WO2002030938A1 - Derives benzhydryle - Google Patents

Derives benzhydryle Download PDF

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Publication number
WO2002030938A1
WO2002030938A1 PCT/JP2001/008902 JP0108902W WO0230938A1 WO 2002030938 A1 WO2002030938 A1 WO 2002030938A1 JP 0108902 W JP0108902 W JP 0108902W WO 0230938 A1 WO0230938 A1 WO 0230938A1
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Prior art keywords
group
compound
decane
acceptable salt
oxa
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PCT/JP2001/008902
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English (en)
Japanese (ja)
Inventor
Akio Shiraishi
Takahide Nishi
Hiroaki Maeda
Tohru Tatsuta
Harumi Kuwabara
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Sankyo Company, Limited
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Priority to AU2001294215A priority Critical patent/AU2001294215A1/en
Publication of WO2002030938A1 publication Critical patent/WO2002030938A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
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    • A61P7/06—Antianaemics
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    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a benzhydryl derivative having a selective inhibitory action on Th1 cell immune activity, a pharmacologically acceptable salt thereof, an ester or other derivative thereof, and a pharmaceutical composition containing them as an active ingredient.
  • anti-inflammatory drugs such as steroids have been used for inflammatory reactions caused by abnormal immune responses.
  • Helper T cells which play a central role in the immune response, consist of two different subsets: type 1 helper T cells (hereinafter abbreviated as Thl cells) and type 2 helper T cells (hereinafter T cells). h 2 cells).
  • Thl cells type 1 helper T cells
  • T cells type 2 helper T cells
  • Th1 cells produce cytokines such as interleukin 2 (hereinafter abbreviated as IL-2), interferon-17 (hereinafter abbreviated as IFN-), TF- ⁇ , and are mainly involved in cell-mediated immunity I do.
  • Th2 cells produce cytokins such as interleukin 4 (hereinafter abbreviated as IL-4) and interleukin 10 (hereinafter abbreviated as IL-10), and CJ. Immunol., Vol. 136, 2348-2357, 1986) involved in humoral immunity.
  • IFN- ⁇ produced by Th1 cells inhibits the function of Th2 cells.
  • IL_4 and IL-10 produced by Th2 cells inhibit the function of Th1 cells. It is thought that the balance between Th1 cells and Th2 cells via these cytokines is important for normal immune function in vivo.
  • Th1 / Th2 cells balance are involved in the development of various immune-related diseases.
  • the balance bias toward Th1 cells may be caused by chronic inflammatory diseases such as rheumatoid arthritis, fl-vessel-specific autoimmune diseases [eg, diabetes, multiple sclerosis, inflammatory bowel disease (eg, ulcerative colon) Inflammation, Crohn's disease), glomerulonephritis, hepatitis, liver injury, autoimmune hemolytic anemia, leukopenia, thrombocytopenia, allergic encephalitis, demyelinating disease, Hashimoto's thyroiditis, Addison's disease, hypoparathyroidism Disease, pernicious anemia, localized ileitis, atrophic gastritis, Dalten intolerable enteropathy, Good Pasteur syndrome, streptococcal post-nephritis, myasthenia gravis, rheumatic fever, viral cardiomyopathy, uveitis
  • chronic inflammatory diseases such as r
  • the present inventors have developed a derivative having an action of selectively inducing the production of IL-4 and Z or IL-10 produced from Th2 cells and selectively suppressing the immune activity of Th1 cells.
  • the benzhydryl derivative of the present invention which has a fuel group or a cheel group having a substituent at a specific position, has excellent IL-4 and / or IL-10 production induction.
  • Chronic rheumatoid arthritis which has an action and is a chronic inflammatory disease, and organ-specific autoimmune diseases [eg, diabetes, multiple sclerosis, inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease), thread Glomerulonephritis, hepatitis, hepatic disorder, autoimmune hemolytic anemia, leukopenia, thrombocytopenia, allergic encephalitis, demyelinating disease, Hashimoto's thyroiditis, Addison's disease, hypoparathyroidism, pernicious anemia , Localized ileitis, atrophic gastritis, posie Resistant enteropathy, Good Pasteur syndrome, streptococcal post-nephritis, myasthenia gravis, rheumatic fever, viral cardiomyopathy, uveitis, sympathetic ophthalmitis, pemphigus vulgaris, bullous pemphigoid, Psoriasis] is useful as a therapeutic
  • the compounds of the present invention have high water solubility and high oral absorption , Fast onset of action, high transferability to target organs or target cells, low transferability into the brain, weak side effects (including antihistamine, antiserotonin, and anti-dopamine), safety
  • the present inventors have found that the venom has a wide range of differences in the expression of toxin and its pharmacokinetics (long plasma half-life, large AUC, low tissue accumulation, etc.), and completed the present invention.
  • the present application provides the above-mentioned benzhydryl derivatives, pharmacologically acceptable salts thereof, esters or other derivatives thereof, and pharmaceutical compositions containing them as active ingredients. Further, the present application relates to the use of the above-mentioned benzhydryl derivative, its pharmacologically acceptable salt, its ester or other derivative for producing a pharmaceutical composition, and the above-mentioned benzhydryl derivative, its pharmacologically acceptable salt. Provided is a method for preventing or treating rheumatoid arthritis and the above organ-specific autoimmune diseases by administering a pharmacologically effective amount of a salt, an ester thereof, or another derivative to a warm-blooded animal (particularly, a human). .
  • the benzhydryl derivative of the present invention has the following general formula (I) or (II).
  • R 1 has an arbitrary group selected from substituent group a at the ortho or meta position, and may be independently substituted with 1 to 4 arbitrary groups selected from substituent group a Represents a phenyl group,
  • R 2 represents a phenyl group, a phenyl group, or a phenyl group independently substituted with 1 to 3 arbitrary groups selected from a substituent group a;
  • R 3 represents a lower alkyl group
  • n an integer of 2 or 3
  • Substituent group a is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower A group consisting of an alkoxy group, a lower alkylthio group, a hydroxyl group, an amino group, a nitro group and a cyano group;
  • R 2 is represented by R 1 Show different groups
  • preferred compounds include the following.
  • R 1 has an arbitrary group selected from the substituent group a at the ortho position or the meta position, and may be independently substituted with 1 or 2 arbitrary groups selected from the substituent group a
  • R 1 has an arbitrary group selected from the substituent group a at the ortho position or the meta position, and further may be independently substituted with one arbitrary group selected from the substituent group a.
  • R 1 is the following formula
  • R 4 and R 5 are the same or different and each represents an arbitrary group selected from Substituent Group a.
