WO2000059909A1 - Composes heterocycliques presentant des affinites pour les recepteurs de serotonine - Google Patents

Composes heterocycliques presentant des affinites pour les recepteurs de serotonine Download PDF

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Publication number
WO2000059909A1
WO2000059909A1 PCT/JP2000/001224 JP0001224W WO0059909A1 WO 2000059909 A1 WO2000059909 A1 WO 2000059909A1 JP 0001224 W JP0001224 W JP 0001224W WO 0059909 A1 WO0059909 A1 WO 0059909A1
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hydrogen
lower alkyl
compound according
compound
single bond
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PCT/JP2000/001224
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Japanese (ja)
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Toshiyuki Kamigauchi
Mitsuru Yasui
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Shionogi & Co., Ltd.
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Priority to AU28251/00A priority Critical patent/AU2825100A/en
Publication of WO2000059909A1 publication Critical patent/WO2000059909A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/16—Peri-condensed systems
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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 novel heterocyclic compounds. Since the present compound has an affinity for serotonin receptor, it is useful as a medicament such as a therapeutic drug for central nervous system diseases. It is also useful as a synthetic intermediate thereof.
  • Serotonin (5-hydroxytryptamine) is one of the biological amines and has various physiological activities. For example, it is present in the basal granule cells of the intestine and promotes intestinal motility. In addition, it is released into the blood from platelets during bleeding and is involved in hemostasis by contracting capillaries. Separately, serotonin also acts as a neurotransmitter in the brain and is involved in the regulation of mental activity, pain threshold, body temperature, sleep-wake cycle, etc. via serotonin receptors [Physiol. Rev. 72 (1992) 165-229].
  • Serotonin receptors are roughly classified into seven families, and at least 14 species have been discovered including their subtypes [Pia / ⁇ aco Rev. 46 (1994) 157-203]. It has been reported that each receptor is involved in various physiological functions and disease states, and serotonin receptor binding agents exhibit agonist or antagonist action to prevent or prevent various diseases. Harmacol. Eev. 43 (1991) 509-525, which is expected to be a therapeutic drug.
  • 5-HT 5 A , 5-HT 5 B , 5-HT 6 and 5-HT 7 receptors are the most recently discovered and cloned serotonin receptors [i ⁇ ? Lett. 355 (1994) 242-6, FEB S Lett. 333 (1993) 25-31, J. Neurochem. 66 (1996) 47-56, Neuron, 11 (1993) 449-458], its selective operation. Drugs (agonist) and antagonists (anthus gonist) are rarely reported. All of these receptors are mainly distributed in the central nervous system. Has obviously summer, for example, 5-HT 5 A, 5- HT 5 B receptors to a depth not the hippocampus and cerebral cortex involved in learning and memory [i 1 ⁇ ? Et.
  • 5-HT 6 receptor is involved in the striatum involved in motor function [J. Neurochem. 66 (1996) 47-56], 5-HT 7 receptor Is reported to be present in the suprachiasmatic nucleus, a mammalian biological clock [ ⁇ uro / i, 11 (1993) 449-458]. Therefore, selective agonist or antagonist of these receptors may be an anti-dementia drug, an anti-parkinson's disease drug, an antipsychotic, a drug for treating circadian rhythm disorder, and the like.
  • 5-HT 5 ⁇ , 5 - ⁇ 5 ⁇ already developed selective Agonisu preparative Ya antagonists DOO for the treatment of each 3 ⁇ 4 diseases against 5- ⁇ 6, 5- ⁇ 7 receptor other serotonin receptors
  • DOO selective Agonisu preparative Ya antagonists
  • tetracyclic fused heterocyclic compound for example, the following are known.
  • the W096 / 32944, Erugorin (ergoline) compounds having antagonistic preparative effect on 5-HT 7 receptors have been described.
  • W095 / 28403 describes aveo-ergoline derivatives acting on 5-HT receptors.
  • JP55-124784 (A) describes an indole derivative having a hypotensive action.
  • GB1482871 (A) describes an indole derivative having an adrenergic antagonistic activity and the like. All of these compounds contain N atoms as ring-constituting heteroatoms, but do not contain 0 atoms. Therefore, it cannot suggest the compound of the present invention.
  • serotonin receptors particularly 5-HT 6 and 5 - has been desired to develop a medicine containing novel compounds and it has an affinity against HT 7 receptor.
  • R 1 1 Oyobi 11 2 it it independently hydrogen, lower alkyl or halogen;
  • R 3 and R 4 are each independently hydrogen, lower alkyl, lower alkenyl, lower alkylcarbonyl, ⁇ optionally substituted Reel carbonyl or cyano;
  • R 1 and R 3 may together form a single bond;
  • R 6 is hydrogen, hydroxy, lower alkoxy or lower alkyl carboxy
  • R 7 is hydrogen
  • R 8 and are each independently hydrogen, lower alkylthio or halogen
  • R 7 and R 9 may together form a single bond
  • R 1 Q is hydrogen, lower alkyl, lower alkylcarbonyl, lower alkyloxyl carbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl.
