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WO1994011356A1 - Derive de 2-alcoxytetrahydroquinoxaline, son procede de production, et son utilisation - Google Patents

Derive de 2-alcoxytetrahydroquinoxaline, son procede de production, et son utilisation Download PDF

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Publication number
WO1994011356A1
WO1994011356A1 PCT/JP1993/001590 JP9301590W WO9411356A1 WO 1994011356 A1 WO1994011356 A1 WO 1994011356A1 JP 9301590 W JP9301590 W JP 9301590W WO 9411356 A1 WO9411356 A1 WO 9411356A1
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Prior art keywords
compound
reaction
same
general formula
yield
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PCT/JP1993/001590
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English (en)
Japanese (ja)
Inventor
Hideyuki Watanabe
Masao Yaso
Daisuke Mochizuki
Original Assignee
Asahi Kasei Kogyo 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.)
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Application filed by Asahi Kasei Kogyo Kabushiki Kaisha filed Critical Asahi Kasei Kogyo Kabushiki Kaisha
Publication of WO1994011356A1 publication Critical patent/WO1994011356A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • the present invention relates to a novel 2-alkoxytetrahydroquinoxaline derivative, a method for producing the same, an anti-sickness agent, an anti-sickness agent, an antiemetic, an anti-vertigo agent, an antidepressant, an anxiolytic, and an anti-anxiety agent. And other pharmaceutical uses.
  • JP-A-63-107968 discloses a 2- [2- (4-substituted phenyl-1-piperazinyl) ethoxy] -1,5,6,7,8-tetrahydrido quinoxaline derivative, It has been described that it has an inhibitory action on aggregation, a vasodilatory action, and an inhibitory action on lipid peroxide production, but there is no description on its usefulness related to the serotonin nervous system.
  • the first object of the present invention is to provide the following general formula (1)
  • R and R 2 are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group, and n represents an integer of 2 to 5). Or a non-toxic salt thereof.
  • a second object of the present invention is to provide a compound of the general formula (2)
  • R 1 and R 2 have the same meanings as described above, and reacting the compound represented by the general formula (1) or a nontoxic salt thereof. To provide.
  • a third object of the present invention is to provide a therapeutic agent for serotonin nervous system-related diseases, comprising a compound represented by the general formula (1) or a non-toxic salt thereof as an active ingredient.
  • the compound (1) of the present invention is produced, for example, by reacting a compound represented by the general formula (2) with a compound represented by the general formula (3) in an inert solvent.
  • the group X in the general formula (2) represents a reactive leaving group for alkylation.
  • the term "leaving group” means a group capable of increasing the reactivity with the compound (3) and leaving.
  • Examples thereof include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and an alkyl or arylsulfonyloxy group such as a methanesulfonyloxy group, a benzenesulfonyloxy group, and a p-toluenesulfonyloxy group.
  • a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom
  • an alkyl or arylsulfonyloxy group such as a methanesulfonyloxy group, a benzenesulfonyloxy group, and a p-toluenesulfonyloxy group.
  • the compound (2) is a novel compound that has not been described in the literature.
  • Y represents a halogen atom
  • R 3 represents a lower alkyl group
  • n is the same as defined above.
  • the compound represented by the general formula (7) is reacted in an inert solvent.
  • R 3 and n have the same meanings as described above, and the compound (7) is reduced with a reducing agent in an inert solvent to obtain a compound of the general formula (8)
  • n has the same meaning as described above
  • a halogenating agent such as thionyl chloride or a sulfonylation such as methanesulfonyl chloride in an inert solvent. It is obtained by reacting with an agent and converting to a leaving group X.
  • the compound (2) is obtained by converting the compound (4) into a compound represented by the general formula (9)
  • the compound (7) and the compound (8) are novel compounds not described in any literature.
  • the compound (4) used in the above reaction is a known compound, and can be synthesized according to the method described in JP-B-63-107968.
  • Compound (6) and compound (9) are known compounds and are listed in the reagent catalog.
  • Examples of the alkali metal reagent used in the reaction for obtaining the compound (5) from the compound (4) include lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and potassium methoxide.
  • Metal alkoxides such as lithium hydride, sodium hydride, potassium hydride, and the like; Although the use ratio of the alkali metal reagent may be basically equivalent to that of the compound (4), it is usually used in a slightly excessive amount.
