WO1993012792A1 - Medicament pour les maladies affectant le systeme serotoninergique - Google Patents

Medicament pour les maladies affectant le systeme serotoninergique Download PDF

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Publication number
WO1993012792A1
WO1993012792A1 PCT/JP1992/001639 JP9201639W WO9312792A1 WO 1993012792 A1 WO1993012792 A1 WO 1993012792A1 JP 9201639 W JP9201639 W JP 9201639W WO 9312792 A1 WO9312792 A1 WO 9312792A1
Authority
WO
WIPO (PCT)
Prior art keywords
butoxy
quinoxaline
compound
methylquinoxaline
piperazinyl
Prior art date
Application number
PCT/JP1992/001639
Other languages
English (en)
Japanese (ja)
Inventor
Masao Yaso
Yukio Suzuki
Tetsu Saito
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.)
Filing date
Publication date
Priority claimed from JP4326994A external-priority patent/JPH05331065A/ja
Application filed by Asahi Kasei Kogyo Kabushiki Kaisha filed Critical Asahi Kasei Kogyo Kabushiki Kaisha
Publication of WO1993012792A1 publication Critical patent/WO1993012792A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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 serotonin nervous system such as an anti-anxiety agent, an antidepressant agent, an antiemetic agent (including an anti-motion sickness agent, an anti-sickness agent, an anti-vertigo agent) containing a 2-alkoxyquinoxaline derivative as an active ingredient.
  • a serotonin nervous system such as an anti-anxiety agent, an antidepressant agent, an antiemetic agent (including an anti-motion sickness agent, an anti-sickness agent, an anti-vertigo agent) containing a 2-alkoxyquinoxaline derivative as an active ingredient.
  • the present invention relates to a therapeutic agent for a related disease.
  • the present inventors have synthesized various compounds and have searched extensively for their pharmacological actions.
  • the 2-alkoxyquinoxaline derivative represented by the following formula (I) was found to be an excellent serotonin 1A receptor.
  • the inventors have found that they have one affinity and completed the present invention. Accordingly, the present invention provides the following general formula (I)
  • n represents an integer of 2 to 4
  • R represents a hydrogen atom or a methyl group
  • Rz represents a phenyl group having a substituent.
  • the serotonergic nervous system-related disease means a disease which is treated by a drug having a high affinity for the serotonin 1A receptor.
  • examples include anxiolytics, antidepressants, and antiemetic agents (including anti-sway agents, anti-sickness agents, anti-vertigo, etc.).
  • 2-alkoxyquinoxaline derivative (I) which is an active ingredient of the therapeutic agent for serotonin nervous system-related disease II of the present invention, is a novel compound, but a part of the compound is a known compound.
  • the compound in which R is methyl, R 2 is 0-tolyl and n is 2 is a known compound disclosed in JP-B-48-21949.
  • Japanese Patent Publication No. 48-219993 ⁇ 4 "includes a large number of compounds, only the above compounds are disclosed as compounds of the formula ( ⁇ ).
  • Japanese Patent Publication No. 48-21999 although there is a general disclosure that many of the compounds covered by the patent show or- -sympathetic blockade, they are supported by experiments, etc. Only one compound is described and it has not been determined whether such compounds have such an effect.
  • the compound (II) used in the wood invention is a compound which may be able to be synthesized according to the method disclosed in JP-B-48-21949 described above. The method is more convenient.
  • compound (I) is represented by the following formula (II)
  • compound (II) is a novel compound not described in the literature and is a useful intermediate compound.
  • X represents a leaving group
  • the leaving group means a group capable of increasing the reactivity with the compound (III) and leaving, for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • examples thereof include an halogen atom, an alkyl or arylsulfonyloxy group such as a methanesulfonyloxy group, a benzenesulfonyloxy group and a p-toluenesulfonyloxy group.
  • the compound represented by (III) is commercially available and can be obtained from, for example, Aldrich Co., Ltd., Tokyo Kasei Co., and the like.
  • the inert solvent used in the reaction between the compounds (II) and (III) is not particularly limited as long as it does not adversely affect the reaction.