  • R 11 is hydrogen, lower alkyl or halogen
  • R 12 represents hydrogen or lower alkyl
  • R 1 and R 3 together form a single bond;
  • R 2 is hydrogen or lower alkyl;
  • R 4 is lower alkyl;
  • R 6 is hydrogen;
  • R 7 and R 9 are together A bond is formed;
  • R 8 is hydrogen;
  • R 11 and R 12 are hydrogen;
  • n is 0.
  • R 1 and R 3 together form a single bond
  • R 2 is hydrogen or lower alkyl
  • R 4 is lower alkyl
  • R 6 is hydrogen
  • R 7 and R 9 are together Forming a bond
  • R 8 is hydrogen, lower alkylthio or halogen
  • R 11 and R 12 are each independently hydrogen or lower alkyl
  • n is ⁇ , wherein R is hydrogen, lower alkyloxycarbonyl, or optionally substituted arylcarbonyl.
  • R 1 and R 3 together form a single bond;
  • R 2 is hydrogen or lower alkyl;
  • R 4 is lower alkyl;
  • R 6 is hydrogen;
  • R 7 and R 9 are together
  • R 8 is hydrogen;
  • R 1 . Is a substituted or unsubstituted arylsulfonyl;
  • R 11 and R 12 are hydrogen;
  • n is 0.
  • R 1 and R 3 together form a single bond;
  • R 2 is hydrogen or lower alkyl;
  • R 4 is lower alkyl;
  • R 6 is hydrogen;
  • R 7 , R 8 and R 9 are both hydrogen
  • R 8 is hydrogen;
  • R 1 ° is optionally substituted carbonyl or optionally substituted arylsulfonyl;
  • R 11 and R 12 are hydrogen;
  • n is 0; 2.
  • R 1 and R 3 together form a single bond;
  • R 2 is hydrogen or lower alkyl;
  • R 4 is lower alkyl;
  • R 6 is hydrogen;
  • R 7 and R 9 are — ⁇ to form a single bond;
  • R 8 is halogen;
  • R 1 G is hydrogen;
  • R 1 1 is hydrogen or halogen;
  • R 1 2 is hydrogen;
  • is n 0, compounds of claim 1, wherein the.
  • R 1 and R 3 together form a single bond;
  • R 2 is hydrogen or lower alkyl;
  • R 4 is lower alkyl;
  • R 6 is hydrogen;
  • R 7 and R 9 are both hydrogen or
  • R 8 is hydrogen;
  • ⁇ 1 G is hydrogen;
  • R 11 and R 12 are hydrogen;
  • n is 1.
  • a pharmaceutical composition comprising the compound according to any one of the above 1 to 15.
  • An agent for preventing or treating a disease mediated by a mouth tonine receptor comprising the compound according to any one of the above 1 to 15.
  • An agent for preventing or treating central nervous system diseases comprising the compound according to any one of the above items 1 to 15.
  • central nervous system disease is anxiety, depression, schizophrenia, circadian rhythm disorder, stroke, dementia, pain or Parkinson's disease.
  • a microorganism belonging to the genus Streptomyces which is capable of producing the compound according to any one of 1 to 15 above.
  • a method for preventing or treating a disease mediated by an oral tonin receptor which comprises administering the compound according to any one of the above items 1 to 15.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Lower alkyl includes straight-chain or branched C 1 -C 6 alkyl, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-butyl. —Pentyl, i-pentyl, neo-pentyl, tert-pentyl, n-hexyl and the like. Preferably, it is C 1 -C 4 alkyl, especially methyl, n-propyl, tert-butyl and the like.
  • Lower alkenyl includes straight-chain or branched C2-C6 alkenyl, and includes vinyl, aryl, 1-brodinyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-hexenyl and the like. Is exemplified. Preferably, it is 2-propenyl or the like.
  • the lower alkoxy includes the oxy bonded to the lower alkyl, and examples thereof include methoxy, ethoxy, i-propoxy, t. Ert-butoxy, pentyloxy, and hexyloxy.
  • it is C1-C4 alkoxy, especially methoxy, ethoxy and the like.
  • Aryl means a mono- or condensable aromatic hydrocarbon group, for example, phenyl, hy-naphthyl, naphthyl, anthryl, indenyl, phenanthryl and the like. Preferably it is phenyl.
  • Heteroaryl means an aromatic monocyclic or polycyclic group containing the same or different heteroatoms selected from 0, S and N.
  • the monocyclic group includes a 5- to 7-membered group containing 1 to 4 heteroatoms, and includes furyl, thienyl, tetrazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, oxazinyl, and toxinyl. Liazinyl and the like are exemplified.
  • the polycyclic group includes a bicyclic or tricyclic heterocyclic group containing 1 to 5 heteroatoms.
  • benzofurael isobenzofuranyl, benzochenyl, indolyl, isoindolyl, ingzolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl and the like.
  • Substituents on the aryl or heteroaryl include halogen (eg, Br), hydroxy, amino, carboxy, cyano, nitro, carbamoyl, sulfamoyl, lower alkyl (eg, methyl) , Lower alkyl halides (eg, trifluoromethyl), lower alkyl rubamoyl (eg, methylcarbamoyl), lower alkylsulfamoyl (eg, methylsulfamoyl), lower alkoxy (eg, methoxy), lower alkoxycarbonyl (eg, Examples: ethoxycarbonyl) and the like, but preferably, nitrogen, nitro, lower alkyl and lower alkoxy.
