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WO2009128537A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

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Publication number
WO2009128537A1
WO2009128537A1 PCT/JP2009/057779 JP2009057779W WO2009128537A1 WO 2009128537 A1 WO2009128537 A1 WO 2009128537A1 JP 2009057779 W JP2009057779 W JP 2009057779W WO 2009128537 A1 WO2009128537 A1 WO 2009128537A1
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WIPO (PCT)
Prior art keywords
disorder
thiophen
mmol
piperazin
benzo
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English (en)
Japanese (ja)
Inventor
直明 大谷
展明 伊藤
博司 山下
伸 宮村
素行 宮本
淳 松原
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a novel heterocyclic compound.
  • bipolar disorder etiology of bipolar disorder, mood disorder and emotional disorder including schizophrenia is heterogeneous. Therefore, it is desired to have a plurality of pharmacological actions in order to develop a wide therapeutic spectrum in a drug.
  • Patent Document 1 and Patent Document 2 disclose a compound having a wide therapeutic spectrum, which has both a D2 receptor partial agonist action, a 5-HT2A receptor antagonist action, an ⁇ 1 receptor antagonist action and a serotonin uptake inhibitory action. . However, these patent documents do not disclose the heterocyclic compound of the present invention at all.
  • An object of the present invention is to provide an antipsychotic drug having a broader therapeutic spectrum, fewer side effects, and excellent tolerability and safety compared to known typical antipsychotic drugs and atypical antipsychotic drugs.
  • D2 receptor partial agonist action D2 receptor partial agonist action
  • 5-HT2A receptor antagonist action 5-HT2A receptor
  • ⁇ 1 receptor antagonistic action a novel heterocyclic compound having an antagonistic action and an adrenergic ⁇ 1 receptor antagonistic action ( ⁇ 1 receptor antagonistic action)
  • ⁇ 1 receptor antagonistic action a serotonin uptake inhibitory action
  • serotonin reuptake inhibitory action serotonin uptake inhibitory action
  • the present invention provides a heterocyclic compound or a salt thereof shown in the following items 1 to 8, a pharmaceutical composition containing the compound, use of the compound, and a method for treating or preventing a disease.
  • Item 1. (1) 7- ⁇ 4- [4- (7-hydroxybenzo [b] thiophen-4-yl) piperazin-1-yl] butoxy ⁇ -1H-quinolin-2-one, (2) 7- ⁇ 4- [4- (1-oxobenzo [b] thiophen-4-yl) piperazin-1-yl] butoxy ⁇ -1H-quinolin-2-one, (3) (3S, 4R) -7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -3,4-dihydroxy-3,4-dihydro-1H- Quinolin-2-one, (4) (3R, 4R) -7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1
  • Item 2 A pharmaceutical composition comprising the heterocyclic compound according to claim 1 or a salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • Item 3 A pharmaceutical composition for preventing or treating a central nervous disease comprising the heterocyclic compound or a salt thereof according to claim 1 as an active ingredient.
  • Schizophrenia treatment resistant, refractory or chronic schizophrenia, ataxic emotional disorder, psychotic disorder, mood disorder, bipolar disorder, depression, endogenous depression, major depression, melancholic and treatment resistant depression Dysthymic disorder, circulatory disorder, anxiety disorder, somatic expression disorder, false disorder, dissociation disorder, sexual disorder, eating disorder, sleep disorder, adaptation disorder, substance-related disorder, anxiety, delirium, Cognitive impairment, cognitive impairment associated with neurodegenerative disease, cognitive impairment resulting from neurodegenerative disease, cognitive impairment of schizophrenia, treatment resistance, refractory or cognitive impairment resulting from chronic schizophrenia, vomiting, motion sickness, obesity , Migraine, pain, mental retardation, autistic disorder, towlet disorder, tic disorder, attention deficit / hyperactivity disorder, behavioral disorder, and contract for prevention or treatment of central nervous disease selected from the group consisting of Down syndrome 3.