  • Preferred examples include benzene and toluene. , Xylene, dimethylformamide, acetonitrile, aceton and the like.
  • a deoxidizing agent an inorganic or organic base can be used.
  • potassium carbonate sodium carbonate, sodium hydrogen carbonate and the like can be used.
  • alkaline earth metal carbonates bicarbonates or hydrides, tertiary amines such as triethylamine and pyridine, and the like.
  • the compound (III) and the compound (III) may basically be reacted in an equivalent amount.
  • the compound (III) is used in an amount of 1 to 5 equivalents, particularly preferably 1 () to 2.0 equivalents].
  • it is usually equivalent to compound ( ⁇ )! It is preferable to use?:.
  • the above-mentioned reaction is preferably carried out under heating conditions, for example, under reflux conditions of a solvent, for example, a force that can proceed even at room temperature.
  • the reaction time may be appropriately selected depending on the combination of the compounds, the reaction temperature, and the like, and may be terminated after confirming that the reaction has sufficiently proceeded, but the reaction is usually completed in 1 hour to several hours.
  • the amount of the solvent may be appropriately selected, and examples thereof include a volume of 1 to 2 times () times that of the compound (!).
  • the compound (II) as a starting material is represented by, for example, the general formula (iV)
  • n represents the same meaning as described above, Y represents halogen (child, X ′ represents a hydroxyl group or a halogen atom.)
  • the compound (IV) used here is a known compound and is commercially available from, for example, Aldrich.
  • the compound ((V)) when the group Y and the group X ′ are both halogen atoms, and 3 ⁇ 4 ⁇ ′ may be the same halogen atom or may be different from each other. Is more preferably a more reactive group than 3 ⁇ 4 ⁇ ′.
  • Specific preferred examples of the compound (V) include compounds having a combination of a group ⁇ with bromine and a group X, with a hydroxyl group or a chlorine atom, a group ⁇ with a chlorine atom and a group X 'with a hydroxyl group or the like. As these compounds, commercially available products such as Tokyo Kasei can be advantageously used.
  • an inert solvent used in the reaction between compound (IV) and compound (V) Is not particularly limited as long as it does not adversely affect the reaction.
  • Preferred examples include benzene, tonolene, xylene, dimethylformamide, acetonitrile, aceton, t-butyl alcohol and the like.
  • a deoxidizing agent include lithium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydride, sodium hydroxide, and hydroxide.
  • the substitution product of carbonyl S, which is the target product, with an oxygen atom (referred to as a 0-substituted product) and the substitution product for a nitrogen atom, which is a by-product, (referred to as an N-substituted product) Is generated in various ratios depending on the conditions, so care must be taken in the reaction conditions.
  • a 0-substituted product an oxygen atom
  • N-substituted product 1,8-diazabicyclo [5.4.0] -7-indene
  • the compound (IV) and the compound (V) may basically be reacted in an equivalent amount, but usually, the compound (V) is preferably used in an amount of 1 to 10 equivalents, particularly preferably 1 to 5 equivalents.
  • the deoxidizing agent is preferably used in an equivalent amount to the compound (V).
  • the above reaction may be carried out under heating conditions from room temperature, for example, 50 to 12 O'C.
  • the reaction time may be appropriately selected depending on the combination of compounds, the reaction temperature, and the like, and may be determined to be sufficient after completion of the reaction.
  • the amount of the solvent may be appropriately selected, and an example of the amount is 10 to 200 times the volume of the compound (IV).
  • a reaction for converting the hydroxyl group to a leaving group X is performed.
  • a conventionally known method may be used.
  • a hydroxyl group can be converted to a halogen atom by treating it with a halogenating agent such as thiol-lucide or phosphorus pentachloride.
  • a corresponding alkylsulfurylc or an arylsulfyroxylide for example, a methanesulfurylc or a p-toluene Sulfonyl chloride or the like may be used.
  • These conversion reactions may be performed in an inert solvent, for example, methylene chloride, chloroform, or the like, and the halogenating agent may be used in an amount of about 1 to 1.2 equivalents of the starting compound having a hydroxyl group.
