MXPA97007843A - Compounds of 4-amino-5-oxy-2,6,6-trimethyl-2-ciclohept - Google Patents

Abstract

The 4-amino-5-oxy-2,6,6-trimethyl-2-cycloheptene compounds represented by the general formula (I), pharmacologically acceptable salts thereof, or solvates thereof, wherein R 1 and R 2 each independently represents hydrogen, optionally substituted alkyl or optionally phenyl having hydroxy, lower alkoxy, amino, nitro carboxy, lower alkoxycarbonyl or halogen in its ring, or R1 and R2 together with the nitrogen atom may form a nitrogen-containing heterocycle; R3 represents hydrogen , lower alkyl or lower aliphatic acyl, and W represents oxo, oxime or oximether. The compounds exert effects on a model of peripheral embolism in rats, a spontaneously hypertensive rat and a histamine-induced air path construction model, indicating that they are useful as a remedy for hypertension, peripheral embolism or bronchial asthma.

Description

COMPOUNDS OF 4-AMINO-5-OXI-2.6.6-TRIMETHYL-2-CYCLOHEPTENO DESCRIPTION OF THE INVENTION The present invention relates to compounds of 4-amino-5-oxy-2,6,6-trimethyl-2-cycloheptene which are useful as medicaments and their pharmacologically acceptable salts and solvates. More specifically, it is related to a remedy for hypertension, peripheral arterial occlusion or bronchial asthma whose effective components are compounds of 4-amino-5-oxy-2, 6,6-trimethyl-2-cycloheptene, its pharmacologically acceptable salts and solvates. . The 4,5-dihydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (referred to herein as "Saishin N") from the drug Asarum Siebeldi without purification, as a useful anti-ulcer substance, and a method for its chemical production has been developed, thus presenting a patent application (Japanese Unexamined Patent Publication No. Hei-3- 275640) as well as a patent application for several Saishin N compounds with anti-ulcer effects (Japanese Unexamined Patent Publication No. Hei-5- 213811). It has been found that Saishin N compounds are effective for the treatment of ischemic and reperfusion disorders and the improvement of microcirculatory blood flow, and patent applications are filed therefore (Japanese Unexamined Patent Publications Nos. Hei-7-17852, Hei-7-101858). The present inventors have diligently investigated the aminolysis reactions of eukaryone-4,5-oxide for the purpose of synthesizing Saishin N compounds with amino groups, and have completed the present invention based on the finding that Saishin N compounds with a Amino group selectively introduced at position 4 can be obtained using the method of Marco Chini et al. [Tetrahedron Letters, Vol. 31, 4661 (1990)], and that the resulting 4-amino-5-oxy-2, 6, 6-trimethyl-2-cyclohepten-1-one compounds and their oxime derivatives exhibit an effect against rat models for peripheral artery occlusion, spontaneous hypertensive rats, histamine-induced air trajectory contraction models and passive sensitization models. According to the present invention the compounds 4-amino-5-oxy-2,6,6-trimethyl-2-cyanoheptene represented by the following general formula: (wherein R1 and R2 each independently represents a hydrogen atom, an alkyl group or a phenyl group which may have a hydroxyl group, a lower alkoxy group, an amino group, a nitro group, a carboxyl group, an alkoxycarbonyl group lower or a halogen atom, or R1, R2 and the nitrogen atom together represent a heterocyclic group of saturated nitrogen, R3 represents a hydrogen atom, a lower alkyl group or a lower aliphatic acyl group, and W represents an oxo group, an oxime group or an ether oxime group); and its pharmacologically acceptable salts and solvates, as well as the pharmaceutical position containing them as an effective ingredient. The alkyl group is an acyclic or cyclic alkyl group of 1 to 10 carbon atoms, and preferably 1 to 8 carbon atoms, and this may be substituted with a hydroxyl group, a lower alkoxy group, or amino group, a lower alkylamino group, a lower diallylamino group, or a phenyl group which may have a hydroxyl group, a lower alkoxy group, an amino group, - nitro group, a carboxyl group, a lower alkoxycarbonyl group or a halogen atom. Specific examples thereof include the groups methyl, ethyl, propyl, iscrrr-yl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl-r-epentyl, tert-pentyl, hexyl, isohexyl, heptyl, ---- lime, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-hydroxyethyl, 2-methoxyethyl, 2-dimethylaminoethyl, benzyl, 4-ethoxycarbonylbenzyl, phenethyl and 4-phenylbutyl. The halogen atom can be fluorine, chlorine, bromine or iodine. The nitrogen-saturated heterocyclic group is the pyrrolidine, piperidine, homopiperidine, piperazine, homopiperazine, or morpholine group, which may have a lower alkyl group, a hydroxyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a oxo group or an acetal group thereof in its ring. The oxime ether is a lower alkyl ether or benzyl oxime ether. The term "lower" refers herein to a cyclic or acyclic saturated hydrocarbon group of 1 to 4 carbon atoms. The pharmaceutically acceptable salts of the compounds of the invention include salts of organic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid.; salts of organic acids such as acetic acid, tartaric acid, fumaric acid and maleic acid; salts of sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, acid camphorsulfonic acid, benzenesulfonic acid and toluenesulfonic acid; and salts of alkali metals or alkaline earth metals such as sodium, potassium and calcium. In addition, solvates (including hydrates) of the compounds of the invention, which can be produced by common methods from free compounds of the invention and their salts are also encompassed within the present invention. The stereoisomers of the compounds of the invention which are derived from asymmetric carbon atoms at positions 4 and 5 of the cycloheptene ring and the oximes, and all the stereoisomers and their mixtures are also included within the present invention. A method for) producing the compounds of the invention will now be explained. 4-amino-5-oxy-2,6,6-trimethyl-2-cyclohepten-1-one (compound A) can be obtained by subjecting eukaryone-4,5-oxide to an aminolysis reaction in the presence of a salt metallic (wherein R1 and R2 are as defined above). The metal salt used for the reaction may be a perchlorate such as lithium perchlorate, magnesium perchlorate, or sodium perchlorate; a chlorine such as calcium chloride or zinc chloride; or a trifluoromethanesulfonate of a lanthanide, such as ytterbium trifluoroethanesulfonate, neodinium trifluoromethanesulfonate or gadolinium trifluoromethanesulfonate. The reaction solvent can be any that does not inhibit the reaction, and acetonitrile can be used when the metal salt is a perchlorate or chlorine, while methylene chloride or benzene can be used when the metal salt is a lanthanide trifluoromethanesulfonate. Compound B wherein R2 of compound A is a hydrogen atom can be N-alkylated to obtain compound C. (wherein R1 is as defined above, and R2 represents a lower alkyl group).

The N-alkylation can be carried out by a method of treatment with an aldehyde under reductive conditions, or a treatment method with an alkylating agent such as a lower alkyl halide. Methylation with an aldehyde can be carried out by heating in formic acid. An alcohol such as methanol or ethanol can be added as the reaction solvent. Compound A can be approximated to obtain compound D. (wherein R1 and R2 each independently represent a hydrogen atom, an alkyl group, which may have a substituent, or a phenyl group which may have a hydroxyl group, a lower alkoxy group, an amino group, a nitro group, a carboxyl group, a lower alkoxycarbonyl group or a halogen atom, or R1, R2 and the nitrogen atom together represent a heterocyclic group of saturated nitrogen, and R4 represents a hydrogen atom, a lower alkyl group or a benzyl group.