  • halogen eg, Br
  • hydroxy, amino, carboxy, cyano, nitro, carbamoyl, sulfamoyl lower alkyl (eg, methyl)
  • Lower alkyl halides eg, tri
  • R 1 is preferably formconnection single bond such together with R 3.
  • R 2 is preferably hydrogen, lower alkyl (eg, methyl), or halogen (eg, B r), and particularly preferably hydrogen.
  • R 4 is preferably hydrogen, lower alkyl (eg, methyl, n-propyl), lower alkenyl (eg, 2-propenyl), or cyano, and particularly preferably methyl.
  • R 6 is preferably hydrogen, hydroxy, lower alkoxy (eg, methoxy, ethoxy, etc.), or lower alkyl carbonyloxy (eg, acetyloxy, etc.), and particularly preferably hydrogen.
  • R 7 is preferably formconnection single bond such with R 9.
  • R 8 is preferably hydrogen, lower alkylthio (eg, methylthio), or halogen (eg, Br, C 1, etc.), and particularly preferably hydrogen.
  • R 1 is preferably hydrogen, lower alkyl (eg, methyl, etc.), lower alkyl carbonyl (eg, acetyl, etc.), arylcarbonyl (eg, benzoyl, ⁇ - ⁇ -benzoyl, ⁇ — ⁇ ) 0 2 - Benzoiru etc.), lower alkyl O alkoxycarbonyl (e.g. tert - butoxide deer Lupo sulfonyl, etc.), or ⁇ Li one Rusuruhoniru (e.g. toluenesulfonyl Honyl, p-Br-benzenesulfonyl, p-N ⁇ 2-benzenesulfonyl), and particularly preferably hydrogen.
  • Rusuruhoniru e.g. toluenesulfonyl Honyl, p-Br-benzenesulfonyl, p-N ⁇ 2-benzenesulfonyl
  • R 11 is preferably hydrogen, lower alkyl (eg, tert-butyl, etc.), or halogen (eg, Br, C 1 etc.), preferably hydrogen.
  • R 1 2 is preferably hydrogen or lower alkyl (eg: tert - heptyl etc.) Ru Der, preferably hydrogen.
  • n is preferably 0.
  • Examples of the pharmaceutically acceptable salt of compound (I) include salts formed with inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, halogen ions and the like, or internal salts.
  • Examples of the inorganic base include alkali metals (Na, K, etc.), alkaline earth metals (Ca, Mg, etc.), and examples of the organic base include trimethylamine, triethylamine, choline, proforce, ethanolanol, and the like. Is exemplified.
  • Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • Examples of the organic acid include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, and maleic acid.
  • Examples of the basic amino acid include lysine, arginine, ornithine, histidine and the like. Hydrates, solvates, racemates, optically active forms, and prodrugs of the compound (I) are all included in the present invention.
  • the prodrug is a derivative of the compound (I) having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. is there.
  • Compound (I) is obtained by culturing a Streptomyces strain capable of producing any of the compounds represented by the above formula (I) in a suitable medium, collecting and isolating from the medium, purifying, and optionally, It can be produced by chemical modification.
  • the medium may contain a carbon source, a nitrogen source, sterile salts, vitamins and the like.
  • the carbon source include glucose, sucrose, soluble starch, dextrin, glycerin, fatty acids, organic acids and the like.
  • Nitrogen sources include, for example, soy flour, pinna, corn starch, beef extract, yeast extract, cottonseed powder, polypeptone, wheat malt, sodium nitrate, ammonium nitrate, and the like.
  • Examples of the inorganic salts include calcium carbonate, sodium chloride, potassium chloride, magnesium sulfate, copper sulfate, manganese chloride, zinc sulfate, cobalt chloride, and various phosphates.
  • the culturing temperature is usually about 12 to 44 ° C, preferably about 20 to 40 ° C.
  • the pH of the medium is usually about 6.0 to 8.0, preferably about 6.5 to 7.2.
  • the culture time is usually about 4 to 12 days.
  • the above-mentioned strain is preferably an actinomycete, particularly preferably / • epio ⁇ ces sp, PA-48561 strain (this strain is the Institute of Biotechnology, Institute of Industrial Science and Technology, Ministry of International Trade and Industry (location: Tsukuba East, Ibaraki Prefecture) 1-chome 1-3), deposited on January 11, 1998 under accession number FERM P-17052. On February 7, 2000, changed to an international deposit under accession number FERM BP-7023. ).
  • This strain PA-48561 is a Gram stain-positive, acid-fast stain-negative bacterium. Branches, 0.5 ⁇ 1.0 ⁇ ⁇ in width, does not break. The spores form a spiral spore chain at the tip of the spore stem branched from the aerial hypha. The spore chains are relatively short, most spores are cylindrical to sausage, 1.0-2.0 ⁇ 111 long, 0.5-1.0 0.5 ⁇ wide, and their surfaces are smooth. Neither sporangia nor sclerotia are found.
  • Aerial hyphae grew well on starch inorganic salt agar medium and glycerin-asparagine agar medium, but no aerial hyphae were formed on yeast malt agar medium and oatmeal agar medium.
