Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
  • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
  • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

Definitions

• the present invention provides a compound represented by the general formula (I)
• R 2 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or an aralkyl group
• R 3 represents 1 to 4 lower alkyl groups, lower alkoxy groups, and halogen atoms as substituents.
• the novel benzodioxane derivative represented by These compounds are useful as medicaments having excellent antidepressant and anxiolytic effects. Background art
• benzodiazepine-based drugs have been widely used as anxiolytics.
• side effects such as drowsiness and lightheadedness are generally inevitable, and some drugs have reported antidepressant effects, but their efficacy is weak.
• ipsapirone I ps ap irone
• Gepirone Jenkins et al., J. CI in. Pharmaco 1., 1990; 10 (3, Supp 1.): 775-855
• Japanese Patent Application Laid-Open No. 2-15059 discloses a compound represented by the general formula (II)
• Ra is 1-adamantyl, 3-methyl-1-adamantyl, 3-noradamantyl, unsubstituted or substituted 1-indolyl, 3-indolyl, 2-benzofuranyl or 3-benzofuranyl (substituent is lower alkyl)
• Rb is an unsubstituted or substituted phenyl, benzyl, pyridinyl, pyrimidinyl or pyrazinyl (substituent is selected from lower alkyl, lower alkoxy, trifluoromethyl and halogen)
• Rc is hydrogen or lower alkyl having 1 to 3 carbon atoms, P is an integer of 0 or 1, and Q is an integer of 2 to 5.
• serotonin 2 receptor antagonists have shown anxiolytic effects in animal studies (Stuttmann et al., Neuroscience Letterers, 1991; 128, 4-8) and a series of ipsapi rone. Administration causes a decrease in serotonin 2 receptor in the brain (Shigetar
• buspirone, ipsapirone, and gepirone have weak antidepressant and anxiolytic effects, and decrease locomotor activity, which is thought to be due to dopamine antagonist action.
• gepirone gepirone
• serotonin syndrome which is considered to be caused by the properties of a fluagonist for the serotonin 1A receptor.
• the compound represented by the above general formula [II] has a stronger antidepressant and anxiolytic effect than buspirone, but still leaves room for improvement in practical efficacy.
• the present inventors have solved the above problems, and have conducted intensive studies to develop a drug having both excellent antidepressant and anxiolytic effects and less side effects. As a result, the compound represented by the general formula (I) And completed the present invention.
• a lower alkyl group means an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group. Group, n-butyl group, i-butyl group, s-butyl group, t-butyl group and the like.
• the lower alkoxy group means an alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy. And t-butoxy groups.
• the halogen atom means chlorine, bromine, fluorine and iodine, and is preferably chlorine.
• the lower alkenyl group means an alkenyl group having 2 to 6 carbon atoms, for example, a vinyl group, an aryl group, a 1-propenyl group, an i-propenyl group and the like.
• aralkyl group examples include a benzyl group, a benzhydryl group, a phenethyl group, and a trityl group.
• the lower alkyl group is an alkylcarbonyl group having 2 to 7 carbon atoms including the carbon of the group, and examples thereof include an acetyl group, a propionyl group, a butyryl group, a butyryl group, and a valivalinole group.
• the compound represented by the general formula (I) can be produced, for example, as shown in the following reaction formula.
• the 2-hydroxymethylbenzodioxane derivative 1 is reacted with thionyl chloride in pyridine at 100 ° C. for 1 to 4 hours to obtain 2-chloromethyl-1,4-benzodioxane derivative 2.
• the derivative 2 is heated to reflux with potassium phthalimide in N, N-dimethylformamide for 5 hours to 14 hours to obtain 3, and then an alcohol such as methanol, ethanol, or isopropanol is used as a solvent.
• the mixture was heated and refluxed with hydrazine hydrate in methanol at room temperature or at a reflux temperature for 1 to 14 hours to obtain a 2-aminomethylbenzoxane derivative 4.