  • R 4 and R 5 are the same or different and are a halogen atom, a lower alkyl group, a halogeno lower alkyl group or a nitro group,
  • R 4 and R 5 are the same or different and are a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group or a nitro group,
  • R 1 is 2-fluorophenyl, 3-fluorophenyl, 2-chlorophenol, 3-chlorophenol, 3-methinolephen, 3-trifluoromethylenophenine, 3-nitrophenol Binore, 2,3-diphneololophenylinole, 2,4-difluorophenylenole, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3 A compound which is 2,5-ditrifluoromethylphenyl or a 2_chloro-5-nitrophenyl group,
  • R 1 is 2-fluorophenyl, 3-chlorophenyl, 3-methinolephenyl, 3-nitrophenyl, 2,3-diphleolophenyl, '2,4-difluorophenyl, 2,5'- Diphnoleolopheninole, 3,4-difluoropheninole-3,5-diphneololofeninole 3,5-ditrifluoromethylphenyl or a compound having a 2-chloro-5-trophenyl group
  • R 1 is a phenyl group having an arbitrary group selected from substituent group a at the ortho or meta position, and further independently substituted with two arbitrary groups selected from substituent group a.
  • R 1 is the following formula
  • R 4 , R 5 and R 6 are the same or different and each represents an arbitrary group selected from Substituent Group a.
  • R 4 , R 5 and R e are the same or different and are a halogen atom, a lower alkyl group, a halogeno lower alkyl group or a toro group;
  • R ⁇ R 5 and R 6 are the same or different and are a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group or a nitro group,
  • R 1 is a 3,4,5-triphenylolenophenol, a 3,4,5-trichlorophenol or a 3,4,5-trimethylphenol group
  • R 1 has an arbitrary group selected from the substituent group a at the ortho-position or the meta-position, and is further substituted with 3 or 4 arbitrary groups selected from the substituent group a. Based on A compound,
  • R 1 has an arbitrary group selected from the substituent group a at the ortho position or the meta position, and furthermore, is a phenyl group which is independently substituted with four arbitrary groups selected from the substituent group a.
  • R 1 is a 2,3,4,5,6_pentalower alkylphenyl group, (20) in any one selected from (1) to (4),
  • R 1 is a 2,3,4,5,6_pentamethylphenyl group
  • R 2 is a phenyl group independently substituted with 1 to 3 phenyl groups or an arbitrary group selected from substituent group a,
  • R 2 force a compound that is a fuel group
  • R 2 is a phenyl group independently substituted with 1 to 3 arbitrary groups selected from the substituent group a,
  • R 2 is the following formula
  • R 7 represents an arbitrary group selected from substituent group a.
  • R 7 is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, an ethoxy group or a cyano group, (26) In (24),
  • R 7 is a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a nitro group or a cyano group
  • R 7 is a fluorine atom, a chlorine atom or a cyano group
  • R 2 has an arbitrary group selected from the substituent group a at the ortho or meta position, and may further be independently substituted with one arbitrary group selected from the substituent group a.
  • R 7 and R 8 are the same or different and each represents an arbitrary group selected from Substituent Group a.
  • R 7 and R 8 are the same or different and are a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a toro group or a cyano group,
  • R 7 and R 8 are the same or different and are a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, an ethoxy group or a cyano group; (32) In any one selected from (1) to (20),
  • R 2 is 2-phenolenopheninole, 3-funenole, 2-phenyl-phenyl, 3-chlorophenyl, 3-methylphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 3-nitro Mouth phenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-diphnolelopheel, 3,4-difluorophenole, 3,5- A compound which is difluorophenyl, 3,5-ditrifluoromethylphenyl, 3_cyanophenyl or 2-chloro-5-nitrophenyl group,
  • R 2 is 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-ditrifluoromethylphenyl or 3-cyanophenyl
  • R 2 is a phenyl group having an arbitrary group selected from substituent group a at the ortho-position or meta-position and further independently substituted with two arbitrary groups selected from substituent group a.
  • R 2 is the following formula
  • R 7 , R 8 and R g are the same or different and each represents an arbitrary group selected from substituent group a).
  • RR 8 and R 9 are the same or different and are a halogen atom, a lower alkyl group, a halogeno lower alkyl group or a utro group; (3 7) In (3 5),
  • RR 8 and R 9 are the same or different and are a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group or a -toro group;
  • n 2;
  • the “lower alkyl group” in the definition of R 3 and the substituent group “a” is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butynole, t-butynole, pentynole, isopentyl, 2-methinolebutyl , Neopentinole, 1-ethylinopropyl, hexinole, isohexinole, 4-methinolepentinole, 3-methinolepentinole, 2-methinolepentinole, 1-methinolepentinole.
  • 3,3-dimethinolebuty / twenty two- 1 to 6 carbon atoms such as dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethynolebutynole, 2,3-dimethynoleptinole, 1-ethylbutyl, and 2-ethynolebutynole groups a chain or branched alkyl group, preferably a C "C 4 alkyl group, more preferably -. alkyl group, and most preferably a methyl group in the above formula, the substituent group a "Halogen" in the definition is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • the “halogeno lower alkyl group” in the definition of the substituent group a represents a group in which the above “lower alkyl group” has been substituted with a halogen atom, for example, trifluoromethyl, trichloromethinole, dib / leo Mouth Mechinore, Jiku Moutine, Jib Moutine, Funoleolomechinore, 2,2,2-Trifluoroethyl, 2,2,2-Trichloroethinole,
  • the “lower alkoxy group” in the definition of the substituent group a represents a group in which the above “lower alkyl group” is bonded to an oxygen atom, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, 1-ethynolepropoxy, 2-ethynolepropoxy, neopentoxy, hexinoleoxy, 4-methylpentoxy, 3-methylpentoxy, 2 —Methylpentoxy, 3, 3-Dimethylbutoxy, 2, 2- Straight or branched chain having 1 to 6 carbon atoms such as dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy It is an alkoxy group, preferably a C 4 alkoxy group, more preferably a Ci
  • the “lower alkylthio group” in the definition of the substituent group “a” indicates a group in which the above “lower alkyl group” is bonded to a sulfur atom, and includes, for example, methylthio, ethylthio, propylthio, isopropinorethio, butinorethio.
  • a phenyl group which may be independently substituted by one or two arbitrary groups selected from the substituent group a, or a substituent group a at the ortho or meta position Is a phenyl group having an arbitrary group selected from and further independently substituted by 3 or 4 groups with an arbitrary group selected from the substituent group a.
  • R 4 and R 5 are the same or different and represent any group selected from substituent group a. Or a group having the following formula:
  • R 4 , R 5 and R 6 are the same or different and represent any group selected from substituent group a. Or has an arbitrary group selected from the substituent group a at the ortho or meta position, and is further independently substituted by four groups selected from the substituent group a. And more preferably a compound represented by the following formula:
  • R 4 and R 5 are the same or different and are a halogen atom, a lower alkyl group, a halogeno lower alkyl group or a -toro group. ] Which is a group having the following formula
  • R 4 , R 5 and R 6 are the same or different and are a halogen atom, a lower alkyl group, a halogeno lower alkyl group or a -toro group. Or a 2,3,4,5,6-penta-lower alkylphenyl group, and more preferably a group represented by the following formula:
  • R 4 and R 5 are the same or different and are a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group or a -toro group. ] Is a group having the following formula:
  • R 4 , R 5 and R 6 are the same or different and are a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group or a nitro group.