  • the pharmaceutical composition according. Item 5. A dopamine D 2 receptor partial agonist and / or a 5-HT 2A receptor antagonist and / or a serotonin uptake inhibitor and / or a serotonin reuptake inhibitor comprising the heterocyclic compound or salt thereof according to claim 1 as an active ingredient, and / Or ⁇ 1 receptor antagonist.
  • Item 6. A dopamine D 2 receptor partial agonist and / or a 5-HT 2A receptor antagonist and / or a serotonin uptake inhibitor and / or a serotonin reuptake inhibitor comprising the heterocyclic compound or salt thereof according to claim 1 as an active ingredient, and Use as an ⁇ 1 receptor antagonist.
  • a method for producing a pharmaceutical composition comprising mixing the heterocyclic compound or a salt thereof according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier.
  • the production methods of the compounds (1) to (9) or their salts obtained according to the present invention are described in detail below.
  • the compounds (1) to (9) or salts thereof can be produced by various methods.
  • the compounds (1) to (9) are described in Reference Examples 1 to 36 and Examples 1 to 9 in this specification. It can be manufactured according to the method.
  • Suitable salts of the compounds (1) to (9) are pharmacologically acceptable salts such as alkali metal salts (for example, sodium salts, potassium salts), alkaline earth metal salts (for example, calcium salts, Metal salts such as magnesium salts, ammonium salts, alkali metal carbonates (eg, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogen carbonates (eg, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate) Etc.), salts of inorganic bases such as alkali metal hydroxides (eg, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); eg, tri (lower) alkylamines (eg, trimethylamine, triethylamine, N-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, picoli , Dimethylaminopyridine, dimethylaniline, N-
  • solvates eg, hydrates, ethanolates, etc.
  • Preferred solvates include hydrates.
  • Each target compound obtained by the above production method is usually used for column chromatography, recrystallization, etc., after cooling the reaction mixture, for example, separating the crude reaction product by isolation operation such as filtration, concentration, extraction and the like. From the reaction mixture, it can be isolated and purified.
  • the compounds (1) to (9) of the present invention naturally include isomers such as geometric isomers, stereoisomers and optical isomers.
  • Compounds (1) to (9) and their salts are used in the form of general pharmaceutical preparations.
  • the preparation is prepared by using diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used.
  • diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used.
  • Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment. Representative examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.).
  • various carriers well known in the art can be widely used as carriers.
  • carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, Gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrators such as sodium, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, absorption accelerators such as quaternary ammonium base, sodium lauryl sulfate, glyce
  • a wide variety of carriers conventionally known in this field can be used.
  • carriers conventionally known in this field.
  • examples thereof include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar.
  • excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc
  • binders such as gum arabic powder, tragacanth powder, gelatin and ethanol
  • disintegrants such as laminaran and agar.
  • Conventionally known carriers can be widely used when forming into a suppository form.
  • examples thereof include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like.
  • Capsules are usually prepared by mixing the active ingredient compounds with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules and the like according to conventional methods.
  • solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and are commonly used in this field as diluents when molded into these forms
  • diluents when molded into these forms
  • water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used.
  • a sufficient amount of sodium chloride, glucose or glycerin may be contained in the pharmaceutical preparation to prepare an isotonic solution, and a normal solubilizing agent, buffering agent, soothing agent, etc. may be added. May be.
  • flavor, a flavoring agent, a sweetening agent, etc. and other pharmaceuticals can also be contained in a pharmaceutical formulation as needed.
  • the amount of the compounds (1) to (9) or salts thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited and is appropriately selected from a wide range, but is usually about 1 to 70 in the pharmaceutical composition. % By weight, preferably about 1 to 30% by weight.
  • the administration method of the pharmaceutical preparation of the present invention is not particularly limited, and it is administered by a method according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like.
  • a method for example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally.