• a solvent such as methylene chloride or chloroform, preferably in methylene chloride
• a solvent such as methylene chloride or chloroform, preferably in methylene chloride
• methylene chloride or chloroform preferably in methylene chloride
• Hydrazine hydrate is added in an alcoholic solvent such as ethanol or isopropanol, preferably in ethanol, and the mixture is heated and refluxed at room temperature or reflux temperature for 1 to 14 hours to obtain a primary amine compound 6.
• the reaction is carried out at room temperature with ⁇ -toluenesulfonic acid chloride, preferably using triethylamine in the presence of the base, to obtain 8.
• N-pentinoleethylenediamine and 1-adamantanecarbonic acid chloride are reacted in a solvent such as methylene chloride or chloroform, preferably in methylene chloride for 1 to 2 days at room temperature in the presence of triethylamine.
• the desired product 7 is obtained by catalytic reduction in the presence of palladium hydroxide monocarbon at room temperature or at reflux temperature.
• the starting material 1 was obtained by the method described in the literature (Augstein et al., J. Med. Chem., 196 (8) 446), or according to the following synthesis method. (Equation 1-3).
• Monobenzyl catechol derivative 11 is treated in an organic solvent such as N, N-dimethylformamide, methylene chloride or chloroform, preferably in N, N-dimethylformamide, with sodium hydride, sodium hydroxide, It is reacted with epichlorohydrin or tosylated glycidol at 100 ° C for 1 hour to room temperature for 4 to 6 hours in the presence of a base such as potassium hydroxide, preferably in the presence of sodium hydride.
• an organic solvent such as N, N-dimethylformamide, methylene chloride or chloroform, preferably in N, N-dimethylformamide
• sodium hydride sodium hydroxide
• an organic solvent such as methanol, ethanol, ethyl acetate or the like, preferably methanol in the presence of palladium monocarbon at room temperature for 1 to 3 hours to debenzylate, and then N, N-dimethylform Amide, methylene chloride, black form, etc.
• an organic solvent of, preferably, N, N-dimethylformamide, or in a chloroform solution a base such as sodium hydride, sodium hydroxide, hydroxylated water, N, N-diisopropylethylamine, etc.
• the reaction is carried out at room temperature to 100 ° C. for 1 to 12 hours, preferably in the presence of sodium hydride or N, N-diisopropylethylamine, to obtain 1.
• the carbon atom at the position where the 1,4-benzodioxane ring is substituted becomes an asymmetric carbon, and optical isomers exist.
• positional isomers exist.
• the compound represented by the general formula (1) thus obtained may be in the form of a pharmaceutically acceptable salt.
• Such salts are obtained by reaction with the appropriate organic or inorganic acid, and include, but are not limited to, hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acetate, Acid addition salts such as citrate, fumarate, dalconate, lactate, maleate and succinate.
• the compound represented by the general formula (1) obtained in this manner is generally equal to or superior to the conventional anxiolytics in each of the antidepressant and anxiolytic effects. It has few side effects that have been regarded as problematic, and therefore has an outstanding effect in preventing and treating diseases such as neurosis, psychosomatic disorder, autonomic imbalance, and depression.
• the compound represented by the general formula (1) is prepared by adding suitable excipients, auxiliaries, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, coloring agents, flavoring agents or fragrances, tablets, Orally or parenterally in the form of coated tablets, granules, fine granules, powders, capsules, syrups, elixirs, drops, solutions, suspensions, emulsions, etc. Can be ⁇
• the dose is 1 to 3 Omg per day for an adult, preferably 5 to 10 mg per day.
• Example 1 (according to General Synthesis Method 1)
• the crude product was purified by column chromatography on silica gel using n-hexane monoethyl acetate (6: 1) as the mobile phase to give 2-hydroxymethyl-18-methyl-1,4-benzodioxane 97. 2 mg were obtained as a colorless oil.