  • a 2,3,4,5,6-pentamethynolephenyl group more preferably 2-fluorophenyl, 3-phenylphenol, 2-chlorophenyl, Fuegre, 3-cloth mouth fene./le, 3-methinofurenoinore, 3-triphneoleolomethinolefeninole, 3-nitropheninole, 2,3-difluorophenole, 2,4-difluorophenyl, 2 , 5-Difluorophenyl, 2,6-diphlenolenophenylene, 3,4-difluorophenylene, 3,5-difluorophenylene, 3,5-ditrifluorophenol methyleninole, 2-chloro-5-etrophenole, 3,4,5
  • a fuel group independently substituted by 1 to 3 arbitrary groups selected from the substituent group a” in the definition of R 2 include, for example, 2-fluorophenol, 3-fluorophenol Lofeninole, 2-cloth feninole, 3-cloth feninole, 2-methinolephenyl, 3-methylphenyl, 2-trifluoromethinolefeel, 3-trifenoleon methylephenyl, 2-nitropheninole, 3 —Nitrophenyl, 2,3-difluorophenyl //, 2,4-diphleolopheny //, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5 -Ditrifluoromethyl fuegre, 2-f / f, 5-f / f,
  • R 7 represents an arbitrary group selected from substituent group a.
  • R 7 represents an arbitrary group selected from substituent group a. ] Is a group having the following formula
  • R 7 and R 8 are the same or different and represent any group selected from substituent group a. Or a group having the following formula:
  • R 7 , R 8 and 1 ′ are the same or different and represent any group selected from substituent group a. ], And more preferably a group represented by the following formula:
  • R 7 represents a halogen atom, a lower alkyl group, a halogeno lower alkyl group, an ethoxy group or a cyano group. Or a group having the following formula:
  • R 7 and R 8 are the same or different and represent a halogen atom, a lower alkyl group, a halogeno lower alkyl group or a -toro group. ] Or the following formula:
  • R 7 , R s and R 9 are the same or different and represent a halogen atom, a lower alkyl group, a halogeno lower alkyl group or a nitro group. ] And still more preferably, a group represented by the following formula:
  • R 7 represents a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a nitro group or a cyano group.
  • R 7 and R 8 are the same or different and represent a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group or a -toro group. Or a group having the following formula: Chlorine atom, methyl, more suitable
  • R 7 represents a fluorine atom, a chlorine atom or a cyano group.
  • a pharmacologically acceptable salt thereof means that the compound having the general formula (I) or (II) of the present invention is reacted with an acid when the compound has a basic group such as an amino group. When the compound has an acidic group, it can be converted into a salt by reacting with a base.
  • the salt based on a basic group preferably, hydrofluoride, hydrochloride, hydrobromide, hydrohalide such as hydroiodide, nitrate, perchlorate, sulfuric acid Salt, phosphoric acid Inorganic acid salts such as salts; lower alkanesulfonic acid salts such as methanesulfonate, trifluoromethanesulfonic acid salt and ethanesulfonic acid salt, and arylsulfonic acids such as benzenesulfonic acid salt and ⁇ -toluenesulfonic acid salt
  • Organic salts such as salts, acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates and maleates; and glycine salts, lysine salts, Examples thereof include amino acid salts such as arginine salt, ordinine salt, glutamate and aspartate, and more preferably inorganic or organic acid salts.
  • the salt based on the acidic group is preferably an alkali metal salt such as a sodium salt, a potassium salt, a lithium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, an aluminum salt, an iron salt.
  • Metal salts such as salts; inorganic salts such as ammonium salts, octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, fuenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guadin salts, and getylamine salts.
  • Triethylamine salt Tricyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chlorinated proforce salt, proforce salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine Salt, tetramethylammonium salt, tris (hydroxymethyl) a Amin salts such good Una organic salts Nometan salts; and Darishin salts, lysine salts, arginine salts, Orunichi down, glutamate, Ru can be mentioned Amino acid salts such as Asuparagin acid salt.
  • the compound having the general formula (I) or (II) of the present invention has various isomers since an asymmetric carbon atom is present in the molecule.
  • these isomers and mixtures of these isomers are all represented by a single formula, that is, by the general formula (I) or (II). Accordingly, the present invention includes all these isomers and mixtures of these isomers in any proportion.
  • the compound represented by the general formula (I) or (II) of the present invention absorbs water, becomes adsorbed water, or becomes a hydrate when left in the air or recrystallized. Such hydrates may be included in the salts of the present invention.
  • ester in the above refers to an ester of the compound (I) or (II) of the present invention because it can be converted into an ester, and examples of such an ester include “hydroxyl ester”.
  • Each ester residue is an esterol that is a "general protecting group” or a "protecting group that can be cleaved in vivo by a biological method such as hydrolysis”.
  • General protecting group refers to a protecting group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis.
  • An arylcarbonyl group such as benzoyl, ⁇ -naphthoyl and ⁇ -naphthoyl, an arylcarbonyl group such as 2-bromobenzoinole and 4-chlorobenzoyl, 2,4,6-trimethyl Benzoyl, lower alkylated arylcarbonyl groups such as 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-aesyl, dinitrogenation such as 4-nitrobenzoyl, 2-nitrobenzoyl "Aromatic” such as arylcarbyl group, lower alkoxycarboxylated carbonyl group such as 2- '(methoxycarbonyl) benzoyl, arylated carbyl group such as 4-phenylbenzoyl Methoxy group); methoxycanoleponyl, ethoxycarbol, propoxycanolepoel, butoxycarbonyl, s-butoxycarbo
  • a protective group that can be cleaved in vivo by a biological method such as hydrolysis means a protective group that is cleaved in a human body by a biological method such as hydrolysis to produce a free acid or a salt thereof.
  • a derivative is administered to a laboratory animal such as a rat or a mouse by intravenous injection, and then the body fluid of the animal is examined, and the original compound or a pharmacologically acceptable salt thereof is determined. Can be determined by being able to detect
  • Esters of hydroxyl group such "by biological methods such as hydrolysis in vivo"
  • the cleavable protecting group preferably, formyloxymethyl, acetoxmethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, bivaloyloxymethyl, valeryloxymethyl, isovaleryloxy Methyl, Hexanoyloxymethyl, 1-Formyloxyxetil, 1-Acetoxyethynole, 1-Propioninoleoxyethynole, 1-Butylinoleoxyethy ⁇ 1—Pivalo Kisechil, 1-isovaleryloxexetil, 1-hexanoyloxexetil, 1-formyloxypropyl, 1-acetoxip Mouth pill, 1-propio-roxypropyl, 1-ptyriloxypropyl, 1-pipropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1 —Pro
  • acyloxy “lower alkyl group”; methoxycarbo -Roxy simethinole, ethoxycarboninoleoxymethinole, propoxycanolebonyloxymethinole, isopropoxycarbo-loxymethyl, butoxycarboninoleoxymethinole, isobutoxycanoleponinoleoxymethyl, pentyloxycarbonyloxymethyl , Hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy'methyl, cyclohexyloxycarboxy- (cyclohexyl) methyl, 1- ⁇ Methoxycarboxy-ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarboxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycanoleponinoleoxy) ethyl 1- (t-butoxycarbonyloxy) ethyl, 1-
  • the “other derivative” may be a derivative other than the above “pharmacologically acceptable salt” and the above “ester thereof” when the compound (I) or (II) has an amino group. So its derivatives are shown. Such derivatives include, for example, amide derivatives.