Oximation can be carried out according to the method of E. J. Corey -Tetrahedron Letters, -vol. 27, 2199 (1986)], wherein compound A is reacted with hydroxylamine hydrochloride or alkoxylamine in methanol in the presence of pyridine. The protection of the amino group or the hydroxyl group of the compound B with an acyl group and the oxo group with an ethyloxy to ether can be followed by the alkylation of the hydroxyl group with a lower alkyl halide and then removing the protecting groups to obtain the compound (wherein R1 represents a hydrogen atom, an alkyl group, which may have a substituent, or a phenyl group, which may have a hydroxyl group, a lower alkoxy group, an amino group, a nitro group, a carboxyl group, a lower alkoxycarbonyl group or halogen atoms and R3 represents a lower alkyl group). The acyl group can be an acyl carboxylic group such as acetyl, trifluoroacetyl or benzoyl, or an acyl carbamate group such as tert-butyloxycarbonyl or benzyloxycarbonyl. In the acetylation reaction mentioned above, the acetylation of the amino group occurs when R1 is an alkyl group which may have a substituent, and the acetylation of the hydroxyl group occurs when R1 is a phenyl group. However, the acetyl group on the hydroxyl group is transferred to the amino group during the alkylation reaction, to obtain the 0-alkylated compound E. The alkylation can be carried out using a lower alkyl halide in the presence of a suitable base. The base may be a metal alkoxide such as sodium methoxide, sodium ethoxide or potassium terbutoxide, or sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide or butyllithium. The solvent used for the reaction may be an ether such as diethyl ether, di ethoxyethane, tetrahydrofuran or dioxane or a polar aprotic solvent such as dimethylformamide or dimethylsulfoxide.

Protective groups can be eliminated by heating appropriately diluted hydrochloric acid, hydrobromic acid or sulfuric acid. Effects The pharmacological effects of the compounds of the invention will be explained in detail. [Effect on rat models for occlusion of peripheral arteries] The models are prepared following the method of Iwamoto et al. (Iwamoto, M. et al., Japanese Pharmacology &Therapeutics, vol 14, Suppl S. p 41, 1986). Under minimal dissection of the femoral regions of SD rats (6 per group) with a body weight of 250 ~ 350 g under anesthesia with Nembutal, 0.1 ml of 5% lactic acid is administered intra-arterially. The rats were reared for 14 days under normal conditions, and observed for lesions of the lower extremities. The grade for the lesions is: "1" for black parts only on the tip of the nails. "2" for black parts up to the fingers, "3" for necrosis of the fingers and "4" death of the fingers. Each of the fingers of the lower parts on the side where the lactic acid was administered are graded, and the total degree is determined as the index of lesions. The ratio of the inhibition of the disorder is determined by dividing the injury index in the group administered with the drug by the injury index of the control group. The drugs are dissolved in physiological saline or dimethylsulfoxide, and injected through the caudal vein 5 minutes before the injection of 5% lactic acid. As shown in Table 1. The compounds of the invention inhibit the presence of occlusion of the peripheral arteries. Table 1 Effects on rat models for occlusion of peripheral arteries Compound Solvent Dose Ratio of Inhibi- (mg / kg, iv) tion (%) Compound of Example 1 Solution Sa- 42 * Compound of physiological lina-3 65 * Example 16 logic 30 78 * * Compound of Example 5 DMSO 5 35 * * p < 0.05 * * p < 0.02 [Effect on bronchoconstriction in guinea pigs] After anesthetizing male guinea pigs with urethane (body weight: 350 ~ 450 g, 5 per group, Nihon Crea Co.), A small cannula is inserted into the trachea. Then galamina triethioiodide is administered intravenously (1 mg / kg), and the tracheal cannula is connected to a constant-volume ventilator. Artificial respiration is conducted with a volume of air per breath of 7 '10 ml, a frequency respiratory rate of 60 / minute and an application pulmonary pressure of 10 cm of water. The volume of air overflow from the legs on the lateral cannula is recorded in a polygraph (RM6100: product of Nihon Koden Co.) with a model 7020 bronchospasm transducer (product of Ugo Basile). The hydrochloride is dissolved from the test compounds in physiological saline, and inhalation is performed with reference to the method of Minami et al. (Minami, S. et al., Japanese Journal of Thoracic Diseases, Vol. 21, No. 3, pp. 252, 1983). The inhalation charging apparatus is prepared by directly incorporating an ultrasonic nebulizer into the artificial respiration circuit (Omron ultrasonic aspirator NE-U11B, product of Tateishi Electric Co.). The test compound (mg / 0.5 ml) is administered by inhalation for 30 seconds, and after 2 minutes histamine (3 μg / kg) is administered intravenously and the volume of air overflow is measured. The ratio of bronchoconstriction is calculated as a percentage with 100 which is the height of the contraction when the air path is completely impeded. The inhibition ratio is calculated by dividing the contraction ratio of the test compound group by the contraction ratio of the control group. As shown in Table 2, the compounds of the invention inhibit bronchoconstriction.

