compound was produced from the compound of Production Example 65, using Methylmagnesium iodide, by the method of Example 17 Form: colorless crystals Yield: 56% Melting point: 133.5-136.5 ° C? -NMR (500 MHz, dg-DMSO) d (ppm): 1.31 (t, 3H, J = 7.0Hz); 2.03 (s, 3H); 2.13 (dd, 2H, J = 7.3, 7.9 Hz); 2.59 (dd, 2H, J = 7.9, 8.2 Hz); 3.45 (s, 2H), - 4.00 (dd, 2H, J = 7.0, 13.7 Hz); 6.72 (s, 1H); 6.80 (d, 1H; J = 8.2Hz); 6.88 (d, 1H, J = 6Hz); 7.11 (t, 1H, J = 8.0Hz); 7.49 (s, 1H); 11.76 (width S, 1H). IR (KBr; c "1): 3450, 3070, 2980, 1580, 1460, 1400, 1260, 1060, 990, 820 FAB-MS: 269 (M + l) Elemental Analysis: C17H20N2O2 = 268.36 Calculated: C 76.09, H 7.51, N 10.44 Found: C 75.62, H 7.78, N 10.82.
Production Example 71 Production of 4- [(6-ethoxy-l-methyl-3, 4-dihydro-2-naphthaleniDmethyl] -lH-imidazole: The title compound was produced from the compound of Production Example 67, using methyl iodide -magnesium, by the method of Example 17 Form: colorless crystals Yield: 47% Melting point: 126.0: 127.0 ° C? -NMR (500 MHz, dg-DMSO) d (ppm): 1.29 (t, 3H, J = 7.0Hz), 2.01 (s, 3H), 2.14 (t, 2H, J = 7.3Hz), 2.59 (dd, 2H, J = 7.6, 7.9 Hz); 3.43 (s, 2H); 3.97 (q, 2H, J = 7.0Hz); 6.66 (d, 1H, J = 2.7Hz); 6.70 (dd, 1H, J = 2.7, 8.5 Hz); 6.71 (s, 1 HOUR); 7.13 (d, 1H, J = 8.5 Hz); 7.49 (d, 1H, J = 0.9 Hz); 11.76 (width s, 1H).
IR (KBr; cm1): 3450, 3000, 2830, 1610, 1570, 1500, 1480, 1250, 1160, 1120 FAB-MS: 269 (M + l) Elemental Analysis: C17H20N2O2 = 304.82 Calculated: C 76.09, H 7.51, N 10.44 Found: C 75.86, H 7.22, N 10.39.
Production Example 72 Production of 4- [(7-ethoxy-l-methyl-3, 4-dihydro-2-naphthalenyl) methyl] -1H-imidazole hydrochloride: The title compound was produced from the compound of Production Example 69, using methyl magnesium iodide, by the method of Example 17 Form: colorless crystals Yield: 12% Melting point: 170.5-171.5 ° C? -NMR (500 MHz, dg-DMSO) d (ppm): 1.30 (dd, 3H, J = 6.7, 7.0 Hz); 2.05 (s, 3H); 2.13 (dd, 2H, J = 7.0, 7.6 Hz); 2.58 (dd, 2H, J = 7.6, 7.9 Hz); 3.65 (s, 2H); 3.99 (dd, 2H, J = 7.0, 13.7 Hz); 6.68 (dd, 1H, J = 2.4, 7.9 Hz); 6.80 (d, 1H, J = 2.4 Hz); 7.01 (d, 1H, J = 8.2 Hz); 7.40 (s, 1H); 9.02 (s, 1H); 14.56 (width s, 2H). IR (KBr; cm1): 3400, 3120, 2970, 1510, 1510, 1480, 1440, 1320, 1250, 1050 FAB-MS: 269 (M + l) Elemental Analysis: C17H20N2O2 HCl = 304.82 Calculated: C 66.99, H 6.94; N 9.19 Found: C 66.49, H 7.23, N 9.38.
Production Example 73 Production of 2- [1- (1H-4-imidazolyl) methylidene) -6-propoxy-1,2,3,4-tetrahydro-1-naphthalenone-: The title compound was produced using 6-propoxy-1 -tetralone, by the method of Example 15 Form: brown crystals Yield: 38% Melting point: 156.5-158.0 ° C? -NMR (500 MHz, d6-DMSO) d (ppm): 0.96 (dd, 3H, J = 7.0, 7.3 Hz); 1.73 (dd, 2H, J = 6.7, 13.7 Hz); 2.90 (t, 2H, J = 6.1 Hz); 3.35 (width s, 2H); 4.00 (t, 2H, J = 6.4 Hz); 6.86 (s, 1H); 6.89 (d, 1H, J = 8.8 Hz); 7.52 (s, 1H); 7.58 (s, 1H); 7. 81 (s, 1H); 7.87 (d, 1H, J = 8.6 Hz). IR (KBr; cm "1): 3430, 3130, 2950, 1660, 1600, 1280, 1260, 1120, 1100, 1020 FAB-MS: 283 (M + l) Elemental Analysis: C17H18N202 = 282.34 Calculated: C 72.32, H 6.43, N 9.92 Found: C 72.16, H 5.60, N 9.85.