  • Examples of the reaction solvent used in the reaction for obtaining the compound (5) from the compound (4) include alcohols such as methanol, ethanol, propanol, butanol, and t-butanol.
  • the above reaction may be carried out at a temperature of ⁇ 10 ° C. to room temperature. Usually performed at a temperature between 5 ° and 0 °. The reaction is completed in 10 minutes to 1 hour. The amount of the solvent may be appropriately selected, and the volume is, for example, 5 to 100 times that of the compound (4).
  • the compound (6) is reacted with the obtained compound (5). Examples of the compound (6) used in this reaction include methyl bromoacetate or ethyl ester, methyl methyl acetate or methyl acetate.
  • Methyl ester methyl 3-bromopropionate or ethyl ester, methyl 3-methyl propionate or ethyl ester, methyl 4-bromobutyrate or ethyl ester, methyl 4-methyl butyrate or ethyl ester, 5-methyl methyl valerate or ethyl ester, 5- And methyl valerate methyl or ethyl ester.
  • the inert solvent used in the above reaction is not particularly limited as long as it does not adversely affect the reaction.
  • Preferred solvents include, for example, benzene, toluene, xylene, dimethylformamide, acetonitrile, acetone, t Butyl alcohol and the like can be mentioned.
  • the amount of the inert solvent to be used may be appropriately selected, and an example of the amount is 10 to 200 times the volume of the compound (6).
  • the use ratio of the compound (6) may be basically equivalent to that of the compound (5), but is usually used in a slightly excessive amount.
  • the above reaction may be performed under heating conditions from room temperature, for example, at 50 to 120 ° C.
  • the reaction time may be appropriately selected depending on the combination of the compound (5) and the compound (6), the reaction temperature and the like, and the reaction may be terminated after confirming that the reaction has sufficiently proceeded.
  • the reaction is performed in 1 hour to 1 day. finish.
  • the obtained compound (7) is reduced with a reducing agent to obtain a compound (8).
  • the reducing agent used in this reduction reaction is an alkali hydride such as lithium aluminum hydride. A metal object is mentioned.
  • the ratio of the reducing agent to be used may be basically equivalent to that of the compound (7), but it is usually 1 to 5 equivalents, particularly preferably 1 to 2 equivalents.
  • the inert solvent used in the above reduction reaction is not particularly limited as long as it does not adversely affect the reaction.
  • Preferred examples of the solvent include tetrahydrofuran and 1,4-dioxane.
  • the amount of the solvent may be appropriately selected, and an example of the solvent is 10 to 200 times the volume of the compound (7).
  • the above reaction may be carried out at a temperature of from 120 ° C. to room temperature, for example, from 110 ° C. to 10 ° C.
  • the reaction time is affected by the reaction temperature and the like, but may be terminated after confirming that the reaction has sufficiently proceeded. Usually, the reaction is completed within 1 hour to 1 day.
  • a conventionally known method may be used. For example, a hydroxyl group can be converted to a halogen atom by halogenation with a halogenating agent such as thionyl chloride or phosphorus pentachloride.
  • a hydroxyl group into an alkyl or arylsulfonyloxy group such as a methanesulfonyloxy group, a benzenesulfonyloxy group, or a p-toluenesulfonyloxy group
  • the corresponding alkylsulfonyl chloride or a Reel sulfonyl chloride for example, methanesulfonyl chloride, p-toluenesulfonyl chloride and the like may be used.
  • the above conversion reaction may be carried out in an inert solvent, for example, a solvent such as methylene chloride or chloroform, and the halogenating agent may be about 11.2 equivalents of the compound (8).
  • This conversion reaction may be carried out at room temperature or lower temperature, for example, under ice-cooling, usually for 1 hour to 1 day.
  • the amount of the solvent may be appropriately selected, but preferably the compound (8) 5100 times the capacity of the above is exemplified.
  • a method of reacting the compound (4) with the compound (9) has been described.
  • Examples of the compound (9) used in this reaction include 12-dibromoethane, 12-dichloroethane, 1-bromo-12-chloroethane, 13-dibromopropane, 1,3-dichloropropane, and 1-bromo one 3 - black port Pro 0 emissions, 1, 4-dibromobutane, 1 4-dichloro-butane, 1 - bromo one 4 - chlorobutane, 1 5 - jib port Mopentan, 1 5-dichloro-pentane, 1-bromo-5 _ black port Dihalogenated alkynes such as pentane.