Table 2 Effect on bronchoconstriction models of guinea pigs induced with histamine Compound Dosage Inhibition ratio of (mg / 0.5 ml) bronchoconstriction (%) Compound of Example 9 1.0 57 *** *** Compound of Example 15 3.0 73 *** Compound of Example 16 3.0 32 ** Compound of Example 16 10.0 46 *** Compound of Example 22 3.0 17 * Compound of Example 23 3.0 23 * Compound of Example 26 3.0 53 ** Compound of Example 30 3.0 42 ** (-) Compound of Example 35 10.0 64 *** * p <; 0.05 ** p < 0.02 *** p < 0.01 [Effect on bronchoconstriction of guinea pigs induced with antigen] They are administered intraperitoneally with anti-DNP serum Ascaris male guinea pigs (body weight: 300 ~ 450 g), Nihon Crea Co.) (antibody titre 1024 times) in 0.5 ml / kg. After 25 hours, anesthesia with urethane is inserted a cannula in the trachea, a cannula in the left cervical artery and a cannula for the injection of the drug into the right jugular vein, and galathene triethiodide (1.0 mg / ml) is administered intravenously. 0.5 ml / kg), and connects to an artificial respirator (product of Ugo Basile). For the test, diphenhydramine is administered intraperitoneally. { 60 mg / ml / kg), the compound of Example 16 is inhaled as the test compound after 14 minutes, and the intravenous administration of DNP-bovine albumin serum (1.0 mg protein / 0.5 ml) is continued. / kg) one minute after administration of the test compound, the degree of bronchoconstriction is observed over a period of 15 minutes. The ratio of bronchoconstriction is given as a percentage of maximum air over the volume of flow obtained by the unclogging of the trachea. The compounds tested are inhaled by nebulization for 30 seconds with an ultrasonic nebulizer. As shown in Figure 1, the compounds of the invention inhibit contraction of the air path. [Effect on blood pressure of anesthetized rats] Male SD rats (body weight: 250 ~ 350 g, product of Nihon Crea Co.) are placed under anesthesia with urethane and then a sphygmomanometric pressure transducer is inserted into the left cervical artery and a record is made on the polygraph (RM6100, product of Nihon Koden Co.) using a linear pressure amp (AP-621G, product of Nihon Koden Co.). The test compounds are dissolved in physiological saline and administered intravenously. The change in pressure blood is indicated as the ratio of reduction of the initial value of diastolic blood pressure only before administration of the test compound. As shown in Table 3, the compounds of the invention lower the blood pressure of anesthetized rats. Table 3 Effect on blood pressure of anesthetized rats Reduction of blood pressure (%) Compound Dose (mg / kg) 1 3 10 Compound of Example 2 16 31 Compound of Example 7 Compound of Example 8 Compound of Example 9 14 32 51 Compound of Example 12 Compound of Example 13 Compound of Example 15 Compound of Example 16 6 16 Compound of Example 17 42 [Effect on spontaneous hypertensive rats (SHR)] Male SHR (body weight: 270 ~ 300 g, Nihon Charles River Co.) that have been bred for at least a week undergo blood pressure measurement twice, on the day of the test and one day prior to it, and the average values are used as baseline values. It is measured systolic blood pressure by the method of tying the tail, using a nop-nvansy sphygmomanometer (Programmed Electro-Sphygmomanometer PE-300: Narco Bio-Systems, Inc.). The test compounds are dissolved or suspended in a 0.5% methylcellulose solution and administered orally, and blood pressure is measured 3 hours after the administration. During the measurement of blood pressure, the animals are heated for 15 minutes in an incubator. As shown in Table 4, the compounds of the invention reduce the SHR blood pressure. Table 4 Effect on blood pressure of SHR Compound Dose Reduction of blood pressure (mg / kg, iv) (%) Compound of Example 7 17 Compound of Example 8 11 Compound of Example 9 Compound of Example 10 Compound of Example 13 Compound of Example 15 Compound of Example 16 Compound of Example 17 Enalapril 5 18 [Inhibition on platelet aggregation (in vitro =] Platelet-rich plasma is prepared from white male house rabbits (body weight: 2.5 ~ 3.0 kg) following the method of Suzuki et al. (Suzuki, K. et al., The Clinical Report, Vol.21, No. 13, p.5263, 1987). The resulting platelet-rich plasma cells are appropriately diluted with Tris-Tirode buffer (pH 7.4) to prepare a platelet suspension of 4 x 10 5 platelets / μl to be used for the test. Platelet aggregation is measured using a platelet aggregometer (NBS Hematoracer 601, product of Nikoh Bioscience Co.). Specifically, 250 μl of the platelet suspension is added, 5 μl of a 96 nM calcium chloride solution and 5 μl of the test compound solution diluted in methanol to a cuvette, and after incubating for 1 minute at 37 ° C, add 20 μl of a test agent. aggregation and the maximum degree of aggregation that occurs is determined. The aggregation agents used are the platelet activation factor (PAF) (2.5 ng / ml) and arachidonic acid (68.6 μg / ml). The 50% inhibition concentration (IC50) is calculated from the measurement results with various concentrations of each test compound. As shown in Table 5, the compounds of the invention inhibit platelet aggregation.

Table 5 Effect of inhibition on platelet aggregation Compound c ^ 50 ^^ M ^ RAF Arachidonic acid Compound of Example 1 100 Compound of Example 3 26 36 Compound of Example 4 37 69 Compound of Example 5 66 100 Compound of Example 16 100 Compound of Example 18 98 Compound of Example 28 11 [Effect on calcium contraction (in vitro)] This is investigated according to the method of Ishibashi, et al., (Ishibashi, A. et al., Folia Pharmacologica Japónica, Vol. 82, p.361, 1983). Male SD rats of approximately 300 g body weight are used to prepare specimens of thoracic aortic extracts, which are suspended and immobilized in an organ bath containing 10 ml of Krebs-Henseleit buffer at 37 ° C through the which is passed through a mixed gas of oxygen (95%) and carbon dioxide (5%). After balancing the specimens, they are equilibrated in a buffer solution without calcium chloride and then in a buffer solution of 80 mM potassium chloride free of isotonic calcium replaced with potassium ions, and a resting voltage of 0.2 g is applied. The contraction is induced by addition of calcium chloride at 0.3 mM. The test compounds are added 10 minutes before the addition of the calcium solution. The percent inhibition of the test compounds is calculated using the first contraction as the control (100% contraction). The test compounds are used for the test as solutions in dimethylsulfoxide in a concentration at 1 x 10"7 M. As shown in Table 6, the compounds of the invention inhibit the calcium contraction of the thoracic aorta Table 6 Effect on the contraction of calcium chloride Compound Contraction Inhibition (%) Compound of Example 1 Compound of Example 4 Compound of Example 10 Compound of Example 16 Compound of Example 18 Compound of Example 22 48 These results show that the Compounds of the invention are useful as a means for arterial occlusion, hypertension, occlusion of peripheral arteries and bronchial asthma The compounds of the invention can be combined with common pharmaceutical carriers to prepare solid preparations, such as tablets, soft or hard capsules, powder fine granules or suppositories, or liquid preparations, such as injections, inhalants, syrups, aqueous mixtures, suspensions or emulsions. The combined pharmaceutical carrier can be appropriately selected depending on the desired form of preparation, examples of which are excipients, binders, disintegrants, lubricants, coating agents, solution aids, emulsifiers, suspending agents, surfactants, inhalation aids, stabilizers and solvents. The amount of the same to be used will differ depending on the age, symptoms and mode of administration, but oral administration is usually 0.1 ~ 1000 mg / day, either once or in divided doses. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the effect on contraction of the air path of guinea pigs induced with antigen. The following examples serve to explain the present invention, but are not intended to restrict it. [Example 1] 4-Benzylamino-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one The lithium perchlorate (5.3 g, 50 mmol) and benzylamine (5.4 ml, 50 mmol) are added to a Acetonitrile solution (50 ml) containing eukaryone-4,5-oxide (8.5 g, 50 mmol), and the mixture is heated to reflux for 10 hours. The reaction solution is concentrated, water is added and the resulting aqueous solution is extracted with ethyl acetate. After washing the ethyl acetate solution with brine, it is dried with anhydrous magnesium sulfate. The residue obtained from the concentration of the ethyl acetate solution is purified by column chromatography with silica gel, using benzene / ethyl acetate (5: 1) as the eluent, to obtain 7.52 g (55%) of the 4-benzylamino-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one as a yellow oil iH-R (CDC13, ppm): 0.88 (3H, s), 1.12 (3H, s), 1.84 (3H, t, J = 2Hz), 2.30 (ΔI, d, J = 12Hz), 2.45 (ΔI, d , J = 12Hz), 3.07 (HH, d, J = 9Hz), 3.30 (dm, J = 9Hz), 3.85 (1H, d, J = 13Hz), 4.06 (HH, d, J = 13Hz), 6.44 ( ÍH, broad), 7.27 ~ 7.36 (5H, m) The resulting free base (5.47 g, 20 mmol) is dissolved in ethyl acetate (30 ml) and ethyl acetate-4N HCl solution (6 ml) is added. The crystals that precipitate are filtered to obtain 6.07 g (98%) of the hydrochloride as colorless needles. The melting point fes of 203 ~ 204 ° C (decomposition). The compounds of Examples 2 to 27 are obtained in the same manner as in Example 1.