Production Example 74 Production of 2- (lH-4-imidazolylmethyl) -6-propoxy-1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 73 , by the method of Example 16 Form: colorless crystals Yield: 87% Melting point: 134.5-136.5 ° C -NMR (500 MHz, dg-DMSO) d (ppm): 0.96 (dd, 3H, J = 7.3, 7.6 Hz); 1.66-1.74 (m, 3H); 2.03 (m, 1H); 2.53 (m, 1 HOUR); 2.72 (m, 1H); 1.89 (width s, 1H); 3.12 (d, 1H, J = 11.3 Hz); 3.99 (t, 2H, J = 6.4 Hz); 6.76 (s, 1H); 6.82 (s, 1H); 6. 87 (d, 1H, J = 7.0 Hz); 7.50 (s, 1H); 7.82 (d, 1H, J = 8.6 Hz); 11.74 (width s, 1H). IR (KBr; cm X: 3450, 2950, 1670, 1610, 1480, 1360, 1280, 1220, 1110, 1020 FAB-MS: 285 (M + l) Elemental Analysis: C17H20N2O2 = 284.36 Calculated: C 71.81, H 7.09, N 9.95 Found: C 71.55, H 7.20, N 9.71.
Production Example 75 Production of 4- [(1-methyl-6-propoxy-3, 4-dihydro-2-naph taleniD methyl] -lH-imidazole: The title compound was produced from the compound of Production Example 74, using the methylmagnesium iodide, by the method of Example 17 Form: colorless crystals Yield: 31% Melting point: 91.5-92.0 ° C? -NMR (500 MHz, dg-DMSO) d (ppm): 0.95 (dd, 3H, J = 7.3, 7.6Hz); 1.69 (m, 2H), 2.01 (s, 3H); 2.14 (t, 2H, J = 7.6 Hz); 3.35 (dd, 2H, J = 7.6, 7.9 Hz); 3.42 (s, 2H); 3.88 (t, 2H, J = 6.4 Hz); 6.68-6.71 (m, 3H); 7.13 (d, 1H, J = 8.5 Hz); 7.48 (s, 1H); 11.71 (width s, 1H). IR (KBr; cm "1): 3500, 2950, 1600, 1560. 1490, 1460, 1240, 1010, 980, 790 FAB -MS: 283 (M + l) Elemental Analysis: C18H22N20 = 282. 39 Calculated: C 76. 56, H 7. 85, N 9. 92 Found: C 76.56, H 7.71, N 9.94.
Production Example 76 Production of 2- [1- (1H-4-imidazolyl) methylidene) -6-isobutoxy-1, 2,3,4-tetrahydro-1-naphthalenone: The title compound was produced using 6-isobutoxy-1- tetralone, by the method of Example 15 Form: yellow crystals Yield: 63% .4 • Melting point: 79.0-81.5 ° C? -NMR (500 MHz, d6-DMS0) d (ppm): 0.98 (d, 6H, J = 6.7 Hz); 2.03 (m, 1H); 2.90 (t, 2H, J = 6.7Hz); 3.25-3.40 (width m, 2H); 3.83 (d, 2H, J = 6.4Hz); 6.88 (d, 1H, J = 2.1 Hz); 6.91 (dd, 1H, J = 2.3, 8.5 Hz); 7.51 (width s, 1H); 7.58 (width s, 1H); 7.81 (s, 1H); 7.87 (d, 1H, J = 8.55Hz); 12.4 (width s, 1H). IR (KBr; cm "1): 3420, 1660, 1600, 1580, 1330, 1270, 1130, 1100, 1030, 990 FAB-MS: 297 (M + l) Elemental Analysis: C18H18N202 = 296.37 Calculated: C 72.95, H 6.80, N 9.45 Found: C 72.64, H 7.05, N 9.16.