• This crystal was dissolved in 500 ml of ethanol, 4.3 g of hydrazine hydrate was added, and the mixture was heated under reflux for 3 hours. After the resulting solid was filtered off, ethanol was distilled off under reduced pressure, and 300 ml of water was added. Further, a 6N aqueous solution of sodium hydroxide was added to adjust the pH to 12, followed by extraction with methylene chloride three times. The methylene chloride layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.3 g of a crude product of 2-aminomethyl-1,4-benzodioxane as a colorless oil.
• the obtained colorless oil was dissolved in a mixture of 5 ml of trifluoroacetic acid and 0.5 ml of water and stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel using methylene chloride / methanol / ammonia water (200: 20: 1) as a mobile phase, and N — ⁇ (2- ( 1, 4-base Nzojiokisan one 2- Irumechiru) Amino] Echiru ⁇ tricyclo [3, 3, 1, 1 3 '7] decane one 1 one Karubokishiami de (compound 2) was a 30 Omg as a colorless oil.
• the crude product was purified by column chromatography on silica gel using methylene chloride-hexane (2: 1) as the mobile phase to give 3.8 g of 2-chloromethyl-16-methyl-1,4-benzodioxane. Obtained as a tan oil.
• the crude product was purified by column chromatography on silica gel using methylene chloride-hexane (2: 1) as the mobile phase, yielding 3.8 g of 2-chloromethyl-6-methyl-1,4-benzodioxane. Was obtained as a tan oil.
• N- ⁇ [2- (5-methoxy 1-methyl-2-methyl-5-methoxy-1,4-benzodioxane) was separated and purified by the method described in Example 5.
• Nzojiokisan one 2- Irumechiru) Amino]
• Echiru ⁇ preparative Rishikuro [3, 3, 1, I 3] decane one 1 one Karubokishiami de (compound 6) 2 lom as a colorless oil.
• Example 8 In the same manner as in Example 1, (10) 1-N- ⁇ C2- (8-methyl-1,4-benzodioxane-12-ylmethyl) amino] ethyl ⁇ tricyclo [middle] using (+) glycidyl tosylate on the way 3, 3, 1, I 3 ] decane-111-carboxyamide hydrochloride (compound 8) was obtained (90% ee).
• Example 9 The crude product obtained in Example 9 was dissolved in a solution of 1.08 (2.5 mmo 1) in 30 ml of methanol, and 10 Omg of 5% palladium carbon was added. The mixture was contacted with hydrogen gas at 1 atm at room temperature. Hydrogenation was performed. After the reaction, palladium was filtered off, and the filtrate was concentrated under reduced pressure to obtain 0.9 g of a crude product as a colorless oil.
• the crude product was purified by column chromatography on silica gel using methylene chloride-methanol-ammonia water (200: 2: 1) as the mobile phase, and N — ⁇ [2- (8-methyl-1,1 4 one base Nzojiokisan one 2- Irumechiru) propyl Amino] Echiru ⁇ tricyclo [3, 3, 1, 1 3 '7] decane one 1 one Karubokishia Mi de (compound 10) 0. 58 g as a colorless oil.
• the cortex and hippocampus tissue of the brain of a 7-week-old male SD rat were excised, and a 20-fold amount of Tris-HCl buffer (5 OmM, pH 7.7) was added. The mixture was spun down for 1 minute and the supernatant was discarded. A 40-fold amount of buffer was added to the precipitate, homogenized with a polytron homogenizer, and then centrifuged in the same manner. This operation was repeated twice more, and the final sediment was homogenized with a 40-fold volume of buffer and stored at 180 ° C for at least one. On the day of the binding experiment, it was thawed at room temperature and then incubated at 37 ° C for 20 minutes to remove endogenous serotonin.