  • the colonies on the starch inorganic salt agar medium are white and light yellow brown with sporulation. Soluble dyes do not recognize this.
  • Growth temperature range It grows at 12-44 ° C on the inorganic salt agar medium (ISP-4), and shows the best growth especially at 28-41 ° C.
  • Salt tolerance In Bennett's medium, it grows well up to 7% salt concentration.
  • LL-diaminopimelic acid and glycine were detected from the cell wall, suggesting that the cell wall was type I.
  • glucose and arabinose were detected, but no galactose and xylose were found, and the sugar pattern was type C.
  • MK-9 menaquinone, MK-9 (H6 and 8) was detected.
  • phospholipids phosphatidylethanolamine and phosphatidylinositol were detected, but phosphatidylcholine and unknown glucosamine-containing phospholipids were not detected. II.
  • PA-48561 strain belongs to the genus Streptomyces. Regarding the taxonomic position of this bacterium, see “Bergey's Manual of Systematic Bacteriology Volume 4”, Shiling, EB and Gottl ieb, D. Corporate's' Discipline of Ob 'type'Cultures' of Ob 'Streptomyces II. Speech's' Disc Ription' from 'First' Susday (Cooperative description of type cultures of Streptomyces.il. Species description from first study.), "Inuichi Nishinare, Giananole, Saibu, Systematic, Pacteriology," Vol. 18 (1968) (Int. J. Syst.
  • Streptomyces shioyaensis was listed as the most closely related strain to this strain.
  • This strain and the standard strain IF012820 of Streptomyces shioyaensis were cultured under the same conditions, and the two were compared.
  • the test items shown in Table 2 were used. Significant differences were observed between the two strains. Therefore, this bacterium was regarded as a new species of the genus Streptomyces and named Streptomyses sp. (Table 2)
  • PA-48561 is cultured, and the following natural products (main component ht-13-A, minor component ht-13-) are extracted from the fermented liquor by a conventional method, followed by chromatographic separation and purification. B) was obtained.
  • the present inventors have appropriately modified these natural products by well-known reactions (eg, oxidation, reduction, protection, deprotection, C-C cleavage reaction, halogenation, hydroxylation, alkylation, alkylthiolation). , Demethylation, 0-alkylation, 0- Various derivatives were synthesized by acylation, N-alkylation, N-alkenylation, N-acylation, N-cyanoation, N-sulfonylation and the like.
  • compound (I) Since compound (I) has affinity for various serotonin receptors, it functions as an agonist or antagonist. Therefore, serotonin receptors, especially to 5 - Various central nervous diseases (examples HT 6 or 5 -HT 7 is interposed: sleep-wake disorders, Gaibiri rhythm disorders, anxiety, depression, schizophrenia, stroke , Dementia, pain, Parkinson's disease, etc.) and can be orally or parenterally administered to animals including humans. Examples of the dosage form include granules, tablets, capsules, injections, suppositories and the like.
  • additives may be used as required, for example, excipients (lactose, mannitol, crystalline cellulose, starch, etc.), disintegrants (potassium melomerose, hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, etc.).
  • excipients lactose, mannitol, crystalline cellulose, starch, etc.
  • disintegrants potassium melomerose, hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, etc.
  • a binder methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, etc.
  • a lubricant magnesium stearate, talc, etc.
  • a stabilizer a coloring agent
  • a coating agent for example, excipients (lactose, mannitol, crystalline cellulose, starch, etc.), disintegrants (potassium melomerose, hydroxypropyl methylcellulose, polyvinylpol
  • the dosage may vary depending on the subject's age, body weight, symptoms, administration method, etc., but is usually about 0.001 mg to lg / day per adult, orally or parenterally, and the frequency of administration is 1 ⁇ Several times a day.
  • Agar plate cultures of SrepioHycessp. PA-48561 were punched into this medium with stainless steel pipes of 6 mm diameter, inoculated with 2 pieces of agar, 28 mm in amplitude 70 mm, 180 rpm per minute at 28 ° C. Shaking culture was performed for 4 days.
  • the culture-finished solution of 96 flasks was separated into about 1.5 Kg of wet cells and 8 L of the supernatant using a centrifuge (Beckman J-6M, 4200 rpm, 15 minutes).
  • the cells were leached with 1.5 L of ethanol for 1 day and filtered by suction.
  • the ethanol filtrate containing water was subjected to solvent distillation under reduced pressure, and the remaining aqueous layer was extracted with 1 L of ethyl acetate, and then washed with saturated saline.
  • the ethyl acetate layer was concentrated to dryness to obtain 0.5 g of a crude extract.
  • 0.5 g of the crude extract was used as a 50 mL solution of ethyl acetate, and extracted with 50 mL of 0.1 N hydrochloric acid.
  • the hydrochloric acid layer was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate, extracted with 100 mL of ethyl acetate, washed with saturated saline, and concentrated to dryness to obtain 25 mg of a base fraction.