  • the compound having the general formula (I) or (II) of the present invention include, for example, the compounds shown in Table 1 below.
  • the present invention is not limited to these compounds.
  • the compounds in Tables 1 and 2 have the structural formulas (I) and (II), respectively.
  • the abbreviations in the table are as follows.
  • T h i (2) a 2-phenyl group.
  • Exemplary Compound No. 59 8- ⁇ 2-[(3,5-difluorophenyl) phenylmethoxy] ethyl ⁇ -1-oxa-3,8-diazaspiro [4.5] decane-2-one;
  • Exemplified Compound No. 4 8- ⁇ 2-[(2-fluorophenyl) (4-fluorophenyl) methoxy] ethyl ⁇ -1-oxa-3,8-diazaspiro [4.5] decane-2-one;
  • Exemplified Compound No. 50 8- ⁇ 2- [bis- (2,3-difluorophenyl) methoxy] ethyloxa-3,8-diazaspiro [4,5] decane-2-one,.
  • Exemplified Compound No. 58 8- ⁇ 2- [bis- (3,4-difluorophenyl) methoxy] ethyloxa-3,8-diazaspiro [4,5] decane-2-one,
  • Exemplified Compound No. 77 8- ⁇ 2-[(3_cyanophenyl) (3 ', 4, -difluorophenyl) methoxy] ethyloxa-3,8-diazaspiro [4,5] decane-2-one;
  • Exemplified Compound No. 78 8- ⁇ 2-[(3-cyanophenyl) (3, -trifluoromethylphenyl) methoxy] ethyl ⁇ -1-oxa-3,8-diazaspiro [4,5] decane-2 -on,
  • the compound having the general formula (I) or (II) of the present invention can be produced according to the method described below.
  • Method A is a method for producing compounds (I) and (II).
  • R la and R 2a are aminos contained as a substituent in the groups R 1 and R 2.
  • the group Z or the hydroxyl group is an amino group which may be protected and the group Z or a hydroxyl group, and the same groups as those defined in the definition of the groups R 1 and R 2 , and X is chlorine, bromine Halogen atoms such as iodine; C 6 alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfoninoleoxy; benzenesulfonyloxy, p-TsO (p-tosyloxy), OTf (triflorenolomethanesulfonyl) Oxy), pentafluoroethanes-norlephoninoleoxy, and may be substituted with 1 to 3 groups selected from the above-mentioned lower al
  • Negative charges such as arylsulfonyloxy groups, reduce anions in the definition of X— It represents a group that can be represented, and Q is not particularly limited as long as it is a group which is usually eliminated as a nucleophilic residue, but is preferably a halogen atom such as chlorine, bromine or iodine; Trihalogenomethyloxy groups, such as methanesulfonyloxy and ethanesulfonyloxy, and lower alkenyl sulfonyloxy groups; halogeno lower alkenyl groups, such as trifluoromethanesulfoninoleoxy and pentafuronolene.
  • the “protecting group” of the “optionally protected amino group” in the definition of R la and R 2a is not particularly limited as long as it is a protecting group for an amino group used in the field of synthetic organic chemistry.
  • acetyl group a halogeno C 2 -C 7 alkylcarbonyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl, and a C 6 alkoxy group such as methoxyacetyl.
  • a halogeno C 2 -C 7 alkylcarbonyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl
  • C 6 alkoxy group such as methoxyacetyl.
  • Aliphatic acyls such as C 2 -C 7 alkylcarbol groups; C 6 _.
  • aromatic acyl such as a C 7 —Cu aromatic acyl group substituted with aryl; the aforementioned C 2 —C 7 alkoxycarbonyl group, 2,2,2-trichloroethoxycanoleponinole; 2-trimethylsilyl E butoxy carbo - C 2 substituted with C androgenic or tri CI- C 6 alkylsilyl such as Le - C 7 alkoxycarbonyl - “Alkoxycarbonyls” such as benzyl group; bieroxycarbonyl, aryloxy force “alkene / reoxycarbonyls” such as rubonyl; benzyloxycarbel, 4-methoxybenzyloxycarbol, 3, 4 1 to 2 ⁇ - ⁇ 6 alkoxy or -toro, such as —dimethoxybenzyloxycarbonyl, 2-dibenzobenzyloxycarbonyl, 4-12-benzyloxycarbonyl An arylalkyl group optional
  • Sopurobirushiriru, Mechiruji t- Puchirushiriru, tri Ci-Ce alkyl silyl group such cowpea of triisopropoxide building silyl, diphenyl methyl silyl, is three substituents on the selected group from di Hue El Petit Resid reels and single C 6 alkyl "Silinoles" such as silyl group; benzinole, phenetinole, 3-phenenolepropinole, ⁇ -naphthyl / remethinole, S-naphthylmethyl, diphenylmethyl, triphenylmethyl, 1-naphthyldiphenylmethyl, 9-anthrylmethyl from 1-3 Ariru been Ci one C s alkyl group substituted with groups such as, 4 _ methylbenzyl, 2, 4, 6-trimethyl-benzyl, 3, 4, 5-trimethyl-benzyl, 4-main Tokishibenjiru, 4-Met
  • the “protecting group” of the “optionally protected hydroxyl group” in the definition of R la and R 2a is not particularly limited as long as it is a hydroxyl protecting group used in the field of synthetic organic chemistry.
  • it has the same meaning as the above-mentioned “general protecting group for an ester of a hydroxyl group”, and is preferably an aliphatic acyl, an aromatic acyl or a silyl, and most preferably a silyl. is there.
  • Step A1 is a step of producing a compound having the general formula (V), and using an acid as a catalyst in the presence or absence (preferably in the presence) of an inert solvent to obtain a compound of the general formula (III)
  • the reaction is carried out by reacting a compound having the general formula (IV) with a compound having the general formula (IV).
  • the inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • aromatic hydrocarbons such as benzene, toluene, and xylene.
  • Aliphatic hydrocarbons such as hexane, heptane, rig-mouth, petroleum ether, ethers such as dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethinol ether
  • aromatic hydrocarbons such as benzene, toluene, and xylene.
  • Aliphatic hydrocarbons such as hexane, heptane, rig-mouth, petroleum ether, ethers such as dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethinol
  • the acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a normal reaction, and examples thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid.
  • Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid.
  • Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid.
  • Inorganic acids acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, organic acids such as trifluoroacetic acid, trifluoromethanesulfonic acid, etc.brensted acid, zinc chloride, tin tetrachloride, and polon trifluoro
  • It is a Lewis acid such as lid or boron tripromide, or an
  • the reaction temperature varies depending on the starting compound, the inert solvent used, and the type of acid. Usually, it is 0 ° C. to 200 ° C. (preferably, 20 ° C. to 150 ° C.).