Production Example 77 Production of 2- (1H-4-imidazolylmethyl) -6-isobutoxy-1,2,3,4-tetrahydro-1-naphthalenone: The title compound was produced from the compound of Production Example 76, by the method of Example 16. Form: colorless crystals Yield: 66% Melting point: 114.5-115.90? -NMR (500 MHz, dg-DMSO) d (ppm): 0.96 (d, 6H, J = 6.7 Hz), 1.67 (m, 2H); 2.02 (m, 1H); 2.05 (m, 1H); 2.63 (m, 1H); 2.72 (m, 1H); 2.88 (m, 2H); 3.12 (dt, 1H, J = 3.1, 14.3 Hz); 3.81 (d, 2H, J = 6.4 Hz); 6.62-6.88 (m, 3H); 7.49 (d, 1H, J = 14.3 Hz); 7.82 (d, 1H, J = 8.9 Hz); 11.74 (d, 1H, J = 17.7 Hz). IR (KBr; cm "1): 3450, 1670, 1590, 1470, 12400, 1100, 1010, 940, 820, 660. FAB-MS: 299 (M + l) Elemental Analysis: C1SH22N202 = 298.39 Calculated: C 72.46, H 7.43, N 9.39 Found: C 72.40, H 7.16, N 9.44.
Production Example 78 Production of 4- [(6-isobutoxy-l-methyl-3,4-dihydro-2-naphthaleniDmethyl] -lH-imidazole The title compound was produced from the compound of Production Example 77, using Methylmagnesium iodide, by the method of Example 17 Form: colorless crystals Yield: 67% Melting point: 96.0-97.0 ° C? -NMR (500 MHz, d6-DMSO) d (ppm): 0.96 (d, 6H, J = 6.7 Hz); 1.97 (m, 4H); 2.09 (m, 1H); 2.16 (dd, 1H, J = 6.7, 7.3 Hz); 2.57 (dd, 2H, J = 6.7, 7.3Hz); 3.39 (width s, 1H), 3.47 (width s, 1H), 3.70 (d, 2H, J = 6.4 Hz); 6.60-6.71 (m. 3H); 7.13 (dd, 1H, J = 8.4, 15.4 Hz); 7.47 (d, 1H, J = 10.1 Hz); 11.72 (width s, 1H) IR (KBr; cm "1): 3430, 1620, 1490, 1470, 1250, 1070, 1030, 990, 860, 830, 800 FAB-MS: 298 (M + l) Elemental Analysis: C19H24N20 = 294.41 Calculated: C 76.99, H 8.16, N 9.45 Found: C 76.95, N 8.06, N 9:58.
Test Example 1 Inhibitory activity of 17a-hidsroxylase / C17.: In-lyase The experiment was carried out as follows, according to the method of T. Sergejew and RW Hartman (J. Enzyme Inhibition 8, 113, 1994): Rat tests SD male or tests on human tissues surgically removed, homogenized and then centrifuged to obtain microsomes. A test compound was introduced into a microtube (1.5 ml, Eppendolf), then 100 μl of microsome protein, where the protein concentration was adjusted to 0.1 mg / ml with a 50 mM phosphate buffer (pH 7.4) , 140 μl of a 125 nmol NADPH solution, and 10 μl of 6.25 nmol progesterone were added, and the mixture was incubated at 37 ° C for 20 minutes. To this was added 50 μl of IN hydrochloric acid, then 1 ml of ethyl acetate and the mixture was mixed and then centrifuged. The resulting ethyl acetate layer was washed with 250 μl of a 50 mM phosphate buffer (pH 7.4) and 50 μl of IN hydrochloric acid. After centrifugation and concentration, the resulting concentrate was dissolved in 100 μl of acetonitrile. A portion of this solution (10 μl) was subjected to high performance liquid chromatography. The amounts of substrates and products, i.e., 17-hydroxyprogesterone, androstenedione and testosterone, were measured to calculate the activities of the enzymes. In the control groups, no test compound was added. The inhibitory activity of 17a-hydroxylase / C17_20-lyase (%) was calculated, calculated from the amounts of the substrate and corresponding product, using the following calculation formula. The results are shown in Table 1 and Table 2. Calculation Formula I: Inhibitory activity (%) = 100- (enzyme activity with inhibitor / enzyme activity without inhibitor) x 100 Table 1: Inhibitory activity of 17a-hydroxylase / C17.2n-lyase Activity IC50 (μM) Activity Example of Inhibitory (%) relative Production Human Rat Human Rat Human Rat 84 42 14.3 - * 1 5 - 16 86 79 12 0.63 6 1 17 93 84 3.6 0.61 10 1 18 77 42 - - - - 23 82 36 16 - 4 - 24 86 79 2.6 0.51 26 1 25 98 88 1.8 * 0.28 37 3 19 99 91 1.8 - 37 - 20 99 98 0.57 - 130 - 21 99 94 1.1 0.15 60 5 22 99 96 0.62 0.064 110 11 26 95 85 0.38 0.12 180 6 27 100 99 0.11 0.036 610 20 28 100 99 0.27 0.058 250 13 37 - 98 - 0.072 - 10 Table 1 (Continued) 42 98 92 1.1 0.22 60 3 43 98 89 - 0.31 - 2 44 100 88 2.1 0.28 30 3 45 100 95 1.7 0.16 40 3 46 100 90 1.3 0.13 50 6 49 -. 49 - 96 - - - - Undetermined Enzyme source: rat test microsomes Inhibitory concentration: 125 μM (calculated inhibitory activity (%)) Substrate concentration: 25 μM (progesterone) NADPH concentration: 250 μM Relative activity: Ketoconazole = 1 (IC50 = 67 μM) Source of enzymes: human test microsomes Inhibitory concentration: 2.5 μM (calculated inhibitory activity (%)) Substrate concentration: 25 μM (progesterone) NADPH concentration: 300 μM Relative activity: Ketoconazole = 1 (IC50 = 0.74 μM).