  • Solubility Soluble in ethyl acetate, acetone, black form, and methanol; insoluble in water Melting point: 234 ⁇ 237 ° C
  • IR (KBr) cm— 1 3144, 3098, 3060, 3033, 1621, 1510, 1456, 1344, 1293, 1242,
  • UV (methanol) ma ma (£): 221 (28,500), 275 (6,200), 287 (6,000), 297 (5,600)
  • 0.5% soluble starch 0.5% glucose, 0.5% polypeptone (fine granules, manufactured by Nippon Pharmaceutical Co., Ltd.), 0.5% beef extract (manufactured by Difco), 0.5% yeast extract (Difco) 0.25% sodium chloride, 0.25% sodium chloride, and tap water (adjusted to pH 7.0, diluted caustic soda) into a 2 L triangular flask with a branch. 800 mL was dispensed and sterilized at 121 ° C for 20 minutes. This medium was inoculated with 4 mL of a 20% glycerin-storing vial (storage at 180 ° C) of Streptomyces sp. PA—485851 strain, and the amplitude was 7 O mm, and the rotation was 180 rpm. Shaking culture was performed for 28 and 24 hours.
  • soluble starch 1.5%, glucose 1.0%, dried yeast (beast, manufactured by Iwaki Seiyaku Co., Ltd.) 0.5%, defatted soy flour (GP-SL, manufactured by Yoshiwara Oil Co., Ltd.) 2.0 %, Sodium chloride 0.25%, Adekinol LG-121 (manufactured by Asahi Denka Kogyo Co., Ltd.) 0.03%, medium 30 L of tap water (without pH adjustment) was injected into a 50 L capacity fermenter, sterilized at 121 ° C for 25 minutes, inoculated with the entire amount of the above culture, and aerated and stirred at 23 ° C for 6 days (aerated). : 150 L / min, stirring: 150 rotations / min).
  • 53.6 L of culture termination solution is KS type ultra high speed centrifuge (Kansai Centrifuge) The mixture was subjected to continuous centrifugation at 18, 212 revolutions per minute (19, 292) at a flow rate of 5 L / min to obtain 6.7 kg of wet bacterial cells. Acetone (18 L) was added to the wet cells, and the mixture was stirred for about 1 hour (at this time, the pH was adjusted to 2.0 with a dilute hydrochloric acid aqueous solution). A filter cloth centrifugal filter (Kansai Centrifuge Co., Ltd. Company, KAN15) was used to obtain 24 L of filtrate.
  • the filtrate was adjusted to pH 7.0 using sodium bicarbonate, and concentrated under reduced pressure to obtain 6 L of an aqueous phase.
  • 5 L of water was added, and extracted twice with ethyl acetate (7 L, 3 L).
  • This ethyl acetate solution was extracted twice with 0.1 N aqueous hydrochloric acid (5 L, 5 L) to obtain 10 L of 0.1 N aqueous hydrochloric acid.
  • This 0.1 N hydrochloric acid aqueous solution was adjusted to pH 7.0 using sodium bicarbonate, and extracted twice with ethyl acetate (3 L, 2 L).
  • This ethyl acetate solution was washed with 800 mL of water and concentrated under reduced pressure to obtain 0.37 g of an oily substance.
  • 0.5% soluble starch 0.5% glucose, 0.5% polypeptone (fine granules, manufactured by Nippon Pharmaceutical Co., Ltd.), 0.5% beef extract (manufactured by Difco), 0.5% yeast extract (Difco) 0.25% sodium chloride, 0.25% sodium chloride, and tap water (adjusted to pH 7.0, diluted caustic soda) into a 2 L triangular flask with a branch. 800 mL was dispensed and sterilized at 121 ° C for 20 minutes. In this medium
  • Streptomyces sp. PA Inject 4 mL of 20% glycerin storage vial (stored at 180 ° C) of 4 strains, and shake at 28 ° C at an amplitude of 70 mm at 180 rpm. C, 24:00 Shaking culture was performed.
  • soluble starch 4.0%, glucose 2.0%, dried yeast (Bist, Iwaki Seiyaku Co., Ltd.) 1.0%, defatted soy flour (GP-SL, Yoshihara Oil Co., Ltd.) 4 0%, sodium chloride 0.25%, Adecanol LG-121 (manufactured by Asahi Denka Kogyo Co., Ltd.) 0.03%, medium with tap water (without pH adjustment) 150 L was poured into a 250 L tank, sterilized at 121 C for 25 minutes, inoculated with 6 L of the above culture, and aerated and stirred at 23 ° C for 1 day (aeration). : 75 LZ min, stirring: 120 revolutions / min).
  • This 0.1 N hydrochloric acid aqueous solution was adjusted to pH 7.5 using a dilute sodium hydroxide solution, and extracted twice with ethyl acetate (8 L, 5 L). The ethyl acetate solution was washed with 1.0 L of water and concentrated under reduced pressure to obtain 1.06 g of an oily substance.
  • the crude extract was divided into two portions and subjected to preparative HPLC (0 DSS—15 / 305 c Fractionation was performed using m ⁇ x50 cm (YMC), 15% acetonitril (0.1% TFA), flow rate: 6 OmL / min, to obtain 2.0 L of an effective fraction. This fraction was adjusted to pH 7.6 using a dilute caustic soda solution, and concentrated under reduced pressure to obtain about 1.7 L of an aqueous phase.