  • the inert solvent used in the reaction between compound (4) and compound (9) may be any solvent that does not adversely affect the reaction, and is not particularly limited.
  • Preferred examples of the solvent include benzene, toluene, and xylene Dimethylformamide, acetonitrile, acetone and the like.
  • the amount of the inert solvent may be appropriately selected, and an example of the amount is 100,000 times the volume of the compound (4).
  • a deoxidizing agent include inorganic or organic bases, such as carbonates, bicarbonates or hydrides of alkali metal such as potassium carbonate, sodium carbonate, sodium bicarbonate, and sodium hydride, or triethylamido.
  • Pyridine, Tertiary amines such as 1,8-diazabicyclo [5.4.0] pendecar 7-ene (DBU).
  • reaction accelerator such as sodium iodide or potassium iodide may be added.
  • the compound (4) and the compound (9) may be used in the equivalent ratio basically, but usually 1 to 5 equivalents, particularly preferably 1.2 to 2.0 equivalents of the compound (9) are used. Can be Further, it is generally preferable to use an equivalent of the deoxidizing agent with the compound (9).
  • the above reaction can proceed at room temperature, but is usually preferably performed under heating conditions, for example, under solvent reflux conditions.
  • the reaction time is affected by the combination of the compound (4) and the compound (9), the reaction temperature and the like, but may be terminated after confirming that the reaction has sufficiently proceeded.
  • the reaction is usually completed in one hour to several days.
  • the compound (2) thus obtained is reacted with the compound (3) to obtain the target compound (1) of the present invention.
  • the compound (3) used in this reaction is represented by the general formula (1)
  • R 2 and R 2 in 3 are the same or different and are each defined as a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group.
  • the halogen atom defined above means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the lower alkyl group means an alkyl group having 1 to 4 carbon atoms which may have a branched chain, for example, a methyl, ethyl, propyl, isopropyl, butyl group and the like.
  • the lower alkoxy group means an alkoxy group having 1 to 4 carbon atoms which may have a branched chain, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy and butoxy groups.
  • the above compound (3) is a known substance, and many of them are commercially available and can be obtained from reagent catalogs and the like. Further, it can be synthesized by a known method.
  • the inert solvent used in the reaction between compound (2) and compound (3) may be any solvent that does not adversely affect the reaction, and is not particularly limited. Preferred solvents include, for example, benzene, toluene, xylene, dimethylformamide, acetonitrile, acetone and the like.
  • the amount of the solvent may be appropriately selected, and an example of the solvent amount is 10 to 200 times the volume of the compound (2).
  • the deoxidizing agent examples include inorganic or organic bases, for example, carbonates, bicarbonates or hydrides of alkali metals such as potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydride, and triethylamid. Pyridine, tertiary amines such as 1,8-diazabicyclo [5.4.0] pendant 7-ene (DBU).
  • the compound (2) and the compound (3) may basically be reacted in an equivalent amount, but usually the compound (3) is used in an amount of 1 to 5. equivalents, particularly preferably 1.2 to 2.0. Used in equivalent.
  • the deoxidizing agent is preferably used in an equivalent amount to the normal compound (3).
  • the above reaction can proceed at room temperature, but is usually preferably performed under heating conditions, for example, under solvent reflux conditions.
  • the reaction time may be appropriately selected depending on the combination of the compounds, the reaction temperature, and the like, and may be appropriately terminated by confirming that the reaction has sufficiently proceeded by thin layer chromatography, high performance liquid chromatography, or the like.
  • the reaction is usually completed in one hour to several days.
  • the insolubles in the reaction mixture are removed by filtration, the filtrate is concentrated, and the residue is subjected to column chromatography using silica gel or the like. It is carried out by first separating and purifying.
  • the compound (2) and the precursor compound used in the production of the target compound (1) of the present invention may or may not be purified from each reaction product, but in the case of purification, for example, It is preferable to purify by a known purification method such as column chromatography using a carrier such as silica gel.
  • target compound (1) of the present invention include the compounds shown in Table 1 below.
  • the compound (1) of the present invention can be converted into a pharmaceutically acceptable non-toxic salt thereof, if necessary.
  • salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, tartaric acid, citric acid, glycolic acid, gluconic acid, succinic acid, lingic acid, glutamic acid.