[Example 2] 4 - (2-Phenylethylamino) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1 -one 32% yield, colorless prisms, melting point: 100.5 ~ 101.5 ° C. iH-NMR (CDC13, ppm): 0.97 (3H, s), 1.13 (3H, s), 1. 80 (3H, t, J = 2Hz), 2.32 (1H, d, J = 12Hz), 2.48 (1H, d, J = 12Hz), 2.81 ~ 2.96 (3H, m), 3.01 (ÍH, d, J = 9Hz), 3.11 ~ 3.22 (2H, m), 4.85 (ÍH, broad), 6.25 (ÍH, m), 7.22 ~ 7.30 (5H, m) Hydrochloride: 89% yield, colorless crystals, melting point: 188.5 ~ 199.5 ° C (decomposition) .

[Example 3] 4- (4-ethoxycarbonylphenylamino) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one 28% yield, colorless needles, melting point: 123 ~ 124.5 ° C. iH-RM (CDC13 + D20, ppm): 1.08 (3H, s), 1.17 (3H, s), 1. 37 (3H, t, J = 7Hz), 1.83 (3H, t, J = 2Hz), 2.45 (ÍH, d, J = 12Hz), 2.67 (HH, d, J = 12Hz), 3.41 (HH, d, J = 9Hz), 4.19 (HH, dm), 4.33 (2H, q, J = 7Hz), 6.35 (HH, m ), 6.68 (2H, d, J = 9Hz). 7. 92 (2H, d, J = 9Hz) [Example 4] 5-hydroxy-4- (4-ethoxycarbonylbenzylamino) -2,6,6-trimethyl-2-cyclohepten-l-one 43% yield, slightly yellow oil. 1 H-NMR (CDC13, ppm): 0.90 (3H, s), 1.14 (3H, s), 1. 40 (3H, t, J = 7Hz), 1.86 (3H, t, J = 2Hz), 2.32 (ÍH, d, J = 12Hz), 2.45 (HH, d, J = 12Hz), 3.13 (HH, d, J = 9Hz), 3.29 (HH, m), 3.94 (HH, d, J = 14Hz), 4.14 (HH, d, J = 14Hz), 4.38 (2H, d, J = 7Hz), 6.44 (HH, m), 7.44 (2H, d, J = 8Hz), 8.04 (2H, d, J = 8Hz) [Example 5] 5-Hydroxy-4-phenylamino-2,6,6-trimethyl-2-cyclohepten-l-one 62% yield, slightly yellow oil Hydrochloride: 94% yield , colorless crystals, melting point: 173 ~ 178 ° C (foaming) 1H-NMR (CDC13, ppm): 0.97 (3H, s), 1.04 (3H, s), 1.79 (3H, t, J = 2Hz) , 2.41 (HH, d, J = 12Hz), 2.44 (HH, d, J = 12Hz), 3.77 (HH, d, J = 9Hz), 4.3 3 (HH, dm), 6.44 (HH, m), 7.51 (3H,), 7.81 (2H, n) [Example 6] 4- (4-pheny1-1-butylamino) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-l-one 41% yield , colorless oil 1H-NMR (CDC13, ppm): 0.96 (3H, s), 1.12 (3H, s), 1. 58 (2H, m), 1.69 (2H, m), 1.81 (3H, t, J = 2Hz), 2.31 (HH, d, J = 12Hz), 2.48 (HH, d, J = 12Hz), 2.63 (3H, m), 2.89 (HH, m), 3.00 (HH, d, J = 9Hz), 3.0 ~ 3.5 ( ÍH, broad, overlap), 3.18 (H, m), 6.33 (H, broad), 7.1"7.3 (5H, m) Hydrochloride: 89% yield, colorless crystals [Example 7] 4-Cyclopentylamino-5-hydroxy-2-hydrochloride , 6, 6-trimethyl-2-cyclohepten-1-one 27% yield, colorless needles, melting point: 164 ~ 166 ° C 1 H-NMR (CDC13, ppm): 1.06 (3H, s), 1.13 (3H , s), 1.6" 1. 8 (2H, m), 1.89 (3H, t, J = 2Hz), 1.9"2.2 (6H, m), 1.94 (2H, s), 3.65 (ÍH, broad), 3.76 (ÍH, broad), 3.92 ( ÍH, broad), 5.32 (ÍH, broad), 6.93 (ÍH, m), 8.56 (ÍH, broad), 9.99 (ÍH, broad) [Example 8] 4-Cyclohexylamino-5-hydroxy-2,6 hydrochloride, 6-trimethyl-2-cyclohepten-1-one 31% yield, colorless needles, melting point: 195 ~ 197 ° C (decomposition) 1 H-NMR (CDC13, ppm): 1.05 (3H, s), 1.13 (3H , s), 1.30 (3H, m), 1.70 (5H, m), 1.89 (3H, t, J = 2Hz), 2.23 (2H, m), 2.47 (2H, s), 3.24 (ÍH, broad), 3.67 (ÍH, d , J = 9Hz), 5.36 (ÍH, broad), 6.89 (ÍH, m), 8.37 (ÍH, broad), 9.88 (ÍH, broad) [Example 9] 4- (1-Butylamino) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-l-one hydrochloride 22% yield, colorless crystals, melting point: 151 ~ 154 ° C 1 H-NMR (CDC13, ppm): 0.98 (3H, t, J = 7Hz), 1.08 (3H, s), 1.15 (3H, s), 1.48 (2H, m), 1.91 (5H, m), 2.42 ( ÍH, d, J = 12Hz), 2.49 (HH, d, J = 12 Hz), 3.0 5 (HH, m), 3.19 (HH, m), 3. 51 (ÍH,), 4.14 (ÍH, broad), 4.64 (ÍH, broad d), 6.67 (ÍH, m), 9.23 (ÍH, broad), 9.45 (ÍH, broad) [Example 10] 5 -hydroxy -4 - (2-methoxyethylamino) -2,6,6-trimethyl-2-cyclohepten-1-one 24% yield, slightly brown crystals 1H-NMR (CDC13, ppm): 0.98 (3H, s), 1.15 (3H, s), 1. 83 (3H, t, J = 2Hz), 2.33 (HH, d, J = 12Hz), 2.50 (HH, d, J = 12Hz), 2.82 (HH, m), 3.06 (2H, m), 3.23 (HH) , m), 3.39 (3H, s), 3.53 (2H, m), 6.40 (H, m) Hydrochloride: 92% yield, slightly brown crystals [Example 11] 4- (1-octylamino) -5- hydrochloride hydroxy-2,6,6-trimethyl-2-cyclohepten-l-one 15% yield, colorless crystals, melting point: 114 ~ 118 ° C 1 H-NMR (CDC13, ppm): 0.87 (3H, as t.), 1.08 (3H, s), 1.14 (3H, s), 1.2-1.5 (10H, m), 1.90 (3H, broad s), 1.90 (2H, m, overlap), 2.4 2 (HH, d, J = 13Hz), 2.48 (HH, d, J = 13Hz), 3.05 (HH, broad m), 3.22 (HH, broad m), 3.50 ( ÍH, t, J = 10Hz), 4.14 (ÍH, broad), 4.61 (ÍH, d, J = 10Hz), 6.66 (ÍH, broad), 9.25 (ÍH, broad), 9.45 (ÍH, broad) [Example 12] 5-hydroxy-4- (tert-butylamino) -2,6,6-trimethyl-2-cyclohepten-1-one 26% yield, colorless crystals, melting point: 103 ~ 105 ° C 1H-NMR ( CDC13, ppm): 0.99 (3H, s), 1.15 (3H, s), 1.84 (9H, s), 1.82 (3H, t, J = 2Hz), 2.34 (ÍH, d, J = 12Hz), 2.55 ( HH, d, J = 12Hz), 2.82 (HH, d, J = 9Hz), 3.35 (HH, m), 6.36 (HH, m) Hydrochloride: 74% yield, colorless crystals [Example 13] 4-diethylamino -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one 48% yield, colorless plates, melting point: 71 ~ 71.5 ° C 1 H-NMR (CDC13, ppm): 0.98 (3H, s), 1.11 (6H, t, J = 7Hz), 1.17 (3H, S), 1.84 (3H, t, J = 2Hz), 2.3 4 (ÍH, d, J-12Hz), 2.48 (HH, d, J = 12Hz), 2.60 (2H, broad), 3.12 (HH, d, J = 9Hz), 3.44 (HH, dm, J = 9Hz), 5.09 (HH, s ), 6.43 (1H, m) Hydrochloride: 98% yield, colorless crystals, melting point: 186.5 ~ 187.5 ° C (decomposition) [Example 14] 4-Di (1-propylamino) -5-hydroxy-2 hydrochloride , 6, 6-trimethyl-2-cyclohepten-l-one 44% yield, colorless crystals, melting point: 180 ~ 181.5 ° C (decomposed) 1 H-NMR (CDC13, ppm): 1.02 (3H, t, J = 7Hz), 1.05 (3H, t, J = 7Hz), 1.14 (3H, s), 1.20 (3H, s), 1.95 (3H, broad s), 1.9"2.3 (4H, m), 2.46 (2H, s), 2.8"3.0 (ÍH, m), 3.1" 3.5 (4H, m), 4.30 (ÍH, broad, dd, J = 6, 2Hz), 5.45 (ÍH, broad), 6.42 (ÍH, s broad) , 10.7 (ÍH, broad) [Example 15] 5-Hydroxy-4-pyrrolidino-2,6,6-trimethyl-2-cyclohepten-l-one hydrochloride 28% yield, colorless crystals 1H-NMR (CDC13, ppm ): 1.13 (3H, s), 1.16 (3H, s), 1.95 (3H, t, J = 2Hz), 2.13"2.29 (4H, m), 2.46 (ÍH, d, J = 12Hz), 2.48 (HH, d, J = 12Hz), 3.04 (HH, m), 3.23 (HH, m), 3. 37 (ÍH, d, J = 9Hz), 3.67 (2H, broad), 4.00 (2H, m), 4.38 (ÍH, m), 6.28 (ÍH, m), 11.21 (ÍH, s broad) [Example 16] 5-Hydroxy-4-piperidino-2,6,6-trimethyl-2-cyclohepten-l-one hydrochloride 52% yield, colorless crystals, melting point: 218.5 ~ 219.5 ° C (decomposition) 1H -NRM (CDC13, ppm): 1.08 (3H, s), 1.09 (3H, s), 1. 59"2.07 (6H, m), 1.93 (3H, t, J = 2Hz), 2.35 (ÍH, d, J = 12Hz), 2.66 (HH, d, J = 12Hz), 3.19 (HH, m), 3.36 (2H, m), 3. 42 (HH, d, J = 9Hz), 3.58 (HH, m), 4.23 (HH, m), 6.84 (HH, m) The hydrochloride obtained here dissolves in water, a solution of aqueous sodium hydroxide is added to the IN, and extraction with hexane and concentration produces a free base. Colorless needles, melting point: 77.5 ~ 79 ° C. [Example 17] 4-hexamethyleneimino-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one 71% yield, colorless needles, melting point: 82.5 ~ 83.5 ° C. 1 H-NMR (CDC13, ppm): 0.98 (3H, s), 1.17 (3H, s), 1. 