Table 2: inhibitory activity of 17a-hydroxylase / C17_20-lyase Enzyme source: rat test microsome Inhibitor concentration: 50 μM Substrate concentration: 25 μM (progesterone) NADPH concentration: 250 μM Test Example 2 Test of the inhibitory activity of thromboxane A2 synthesis Measurements were made as follows, according to the method of Rolf W. Hartmann et al (Arch. Pharm, Pharm, Med. Chem., 329, 251, 1996). To 0.5 ml of whole human blood, treated with citric acid, 10 μl of a buffer solution of ethanol phosphate / K-Na (pH 7.4) containing a test compound was added, and the mixture was previously incubated at 37 ° C. C for 10 minutes. Dazoxiben hydrochloride (100 μM) was added to the reference solutions. Then, 50 μl of a collagen solution (final collagen concentration: 53.6 μg / ml) were added and the incubation was continued at 37 ° C for 10 minutes. The reaction was stopped by adding 0.4 ml of a 20% trichloroacetic acid solution in 0.6 M hydrochloric acid, and the mixture was centrifuged at 4400 x g, for 10 minutes. The resulting supernatant (0.5 ml) was fractionated and added to 0.5 ml of a 0.53% thiobarbituric acid solution (solvent: K-Na phosphate buffer (pH 7.4), and the mixture was heated for 70 minutes and then it was allowed to stand at room temperature for 30 minutes.This sample was measured by a fluorophotometer (excitation wavelength: 533 nm, measurement wavelength: 550 nm) .The control samples without the test compounds were tested for the same way The inhibitory activity (%) was calculated from the measurements using formula I. The results are shown in Table 3.
Table 3: Inhibitory activity of thromboxane A synthesis, Enzyme source: whole human blood treated with citric acid Inhibitor concentration: 50 μM (calculated inhibitory activity (%)) Substrate concentration: 25 μM (progesterone Test example 3 Aromatase inhibitory activity test: Measurement was made according to the method of Rolf Hartmann and Christine Batzl (J. Med. Chem., 29, 8, 1368, 1986). (1) Preparation of aromatase: The aromatase of the microsome fraction of the placental tissue was prepared human, according to the method of Thompson and Siiteri (J. Biol. Chem., 249, 5346, 1974) .The obtained microsomes were suspended in a phosphate buffer (0.05 M, pH 7.4) and stored at - 30 ° C. The stored enzyme showed no change in activity for 4 months. (2) Aromatase inhibitory activity: The activity of the enzyme was evaluated by measuring the amount of 3H20 produced by [lß, 2ß-3H] testosterone , during the reaction, according to the method s of Foster AB et al (Foster AB et al., J. Med. Chem., 26, 50, 1983) and Graves PE and Salhanick HA (Endocrinology, 105, 52, 1979) as follows: To a test tube, containing 0.225 μCi of [lß, 2ß-3H] testosterone, 5 μM of unlabeled testosterone, 2 mM of NADPH, 20 mM of glucose-6-phosphate, 1 EU of glucose-6-phosphate dehydrogenase and a compound of test (0-250 μM) dissolved in a phosphate buffer (0.05 M, pH 7.4). The test compound was dissolved in ethanol and diluted with the phosphate buffer. The final concentration of ethanol in the reaction solution of the control and the test compound was 2%. This test tube was previously incubated in a water bath at 30 ° C for 5 minutes. Then, 0.5 mg of the microsome enzyme was added to start the reaction. The total volume of the reaction solution was 0.5 ml. Portions (100 μl) of aqueous phase were taken at 0, 7, 14 and 21 minutes after starting the reaction and added to 200 μl of cold 1 mM HgCl. To this was added 200 μl of a suspension of activated carbon treated with 2% dextran (DCC). The mixture was shaken for 20 minutes and then centrifuged at 1500 x g for 5 minutes, to isolate the steroid adsorbed on the DCC. The amount of 3H20 produced in the fractionated supernatant was counted by the liquid scintillation counter. Control samples without the test compound were tested in the same manner. The inhibitory activity (%) of the measurement was calculated, using the calculation formula I. The results are shown in Table 4.