  • This conversion reaction may be carried out at room temperature or lower, for example, under ice-cooling conditions, usually for 1 hour to overnight.
  • the amount of the solvent may be appropriately selected, but preferably the capacity is 5 to 100 times the capacity of the starting compound having a hydroxyl group.
  • the compound (I) of the present invention may or may not be purified from the reaction product of the compound (II) and the compound (II), but a carrier such as silica gel is used.
  • compound (I) can be used as a pharmaceutically acceptable non-toxic salt thereof.
  • salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, acetic acid, propionic acid, tartaric acid, citric acid, glycolic acid, dalconic acid, succinic acid, malic acid, glutamic acid, and aspartic acid.
  • salts with organic acids such as methanesulfonic acid.
  • an equivalent amount of methanol solution of hydrochloric acid Z may be added to the compound (I) of the present invention to elute hydrochloride, which may be recovered. If it is difficult to produce salt, an organic solvent such as getyl ether may be added to this.
  • the compound (I) thus obtained and the salt thereof have a high affinity for the mouth tonin 1A receptor, and furthermore, a disease involving the serotonin nervous system such as an anxiolytic effect by animal experiments.
  • compound (I) or a salt thereof is pharmaceutically acceptable. What is necessary is just to combine with an acceptable pharmaceutical carrier and formulate it by a well-known method.
  • the agent for treating a nervous system-related disease of the oral nervous system may be administered orally or parenterally, such as by injection with intravenous infusion, depending on the administration route, age, body weight, It varies according to the symptoms and the like, generally or Ah 1 day adult to 0. may be set to Lmg ⁇ 2 0 0 m Roh k g about as compound (I).
  • Dosage forms for the above formulation include injections, drops, tablets, pills, powders, granules, capsules, etc.
  • Various kinds of medical carriers that are acceptable are used.
  • excipients such as powder killing, lactose, sucrose, mannite, carboxymethylcellulose, corn starch, inorganic salts, methylcellulose, carboxymethyl Binders such as sodium cellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol, starch, hydroxypropylstarch, carboxymethylcellulose, carboxymethylcellulose Disintegrators such as sodium and hydroxypropylcellulose; surfactants such as sodium lauryl sulfate, soy lecithin, sucrose fatty acid ester, polysorbate 80, talc, mouth water, hydrogenated vegetable oil Lubricants such as sucrose fatty acid ester, magnesium stearate, calcium stearate and the like, fluidity promoters, flavoring agents and the like can be used.
  • the drug of the present invention can also be used as an emulsion, syrup or elixi
  • distilled water for injection physiological saline, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol and the like can be used as a diluent.
  • bactericides, preservatives, stabilizers, tonicity agents, soothing agents and the like may be added. Action
  • Rat hippocampal membrane fraction prepared above (approximately 100-200 ⁇ & protein) and 3H-8-0H-DPAT (New England 'Nuclea, NBN) (final concentration 0.5 nM ) and pargyline (par g Yline, after reacting for 30 minutes at 3 ⁇ ⁇ a sigma) (final concentration 1 0 / M), the reaction is stopped by suction filtration the reaction solution Wa Tsu Toman GFZC filter The radioactivity adsorbed on the filter was measured with a liquid resting scintillation force counter, and the measured value was defined as the total binding amount ( ⁇ ).
  • the binding inhibition rate of the sample at a certain concentration was calculated by the following formula.
  • Binding inhibition rate (%) 100 XI 00
  • TB-NB Calculate the binding skin damage rate at an appropriate concentration (from high concentration to low concentration) for each sample, plot the logarithmic value of the concentration on the horizontal axis and the binding inhibition rate on the vertical axis, and use the nonlinear least squares method. pull the curve at, C 5 of each specimen. The value (concentration of 131% at 50%) was determined.
  • CD concentration of radioligand used in the experiment (0.2 nM)
  • IC s A drug concentration that inhibits binding of the receptor to the radioligand by 50%