5"1.9 (8H, broad), 1.85 (3H, t, J = 2Hz), 2.34 (HH, d, J = 12Hz), 2.46 (HH, d, J = 12Hz), 2.4 ~ 3.0 (4H, broad ), 3.14 (ÍH, d, J = 9Hz), 3.25 (ÍH, n), 5.07 (ÍH, s), 6.39 (ÍH, m) Hydrochloride: 92.4% yield, colorless crystals, melting point: 209 ~ 213 ° C (decomposition) [Example 18] 5-hydroxy-4-morpholino-2,6,6-trimethyl-2-cyclohep-ten-1- ona 66% yield, colorless crystals, melting point: 139 ~ 140 ° C 1H-NMR (CDC13, ppm): 0.99 (3H, s), 1.18 (3H, s), 1.88 (3H, t, J = 2Hz ), 2.35 (HH, d, J = 12Hz), 2.48 (HH, d, J = 12Hz), 2.61 (2H, m), 2.75 (2H, m), 3.22 (2H, m), 3.76 (4H, m ), 4.81 (H, s), 6.43 (H, m) Hydrochloride: 87% yield, colorless powder, melting point: 213 ~ 216 ° C (decomposition) [Example 19] 4- (2-methylpiperidino) hydrochloride -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-l-one 37% yield, colorless crystals, melting point: 183 ~ 186 ° C (decomposition) [Example 20] 4- (3-Hydrochloride -methylpiperidino) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-l-one 57% yield, colorless crystals, melting point: 197.5 ~ 201 ° C (decomposition) [Example 21] _ 4- (4-Methylpiperidino) -5-hydroxy-2,6,6-trime-l-2-cyclohepten-l-one hydrochloride 47% yield, colorless crystals, melting point: 232 ~ 236 ° C (decomposition) [Example 22] 5-Hydroxy-4- (4-methylpiperazino) -2,6,6-trimethyl-2-cyclohepten-1-one 43% yield, colorless crystals Hydrochloride: 98% yield, colorless powder, melting point: 229.5 ~ 231.5 ° C (foamy decomposition) iH-RM (CD3OD, ppm): 1.09 (3H, s), 1.10 (3H, s), 1.95 (3H, t, J = 2Hz), 2.37 (HH, d, J = 12Hz), 2.65 (HH, d, J = 12Hz), 3.02 (3H, s), 3.4 8 (HH, d, J = 9Hz), 3.56 ~ 3.85 (8H, broad), 4.44 (HH, m), 6.82 (HH, m) [Example 23] 4- (4-hydroxypiperidino) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1 -one 57% yield, oil colorless iH-NMR (CD3OD, ppm): 0.98 (3H, s), 1.17 (3H, s), 1. 50"1.78 (4H, m), 1.86 (3H, t, J = 2Hz), 1.93" 2.00 (2H,), 2.29"2.49 (3H, m), 2.60" 2.90 (3H, m), 2.23 (2H, m), 3.12 (H, broad), 4.92 (H, broad), 6.41 (H, broad) Hydrochloride: 74% yield, colorless crystals, melting point: 215.5 ~ 222 ° C (decomposition) [Example 24] 4- (-ethoxycarbonylpiperidino) -5-hydroxy -2,6,6-trimethyl-2-cyclohepten-l-one 65% yield, colorless oil Hydrochloride: 85% yield, colorless crystals, melting point : 120 ~ 128 ° C (decomposition) lH-NMR (CD3OD, ppm): 1.08 (3H, s), 1.10 (3H, s), 1.30 (3H, t, J = 7Hz), 1.80"1.94 (H, m) ), 2.36 (HH, d, J = 12Hz), 2.66 (1H, d, J = 12Hz), 3.25"3.50 (4H, m), 4.19 (2H, c, J-7Hz), 4.31 (HH, m) 6.84 (H, broad) [Example 25] 4- (4-carboxypiperidino) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one 4- (4-ethoxycarbonylpiperidino) -5- hydroxy-2,6,6-trimethyl-2-cyclohepten-l-one obtained in Example 24 (0.68 g, 2.1 mmol) is dissolved in acetic acid (5 mL), 6N hydrochloric acid (2 mL) is added and the mixture is heated at 80 ° C for 90 minutes. Concentration to dryness followed by washing with ethyl acetate gives 0.56 g (80.2%) of 4- (4-carboxypiperidino) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one hydrochloride. Colorless crystals, melting point: 232 ~ 233.5 ° C (decomposition) 1H-NMR (CD3OD, ppm): 1.08 (3H, s), 1.10 (3H, s), 1.80"1.94 (H, m), 1.94 (3H , broad), 2.15"2.34 (3H, m), 2. 36 (HH, d, J = 12Hz), 2.66 (HH, d, J = 12Hz), 2.75 (HH, m), 3.20"3.45 (4H, m), 3.67 (HH, m), 4.29 (HH, m ), 6.83 (1H, broad) [Example 26] 4- (1, 4-dioxa-8-aza-spiro [5.4] decan-8-yl) -5-hydroxy-2, 6, 6-rimethyl-2 -cyclohepten-1-one 58% yield, colorless crystals, melting point: 167.5-168.5 ° C. 1 H-NMR (CDC13, ppm): 0.98 (3H, s), 1.17 (3H, s), 1.58 (1H) , s), 1.79 (4H, m), 1.85 (3H, m), 2.33 (H, d, J = 12Hz), 2.47 (HH, d, J = 12Hz), 2.64 (2H, m), 2.81 (2H, broad), 3.21 (HH, d, J = 9Hz), 3.26 (HH, m), 3.98 ( 4H, s), 4. 91 (ÍH, broad), 6.44 (ÍH, m) Hydrochloride: 82% yield, colorless crystals, melting point. 220 ~ 223 ° C (decomposition) [Example 27] 4- (4-oxopiperidino) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one It is added to a solution of ethanol (5 ml). ) containing the 4- (1,4-dioxa-8-aza-spiro [4.5] decan-8-yl) -5-hydroxy-2,6,6-dimethyl-2-cyclohepten-1-one obtained in the Example 26 (1 g, 3.24 mmol) 6N hydrochloric acid (2 ml), and the mixture is stirred at 75 ° C for 4 hours. The reaction solution is concentrated, water is added, and aqueous sodium hydroxide solution is used at neutralization. The aqueous solution is subjected to extraction with ethyl acetate and dried over anhydrous magnesium sulfate. The unpurified product obtained by the concentration of the ethyl acetate solution is recrystallized from a mixed solvent of benzene-hexane to obtain 0.53 g (60.9%) of the 4- (4-oxopiperidino) -5-hydroxy-2, 6 , 6-trimethyl-2-cyclohepten-1-one as colorless crystals. 1 H-NMR (CDC13, ppm): 1.02 (3H, s), 1.20 (3H, s), 1.57 (HH, s), 1.86 (3H, m), 2.38 (HH, d, J = 12Hz), 2.42" 2.60 (5H, m), 2.87 (2H, m), 3.08 (2H, m), 2.28 (H, d, J = 9Hz), 3.44 (H, m), 4.63 (H, s), 6.32 (H, m) This free base is treated with acid chloride according to Example 1 to obtain 0.47 g (78%) of the hydrochloride as colorless crystals. [Example 28] 5-Hydroxy-4- (N-methylbenzylamino) -2.6, 6 - trimethyl-2-cyclohepten-1 -one The 4-benzylamino-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 1 is dissolved. (5.86 g, 21.5 mmol) in formic acid (30 ml), formalin (30 ml) is added, and the mixture is heated at 90 ° C for 3 hours. The reaction solution is concentrated and brought to alkaline pH with 1% aqueous sodium hydroxide solution. The aqueous solution is subjected to extraction with benzene, washed with water, and dried with anhydrous potassium carbonate. The benzene solution is concentrated, and the resulting residue is subjected to column chromatography with hexane-ethyl acetate (9: 1) gel as the eluent, to obtain 2.95 g of the unpurified product which is then recrystallized from hexane to give 2.39 g (39%) of the 5-hydroxy-4- (N-methylbenzylam ino) -2,6,6-trimethyl-2-cyclohepten-1-one as colorless crystals. Melting point: 78.5 ~ 80 ° C. 1 H-NMR (CDC13, ppm): 0.81 (3H, s), 1.16 (3H, s), 1.89 (3H, t, J = 2Hz), 2.2 9 (1H, d, J = 12 H z), 2.3 3 (3H, s), 2.38 (HH, d, J = 12 Hz), 3.23 (HH, d, J = 9Hz), 3.35 (HH, m), 3.65 (HH, m), 3.83 (HH, d, J = 13Hz), 4.94 (HH, s), 6.48 (HH, m), 7.25"7.39 (5H, m) [Example 29] 5-Hydroxy-4-piperidino-2,6,6-trimethyl-2-methyloxime cyclohepten-1-one is added to a methanol solution (30 ml) containing the 5-hydroxy-4-piperidino, 2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 16 (3 g , 12.5 millimoles) in methoxyamine hydrochloride (1.57 g, 18.8 millimoles) and pyridine (3.0 g) and the mixture is stirred first at room temperature and then heated slightly to 55 ° C, and after 5 hours of stirring at that temperature, it is allowed to stand at room temperature overnight. The reaction solution is then poured into water and brought to an alkaline pH with a 10% aqueous sodium hydroxide solution (20 ml). The aqueous solution is extracted with benzene and dried with anhydrous magnesium sulfate. Concentrate the benzene solution under reduced pressure to obtain 3.49 g of 5-hydroxy-4-piperidino-2,6,6-trimethyl-2-cyclohepten-1-one as unpurified crystals. 1 H-NMR (CDC13, ppm): 0.95 (3H, s), 1.32 (3H, s), 1.20"1.65 (7H, broad), 1.81 (HH, d, J = 12Hz), 1.93 (3H, m), 2.45 (2H, broad), 2.64 (2H, m), 1.92 (HH, d, J = 12Hz), 3.08 (HH, m), 3.19 (HH, d, J = 9Hz), 3.83 (3H, s), 5.14 (H, broad), 5.84 (H, broad) The unpurified crystals obtained from the free base are treated with acid chloride according to Example 1 to obtain 3.65 g (93%) of the hydrochloride. ~ 257 ° C. The compounds of Examples 30 and 31 are obtained in the same manner as Example 29. The compound of Example 30 is also acetylated to obtain the compound of Example 32.