  • salts with organic acids such as acetic acid, aspartic acid and methanesulfonic acid.
  • these salts can be produced by a known method for obtaining a salt from a free base.
  • a methanol solution of hydrochloric acid Z may be added to the compound of the present invention (1) to precipitate a hydrochloride, which may be recovered.
  • an organic solvent such as gethyruether may be added thereto.
  • the thus-obtained compound (1) of the present invention and the nontoxic salt thereof have a high affinity for the serotonin 1A receptor as described later, and have a serotonin nervous action such as an anti-motion sickness effect by animal experiments.
  • the therapeutic agent for serotonergic nervous system-related diseases of the present invention may be administered orally or parenterally, such as by injection including intravenous drip. However, it is generally about 0.1 mg 20 mg Og Z kg as compound (1) per adult day.
  • Dosage forms for the above formulation include injections, tablets, pills, powders, granules, capsules, etc., and for the production thereof, are pharmaceutically acceptable according to these formulations
  • Various pharmaceutical carriers and the like can be used.
  • excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts, methylcellulose, sodium carboxymethylcellulose, hydrid Binders such as roxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol, starch, hydroxypropyl starch, carboxymethylcellulose, sodium carboxymethylcellulose, disintegrators such as hydroxypropylcellulose, sodium lauryl sulfate Surfactants such as soy lecithin, sucrose fatty acid ester, polysorbate 80, talc, wax, hydrogenated food oil, sucrose fatty acid ester, polysorbate 80, talc, wax, hydrogenated food oil,
  • the drug of the present invention can also be used as an emulsion, syrup or elixir.
  • distilled water for injection physiological saline, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol and the like can be generally used as a diluent. If necessary, disinfectant, preservative, safe Thickening agents, tonicity agents, soothing agents and the like may be added.
  • the compound (1) of the present invention to be tested is indicated by the compound number described in the Examples and used in the form of its hydrochloride.
  • Rat hippocampal membrane fraction prepared above (approximately 1 0 0 ⁇ 2 0 0 g protein content) and 3 H - 8 -OH-D P AT (. New England 'New CLEA NEN) (final concentration 0. 5 n M) and pargyline (pargy 1ine, manufactured by Sigma) (final concentration of 10 was allowed to react at 30 ° C for 30 minutes, and the reaction was stopped by suction filtration with a Kettmann GFZC filter to stop the reaction. The radioactivity adsorbed by the filter was measured with a liquid scintillation counter, and the obtained measurement value was used as the total binding amount (TB) Serotonin (final concentration: 10 fiM) was added to the above composition and reacted similarly. The measured value of each compound was defined as the non-specific binding amount (NB) A sample of each compound at an appropriate concentration was added instead of serotonin and reacted to obtain a measured value (DTB). (C) K i value calculation method
  • the binding inhibition rate of the sample at a certain concentration was calculated by the following formula.
  • Binding inhibition rate (%) 100-(DTB-NB) ⁇ (TB-NB) x 100 Determine the binding inhibition rate at an appropriate concentration (from high concentration to low concentration) for each sample, and plot the concentration on the horizontal axis. The binding inhibition ratio was plotted on the vertical axis and the logarithmic value of, and a curve was drawn by the nonlinear least squares method to determine the IC 50 value (concentration that inhibits 50% binding) of each sample.
  • the Ki value was calculated by the following formula.
  • Table 2 shows the results of measuring the Ki value for the serotonin 1 A (5HT 1 A) receptor.
  • Sunks were used as experimental animals. Sunks are small animals of the shrew family, and are known to cause motion sickness and vomiting [Biological Science 41, 538 (1990)]. When a simple acceleration stimulus is applied to Suntas, it causes symptoms equivalent to motion sickness in humans (motion sickness) and eventually causes vomiting. It is said that the cause of motion sickness is that abnormalities occur between information such as vision and sense of balance, or when a stimulus that is not remembered in the past is felt. It is thought that higher-order functions are involved. Therefore, if this vomiting can be suppressed by a drug, it is useful as an anti-sway agent, an anti-sickness agent, an antiemetic, an anti-vertigo agent and the like.
  • test compound was intraperitoneally administered to Sunks, 30 minutes later, an acceleration stimulus having an amplitude of 4 cm and a frequency of 1 Hz was given, and the occurrence of vomiting was observed for 10 minutes.