  • it is administered intravenously alone or mixed with a normal fluid such as glucose and amino acids, and further administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary.
  • a suppository it is administered intrarectally.
  • the dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the age of the patient, sex and other conditions, the degree of disease, etc.
  • the amount of the active ingredient compound is about 0.1 to 1 kg / kg body weight per day. It should be about 10 mg.
  • the active ingredient compound is preferably contained in the dosage unit form in a range of about 1 to 200 mg.
  • the compound of the present invention has a D2 receptor partial agonist action, a 5-HT2A receptor antagonist action, and a serotonin uptake inhibitory action (or a serotonin reuptake inhibitory action).
  • the D2 receptor partial agonist action suppresses this when dopamine (DA) -operated neurotransmission is enhanced, while promoting it when DA-acting neurotransmission is reduced. It has a function to stabilize nerve transmission to a normal state (dopamine system stabilizer, dopamine system stabilizer). By this function, without causing side effects, excellent clinical improvement action, such as positive and negative symptom improvement action, cognitive impairment improvement action, depressive symptom improvement, on symptoms based on DA neurotransmission abnormality (up and down) (Miyako: Psychiatry, 46, 855-864 (2004), Tetsuro Kikuchi and Satoshi Hirose: Brain Science, 25, 579-583 (2004) and Harrison) , T. S. and Perry, C. M .: Drugs 64: 1715-1736, 2004).
  • the 5-HT2A receptor antagonistic action reduces the extrapyramidal side effects and exhibits excellent clinical effects, and is effective, for example, in improving negative symptoms, cognitive impairment, depressive symptoms, and insomnia (Ishigooka) Jun and Ken Inada: Clinical Psychopharmacology, Volume 4, pp. 1653-1664 (2001), Mitsukuni Murasaki: Clinical Psychopharmacology, Volume 1, pp. 5-22 (1998), Pullar, IA et al.,: Eur. J. Pharmacol., 407: 39-46, 2000 and Meltzer, H.ltY. Et al .: Prog. Neuro-psychopharmacol. Biol. Psychiatry 27: 1159-1172, 2003).
  • Serotonin uptake-inhibiting action (or serotonin reuptake-inhibiting action) is effective, for example, in improving depressive symptoms (see Murazaki Mitsukuni: Clinical Psychopharmacology, Vol. 1, pp. 5-22 (1998)).
  • the compounds of the present invention are all excellent in these three actions, or one or two of these actions are remarkably excellent.
  • ⁇ 1 receptor antagonistic action is effective in improving the positive symptoms of schizophrenia (see Svensson, T. H .: Prog. Neuro-psychopharmacol. Biol. Psychiatry 27: 1145-1158, 2003).
  • the compound of the present invention has a broad therapeutic spectrum for schizophrenia and other central nervous diseases, and has an excellent clinical effect.
  • the compounds of the present invention can be used to treat schizophrenia, refractory, refractory or chronic schizophrenia, ataxic emotional disorders, psychotic disorders, mood disorders, bipolar disorders (eg, bipolar type I disorder and bipolar II Type disorders), depression, intrinsic depression, major depression, melancholic and treatment-resistant depression, mood modulation disorders, mood circulation disorders, anxiety disorders (eg, panic attacks, panic disorders, agoraphobia, social phobia) Obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute stress disorder, etc.), somatic expression disorder (eg hysteria, somatization disorder, conversion disorder, pain disorder, psychosis), falseness Disorders, dissociative disorders, sexual disorders (eg, sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile dysfunction), eating disorders (eg, anorexia nervosa, bulimia nervosa, etc.), Sleep disorders, adaptation disorders, substance-related Harm (eg alcohol abuse, addiction and drug abuse, stimul
  • the compound of the present invention has few side effects and is excellent in tolerability and safety.