  • This aqueous phase was extracted twice with 200 mL of ethyl acetate, and the ethyl acetate phase was concentrated under reduced pressure to dryness, crystallized from a small amount of ethyl acetate and n-hexane, and ht-13-A was colorless. Acicular crystals (a total of 420 mg) were obtained.
  • Solubility Ethyl acetate, Acetone, Black form, Soluble in methanol, Insoluble in water Melting point: 182 ⁇ 184 ° C
  • IR (Or) cm- 1 3144, 3101, 3054, 3033, 1621, 1509, 1454, 1342, 1295, 1245, 1065, 774, 739
  • ht-13- ⁇ (10 mg) was dissolved in THF (2 mL), and NaH (about 60% oil suspension, 4 mg) was added. After stirring at room temperature under a nitrogen stream for 5 minutes, methyl iodide (20 ⁇ L) was added, and the mixture was stirred at room temperature under a nitrogen stream for 2 hours.
  • Solubility Ethyl acetate, Acetone, Soluble in black form, insoluble in water
  • Solubility Soluble in ethyl acetate, acetate, and black form, insoluble in water
  • Solubility Insoluble in water soluble in ethyl acetate, acetone, black form, and methanol ESI-MS: m / z 307 ([M + H] +: Br), 309 ([M + H] + : siBr)
  • Solubility Ethyl acetate, Acetone, Soluble in black form, insoluble in water
  • HPLC retention time 4.4 min (Devosyl 0DS-5 4.6 ⁇ x 150 mm (Nomura Chemical Co., Ltd.), mobile phase 30% acetonitrile monohydrate (0.1 trifluoroacetic acid), flow rate 1 mL / min, detection UV 210 nm)
  • HPLC 0.1% trifluorocoacetic acid [30% ⁇ (7 minutes) 95%] acetonitrile monohydrate was used as the mobile phase using a silica gel ODS-54.6 ⁇ X 150 mm (Nomura Chemical Co., Ltd.) as the column.
  • the flow rate was set to 1 mL / min and the detection was performed at UV 210 nm, the retention time was 7.5 minutes.
  • Example 9 L-i-Butyl-5-SMeht-13-A (4 mg) of Example 9 was dissolved in ethanol (1 mL), and Raney nickel (50 mg) was added. After heating under reflux for 1 hour, Raney nickel was removed by mouth and the solvent was distilled off under reduced pressure. The residue was fractionated by TLC (Merck Pre-Trade TLC Blade Silica Gel 60F254, thickness 0.25 mm, form: methanol: 95: 5) to obtain 3.5 mg of the title compound.
  • TLC Merck Pre-Trade TLC Blade Silica Gel 60F254, thickness 0.25 mm, form: methanol: 95: 5
  • Solubility soluble in ethyl acetate, acetone, black form, methanol, insoluble in water LSIMS: m / z 284 [ ⁇ ] + , 285 [ ⁇ + ⁇ ] +
  • Solubility Soluble in ethyl acetate, acetone, black form, methanol, insoluble in water LSIMS: m / z 340 [M] +, 341 [ ⁇ + ⁇ ] + , 681 [2 ⁇ + ⁇ ] +
  • HPLC Using a column, "Herosil ODS-54.6 ⁇ X 150 mm (Nomura Chemical Co., Ltd.)" as the mobile phase,,, lash, ent (0.1% trif acetic acid 30 ° / 0 ⁇ 95% acetonitrile) Using water / water 7 min, 0.1% trif D mouth acetic acid 95% acetonitrile / water 7 min), and the flow rate was lm L / min, the retention time was 8.6 min when detected at UV 210 nm.
  • Solubility Soluble in ethyl acetate, acetone, black form, methanol, insoluble in water.
  • ht-13- ⁇ (10 mg) was dissolved in 1 mL of acetic acid at triflou mouth, 5 nig of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour. Then, the mixture was diluted with 2 mL of water under ice cooling, neutralized with ammonia water, and extracted with 10 mL of ethyl acetate. After the ethyl acetate layer was washed with a saturated saline solution, the solvent was distilled off to obtain 10.4 iug of a residue.
  • Solubility Ethyl acetate, Acetone, Black form, Soluble in methanol, Insoluble in water ESI-MS: m / z 231 [ ⁇ + ⁇ ] ⁇
  • Solubility Soluble in ethyl acetate, acetone, black form, methanol, insoluble in water
  • ht-13- ⁇ (20 mg) was dissolved in methanol (4 mL), DDQ (44 mg) was added at room temperature in a nitrogen stream, and the mixture was stirred for 1 hour. 36 mL of I-yl acetate was added to the reaction mixture, and the mixture was made ⁇ -into an alumina column (4 g of aluminum metal oxide). 90% ethyl acetate-methanol 50 m
  • Solubility Soluble in ethyl acetate, acetone, black form, and methanol. Insoluble in water.
  • LSIMS m / z 227 [M-0CHJ +, 259 [M + H] 517 [2M + H] +
  • HPLC Use ⁇ S "0DS-5 4.6 X 150 mm (Nomura Chemical Co., Ltd.) as the mobile column, and use a mobile phase as a mobile phase, such as ash, lash, ent (0.1% trif acetic acid, 30% ⁇ 95% acetonitrile / water). 7 min, 0.1 ° /. Trif D mouth acetic acid, 95 acetonitrile / water 3 min), the retention time was 3.0 min when the flow rate was 1 mL / min and the detection was performed at UV 220 nm.