[Example 30] 5-Hydroxy-4-piperidino-2,6,6-trimethyl-2-cyclohepten-1-yl oxime Hydrochloride: 96% yield, colorless powder, melting point: 237 ~ 242 ° C (decomposition) ) Free base: 1H-NMR colorless crystals (CDC13, ppm): 0.98 (3H, s), 1.18 (3H, s), 1. 20"1.70 (7H, broad), 1.83 (ÍH, d, J = 13Hz), 1.92 (3H, m), 2. 46 (2H, broad), 2.66 (2H, m), 2.03 (HH, d, J = 13Hz), 3.10 (HH, m), 3.20 (1H, d, J = 9Hz), 5.15 (HH, broad) , 5.88 (ÍH, broad), 8.03 (ÍH, broad) [Example 31] 5-hydroxy-4-pyrrolidino-2,6,6-t-methyl-2-cyclohepten-1-one oxime Hydrochloride: 84% yield, colorless crystals, melting point: 241 ~ 242 ° C (decomposition) ) 1-H-NMR (CD3OD, ppm): 1.03 (3H, s), 1.07 (3H, s), 1.79 (ΔH, d, J = 13Hz), 1.99 (3H, broad), 2.0"2.2 (4H, m), 3.18 (HH, d, J = 13Hz), 3.15"3.23 (HH, m), 3.35 (HH, d, J = 10Hz), 3.36" 3.45 (2H, m), 3.53"3.62 (HH, m ), 3.31 (ÍH, broad d, J = 10Hz), 5.77 (ÍH, broad) [Example 32] 5-Acetoxy-4-piperidino-2,6,6-trimethyl-2-cyclohepten- 1 -one acetoxychloride : 93% yield, colorless crystals Free base: 1H-NMR colorless oil (CDC13, ppm): 1.02 (6H, s), 1.15"1.62 (6H, broad), 2.03 (3H, m), 2.10 (3H, s) ), 2.22 (3H, s), 2.39 (HH, d, J = 14 Hz), 2.44 (2H, m), 2.58 (2H, m), 2.77 (HH, d, J = 12Hz), 3.31 (HH, m), 4.83 (ÍH, d, J = 9Hz), 5.01 (ÍH, s broad) [Example 33] 4-benzylamino-5-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one Step 1: 4-Benzylamino-5-hydroxy-2,6,6-trimethyl-2- is dissolved cyclohepten-l-one obtained in Example 1 (17.3 g, 63.4 mmol) in tetrahydrofuran (100 ml), triethylamine (19.2 g, 190 mmol) is added, and "acetic anhydride (12.9 g, 127 mmol) is added dropwise while stirring on ice. reaction solution at 50 ° C for 3 hours, it is drained in ice water (300 ml.) After 30 minutes the aqueous solution is extracted with benzene, washed with water, and then dried with anhydrous magnesium sulfate. The benzene is removed by distillation, and the resulting residue is recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 19.0 g (95%) of 4- (N-acetylbenzylamino) -5-hydroxy-2,6,6- trimethyl-2-cyclohepten-l-one Stage 2 The 4- (N-acetylbenzylamino) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-l-one obtained in step 1 (19.0 g, 60.3 mmol) ) is treated according to Example 29, to obtain 14.5 g (70%) of the methyloxime of 4- (n-acetylbenzylamino) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one as a inc oil Stage 3 To a solution of tetrahydrofuran (40 ml) containing methyloxime of 4- (N-acetylbenzylamino) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-l-one obtained in step 2 (FIG. 9.5 g, 27.6 mmol) is gradually added to 55% sodium hydride (3.6 g) while cooling on ice.