  • the medicament and pharmaceutical preparation of the present invention are currently used clinically as exemplified below (1) mood stabilizer, (2) serotonin reuptake inhibitor, (3) norepinephrine reuptake inhibitor, (4 ) Serotonin and norepinephrine reuptake inhibitors, and (5) Administration in combination with at least one drug selected from the group consisting of anxiolytics, reducing dosage and improving side effects that were not possible with conventional therapies Effects such as therapeutic effect enhancement can be obtained.
  • mood stabilizers compounds that function as mood stabilizers can be widely used and are known to those skilled in the art.
  • Non-limiting lists of mood stabilizers that can be used in the present invention include lithium, valproic acid, divalprox sodium, carbamazepine, oxcarbamazepine, zonisamide, lamotrigine, topiramate, gabapentin, levetiracetam, clonazepam, phenytoin, thyroid hormone Tiagabine and omega-3 fatty acids.
  • Serotonin reuptake inhibitor As the serotonin reuptake inhibitor, known compounds can be widely used as long as they function as serotonin reuptake inhibitors. Among serotonin reuptake inhibitors, IC 50 value (serotonin reuptake is inhibited by 50% by the conventional standard pharmacological assay method, Wong et al. (Neuropsychopharmacology, 8, pp337-344 (1993)). Preferably, the drug concentration is about 1000 nM or less.
  • serotonin reuptake inhibitors include fluvoxamine (5-methoxy-1- [4- (trifluoromethyl) phenyl] -1-pentanone-O- (2-aminoethyl) oxime), fluoxetine (N -Methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine), paroxetine (trans-(-)-3-[(1,3-benzodioxol-5-yloxy) methyl] -4- (4-fluorophenyl) piperidine), sertraline (1S-cis) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthylamine hydrochloride), venlafaxine (1- [2-dimethylamino-1- (4-methoxyphenyl) ethyl] cyclohexanol), milnacipran ( , N-
  • Norepinephrine reuptake inhibitor As the norepinephrine reuptake inhibitor, known compounds can be widely used as long as they function as norepinephrine reuptake inhibitors. Examples of such norepinephrine reuptake inhibitors include reboxetine, atomoxetine and bupropion. Preferably, reboxetine and atomoxetine are used.
  • Serotonin and Norepinephrine Reuptake Inhibitors As serotonin and norepinephrine reuptake inhibitors, known compounds can be widely used as long as they function as serotonin and norepinephrine reuptake inhibitors. Examples of such serotonin and norepinephrine reuptake inhibitors include venlafaxine, duloxetine and milnacipran.
  • Anti-anxiety drugs A non-limiting list of anti-anxiety drugs includes diazepam, chlordiazepoxide, cloxazolam, clothiazepam, alprazolam, benzodiazepine anti-anxiety drugs such as tandospirone, buspirone, serotonin 5-HT1A receptors And body agonist anti-anxiety agents.
  • drugs may be racemic or R and S enantiomers.
  • a single drug may be used alone, or two or more drugs may be used in combination as required.
  • a single drug is preferred.
  • Reference example 1 13.5 ml (128 mmol) of boron trifluoride dimethyl sulfide complex in a dichloromethane solution (200 ml) of 4-bromo-7-methoxybenzo [b] thiophene (10.4 g, 42.8 mmol) at 0 ° C. under an argon atmosphere. And stirred at room temperature for 20 hours. The reaction solution was cooled to 0 ° C., 500 ml of water was added and stirred. The insoluble material was removed by filtration, and dichloromethane was added to the filtrate for liquid separation. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Reference example 4 4. 4.3 g (17 mmol) of 7- (4-chlorobutoxy) -1H-quinolin-2-one, 1- [7- (tetrahydropyran-2-yloxy) benzo [b] thiophen-4-yl] piperazine 4 g (17 mmol), 2.8 g (20 mmol) of potassium carbonate and 2.6 g (17 mmol) of sodium iodide were added to 45 ml of dimethylformamide (DMF), and the mixture was stirred at 80 ° C. for 4 hours. After cooling to room temperature, water and ethyl acetate were added to the reaction solution, and the precipitated crystals were collected by filtration.
