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WO2002016337A1 - Composés tricycliques et compositions pharmaceutiques les contenant - Google Patents

Composés tricycliques et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO2002016337A1
WO2002016337A1 PCT/JP2001/007073 JP0107073W WO0216337A1 WO 2002016337 A1 WO2002016337 A1 WO 2002016337A1 JP 0107073 W JP0107073 W JP 0107073W WO 0216337 A1 WO0216337 A1 WO 0216337A1
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WO
WIPO (PCT)
Prior art keywords
compound
sleep
rhythm
therapeutic agent
composition according
Prior art date
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PCT/JP2001/007073
Other languages
English (en)
Japanese (ja)
Inventor
Shigenori Ohkawa
Masaomi Miyamoto
Original Assignee
Takeda Chemical Industries, Ltd.
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
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU2001278754A priority Critical patent/AU2001278754A1/en
Publication of WO2002016337A1 publication Critical patent/WO2002016337A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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

Definitions

  • the present invention relates to a tricyclic compound having excellent affinity for melatonin receptor (ML ⁇ ) and a pharmaceutical composition containing the compound.
  • Melatonin N-acetyl-5-methoxytryptamine
  • Melatonin is a hormone synthesized and secreted mainly by the pineal gland of the brain, and increases in the dark environment and decreases in the light environment. Melatonin acts suppressively on pigment cells and female gonads, and is involved in photoperiodic signaling to act as a synchronizing factor for the biological clock. Therefore, melatonin is considered to be used for the treatment of disorders related to melatonin activity, such as reproductive and endocrine disorders, sleep-wake rhythm disorders, jet lag, and various disorders associated with aging.
  • N- [2— (1,6,7,8-tetrahydro-2H— ⁇ fndeno [5,4—b] furan-8— Yl) ethyl acetoamide is described in WO 97 32871.
  • WO 99/63977 describes a sleep disorder prophylactic / therapeutic agent comprising a combination with a species.
  • Melatonin agonist which differs in structure from melatonin, has excellent affinity for melatonin receptors, and has excellent brain translocation and metabolic stability, can be expected to have a therapeutically superior effect to melatonin.
  • the melatonin receptors are classified into ML and ML 2, ML is involved in inhibiting the like of adenyl two Le cyclase.
  • no satisfactory drug has been found in terms of melatonin receptor agonizing activity, metabolic stability, and brain localization. Therefore, there is a strong demand for the development of a compound having a superior melatoene receptor agonistic activity or antagonistic activity and sufficiently satisfactory as a pharmaceutical.
  • composition according to the above (3) which is a melatonin receptor affinity composition
  • composition according to the above (3) which is a biological rhythm regulator
  • composition according to the above (3) which is a sleep-wake rhythm regulator.
  • composition according to (3) which is a jet lag regulator.
  • composition according to the above (3) which is a therapeutic agent for sleep disorder
  • composition according to the above (3) which is a therapeutic agent for circadian rhythmic sleep disorder
  • a method for regulating a biological rhythm, a sleep-wake rhythm, or a circadian rhythm which comprises administering the compound according to (1) above;
  • FIG. 1 shows an X-ray diffraction spectrum chart of the crystals of the compound obtained in Example 1.
  • Embodiment of the Invention (S) — N— [2 -— (1,6,7,8-tetrahydro-1H-indeno [5,4-b] furan-1-yl) ethyl] acetoamide [hereinafter abbreviated as compound (I) May be a hydrate or a non-hydrate.
  • the “hydrate” includes 0.5 hydrate to 5.0 hydrate. This
  • Compound (I) is optically converted to (N) -N- [2- (1,6,7,8-Tetrahydro 2 II-Indeno [5,4-b] furan-18-yl) ethinole] acetamide It can be obtained by separation with a column for isomer separation (chiral column). For example, for liquid mouth chromatography, C er amo s ph er e series
  • Compound (I) is synthesized by reacting compound (II) with acetic acid, acetate or a reactive derivative thereof in the presence of a deoxidizing agent as required.
  • a deoxidizing agent as required.
  • an alkali metal salt such as sodium acetate, potassium acetate and lithium acetate, an amine salt such as ammonium acetate and the like are used.
  • Reactive derivatives of acetic acid include acid halides (eg, acid chlorides, acid bromides, etc.), acid amides (eg, acid amides with pyrazole, imidazole, benzotriazole, etc.), acetic anhydride, mixed acid anhydrides (E.g., monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate, etc.), acid azide, active ester (e.g., diethoxy phosphate, p-etropheninolethanestenole, 2,4-jutopheninoleestenole, N-hydroxysuccinimide) Ester, N-hydroxy phthalate / ester, ester with 1-hydroxybenzotriazole, etc., activated thioester (eg 2-pyridylthioester, 2-benzothiazolylthioester, etc.) ) Is used.