  • Solubility Soluble in ethyl acetate, acetone, black form, methanol, insoluble in water. Molecular formula: CnHjoNiOj
  • HPLC Using a column of ⁇ , D, D-sil 0DS-5 4.6 ⁇ ⁇ 150 mm (Nomura Chemical Co., Ltd.), and using 0.1% triflo-D acetic acid-30% acetate :: tolyl / water as the moving bed and a flow rate of 1%.
  • Example 14 The 6-OH ht-13-A (8 mg) of Example 14 was chick. Dissolved in water (2 mL), acetic anhydride (200 ⁇ L) was added, and the mixture was stirred at room temperature for 15 hours. Methanol (5 mL) was added to the reaction solution, and the mixture was stirred for 5 minutes, and then the solvent was distilled off. Aqueous sodium bicarbonate was added, the mixture was partitioned with ethyl acetate, and the ethyl acetate layer was washed with saturated brine, dried with polish, and the solvent was distilled off.
  • Solubility Soluble in ethyl acetate, acetone, black form, methanol, insoluble in water ESI-MS: m / z 215 [M + H] +
  • HPLC using Deverosil ODS-T-54.6 ⁇ X 150 mm (Nomura Chemical Co., Ltd.) for the column, and 0.1% trifluoroacetic acid mono [20% ⁇ (15 minutes) 50%] acetonitrile reluuwater gradient as the mobile phase
  • the retention time was 6.4 minutes when the flow rate was ImL / min and the detection was performed at UV 210 nm.
  • Solubility Soluble in ethyl acetate, acetone, black form, methanol, insoluble in water
  • TLC Merck Pre-Ted TLC plate Using silica gel 60F254, the Rf value was 0.54 when the developing solvent was 9: 1 chloroform-form: methanol.
  • HPLC Develosil ODS-T-54.6 ⁇ x 150 mm (Nomura Chemical Co., Ltd.) on the column, 0.1% trifluoroacetic acid mono [20% ⁇ (15 minutes) 50%] acetonitrile monohydrate gradient as the mobile phase
  • the retention time was 9.2 minutes when the flow rate was lm L / min and the detection was performed at UV 210 nm.
  • HPLC Derosil ODS-T-54.6 ⁇ x 150 mm (Nomura Chemical Co., Ltd.) on the column, 0.1% trifluoroacetic acid monoacetic acid [20 ° /. ⁇ (15 min) 50%] Using acetonitrile Lilue water gradient, the retention time was 9.5 min when the flow rate was I mL / min and detected at UV 210 nm.
  • ht-13-II (10 mg) was dissolved in tetrahydrofuran (2 mL), and sodium hydride (oil suspension containing about 60% oil, 10 mg) was added under ice-cooling. After stirring at room temperature under a nitrogen stream for 20 minutes, parabromobenzenesulfonyl chloride (23 mg) was added, and the mixture was stirred at room temperature under a nitrogen stream for 1 hour.
  • Solubility Soluble in ethyl acetate, acetone, black form, methanol, insoluble in water ESI-MS: m / z 447 ([M + H] + ; "Br), 449 ([ ⁇ + ⁇ ] + : 81 ⁇ )
  • ht-13- ⁇ (10 mg) was dissolved in tetrahydrofuran (2 mL), and sodium hydride (about 60% oil suspension, 10 mg) was added under ice-cooling. After stirring at room temperature under a nitrogen stream for 20 minutes, paramethoxybenzenesulfonyl chloride (19 mg) was added, and the mixture was stirred at room temperature under a nitrogen stream for 1 hour.
  • the reaction solution was diluted with a saturated aqueous sodium hydrogen carbonate solution and partitioned with ethyl acetate. After washing and drying with a saturated saline solution, the solvent is distilled off, and the residue is subjected to thin gel gel thin layer chromatography (black form: methanol).
  • Solubility Soluble in ethyl acetate, acetone, black form, methanol, insoluble in water
  • HPLC Retention time 10.08 minutes (Develosyl ODS-T-54 ⁇ 6 ⁇ x l50 mm (Nomura Chemical Co., Ltd. Company), mobile phase 35% acetonitrile Lilue water (0.1% trifluoroacetic acid), flow rate 1 m (L / min, detection UV 210 nm)
  • ht-13- ⁇ (10 mg) was dissolved in tetrahydrofuran (2 mL), and sodium hydride (oil suspension containing about 60% oil, 10 mg) was added under ice-cooling. After stirring at room temperature under a nitrogen stream for 20 minutes, paranitrobenzenesulfonyl chloride (20 mg) was added, and the mixture was stirred at room temperature under a nitrogen stream for 1 hour.
  • chloroform: methanol 9: 1: 1
  • Solubility Ethyl acetate, Acetone, Black form, Soluble in methanol, Insoluble in water ESI-MS: m / z 414 [ ⁇ + ⁇ ] +
  • TLC Rf value 0.60 (Merck Pleated TLC plate silica gel 60F254, 917
  • Crude 5-Bromo ht-13-A is for high performance liquid chromatography (column: Develosil ODS-T-510-5 x 250 mm (Nomura Chemical Co., Ltd.), mobile phase: 0.1 ° /.