  • DMF dimethylformamide
  • the purified product was concentrated under reduced pressure to give 4.1 g (yield) of 4- (1-oxobenzo [b] thiophen-4-yl) -4-oxypiperazine-1-carboxylic acid tert-butyl ester as a pale yellow amorphous solid. 75%).
  • Reference Example 24 1.0 g (2.9 mmol) of 3- [4- (4-chlorobutoxy) -2-nitrophenyl] -3-oxopropionic acid ethyl ester was suspended in 35 ml of ethanol, and 2.2 g (29 mmol) of ammonium acetate. Aqueous solution (10 ml) and zinc powder 5.7 g (87 mmol) were added and stirred for 20 minutes under reflux. The reaction solution was filtered through Celite, and the residue was washed with hot ethanol. The filtrate and washings were combined and concentrated under reduced pressure. The residue was washed with methanol and dried to give 578 mg (yield 74%) of 7- (4-chlorobutoxy) -4-hydroxy-1H-quinolin-2-one as a white powder.
  • the purified product was concentrated under reduced pressure to give 918 mg (yield) of pale yellow amorphous solid 4- (1,1-dioxobenzo [b] thiophen-4-yl) -4-oxypiperazine-1-carboxylic acid tert-butyl ester. 84%).
  • Example 1 7- (4- ⁇ 4- [7- (Tetrahydropyran-2-yloxy) benzo [b] thiophen-4-yl] piperazin-1-yl ⁇ butoxy) -1H-quinolin-2-one 4.0 g (7 0.2 mmol) was added to 150 ml of ethanol and dissolved by heating. After cooling to room temperature, 40 ml of 1N hydrogen chloride ethanol solution was added and stirred at room temperature for 20 hours.
  • Example 2 1.0 g (4.3 mmol) of 1- (1-oxobenzo [b] thiophen-4-yl) piperazine is dissolved in a mixed solution of 20 ml of dichloromethane and 20 ml of methanol to give 4- (2-oxo-1,2-dihydro 900 mg (3.9 mmol) of quinolin-7-yloxy) butyraldehyde was added, and the mixture was cooled to 0 ° C. Acetic acid (0.49 ml, 8.6 mmol) and sodium cyanotrihydroborate (536 mg, 8.5 mmol) were added, and the mixture was stirred at room temperature for 3 hours.
  • Example 5 7- (4-Chlorobutoxy) -3-hydroxy-1H-quinolin-2-one 400 mg (1.49 mmol), 1-benzo [b] thiophen-4-ylpiperazine 489 mg (2.24 mmol), potassium carbonate 496 mg (3.6 mmol) and 224 mg (1.49 mmol) of sodium iodide were added to 5 ml of dimethylformamide (DMF) and stirred at 80 ° C. for 14 hours. After cooling to room temperature, water was added to the reaction solution and the precipitated solid was collected by filtration. To the filtrate was added 3.6 ml of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate.
  • DMF dimethylformamide
  • Example 6 7- (4-Chlorobutoxy) -4-hydroxy-1H-quinolin-2-one 400 mg (1.49 mmol), 1-benzo [b] thiophen-4-ylpiperazine 489 mg (2.24 mmol), potassium carbonate 496 mg (3.6 mmol) and 224 mg (1.49 mmol) of sodium iodide were added to 8 ml of dimethylformamide (DMF), and the mixture was stirred at 80 ° C. for 14 hours. After cooling to room temperature, water was added to the reaction solution and the precipitated solid was collected by filtration. To the filtrate was added 3.6 ml of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate.
  • DMF dimethylformamide
  • the purified product was concentrated under reduced pressure and crystallized from dichloromethane: methanol to give white powder 7- [4- (4-benzo [b] thiophen-4-yl-1-oxypiperazin-1-yl) butoxy]- 1.6 g (yield 77%) of 1H-quinolin-2-one was obtained. Melting point 176-179 ° C. (decomposition).