  • acid halides eg, acid chlorides, acid bromides, etc.
  • the deoxidizing agent examples include inorganic bases such as sodium carbonate, carbonated carbonate, sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, triptylamine, and cyclohexyldimethylamine. It is desirable to add tertiary amines such as dimethylamineaminopyridine, N, N-dimethino aniline, N-methylbiperidine, N-methylpyrrolidine and N-methylmorpholine. When acetic acid or acetate is used, a suitable condensing agent may be used.
  • N, N'-disubstituted carbopimides such as N, N'-dicyclohexyl carpimide, 1-ethyl 3- (3-dimethylaminopropyl) carbopimide hydrochloride, , N '— azolides such as lipoeldiimidazoles, N-ethoxycarbo Dehydrating agents such as 2-chloro-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, and alkoxy siacetylene; 2-chloromethylpyridin-dimethodide; 2-fluoro-1-methylpyridinide —Halogenopyridinium salts are used.
  • the acetic acid, acetate or reactive derivative thereof is generally used in an amount of about 0.8 to 10 mol, preferably about 1.0 to 2.0 mol per 1 mol of compound (II).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent is not particularly limited as long as the reaction proceeds, and examples thereof include ethers such as getyl ether, tetrahydrofuran, dioxane, 1,2-dimethyloxetane, and hydrocarbons such as benzene, toluene, and cyclohexane.
  • Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., acetonitrile, Solvents such as -tolyls such as propionitrile, sulfoxides such as dimethyl sulfoxide, and mixed solvents thereof are preferable.
  • the reaction time is about 5 minutes to 72 hours, preferably about 10 minutes to 20 hours, and the reaction temperature is about 120 to 200 ° C, preferably about 0 to;
  • the compound (I) thus obtained can be isolated from the reaction mixture according to a conventional method, and can be easily purified by a separation means such as recrystallization distillation and chromatography. Further, the compound (I) can be obtained as crystals by the recrystallization distillation or the like.
  • Compound (II) can be synthesized by the method described in WO 97/32871, JP-A-11-110073.
  • a prodrug of compound (I) is a compound that is converted into compound (I) by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, a compound (I) that is enzymatically oxidized, reduced, hydrolyzed, or the like. ) Or a compound which is hydrolyzed by stomach acid or the like to change to compound (I).
  • Prodrugs of (I) include compounds in which the imino group of compound (I) is acylated, alkylated, or phosphorylated (eg, the imino group of compound (I) is eicosanoylated, alanylated, pentylaminocaponyl) (5-Methyl_2-oxo- 1,3-dioxolen-41-yl) methoxycarbonylation, tetrahydrofura , Pyrrolidylmethylation, bivaloyloxymethylation, tert-butynolelated compounds, etc.). These compounds can be produced from compound (I) by a method known per se.
  • the prodrug of compound (I) can be obtained from physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, Molecular Design, pp. 163-198. May be changed to compound (I).
  • compound (I) isotope (eg, 3 ⁇ 4 3 3 ⁇ 4, etc. 125 1) may be labeled with a.
  • the compound of the present invention has a high affinity for the melatonin receptor. ⁇ High selectivity for receptors. Compared to the racemic form, the S-form has a higher selectivity for the ML-receptor (approximately 2.7-fold), and the '-form is more remarkable than the R-form.
  • Compound (I) has the advantage of expression with less side effects such as movement disorders and memory deficits after considered Erareru awakening when derived from ML 2. It also has excellent metabolic stability and brain translocation. Furthermore, it is useful as a pharmaceutical because it has low toxicity and few side effects. Furthermore, by obtaining the present compound (I) as crystals, it is possible to provide a drug which is more excellent in operability, purity, stability and the like in the preparation.
  • the compound of the present invention acts on mammals (for example, mice, rats, hamsters, rabbits, cats, dogs, birds, higgs, monkeys, humans, etc.) as melatoninagost or antagoest, Melatoen receptor affinity compositions, which are particularly useful as melatonin receptor agonist compositions, and may be affected by melatonin, such as dysregulation of biological rhythms, such as sleep disorders (e.g., primary Sexual insomnia, circadian rhythm disorder (eg, physical shift due to three shifts, time-band change syndrome (jet lag), sleep-wake rhythm disorder), seasonal depression, reproductive dysfunction, endocrine disease, senile dementia, Alzheimer's disease, aging disorders, cerebral circulation disorders (eg, stroke), head trauma, spinal cord injury, epilepsy, anxiety, depression, manic depression, schizophrenia, alcoholism, Parkinson's disease, hypertension, Prevention and / or treatment of arteriosclerosis, arrhythmia, premenstrual syndrome, glaucoma, cancer, AIDS, diabetes,