Table 4 Maromatase inhibitory activity 46 1.8 * 1: Not determined, Enzyme source: human placental microsomes Inhibitor concentration: 25 μM (calculated inhibitory activity (%)) Substrate concentration: 2.5 μM (testosterone) NADPH concentration: 250 μM.

Claims (1)

1. Novel derivatives of dihydronaphthalene, of the formula (1) R ^ wherein R1 represents hydrogen, hydroxyl or alkyloxy; R 2 represents lower alkyl, aralkyl or phenyl and R 3 represents alkyl, phenyl, pyridyl or imidazolyl. Novel derivatives of dihydronaphthalene of the formula R¿ RJ wherein R 1 represents hydrogen, hydroxyl or C 1 -C 6 alkyloxy, straight or branched chain; R 2 represents hydrogen, straight or branched chain alkyl, phenyl or aralkyl, and R 3 represents pyridyl or imidazolyl. Novel derivatives of dihydronaphthalene of the formula: RA wherein R1 represents straight chain or branched hydrogen, hydroxyl or Cx-C6 alkyloxy; R2 represents hydrogen, straight or branched chain alkyl, phenyl or aralkyl, and R3 represents pyridyl or imidazolyl, with derivatives having an inhibitory activity of 17a-hydroxylase and / or C17_20-lyase, an inhibitory activity of the synthesis of thromboxane A2, and / or an aromatase inhibitory activity.
MXPA/A/2000/003167A 1997-10-02 2000-03-30 Novel dihydronaphthalene compounds and process for producing the same MXPA00003167A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP9/284263 1997-10-02

Publications (1)

Publication Number Publication Date
MXPA00003167A true MXPA00003167A (en) 2001-12-13

Family

ID=

Similar Documents

Publication Publication Date Title
EP1028110B1 (en) Novel dihydronaphthalene compounds and process for producing the same
US4792561A (en) Carbostyril derivatives as combined thromboxane synthetase and cyclic-AMP phosphodiesterase inhibitors
US6133303A (en) Bicyclic inhibitors of protein farnesyl transferase
US4921862A (en) Carbostyril derivatives as combined thromboxane synthetase and cyclic-amp phosphodiesterase inhibitors
US6147080A (en) Inhibitors of p38
US4745120A (en) 3-pyridyl compounds and use as thromboxane synthetase inhibitors
US5807880A (en) Azole derivative and pharmaceutical composition thereof
SK151287A3 (en) Process for producing tolunitriles substituted by a heterocyclic residue
US5418243A (en) Substituted 4-phenyl-pyridones and 4-phenyl-3-alkoxypyridines
WO2010135429A2 (en) Compositions for modulating a kinase cascade and methods of use thereof
JP3186771B2 (en) A new selective aromatase inhibitor
US5239083A (en) Indole derivatives which inhibit steroid 5α reductase
CZ686888A3 (en) Racemic or optically active compound, process of its preparation and pharmaceutical preparations in which it is comprised
HU202227B (en) Process for producing isoindoline derivatives and pharmaceutical compositions containing them
US4965274A (en) Quinolyl methoxy compounds, processes for preparation thereof and pharmaceutical composition comprising the same
WO1995004723A1 (en) Imidazolylalkylamine derivative and pharmaceutical composition thereof
JP2008506753A (en) Selective inhibitors of human corticoid synthase
US6559157B2 (en) Dihydronaphthalene compounds
MXPA00003167A (en) Novel dihydronaphthalene compounds and process for producing the same
EP0356673A2 (en) Substituted 5,6,7,8-tetrahydroimidazo[1,5-a]pyridines and process for their preparation
US4665080A (en) Imidazolyl compounds and their use as medicaments
JPH032168A (en) Novel 4 (5)-imidazole having aromatase inhibitive activity
US4859671A (en) 2-substituted 1,2-benzisothiazol-3(2H)-one 1,1-dioxide useful as an anxiolytic agent
JPH0525131A (en) Indole derivative and its application to medicine
JPWO1999018075A1 (en) Novel dihydronaphthalene compound and method for producing the same