  • Example 8 7- (4-chlorobutoxy) -1H-quinolin-2-one 4.3 g (17 mmol), 4- (1,1-dioxobenzo [b] thiophen-4-yl) piperazine 5.4 g (17 mmol), 2.8 g (20 mmol) of potassium carbonate and 2.6 g (17 mmol) of sodium iodide were added to 45 ml of dimethylformamide (DMF) and stirred at 80 ° C. for 4 hours. After cooling to room temperature, water and ethyl acetate were added to the reaction solution, and the precipitated crystals were collected by filtration. The filtrate was separated, and the organic layer was washed with water and saturated brine.
  • DMF dimethylformamide
  • Cation exchange resin DOWEX TM 50WX4 was added to the reaction solution until pH 7 was reached, and insoluble matter was removed by filtration. The filtrate was washed with methanol, and the filtrate and washings were combined and concentrated under reduced pressure. The residue was dissolved in a small amount of methanol, and ether was added to crystallize.
  • Pharmacological test 1 Dopamine D2 receptor binding experiment Kohler et al. (Kohler C, Hall H, Ogren SO and Gawell L. Specific in vitro and in vivo binding of 3H-raclopride. A potent substituted benzamide drug with high affinity for dopamine D-2 Experiments were performed according to receptors in the rat brain. Biochem. Pharmacol., 1985; 34: 2251-2259).
  • Wistar male rats were decapitated, the brain was immediately removed, and the striatum was removed. Homogenize in 50 mM Tris (hydroxymethyl) aminomethane (Tris) -hydrochloric acid buffer solution (pH: 7.4) 50 times the tissue weight using a homogenizer with a high-speed rotating blade, and 48,000 ⁇ g at 4 ° C. And centrifuged for 10 minutes. The obtained sediment was suspended again in the above buffer of 50 times the tissue weight, incubated at 37 ° C. for 10 minutes, and then centrifuged under the above conditions.
  • Tris hydroxymethyl aminomethane
  • the obtained sediment is suspended in 50 mM Tris-HCl buffer (containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , pH: 7.4) 25 times the tissue weight, and these are bound as a membrane specimen.
  • the sample was stored frozen at ⁇ 85 ° C. until used in the experiment.
  • Binding experiments consisted of 40 ⁇ l membrane specimen, 20 ⁇ l [ 3 H] -Raclopride (final concentration 1-2 nM), 20 ⁇ l test compound and 50 mM Tris-HCl buffer (120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , pH 7.4) with a total volume of 200 ⁇ l (final dimethyl sulfoxide concentration 1%). The reaction was carried out at room temperature for 1 hour and terminated by suction filtration through a glass fiber filter plate using a cell harvester.
  • the glass fiber filter plate was washed with 50 mM Tris-HCl buffer (pH: 7.4), dried, then added with a microplate liquid scintillation cocktail, and the radioactivity was measured with a microplate scintillation counter. Nonspecific binding was defined as the radioactivity in the presence of 10 ⁇ M (+)-butaclamol hydrochloride.
  • IC 50 values were calculated from concentration dependent reactions using a non-linear analysis program. Ki values were calculated from IC 50 values using the Cheng-Prussoff equation. As a result, the compound of Example 3 showed 0.1 nM.
  • Wistar male rats were decapitated, the brain was immediately removed, and the frontal cortex was removed.
  • the tissue was homogenized using a Teflon (registered trademark) glass homogenizer in 0.25 M sucrose of 10 times the tissue weight, and centrifuged at 4 ° C. and 1,000 ⁇ g for 10 minutes.
  • the obtained supernatant was transferred to another centrifuge tube, and the sediment was suspended in 0.25M sucrose, which is 5 times the tissue weight, and centrifuged under the above conditions.