  • Table 3 shows the results of measuring the effects of Sunks motion sickness on vomiting.
  • the compound of the present invention is indicated by a compound number.
  • the saline-administered group exhibited 100% motion sickness and caused vomiting within 2 minutes after the start of stimulation.
  • the compound (1) hydrochloride of the present invention is administered in advance, the onset of vomiting is completely prevented, and these compounds are useful as anti-sway agents, anti-emetic agents, anti-sickness agents, anti-vertigo agents and the like.
  • the compound (1) (hydrochloride) of the present invention exhibits strong affinity for serotonin 1A receptor, and is an anti-inflammatory agent, an anti-sickness agent, an antiemetic, an anti-vertigo agent, an antidepressant. It is useful as a therapeutic agent for serotonin nervous system-related diseases such as drugs, anxiolytics, and eating disorder ameliorating agents.
  • the obtained compound was dissolved in 8.9 N hydrochloric acid / methanol, and crystallized by adding diethyl ether thereto, followed by filtration to obtain a hydrochloride.
  • Example 1 the same reaction was carried out by using 11- (2-fluorophenyl) pidazine hydrochloride 26 O mg (1.2 mM) instead of 11- (2-methoxyphenyl) pidazine.
  • the title compound was obtained. Yield 208 mg (54.2% yield)
  • a hydrochloride was obtained in the same manner as in Example 1.
  • Example 1 a similar reaction was carried out using 1- (3-trifluoromethylphenyl) piperazine (276 mg, 1.2 mM) instead of 1- (2-methoxyphenyl) piperazine. Performed to give the title compound. Yield 401 mg (Yield 92.4%)
  • a hydrochloride was obtained in the same manner as in Example 1.
  • a hydrochloride was obtained in the same manner as in Example 1.
  • a hydrochloride was obtained in the same manner as in Example 1.
  • Example 6 [4- ⁇ 4- (2,3-xylyl) -11-piperazinyl ⁇ butoxy] -5,6,7,8-tetraquinoline [compound 4995]
  • Example 5 1- The same reaction was carried out using 27_2 mg (1.2 mM) of 1_ (2,3-xilyl) pidazine hydrochloride instead of phenylbiperazine to obtain the title compound. Yield 2 64 mg (67% yield)
  • a hydrochloride was obtained in the same manner as in Example 1.
  • a hydrochloride was obtained in the same manner as in Example 1.
  • a hydrochloride was obtained in the same manner as in Example 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé représenté par la formule générale (1), ou un sel non toxique de celui-ci, procédé de production de ce composé, et remède contre des maladies associées au système neuronal sérotoninergique, contenant ledit composé comme ingrédient actif. Dans ladite formule R1 et R2, qui peuvent être identiques ou différents, représentent chacun hydrogène, halogène, alkyle inférieur, alcoxy inférieur ou trifluorométhyle; et n représente un nombre entier compris entre 2 et 5. Le composé (1) et ses sels non toxiques ont une grande affinité pour les récepteurs de la sérotonine 1A et peuvent être utilisés en tant que remèdes contre des maladies du système neuronal sérotoninergique, tels que remède contre le mal des transports, remède contre le mal de l'espace, antiémétique, remède contre le vertige, antidépresseur, anxiolytique, et remède contre les troubles de l'appétit.
PCT/JP1993/001590 1992-11-18 1993-11-04 Derive de 2-alcoxytetrahydroquinoxaline, son procede de production, et son utilisation WO1994011356A1 (fr)

Applications Claiming Priority (2)

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JP30878692 1992-11-18
JP4/308786 1992-11-18

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WO1994011356A1 true WO1994011356A1 (fr) 1994-05-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7189753B1 (en) 1997-11-06 2007-03-13 Cady Roger K Preemptive prophylaxis of migraine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63107968A (ja) * 1986-06-30 1988-05-12 Toyo Jozo Co Ltd ２−置換アルコキシ−３−置換−ピラジン類化合物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63107968A (ja) * 1986-06-30 1988-05-12 Toyo Jozo Co Ltd ２−置換アルコキシ−３−置換−ピラジン類化合物

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7189753B1 (en) 1997-11-06 2007-03-13 Cady Roger K Preemptive prophylaxis of migraine

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