  • the reaction time varies depending on the starting compound, the inert solvent used, the type of acid, and the reaction temperature, but is usually 15 minutes to 48 hours (preferably 30 minutes to 12 hours).
  • the reaction can be promoted by using a dehydration device such as Dean-Stark.
  • the target compound (V) of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. It is obtained by washing with water or the like, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent.
  • Step A2 is a process for producing a compound having the general formula (VII), and converting the compound (V) into a compound having the general formula (VI) or an acid addition salt thereof in an inert solvent in the presence of a base.
  • a base for example, mineral salts such as hydrochloride, nitrate, sulfate.
  • the inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, and examples thereof include hexane, heptane, lignin, and petroleum ether.
  • the base used in the above reaction is not particularly limited as long as it is used as a base in a usual reaction.
  • alkali metal iodides such as lithium iodide, sodium iodide, and potassium iodide
  • alkali metal carbonates such as lithium carbonate, sodium carbonate, carbonated lime, lithium bicarbonate, sodium hydrogen carbonate, alkali metal bicarbonates such as lithium hydrogen carbonate, lithium hydride, sodium hydride, hydrogen
  • alkali metal hydrides such as potassium fluoride, or inorganic bases such as lithium metal fluoride, sodium fluoride, and alkali metal fluorides such as lithium fluoride, or ⁇ ⁇ ⁇ -methylmorpholine , Triethylamine, Tripropylamine, Triptylamine, Disopropylethylamine, Dish mouth Xylamine, ⁇ -methylbiperidine, 4-pyrrolidinopyridine, picoline, 4- (, ⁇ -dimethylamino
  • the reaction temperature varies depending on the type of the starting compound, the inert solvent used and the base, but is usually from 0 ° C to 250 ° C (preferably from 70 ° C to 170 ° C).
  • the reaction time varies depending on the starting compound, the inert solvent used, the type of base and the reaction temperature, but is usually from 15 minutes to 48 hours (preferably from 10 hours to 24 hours).
  • the target compound (VII) of the reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off.
  • Step A3 is a step of producing a compound having the general formula (I), and if necessary, removing the amino- and / or hydroxyl-protecting groups in R la and R 2a of compound (VII). Done.
  • the inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycolone resin methinolate ether. Such ethers are preferred.
  • the reaction temperature and the reaction time are not particularly limited, but usually, the reaction temperature is 0 ° C ⁇ 50 ° C And the reaction time is 10 hours to 18 hours.
  • the protecting group for the amino group is an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group or a substituted methylene group forming a Schiff base, an acid or a base is used in the presence of an aqueous solvent. It can be removed by processing.
  • the acid used in the above reaction is not particularly limited as long as it is a commonly used acid and does not inhibit the reaction.
  • examples thereof include hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, An inorganic acid such as nitric acid, preferably hydrochloric acid.
  • the base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound, but is preferably an alkali metal carbonate such as lithium carbonate, sodium carbonate, or carbonated lime. Salts; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and hydroxylating power; Metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, and potassium t-butoxide; ammonia water And ammonia such as concentrated ammonia air methanol.
  • the solvent used in the above reaction is not particularly limited as long as it is a solvent used in a usual hydrolysis reaction.
  • the reaction temperature and reaction time vary depending on the starting compound, solvent and acid or base used, and are not particularly limited.However, in order to suppress a side reaction, the reaction temperature is usually from 0 ° C to 150 ° C. ° C, and the reaction time is 1 hour to 10 hours.
  • the protective group is usually brought into contact with a reducing agent in an inert solvent (preferably by catalytic reduction at room temperature under a catalyst at room temperature). ) A method of removing or using an oxidizing agent is preferred.
  • the inert solvent used for the removal by catalytic reduction is not particularly limited as long as it is inert to the reaction.
  • the inert solvent examples include aliphatic carbons such as hexane, heptane, lignin, and petroleum ether. Hydrogens; Aromatic hydrocarbons such as toluene, benzene, xylene; Esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; Getyl ether, diisopropyl ether, tetrahydrofuran, dioxane , Dimethoxetane, ethers such as diethyleneglycol monomethyl dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-ptanol, isobutanol, t-butanol, isomeryl alcohol, styrene glycolone, glycerin , Oktananore, Si Alcohols such as hexanolone, methinolace
  • the catalyst used for the removal by catalytic reduction is not particularly limited as long as it is usually used for the catalytic reduction reaction, but is preferably palladium monocarbon, Raney-Eckel, platinum oxide, platinum Black, rhodium aluminum monoxide, trifenyl'phosphine rhodium monochloride, and palladium monosulfate barrier are used.
  • the pressure is not particularly limited, but it is usually 1 to 10 atm.
  • reaction temperature and reaction time vary depending on the starting compound, catalyst, inert solvent, etc., but usually the reaction temperature is 0 ° C to 100 ° C, and the reaction time is 5 minutes to 24 hours. is there.
  • the inert solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but is preferably a water-containing organic solvent.
  • organic solvents include, for example, chloroform, dichloromethane, 1,2-dichloroethane, halogenated carbons such as carbon tetrachloride; -tolyls such as acetonitrile, getyl ether, diisopropyl Ethers such as ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether; ketones such as acetone; formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide And sulfoxides such as dimethyl sulfoxide; sulfolane; preferably, halogenated hydrocarbons, ethers or sulfoxides (particularly preferably, halogenated hydrocarbons or sulfoxides). ).
  • the oxidizing agent to be used is not particularly limited as long as it is a compound used for oxidation, but is preferably potassium persulfate, sodium persulfate, ammonium cellite nitrate (CAN), 2, 3- Dichloro-5,6-dicyano-p-benzoquinone (DDQ) is used.
  • reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but usually the reaction temperature is 0 ° C to 150 ° C, and the reaction time is 10 minutes to 24 hours. .
  • the protecting group for an amino group is an aralkyl
  • the protecting group can be removed using an acid.
  • the acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a usual reaction.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid Brensted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfonic acid, trifluoroacetic acid, and organic acids such as trifluoromethanesulfonic acid; zinc chloride, tin tetrachloride, boron trichloride Lewis acids such as lid, poltontrifluoride and boron tripromide; acidic ion-exchange resins; preferably inorganic or organic acids (particularly preferred are hydrochloric acid, acetic acid or trifluoroacetic acid). .
  • the inert solvent used in the above-mentioned reaction is not particularly limited as long as it is inert to the present reaction.
  • examples include, but are not limited to, aliphatic hydrocarbons, such as hexane, heptane, lignin, petroleum ether; aromatic hydrocarbons, such as benzene, toluene, xylene; chloropho / rem, dichloromethane, 1,2 —Halogenated hydrocarbons, such as dichloroethane and tetrahydrocarbon; Estenoles, such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; jetinore ethereol, disopropinoleatenore Ethers such as, tetrahydrofuran, dioxane, dimethoxetane, and methylenglycol / ledimethylether; methanol, ethanol
  • the reaction temperature varies depending on the starting compound, the acid used, the solvent and the like, but is usually ⁇ 20. C to the boiling point (preferably 0 ° C. to 100 ° C.).