  • Trifluoroacetic acid [20 ° /. ⁇ (30 min) ⁇ 25% (acetonitrile monohydrate) gradient], flow rate: 3 mL / min, retention time: 19 to 24 min), and the eluate is sodium hydrogen carbonate
  • the mixture was extracted with ethyl acetate.
  • the ethyl acetate layer was treated in a conventional manner to give 5-Bromo ht-13-A (6 mg).
  • Solubility Soluble in ethyl acetate, acetone, black form, methanol, insoluble in water ESI-MS: m / z 307 ([M + H] +: 79 Br), 309 ([M + H] +: "Br)
  • Solubility Soluble in ethyl acetate, acetone, black form, methanol, insoluble in water
  • ht-13-A (10 mg) was dissolved in dichloromethane (1. ⁇ mL), and methacrylic acid perbenzoic acid (9 mg) was added, followed by stirring at room temperature for 30 minutes.
  • Solubility Solubility in methanol, ethanol and dimethyl sulfoxide
  • ht-13-B (2 mg) was dissolved in 0.4 mL of dichloromethane, to which was added peroxybenzoic acid (2.5 mg), followed by stirring at room temperature for 1 hour.
  • Solubility Solubility in methanol, ethanol and dimethyl sulfoxide
  • Solubility Soluble in methanol, ethanol, dimethyl sulfoxide, water
  • [L] indicates the radioligand concentration used, and Kd indicates the dissociation constant.
  • Table 3 shows the experimental conditions for each receptor.
  • Table 4 shows the results.
  • Example 1 An appropriate amount of ht-13-A, microcrystalline cellulose, and magnesium stearate of Example 1 is mixed and tableted to give a tablet.
  • a capsule is obtained by filling the granules obtained as in Formulation Example 2 into capsules.
  • This compound has an affinity for various serotonin receptors and is therefore useful as a preventive or therapeutic agent for various central diseases.

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Abstract

Composés représentés par la formule (I) et présentant des affinités pour différents récepteurs de sérotonine (tels que 5HT-1A, 2, 6, 7 etc.). Ces composés sont, de ce fait, utiles en tant qu'agents thérapeutiques pour traiter, par exemple, des maladies du système nerveux central : (I) dans laquelle R1 et R2 représentent chacun indépendamment hydrogène, alkyle inférieur, par exemple ; R3 et R4 représentent chacun indépendamment hydrogène, alkyle inférieur, par exemple ; ou R1 et R3 peuvent être reliés de manière à créer une liaison simple ; n est 0 ou 1 ; R5 représente hydrogène ; R6 représente hydrogène, hydroxyle, par exemple ; R7 représente hydrogène ; R8 et R9 représentent chacun indépendamment hydrogène, alkylthio inférieur, par exemple ; ou R7 et R9 peuvent être reliés de façon à créer une liaison simple ; R10 représente hydrogène, alkyle inférieur, par exemple ; R11 représente hydrogène, alkyle inférieur, par exemple ; R12 représente hydrogène ou alkyle inférieur.
PCT/JP2000/001224 1999-03-30 2000-03-02 Composes heterocycliques presentant des affinites pour les recepteurs de serotonine WO2000059909A1 (fr)

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AU28251/00A AU2825100A (en) 1999-03-30 2000-03-02 Heterocyclic compounds having affinities for serotonin receptors

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1325909A1 (fr) * 2000-09-22 2003-07-09 Shionogi & Co., Ltd. Composes indol tricycliques possedant une affinite pour le recepteur de serotonine
US10966959B2 (en) 2018-06-19 2021-04-06 Wisconsin Alumni Research Foundation Use of a rotifer-derived compound and its analogs for preventing schistosomiasis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995028403A1 (fr) * 1994-04-18 1995-10-26 Pharmacia S.P.A. Derives abeo-ergoline en tant que ligands du 5ht1a
EP0738513A1 (fr) * 1995-04-18 1996-10-23 Eli Lilly And Company Procédé d'utilisation de dérivés d'ergoline pour influencer les fonctions physiologiques et pathologiques au niveau des récepteurs 5-HT7

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995028403A1 (fr) * 1994-04-18 1995-10-26 Pharmacia S.P.A. Derives abeo-ergoline en tant que ligands du 5ht1a
EP0738513A1 (fr) * 1995-04-18 1996-10-23 Eli Lilly And Company Procédé d'utilisation de dérivés d'ergoline pour influencer les fonctions physiologiques et pathologiques au niveau des récepteurs 5-HT7

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1325909A1 (fr) * 2000-09-22 2003-07-09 Shionogi & Co., Ltd. Composes indol tricycliques possedant une affinite pour le recepteur de serotonine
EP1325909A4 (fr) * 2000-09-22 2004-12-08 Shionogi & Co Composes indol tricycliques possedant une affinite pour le recepteur de serotonine
US10966959B2 (en) 2018-06-19 2021-04-06 Wisconsin Alumni Research Foundation Use of a rotifer-derived compound and its analogs for preventing schistosomiasis

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