  • the obtained supernatant was combined with the previously obtained supernatant and adjusted to 40 times the tissue weight with 50 mM Tris-HCl buffer (pH: 7.4), and 10 minutes at 4 ° C. and 35,000 ⁇ g. Centrifuged.
  • the obtained sediment was suspended again in the buffer solution 40 times the tissue weight and centrifuged under the above conditions.
  • the obtained sediment was suspended in the above buffer solution of 20 times the tissue weight, and these were stored frozen at ⁇ 85 ° C. until they were used as membrane specimens for binding experiments.
  • the binding experiment was performed with a membrane sample of 40 ⁇ l, [ 3 H] -ketanserin 20 ⁇ l (final concentration 1-3 nM), test compound 20 ⁇ l and 50 mM Tris-HCl buffer (pH: 7.4) to a total volume of 200 ⁇ l (final) Dimethyl sulfoxide concentration 1%).
  • the reaction was carried out at 37 ° C. for 20 minutes and terminated by suction filtration through a glass fiber filter plate using a cell harvester.
  • the glass fiber filter plate was washed with 50 mM Tris-HCl buffer (pH: 7.4), dried, added with a microplate liquid scintillation cocktail, and the radioactivity was measured with a microplate scintillation counter. Radioactivity in the presence of 10 ⁇ M spiperone was defined as nonspecific binding.
  • IC 50 values were calculated from concentration dependent reactions using a non-linear analysis program. Ki values were calculated from IC 50 values using the Cheng-Prussoff equation. As a result, the compound of Example 3 showed 1.9 nM.
  • the male Wistar rats were decapitated, the brain was immediately removed, and the cerebral cortex was removed. Homogenized in 50 mM Tris-HCl buffer (100 mM NaCl, 2 mM ethylenediaminetetraacetic acid disodium dihydrogen acetate, pH: 7.4) 20 times the tissue weight using a homogenizer with a high-speed rotary blade, 4 ° C., 80 Centrifugation was performed at 1,000,000 g for 20 minutes. The obtained sediment was suspended in the above buffer solution having a volume 20 times the tissue weight, incubated at 37 ° C. for 10 minutes, and then centrifuged under the above conditions.
  • Tris-HCl buffer 100 mM NaCl, 2 mM ethylenediaminetetraacetic acid disodium dihydrogen acetate, pH: 7.4
  • the obtained sediment was suspended again in the above buffer solution having a volume 20 times the tissue weight, and centrifuged under the above conditions.
  • the obtained precipitate was suspended in 50 mM Tris-HCl buffer solution (containing 1 mM ethylenediaminetetraacetic acid dihydrogen disodium, pH: 7.4) 20 times the tissue weight, and these were used as membrane specimens for binding experiments— It was stored frozen at 85 ° C.
  • Binding experiments were performed entirely with 40 ⁇ l of membrane preparation, 20 ⁇ l of [ 3 H] -prazosin (final concentration 0.2-0.5 nM), 20 ⁇ l of test compound and 50 mM Tris-HCl buffer (containing 1 mM EDTA, pH: 7.4). The volume was 200 ⁇ l (final dimethyl sulfoxide concentration 1%). The reaction was carried out at 30 ° C. for 45 minutes, and was completed by suction filtration through a glass fiber filter plate using a cell harvester.
  • the glass fiber filter plate was washed with 50 mM Tris-HCl buffer (pH: 7.4), dried, added with a microplate liquid scintillation cocktail, and the radioactivity was measured with a microplate scintillation counter. Radioactivity in the presence of 10 ⁇ M phentolamine hydrochloride was defined as nonspecific binding.
  • IC 50 values were calculated from concentration dependent reactions using a non-linear analysis program. Ki values were calculated from IC 50 values using the Cheng-Prussoff equation. As a result, the compound of Example 3 showed 0.3 nM.