• Tris-HCl buffer 5 OmM, pH 7.7
• centrifuge at 39800xg for 20 minutes repeat the operation of adding 40 volumes of buffer to the sedimentation and homogenizing three times, and then 65 times the amount of serotonin 1A receptor and serotonin 2 receptor in the final sedimentation In the case of the body, it was homogenized by adding an 80-fold amount of buffer and subjected to the following binding experiment. All operations except cryopreservation and thawing at room temperature were performed at 4 ° C.
• Serotonin 1 A receptor binding experiment: final volume 1. 3 .eta. 8- Hyde port 0. 5 nM final concentration in a buffer in one of 0ml carboxymethyl one 2- (Gee ⁇ - Puropiruamino) Tet Lalin (8- OH @ - DPAT :), 0.1% ascorbic acid, and 501 brain homogenates were incubated at 25 ° C for 30 minutes. Thereafter, the reaction solution was immediately filtered through a glass filter, and the filter was quickly washed three times with 3 ml of an ice-cooled buffer, and put into a scintillation well together with a scintillation cocktail. And left at 4 ° C.
• Test compound As an index of the affinity of the objects of the receptor, determined using a 3 H- 50% inhibitory harm concentration specific binding DPAT (IC 50, M) the computer software EBDAZL I GAND (B i 0 s 0 ft) Was.
• Serotonin 2 Receptor Binding Experiment: final volume 1. The reaction solvent solution containing 3 H- ketanserin and 500 ⁇ 1 brain homogenate 0. 5 nM final concentration in a buffer in one of the 0 ml, 30 min ink at 30 ° C I did it. Thereafter, the same operation as in the case of the serotonin 1A receptor was performed to obtain IC 5D (M). The specific binding was a value obtained by subtracting the amount of binding in the presence of excess unlabeled methysergide (2 nM) from the total binding. As shown in Table 1, the compound of the present invention showed higher affinity for serotonin 1A and serotonin 2 receptors than the existing drugs, suggesting that it has strong anti-anxiety and antidepressant activity. Was.
• Table 2 shows the effect of 2 Omg / kg administration.
• Compounds 2, 5, 1, 6 and 18 showed an antidepressant effect exceeding that of WY-50324, and compounds 3, 4 and 12 also showed an effect of WY- The effect was almost the same as 50324.
• the antidepressant effect of MD L-73005 was extremely weak.
• the P r 0 ED 5 Q value determined by bit method is WY one 50324 is the compound 24. 3 mg / kg with respect to 8.
• LmgZkg of Compound 1 1 showed 3.0 times the activity of WY-50324.
• Table 3 shows the effect of 20 mg Zkg, but Compounds 1 and 18 surpassed the action of MDL-73005, Compounds 3, 4 and 17 showed the same effect as MDL-73005, and Compound 2 , 5 and 16 showed almost the same effect as WY-50324.
• Table 3 shows the effect of 20 mg Zkg, but Compounds 1 and 18 surpassed the action of MDL-73005, Compounds 3, 4 and 17 showed the same effect as MDL-73005, and Compound 2 , 5 and 16 showed almost the same effect as WY-50324.
• the drug was orally administered to 7-week-old male S.D. rats, and the locomotor activity was measured using Animex for 10 minutes from 30 minutes later.
• buspirone reduced locomotor activity in a dose-dependent manner from 20 mg Z kg, but Compound 1, WY-50324, and MDL-73005 did not affect locomotor activity and had a sedative effect. was not found.
• apomorphine apomo rphine
• a dopamine agonist a dopamine agonist
• test compound was orally administered in an amount of 20 mgZkg, and the anxiolytic and antidepressant effects were maintained until 0.5, 2, and 4 hours later.
• Table 7 shows the results.
• the compound of the present invention represented by the general formula (I) has an antidepressant action and an anxiolytic action and is an excellent drug with few side effects, and is capable of preventing neurosis, psychosomatic disorder, autonomic imbalance, and depression. ⁇ Effective for treatment.

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