  • the reaction time varies depending on the starting compound, the acid used, the inert solvent, the reaction temperature and the like, but is usually from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours).
  • the protecting group of the amino group is an alkenyloxycarbel
  • the protecting group of the amino group is substituted with the above-mentioned aliphatic acyl, aromatic acyl, alkoxycarbonyl or Schiff base. It is carried out by treating with a base in the same manner as the conditions for the removal reaction in the case of the methylene group that has been removed.
  • aryloxycarbonyl group in particular, a method of removing it using palladium, and triphenylphosphine or nickel tetracarbonyl is simple and can be carried out with few side reactions.
  • a silyl group When a silyl group is used as a protecting group for a hydroxyl group, it usually produces fluorine anions such as tetrabutylammonium fluoride, hydrofluoric acid, hydropyridine monopyridine, and potassium fluoride.
  • Treatment with a compound or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoro It can be removed by treating with an organic acid such as acetic acid or trifluoromethanesulfonic acid.
  • a compound or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoro It can be removed by treating with an organic acid such as acetic acid or trifluoromethanesulfonic acid.
  • reaction when removing with fluorine ion, the reaction may be accelerated by adding an organic acid such as formic acid, acetic acid or propionic acid.
  • organic acid such as formic acid, acetic acid or propionic acid.
  • the inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.
  • the solvent is dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, diethylene glycol dimethyl ether.
  • Ethers such as acetonitrile and nitriles such as isopti nitrile; organic acids such as acetic acid; water; mixed solvents of the above solvents;
  • reaction temperature and reaction time vary depending on the starting compound, catalyst, inert solvent, etc., but usually the reaction temperature is from 0 ° C to 100 ° C (preferably from 10 ° C to 50 ° C). ), And the reaction time is 1 hour to 24 hours.
  • the protecting group for the hydroxyl group is an aralkyl group or an aralkyloxycarbol group
  • the protecting group is usually brought into contact with a reducing agent in an inert solvent (preferably, at room temperature under a catalyst at room temperature).
  • an inert solvent preferably, at room temperature under a catalyst at room temperature.
  • a method of removing or using an acid reagent is suitable.
  • the inert solvent used for the removal by catalytic reduction is not particularly limited as long as it does not participate in this reaction.
  • Aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; toluene Aromatic hydrocarbons such as benzene, xylene; esters such as ethyl acetate, propyl acetate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, diethylene glycol dimethyl ether; Methanol, ethanol, ⁇ B Nono 0 Nonore, isopropanol, n- butanol one Honoré, alcohols such as isobutanol one Honoré, t-butanol one Le, I Soa mill alcohol, diethylene glycol, glycerin, Okutanoru, hexanol consequent opening, Mechiruse port cellosolve; formamide Amides such as dimethinolephonoremamide, dimethinoleacetamide, N-
  • the catalyst used for the removal by catalytic reduction is not particularly limited as long as it is usually used for the catalytic reduction reaction.
  • the catalyst used for the removal by catalytic reduction is not particularly limited as long as it is usually used for the catalytic reduction reaction.
  • palladium-carbon palladium-black, Raney-Keckel, platinum oxide, platinum Black, rhodium aluminum monoxide, triphene / lephosphine rhodium monochloride, palladium monosulfate, and preferably palladium carbon.
  • the pressure is not particularly limited, but it is usually 1 to 10 atm.
  • reaction temperature and reaction time vary depending on the starting compound, catalyst, inert solvent, etc., but usually the reaction temperature is from 0 ° C to 100 ° C (preferably from 20 ° C to 70 ° C). ), And the reaction time is 5 minutes to 48 hours (preferably 1 hour to 24 hours).
  • the inert solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but is preferably a water-containing organic solvent.
  • organic solvents include ketones such as acetone; halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride; nitriles such as acetoetrile; getyl ether; Ethers such as drofuran and dioxane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide; and sulfoxides such as dimethylsulfoxide.
  • ketones such as acetone
  • halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride
  • nitriles such as acetoetrile
  • getyl ether Ethers such as drofuran and dioxane
  • amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide
  • sulfoxides such as dimethylsulfoxide.
  • the oxidizing agent to be used is not particularly limited as long as it is a compound used for oxidation, but is preferably potassium persulfate, sodium persulfate, or ammonium cell sodium tray. (CAN) and 2,3-dichloro-5,6-dicyano_ ⁇ -benzoquinone (DDQ) are used.
  • reaction temperature and reaction time vary depending on the starting compound, catalyst, inert solvent, etc., but usually the reaction temperature is 0 ° C to 150 ° C, and the reaction time is 10 minutes to 24 hours. is there.
  • the reaction temperature is 0 ° C to 150 ° C
  • the reaction time is 10 minutes to 24 hours. is there.
  • liquid ammonia or in methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol isoamyl alcohol, diethylene glycol, glycerin, cytano mono, cyclohexanol, and methyl sorbanol In such alcohols, it can also be removed by allowing alkali metals such as metallic lithium and metallic sodium to act at 178 ° C to 0 ° C.
  • an alkylsilyl halide such as aluminum chloride sodium iodide or trimethylsilyl iodide in an inert solvent.
  • the inert solvent used is not particularly limited as long as it does not take part in the reaction, but is preferably a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride; and acetonitrile. Such nitriles; mixed solvents of the above solvents;
  • reaction temperature and the reaction time vary depending on the starting compound, the inert solvent and the like, but usually the reaction temperature is 0 ° C to 50 ° C, and the reaction time is 5 minutes to 72 hours.
  • reaction substrate has a sulfur atom
  • aluminum chloride sodium iodide is used.
  • the protecting group for a hydroxyl group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it is removed by treating with a base in an inert solvent.
  • the base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound.
  • alkali metal carbonates such as lithium carbonate, sodium carbonate and carbon dioxide
  • Lithium hydrogen, sodium hydrogen carbonate, Alkali metal bicarbonates such as lithium hydrogen carbonate
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide
  • Metal alkoxides such as rimu-t-butoxide
  • ammonia such as aqueous ammonia and concentrated ammonium hydroxide
  • alkali metal hydroxides, metal alkoxides or ammonia particularly preferred.
  • the inert solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and examples thereof include getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethyleneglycol monoresinmetholone ether, and the like.
  • Ethers such as methanol, ethanol, n-propanol, isopropanol, n-ptanol, isoptanol, t-butanol, isoamyl alcohol, diethylene glycolone, glycerin, octanolone, cyclohexanol, methylhexanol Preferred are such alcohols; water; and mixed solvents of the above solvents.
  • the reaction temperature and reaction time vary depending on the starting compound, the base used, the inert solvent, and the like, and are not particularly limited. The temperature was 150 ° C., and the reaction time was 1 hour to 10 hours.