  • Pharmacological test 2 Partial agonistic effect on dopamine D2 receptor using cells expressing dopamine D2 receptor (partial agonist)
  • cyclic AMP production inhibitory effect of the measured compound in dopamine D2 receptor-expressing cells induced by forskolin to induce cyclic adenosine 3 ′, 5′-monophosphate (cyclic AMP) production
  • dopamine D2 The partial agonistic property with respect to the receptor was evaluated.
  • IMDM medium Iscob modified Dulbecco medium
  • 10% fetal calf serum 50 IU / ml penicillin
  • 50 ⁇ g / ml streptomycin 50 ⁇ g / ml
  • 200 ⁇ g / ml Geneticin, 0.1 mM sodium hypoxanthine, 16 ⁇ M thymidine
  • a 96-well microplate coated with poly-L-lysine was seeded with 10 4 cells / well and cultured under the
  • IMDM medium 0.1 mM hypoxanthine sodium, 16 ⁇ M thymidine
  • test compound-added medium IMDM medium, 0.1% sodium ascorbate, 0.1 mM hypopoxine
  • test compound-added forskolin-stimulated medium IMDM medium, 0.1% sodium ascorbate, 0.1 mM sodium hypoxanthine, 16 ⁇ M thymidine, 10 ⁇ M forskolin, 500 ⁇ M 3-isobutyl-1-methylxanthine
  • IMDM medium 0.1% sodium ascorbate
  • 0.1 mM sodium hypoxanthine 16 ⁇ M thymidine
  • 10 ⁇ M forskolin 500 ⁇ M 3-isobutyl-1-methylxanthine
  • 200 ⁇ l of Lysis 1B aqueous solution (Amersham Biosciences cyclic AMP biotrack enzyme immunoassay system attached reagent) was dispensed and shaken for about 10 minutes. The aqueous solution in each well was used as a measurement sample.
  • a cyclic AMP amount was measured on a measurement sample diluted 4-fold.
  • the inhibition rate of each test compound was calculated with the amount of cyclic AMP in a well to which no test compound was added as 100%.
  • dopamine used as a control drug suppressed the amount of cyclic AMP to about 10% as the maximum activity.
  • test compound Since the test compound has a partial agonistic property to the dopamine D2 receptor, it can stabilize dopamine neurotransmission in a schizophrenic patient to a normal state, and as a result, without causing side effects, for example, It can exert clinical improvement effects such as positive and negative symptom improvement action, cognitive impairment improvement action and the like.

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Abstract

L'invention concerne un composé hétérocyclique qui peut être utilisé en tant qu'agent antipsychotique ayant un spectre thérapeutique plus large en comparaison des agents antipsychotiques typiques connus et des agents antipsychotiques atypiques connus, qui présente peu d'effets secondaires indésirables et qui présente une excellent tolérabilité et une excellente sûreté. Le composé hétérocyclique est (1) la 7-[4-[4-(7-hydroxybenzo[b]thiophén-4-yl)pipérazin-1-yl]butoxy]-1H-quinolin-2-one, (2) la 7-[4-[4-(1-oxobenzo[b]thiophén-4-yl)pipérazin-1-yl]butoxy]-1H-quinolin-2-one, (3) la (3S,4R)-7-[4-(4-benzo[b]thiophén-4-yl-pipérazin-1-yl)butoxy]-3,4-dihydroxy-3,4-dihydro-1H-quinolin-2-one ou analogue.
PCT/JP2009/057779 2008-04-18 2009-04-17 Composé hétérocyclique Ceased WO2009128537A1 (fr)

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US10100040B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
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US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006316052A (ja) * 2005-04-14 2006-11-24 Otsuka Pharmaceut Co Ltd 複素環化合物
JP2008115172A (ja) * 2006-10-13 2008-05-22 Otsuka Pharmaceut Co Ltd 医薬

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006316052A (ja) * 2005-04-14 2006-11-24 Otsuka Pharmaceut Co Ltd 複素環化合物
JP2008115172A (ja) * 2006-10-13 2008-05-22 Otsuka Pharmaceut Co Ltd 医薬

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