Methyl iodide (7.8 g, 55.2 mmol) is then added and - stirring is carried out for 30 minutes, the mixture is brought to room temperature and stirring is continued for 1 hour. The reaction solution is poured into ice water (100 ml) containing acetic acid (1 ml), and extracted with benzene. After washing the benzene solution with water, drying is anhydrous magnesium sulfate. The benzene is distilled off, and the resulting residue is subjected to column chromatography with silica gel with benzene-ethyl acetate (9: 1) as the eluent, to obtain 8.51 g (86%) of 4- ( N-Acetylbenzylamino) -5-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one as a colorless oil. Step 4: To a solution of ethanol (40 ml) containing methyloxime of 4- (N-acetylbenzylamino) -5-methoxy-2,6,6-trimethyl-2-cyclohepten-l-one obtained in step 3 (8.5 g) , 23.7 millimoles) is added pyruvic acid (4.18 g, 47.4 millimoles) and 6N hydrochloric acid (40 ml), and the mixture is heated at 75 ° C for 4 hours. The reaction solution is concentrated and the resulting residue is dissolved in methanol (50 ml) and then neutralized with 10% aqueous sodium hydroxide solution while stirring on ice. HE. add water (100 ml), extract it with benzene, and after washing the benzene solution with water, dry it with anhydrous magnesium sulfate. The distillation is benzene and the resulting residue is subjected to column chromatography with silica gel with benzene-ethyl acetate (19: 1) as the eluent, to obtain 4.72 g (69%) of the 4-benzylamino-5-methoxy-2, 6, 6-trimethyl-2-cyclohepten-l-one as a colorless oil. 1H-NMR (CDC13, ppm) 0.90 (3H, s), 1.12 (3H, s), 1.84 (3H, t, J = 2Hz), 2.25 (H, d, J = 12Hz), 2.51 (H, d, J = 12Hz), 2.83 (HH, d, J = 9Hz), 3.52 (3H, s), 3.50"3.56 (HH, m), 3.78 (HH, d, J = 14Hz), 4.05 (HH, d, J = 14Hz), 6.61 (HH, m), 7.30 (5H, m) [Example 34] 5-methoxy-4-phenylamino-2,6,6-trimethyl-2-cyclohepten-1-one Step 1 The 5- hydroxy-4-phenylamino-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 5 (13.7 g) is treated according to step 1 of Example 33 and crystallized from a mixed solvent of benzene and hexane, to obtain 14.6 g (92%) of 5-acetoxy-4-phenylamino-2,6,6-trimethyl-2-cyclohepten-1-one as colorless crystals. -H-RMNÍCDClg, ppm): 1.03 (3H, s), 1.15 (3H, s), 1.78 (3H, s), 1.86 (3H, t, J = 2Hz), 2.47 (ÍH, d, J = 12Hz) , 2.72 (HH, d, J = 12Hz), 3.7"4.1 (HH, broad), 4.45 (HH, m), 4.73 (HH, d, J = 9Hz), 6.42 (HH, m), 6.61 (2H) , m), 6.74 (ÍH,), 7.18 (2H, m) Stage 2 5-Acetoxy-4-phenylamino-2,6,6-trimethyl-2-cyclohepten-l-one methyloxime 5-Acetoxy-4-phenylamino- 2,6,6-trimethyl-2-cyclohepten-1- one obtained in step 1 (4.0 g) is treated according to Example 29 to obtain 3.27 g (75%) of 5-acetoxy-4-phenylamino-2,6,6-trimethyl-2-cyclohepten-1 methyloxime. ona as colorless crystals. iH-RMNtCDCl-j, ppm): 0.97 (3H, s), 1.14 (3H, s), 1.72 (3H, s), 1.92 (3H, t, J = 2Hz), 2.04 (ÍH, d, J = 13Hz ), 3.08 (ÍH, d, J = 13Hz), 3.7"4.0 (ÍH, broad), 3.90 (3H, s), 4.36 (ÍH, m), 4.69 (ÍH, d, J = 9Hz), 5.77 ( HH, m), 6.58 (2H, m), 6.69 (HH, 0), 7.15 (2H, m) Step 3 Methyloxime 5-methoxy-4 - [N-acetylphenylamino) -2,6,6-trimethyl-2- cyclohepten-1-one The methyloxime of 5-acetoxy-4-phenylamino-2,6,6-trimethyl-2-cyclohepten-1-one obtained in step 2 (3.27 g) is treated according to step 3 of Example 33 to obtain 2.11 g (62%) of methyloxime of 5-methoxy-4- (N-acetylphenylamino) -2,6,6-trimethyl-2-cyclohepten-l-one as a colorless oil.1H-NMR (CDC13, ppm ): 0.88 (3H, s), 1.11 (3H, s), 1.80 (ÍH, d, J = 13Hz), 1.85 (3H, s), 1.92 (3H, t, J = 2Hz), 2.82 (HH, d, J-13Hz), 3.51 (3H, s), 3.64 (HH, d, J = 9 Hz), 3.86 (3H, s), 4.04 (HH, m), 6.07 (HH, d), 7.30 (5H, m) -Stage 4 5 -methoxy-4-phenylamino-2,6,6-trimethyl-2-cyclohepten-1-one The methyloxime of 5-methoxy-4- (N-acetylphenylamino) -2,6 , 6-trimethyl-2-cyclohepten-l-one obtained in step 3 (1.66 g) is treated according to step 4 of Example 33 to obtain 0.68 g (52%) of 5-methoxy-4-phenylamino-2,6,6-trimethyl-2-cyclohepten-1-one as an oil colorless. 1 H-NMR (CDC13 ppm): 1.01 (3H, s), 1.15 (3H, s), 1.84 (3H, t, J = 2Hz), 2.38 (ΔH, d, J = 12Hz), 2.71 (ΔI, d, J = 12Hz), 3.02 (HH, d, J = 9Hz), 3.60 (3H, s), 4.07 (HH, m), 6.56 (HH, m), 6.73 (2H, m), 6.84 (HH, m) , 7.25 (2H, m) [Example 35] (+) and (-) - 5-hydroxy-4-piperidino-2,6,6-trimethyl-2-cyclohepten-1-one To a solution of ethanol (20 ml) ) containing the 5-hydroxy-4-piperidino-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 16 (5.0 g, 20 mmol) is added a solution of ethanol (20 ml) which contains (-) - dibenzoyl tartrate (3.76 g, 10 mmol), and the resulting crystals are filtered and dissolved in methanol (30 ml). After concentration of the solution, it is recrystallized from ethanol to obtain 3.3 g of sodium tartrate salt. dibenzoyl. This is dissolved in water, brought to alkaline pH - with a 10% aqueous sodium hydroxide solution, and the aqueous solution is extracted with hexane. The residue obtained by concentrating the hexane solution is recrystallized from hexane to obtain 1.6 g (32%) of (+) - 5-hydroxy-4-piperidino-2,6,6-trimethyl-2-cyclohepten-1- ona as colorless needles. [224] D20: + 119 ° (c = 1.00, ethanol). Melting point: 69 ~ 70 ° C. Hydrochloride: colorless crystals, melting point: 227 ~ 228 ° C (decomposition). The first crystalline mother liquor is concentrated, brought to alkaline pH with 10% aqueous sodium hydroxide solution and extracted with hexane. The residue obtained by concentrating the hexane solution is dissolved in ethanol (20 ml), and a solution of ethanol (20 ml) is added, containing (+) - dibenzoyl tartrate (3.15 g, 8.4 mmol) thereto. The procedure described above is then continued to obtain 1.5 g (30%) of (-) - 5-hydroxy-4-piperidino-2,6,6-trimethyl-2-cyclohpeten-1-one, [ot] D20: - 119 ° (c = 1.00, ethanol), Melting point: 71 ~ 2 ° C. Hydrochloride: colorless crystals, melting point: 226 ~ 228 ° C (decomposition).