  • the compound of the present invention has low toxicity, and can be used as it is or according to a method known per se, in the form of a pharmaceutical composition containing a pharmacologically acceptable carrier, such as tablets (including sugar-coated tablets and film-coated tablets), powders, and granules. Tablets, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, patches, etc., as well as chewing gum, etc., orally or parenterally (eg, topically, rectally, intravenously, etc.) It can be safely administered.
  • the content of the compound of the present invention in the preparation of the present invention is about 0.01 to 100% by weight of the whole preparation.
  • the dose varies depending on the administration subject, administration route, disease and the like.
  • the compound is about 0.0005 to 2 mgZkg body weight, preferably about 0.001 to lmg / kg body weight, more preferably about 0.001 to 0.5 mgZkg body weight, usually 0.01 kg to 0 kg. 6 mg / kg. It can be administered in 1 to 1 or several divided doses.
  • the preparation contains about 0.1 to about 100 mg, more preferably about 0.3 to about 64 mg, and still more preferably about 1 to about 16 mg of the present compound.
  • Pharmaceutically acceptable carriers that may be used in the formulation of the present formulation include various organic or inorganic carrier materials commonly used as formulation materials, such as excipients, lubricants, and binders in solid formulations.
  • conventional additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used.
  • Excipients include, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light caffeic anhydride and the like.
  • lubricant examples include magnesium stearate, calcium stearate, Tanolek, colloid silica and the like.
  • Binders include, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropinoresenololose, hydroxypropinolemethinoresenorelose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose And carboxymethyl senorelose sodium.
  • Disintegrants include, for example, starch, carboxymethylcellulose, carboxymethinoresenolerose kanoresum, croscarnomelose sodium, strength / reoxymethyl starch sodium, L-hydroxypropylcellulose and the like.
  • solvent examples include water for injection, alcohol, propylene glycol, Mackerel gall, sesame oil, corn oil, olive oil and the like.
  • solubilizing agent examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, alcohol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinyl alcohol Examples include hydrophilic polymers such as sodium / vinyl acetate, sodium carboxymethylcellulose, methinolace / rerose, hydroxymethinoresenorelose, hydroxyshethylcellulose, and hydroxypropylcellulose.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
  • polyvinyl alcohol polyvinyl alcohol
  • hydrophilic polymers such as sodium / vinyl acetate, sodium carboxymethylcellulose, methinolace /
  • tonicity agent examples include glucose, D-sorbitol, sodium chloride, glycerin, D-mantol and the like.
  • buffer examples include buffers such as phosphate, acetate, carbonate, and citrate.
  • soothing agent examples include benzyl alcohol and the like.
  • preservative examples include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • antioxidant examples include sulfite, ascorbic acid, sodium tocopherol and the like.
  • the compound of the present invention may be used in combination with at least one selected from zolpidem, zopiclone, triazolam, protizolam and zaleplon. That is, a preventive / therapeutic agent for sleep disorders comprising a combination of the compound of the present invention and at least one selected from zolpidem, zopiclone, triazolam, brotizolam and zaleplon is safer than when each is used alone. Excellent effect as a clinically used drug, such as a remarkable effect of preventing and treating sleep disorders with almost no side effects such as recoil insomnia, memory impairment, wobbling after awakening, and drowsiness Having.
  • Zolpidem is N, N, 6_trimethyl-2_ (4-methylphenyl) -imidazo [1,2-a] pyridine_3_acetamide, and #! J is described in Japanese Unexamined Patent Publication No. Sho 63-83384 (USP 4 , 794, 185), or a method analogous thereto.
  • Zoiclone is 4-methyl-1-piperazinecarboxylic acid 6- (5-chloro-2--2-pyridmyl) -1,6,7-dihydro-7-oxo-5H pyrrolo [3,4-b] pyrazin-5- yl ester and is produced, for example, by the method described in JP-A-48-76892 (USP 3,862,149) or a method analogous thereto.
  • Triazolam (trade name: Halcyon) is 8-chloro- 6- (2-chlorophenyl) —1-methyl—4H— [1, 2, 4] triazolo [4, 3_a] [1, 4] benzodiazepine. For example, it is produced by the method described in JP-B-49-42039 (US Pat. No. 3,987,052) or a method analogous thereto.
  • Brotizolam (Blotizolam, trade name: Lendormin) is 8-brorao—6— (o-chloropheny ⁇ methyl—4H——S—triazolo L3,4c ”thieno [2,3e] 1,4 diazepine.