  • each compound used as a specimen was prepared in advance as a hydrochloride.
  • Table 1 shows the measurement results.
  • ICR strain male mice (5-week-old) were measured by the waterwheel forced swimming method (Sanr ⁇ literature; European Journalof Phar). ma cology _8_3_, (1 9 8 2), 1 7 1— 1 73).
  • the number of mouse rotations was measured. The day before the test, a mouse was thrown into the experimental device to remove individuals with significantly lower or higher turbine speeds. The experiment was performed with one group consisting of six animals.
  • the compound to be evaluated is the compound (I) hydrochloride (10 m & kg ) suspended in 0.5% carboxymethylcellulose sodium salt (CMC-Na). Was administered 30 minutes before the test, and in the case of oral administration, 60 minutes before the test. The results are as shown in Table 2.
  • test compound to be evaluated was used by suspending its hydrochloride (1 O mg / kg) in 0.5% carboxymethylcellular sodium salt (CM C-Na) for 30 minutes. Administered intraperitoneally before. The results are shown in Table 3.
  • Sunks were used as experimental animals. Sunks are small animals of the shrew family, known to cause sickness and vomiting. Science, 42, 538 (1990)). Sunks, when subjected to simple acceleration stimuli, exhibit symptoms (motion sickness) corresponding to motion sickness in humans, eventually causing vomiting. It is also known that administration of drugs such as cisplatin causes vomiting. Therefore, if this vomiting can be suppressed, it is effective as an antiemetic and is also useful as an anti-motion sickness agent, an anti-sickness agent, an anti-vertigo agent and the like.
  • test compound was intraperitoneally administered to Sunks, and 30 minutes later, an acceleration stimulus having an amplitude of 4 cm ⁇ and a frequency of 1 Hz was applied to observe whether or not vomiting had occurred.
  • the results are as shown in Table 4.
  • the saline administration group exhibited 100% motion sickness and caused vomiting within 5 minutes after the start of stimulation.
  • the compound (I) of the present invention is administered in advance, the onset of vomiting is completely suppressed. It is useful as a chemical agent. The invention's effect
  • the compound (I) of the present invention and a salt thereof exhibit strong affinity for the serotonin 1A receptor, and have an anxiolytic, an antidepressant, an antiemetic (an anti-sway agent, an anti-universe). It is useful as a therapeutic agent for serotonin nervous system related diseases such as sickness medicine and anti-vertigo.
  • the black-mouthed form solution was dried over sodium sulfate and concentrated under reduced pressure.
  • hydrochloride of the title compound was obtained by dissolving the title compound in a 5 N hydrochloric acid-methanol solution, adding ether thereto, and depositing crystals.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Médicament pour maladies affectant le système sérotoninergique, du type anxiolytique, anti-dépresseur, anti-émétique, anti-cétonique, anti-nausée, anti-vertige ou autres, qui renferme un dérivé 2-alcoxyquinoxaline, représenté par la formule générale (I), ou celle non toxique dérivée de cette substance et employée comme ingrédient actif présentant une forte affinité pour le récepteur de la sérotonine 1A dans laquelle n représente un entier de 2 à 4, R1 représente l'hydrogène ou un méthyle, et R2 représente un phényle de substitution.
PCT/JP1992/001639 1991-12-20 1992-12-16 Medicament pour les maladies affectant le systeme serotoninergique WO1993012792A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP35430191 1991-12-20
JP3/354301 1991-12-20
JP4/326994 1992-12-07
JP4326994A JPH05331065A (ja) 1991-12-20 1992-12-07 セロトニン神経系関連疾患治療剤

Publications (1)

Publication Number Publication Date
WO1993012792A1 true WO1993012792A1 (fr) 1993-07-08

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1992/001639 WO1993012792A1 (fr) 1991-12-20 1992-12-16 Medicament pour les maladies affectant le systeme serotoninergique

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1946172A1 (de) * 1969-09-12 1971-03-18 Hoechst Ag Neue heterocyclische AEther und Verfahren zu ihrer Herstellung

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1946172A1 (de) * 1969-09-12 1971-03-18 Hoechst Ag Neue heterocyclische AEther und Verfahren zu ihrer Herstellung

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