  • the acid is usually added in an inert solvent. It is removed by treating with.
  • the acid to be used is not particularly limited as long as it is usually used as Brenstead acid or Lewis acid, and is preferably hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid; or acetic acid or trifluoromethane.
  • Acetic acid, methanesulfonic acid, p-toluenesulfonic acid Brenstead acids such as organic acids such as: Lewis acids such as boron trifluoride, but strongly acidic cation exchange resins such as Dowex 50 W can also be used.
  • the inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.
  • Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; ethylethyl formate, ethylethyl acetate Esters such as propyl acetate, butyl acetate, and getyl carbonate; ethers such as getyl ether, disopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, Alcohols such as isobutanol, t-butanol,
  • the reaction temperature and the reaction time vary depending on the starting compound, the acid used, the inert solvent and the like, but usually the reaction temperature is from -10 ° C to 200 ° C (preferably from 0. The reaction time is 5 minutes to 48 hours (preferably 30 minutes to 10 hours).
  • the hydroxyl-protecting group is an alkoxycarbonyl group
  • the removal reaction is usually performed when the hydroxyl-protecting group is an aliphatic acyl, an aromatic acyl or an alkoxycarbol. It is achieved by treating with a base in the same manner as in the conditions. In the case of aryloxycarbel groups, palladium and triphenylphospho are particularly preferred.
  • the removal of the protecting group for the amino group and / or the hydroxyl group can be carried out in any order, and the desired removal reaction can be sequentially performed.
  • the target compound (I) of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added. It is obtained by separating, washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent.
  • Step A4 is a step of producing a compound having the general formula (II), and converting the compound (VII) into a compound of the general formula (VIII) in the presence or absence (preferably, in the presence) of an inert solvent. )), And if necessary, removing the protecting group for the amino group and Z or the hydroxyl group in R la and R 2a .
  • the inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.
  • examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; Aromatic hydrocarbons such as benzene, toluene, and xylene; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; acetone, methylethylketone, and methylisobutylketone And ketones such as isophorone and cyclohexanone; nitriles such as acetotrinole and isobutylonitrile, and are preferably aromatic hydrocarbons.
  • the reaction temperature varies depending on the starting compound, the inert solvent used, and the type of acid. Always o ° c to 200. c (preferably ⁇ ° ⁇ to i oo ° c).
  • the reaction time varies depending on the starting compound, the inert solvent used, the type of acid, and the reaction temperature, but is usually 10 minutes to 48 hours (preferably 30 minutes to 24 hours).
  • the method of removing the amino group and the protecting group of Z or the hydroxyl group in R la and R 2a, which is performed as desired, is the same as the method of removing the protecting group of the amino group and / or the hydroxyl group in Step A3 of Method A described above.
  • the target compound (II) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture. If necessary, the desired compound obtained can be combined with a conventional method, for example, recrystallization, reprecipitation, or the like, which is usually used for the separation and purification of organic compounds. It can be separated and purified by elution.
  • the starting compounds (II1), (IV), (VI) and (VIII) are easily produced according to known compounds or known methods or methods analogous thereto. For example, compound (III) can be produced according to the method described in J. Med. Chem. 23, 149 (1980) and the like.
  • Method B is a method for producing compound (VI).
  • R 1 Represents a lower alkoxycarbonyl group (a group in which the above-mentioned "lower alkoxy group” is bonded to a carbonyl group, such as methoxycarbon, ethoxycarbinole, propoxycanoleboninole, isopropoxycanoleboninole, butoxycanolepo Binore, isobutoxy force / report, s-butoxycarbel, t-butoxycarbonyl, ⁇ Toxoxy canoleboenole, isopentoxy canola benole, 2-methinolebutoxy canola repo-norre, neopentoxycarbonyl, hexyloxy canola reole group, preferably C 1 —C 4 It is an alkoxycarboyl group, most preferably a t-butoxycarbonyl group. ).
  • Step B1 is a step of producing compound (VI), which is carried out by treating a compound having
  • the inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; benzene , Toluene, xylene; aromatic hydrocarbons; chlorophonolem, dichloromethane, 1,2-dichloroethane, halogenated hydrocarbons, such as carbon tetrachloride; methyl acetate, ethyl ethyl ether, propyl nitrate, butyl ethyl acetate Estenoles such as getyl carbonate; ethers such as jetinole ether, diisopropinole ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol;
  • the acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a normal reaction, and examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid.
  • Acids Prensted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, and organic acids such as trifluoromethanesulfonic acid; zinc chloride, tin tetrachloride, boron trichloride Lid, A Lewis acid such as boron trifluoride or boron tribromide; an acidic ion-exchange resin; preferably an inorganic acid or an organic acid (particularly preferably, hydrochloric acid, acetic acid or trifluoroacetic acid).
  • acetic acid formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, and organic acids such as trifluoromethanesulfonic acid
  • zinc chloride tin
  • the reaction temperature varies depending on the starting compound, the acid used, the inert solvent and the like, but is usually from ⁇ 20 ° C. to the boiling point (preferably from 0 ° C. to 100 ° C.).
  • the reaction time varies depending on the starting compound, the acid used, the inert solvent, the reaction temperature and the like, and is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours).
  • the target compound (VI) of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off.
  • the obtained target compound can be combined with a conventional method, such as recrystallization, reprecipitation, etc., which is commonly used for the separation and purification of organic compounds, as appropriate, and by applying chromatography to a suitable eluent. Can be separated and purified.
  • the starting compound (IX) is a known compound or is easily produced according to a known method or a method similar thereto.
  • compound (IX) can be produced according to the method described in J. Med. Chem., 38, 3772-3779 (1995) and the like.
  • Method C is a method for producing compound (III).
  • the CI step is a step of producing the compound (III), which is performed using a base, a metal or an organometallic reagent in the presence or absence (preferably in the presence) of an inert solvent. It is carried out by reacting a compound having the formula (X) with a compound having the general formula (XI).
  • the inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to a certain extent.
  • aromatic solvents such as benzene, toluene, and xylene
  • Aliphatic hydrocarbons such as petroleum ether, dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycolone resin Ethers such as ter, preferably ethers.
  • the base used in the above reaction is not particularly limited as long as it is used as a base in a usual reaction, but is preferably a metal alkoxide such as potassium rhumbutoxide, sodium ethoxide, and sodium methoxide.
  • the metal used in the above reaction is not particularly limited as long as it is a metal used in a normal reaction, but is preferably lithium, potassium or sodium.
  • the organometallic reagent used in the above reaction is not particularly limited as long as it is used as an organometallic reagent in a normal reaction.
  • organometallic reagent used as an organometallic reagent in a normal reaction.
  • the reagent used in this step is preferably an organometallic reagent.
  • the reaction temperature varies depending on the starting compound, the inert solvent used and the type of the reagent, but is usually from 120 ° C to room temperature (preferably from 100 ° C to 0 °).