  • Zaleplon is manufactured by N— [3— ( 3— cyanopyrazolo [1, 5_a] pyrimidin— 7— yl) phenylj — N—ethylacetamide, for example, the method described in USP 5, 714, 607, EP—A— 770 698, or
  • the compound of the present invention is used in combination with at least one selected from zonolepidem, zopiclone, triazolam, brotizolam and zaleplon, for example,
  • the content of the active ingredient in such a preparation is usually about 0.01 to about 100% by weight. /. It is.
  • the preparation may be in any form as long as it can be administered orally to a patient, and examples include tablets, fine granules, capsenolle, granules and the like. Among them, tablets, fine granules, capsules and the like are preferable.
  • the dose of the compound of the present invention when used in combination with other drugs varies depending on the administration subject, administration route, disease, type of active ingredient to be used, etc., and is set for an adult with sleep disorder (body weight of about 60 kg).
  • the following doses of the active ingredient may be administered once or several times a day, and each ingredient may be used simultaneously or with a time difference of 30 minutes to 3 hours. It is good to administer in combination.
  • the dosage of the compounds of the present invention is from about 0.05 mg to about 10 mg per dose, preferably from about 0.1 mg to about 3 mg per dose.
  • the dosage of zolpidem is from about 0.2 mg to about 10 mg per dose, preferably from about 0.5 mg to about 5 mg per dose.
  • the dose of zopiclone is about 0.2 mg to about 10 mg per dose, preferably about 0.5 mg to about 5 mg per dose.
  • the dosage of triazolam is from about 0.1 mg to about 0.5 mg per dose, preferably from about 0.02111 ⁇ to about 0.3 mg per dose.
  • the dosage of brotizolam is from about 0.01 mg to about lmg per dose, preferably from about 0.5111 to about 0.3 mg per dose.
  • the dosage of zaleplon is from about lmg to about 30 mg per dose, preferably from about 2 mg to about 20 mg per dose.
  • the combination ratio (administration ratio) of the compound of the present invention and at least one selected from zolpidem, zopiclone, triazolam, protizolam and zaleplon is 1 part by weight of the compound of the present invention to zolpidem, zopiclone, triazolam, protizolam And / or zaleplon 0.1 to 30 parts by weight.
  • the compound of the present invention may further contain other active ingredients (for example, benzodiazepines such as diazepam, alprazolam and estazolam which are benzodiazepines), sleep rhythm regulators such as fatty acid derivatives butocamide or salts thereof, Sleeping substances such as 9,10-octadecenoamide) may be used in appropriate combination in appropriate amounts.
  • active ingredients for example, benzodiazepines such as diazepam, alprazolam and estazolam which are benzodiazepines
  • sleep rhythm regulators such as fatty acid derivatives butocamide or salts thereof
  • Sleeping substances such as 9,10-octadecenoamide
  • the other active ingredient and the compound of the present invention or the compound of the present invention are mixed with zolpidem, zopiclone, triazolam, protizolam and zaleplon according to a means known per se, and mixed with a pharmaceutical composition (for example, tablet, Powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc.) or separately formulated at the same time or with a similar time interval as the preparation of the present invention. And may be administered to the same subject.
  • a pharmaceutical composition for example, tablet, Powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc.
  • a pharmaceutical composition for example, tablet, Powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc.
  • a pharmaceutical composition for example, tablet, Powders
  • FIG. 1 shows an X-ray diffraction spectrum chart of the obtained crystal.
  • powder X-ray diffraction was measured using RINTU1tima + 2100 manufactured by Rigaku Corporation.
  • the forebrain was excised from a 7-day-old chick (white leghorn), and homogenized with ice-cold Atsushi buffer (50 mM Tris-HC1, pH 7.7, 25 ° C) to obtain 44,000 X g, 10 A sediment was obtained by centrifugation for minutes. This was washed once with the same buffer solution, and then homogenized with an Acety buffer solution to a concentration of 0.3 to 0.4 mg protein / mL to obtain a membrane sample.
  • ice-cold Atsushi buffer 50 mM Tris-HC1, pH 7.7, 25 ° C
  • the compound of the present invention Since the compound of the present invention has excellent properties as a melatonin agonist, it can provide a clinically useful preventive / therapeutic agent for a disease (eg, sleep disorder) related to the action of melatonin in a living body. it can. Further, the compound of the present invention is particularly excellent in MLL receptor selectivity, metabolic stability, and also excellent in brain translocation.
  • a disease eg, sleep disorder