Claims (6)

1. CLAIMS 1. A compound of 4-amino-5-oxy-2,6,6-trimethyl-2-cycloheptene, characterized in that it is represented by the general formula: (wherein R1 and R2 each independently represents a hydrogen atom, an alkyl group of 1 to 10 carbon atoms, which may be a substituent, or a phenyl group, which may have a hydroxyl group, a lower alkoxy group , an amino group, a nitro group, a carboxyl group, a lower alkoxycarbonyl group or a halogen atom, or R1, R2 and the nitrogen atom together represent a saturated nitrogen heterocyclic group, R3 represents a hydrogen atom, an alkyl group lower or a lower aliphatic acyl group, and W represents an oxo group, an oxime group or an ether oxime group); or a pharmacologically acceptable salt or solvate thereof.
2. 2. The compound according to claim 1, characterized in that the alkyl group of R1 and / or R2 is an alkyl group of 1 to 10 carbon atoms substituted with a lower alkoxy group, an amino group, an group alkylated lower, a lower dialkylamino group or - a phenyl group, which may have a hydroxyl group, a lower alkoxy group, an amino group, a nitro group, a carboxyl group, a lower alkoxycarbonyl group, or a halogen atom on the ring; or a pharmacologically acceptable salt or solvate thereof.
3. 3. The compound according to claim 1, characterized in that the saturated nitrogen heterocyclic group is pyrrolidine, piperidine, homopiperidine, piperazine, homopiperazine, or morpholine which may have a lower alkyl group, a hydroxyl group, a lower alkoxy group, a carboxyl group, an alkoxycarbonyl group, an oxo group or an acetal group thereof on its ring, or a pharmacologically acceptable salt or solvate thereof.
4. 4. The compound according to claim 1 or claim 3, characterized in that it is 5-hydroxy-4-piperidino-2,6,6-trimethyl-2-cyclohepten-1-one, or a pharmacologically acceptable salt or solvate of the same.
5. 5. A pharmaceutical composition whose effective component is a compound of 4-amino-5-oxy-2,6,6-trimethyl-2-cycloheptene, characterized in that it is represented by the following formula: (wherein R1 and R2 each independently represent a hydrogen atom, an alkyl group of 1 to 10 carbon atoms, which may be a substituent, or a phenyl group, which may have a hydroxyl group, a lower alkoxy group , an amino group, a nitro group, a carboxyl group, a lower alkoxycarbonyl group or a halogen atom, or R1, R2 and the nitrogen atom together represent a saturated nitrogen heterocyclic group, R3 represents a hydrogen atom, an alkyl group lower or a lower aliphatic acyl group, and W represents an oxo group, an oxime group or an ether oxime group); or a pharmacologically acceptable salt or solvate thereof.
6. 6. The pharmaceutical composition according to claim 5, characterized in that it is a remedy for hypertension, occlusion of peripheral arteries or bronchial asthma.