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Abstract

La présente invention concerne des composés tricycliques faisant preuve d'une excellente affinité pour le récepteur de la mélatonine (ML1) et des compositions pharmaceutiques contenant ces composés. L'invention concerne plus particulièrement le (S)-N-[2-(1,6,7,8-tétrahydro-2H-indéno[5,4-b]furan-8-yl)éthyl]acétamide, et certains de ces promédicaments.
PCT/JP2001/007073 2000-08-18 2001-08-17 Composés tricycliques et compositions pharmaceutiques les contenant WO2002016337A1 (fr)

Priority Applications (1)

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AU2001278754A AU2001278754A1 (en) 2000-08-18 2001-08-17 Tricyclic compounds and pharmaceutical compositions containing the same

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JP2000-248300 2000-08-18
JP2000248300 2000-08-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8084630B2 (en) 2007-05-31 2011-12-27 Teva Pharmaceutical Industries Ltd. Process for the synthesis of ramelteon and its intermediates

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10287665A (ja) * 1996-03-08 1998-10-27 Takeda Chem Ind Ltd 三環性化合物、その製造法および剤
WO2001013950A1 (fr) * 1999-08-20 2001-03-01 Takeda Chemical Industries, Ltd. Agents d'absorption percutanee

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10287665A (ja) * 1996-03-08 1998-10-27 Takeda Chem Ind Ltd 三環性化合物、その製造法および剤
WO2001013950A1 (fr) * 1999-08-20 2001-03-01 Takeda Chemical Industries, Ltd. Agents d'absorption percutanee

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8084630B2 (en) 2007-05-31 2011-12-27 Teva Pharmaceutical Industries Ltd. Process for the synthesis of ramelteon and its intermediates

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