  • the reaction time varies depending on the starting compound, the inert solvent used, the type of reagent, and the reaction temperature, but is usually 5 minutes to 48 hours (preferably 5 minutes to 1 hour).
  • the target compound (III) of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound.
  • the target compound obtained c obtained by distilling off the solvent if necessary, a conventional method, for example, Separation and purification can be performed by appropriately combining commonly used methods for separation and purification of organic compounds, such as recrystallization and reprecipitation, by applying chromatography and eluting with an appropriate eluent.
  • Method D is a method of synthesizing compound (V) separately from method A.
  • Step D1 is a step for producing a compound having the general formula (XII), which is carried out by converting a hydroxyl group of compound (III) into a functional group which is eliminated as a nucleophilic residue.
  • the method of converting a hydroxyl group into a functional group can be carried out as follows by a method generally known in the art of organic synthetic chemistry, which depends on the desired functional group.
  • Target functional group power In the case of a halogen atom, the reaction is carried out by reacting compound (III) with a halogenating reagent in the presence or absence (preferably in the presence) of an inert solvent.
  • the inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • aromatic hydrocarbons such as benzene, toluene and xylene.
  • Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene; organic acids such as acetic acid, formic acid, and propionic acid; formamide; Amides such as, ⁇ -dimethylformamide and ⁇ , ⁇ -dimethylinoleacetamide; water; preferably, aromatic hydrocarbons, halogenated hydrocarbons or water.
  • the halogenating reagent used in the above reaction is not particularly limited as long as it is a halogenating reagent used in a usual reaction.
  • examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid and hydroiodic acid, and bromine.
  • Halogen molecules such as chlorine, chlorine; phosphorus reagents such as phosphorus trichloride, phosphorus tribromide, phosphorus pentabromide, phosphorus pentachloride, and phosphorus oxychloride; thiol chloride, thiol bromide, and toluene Sulfinic acids such as sulfonic acid oxalate; sulfonic acid reagents; and preferably phosphorus reagents.
  • the reaction temperature varies depending on the type of the starting compound, the inert solvent used, and the type of halogenating reagent, but it is usually from 180 ° C to 200 ° C (preferably from 78 ° C to 100 ° C). C).
  • the reaction time varies depending on the starting compound, the inert solvent used, the halogenating reagent and the reaction temperature, but is usually 5 minutes to 48 hours (preferably 15 minutes to 3 hours).
  • the compound is used in the presence or absence (preferably in the presence) of an inert solvent
  • This reaction can be carried out by reacting (III) with the corresponding acid halide or acid anhydride using a base.
  • the starting material is there is no particular limitation as long as it can be dissolved to a certain degree.
  • aromatic hydrocarbons such as benzene, toluene, and xylene, methylene chloride, chloroform, carbon tetrachloride, dichloromethane, and 1,2.
  • Halogenated hydrocarbons such as dichloroethane, dichlorobenzene, benzene, hexane, heptane, lignin, aliphatic hydrocarbons, such as petroleum ether, getylether, diisopropyl ether, tetrahydrofuran, dioxan Ethers such as dimethoxetane and diethylene glycol dimethyl ether; organic bases such as pyridine and triethylamine; amides such as formamide, ⁇ , ⁇ -dimethylformamide and ⁇ , ⁇ -dimethylacetamide. And are preferably haptic hydrocarbons or organic bases.
  • the base used in the above reaction is not particularly limited as long as it is a commonly used base.
  • the base include alkali metal hydrides such as sodium hydride and lithium hydride, sodium hydroxide, and potassium hydroxide.
  • Metal hydroxides such as lithium carbonate, carbonated lime, metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, pyridine, triethylamine, triisopropylamine, diisopyrupyramine, dicyclo Organic amines such as hexylamine, ⁇ -methylpiperidine, picoline, 4-dimethylaminopyridine, 1,4-diazabicyclo [4.3.0] octane, 1,8-diazabicyclo mouth [5.4.0] —7-ndecene Yes, preferably organic amines.
  • the acid halide or acid anhydride used in the above reaction is not particularly limited as long as it is a commonly used acid halide or acid anhydride.
  • Examples thereof include fatty acid halides such as acetyl chloride, acetyl acetate, and propionyl chloride.
  • the reaction temperature depends on the starting compound, the inert solvent used, the acid halide, and the acid anhydride. It varies depending on the type, (preferably - 7 8 ° C to room temperature) usually one 7 8 ° C to 1 0 0 ° C Mel in.
  • the reaction time varies depending on the starting compound, the inert solvent used, the acid halide, the acid anhydride, and the reaction temperature.
  • the reaction time is usually 5 minutes to 48 hours (preferably 15 minutes to 3 hours).
  • the target compound (XII) of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound.
  • an immiscible organic solvent such as water and ethyl acetate
  • the solvent is distilled off.
  • the desired compound obtained can be combined with a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds. Can be separated and purified.
  • Step D2 is a step of producing compound (V).
  • Compound (XII) is converted to compound (IV) in the presence or absence (preferably in the presence) of an inert solvent using an acid as a catalyst.
  • the reaction is carried out by reacting the compound with
  • the inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to a certain extent.
  • aromatic hydrocarbons such as benzene, toluene, and xylene.
  • Aliphatic hydrocarbons such as hexane, heptane, rig-mouth, petroleum ether, ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethyleneglycol / resimetinolete-ter And preferably ethers.
  • the acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a normal reaction, and examples thereof include the same acids as those used in the above-mentioned method A, step A1.
  • it is an organic acid.
  • the reaction temperature varies depending on the type of the starting compound, the inert solvent used and the acid, but is usually from 0 ° C to 200 ° C (preferably from 20 ° C to 150 ° C).
  • the reaction time varies depending on the starting compound, the inert solvent used, the acid and the reaction temperature, but is usually from 5 minutes to 48 hours (preferably from 30 minutes to 12 hours).
  • the reaction may be accelerated by using a dehydrator such as Dean-Stark.
  • the target compound (V) of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent.
  • the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for the separation and purification of organic compounds, applying chromatography, and using an appropriate eluent. Separation and purification can be achieved by elution.
  • Method E is a method in which compound (VI la) in which n is 3 in compound (VII) is produced separately from method A.
  • R la , R 2a , Q and Y have the same meanings as described above, and R 11 is a lower alkyl group, a halogeno lower alkyl group or phenyl, ⁇ -tolyl, p-nitro'phenyl.
  • a lower alkyl group such as phenyl; or an aryl group which may be substituted by 1 to 3 nitro groups, and is preferably a lower alkyl group.
  • Step E1 is a process for producing a compound having the general formula (XIV), and using a base in the presence or absence (preferably in the presence) of an inert solvent, the compound (III) It is carried out by reacting a compound having the formula (XIII).
  • the inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • aromatic hydrocarbons such as benzene, toluene, and xylene.
  • aromatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, hydrogen, hydrogen, hexane, heptane, lignin, petroleum ether
  • Aliphatic hydrocarbons, ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxan, dimethoxetane, diethylene glycol dimethyl ether
  • amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide, preferably amides or ethers. It is.
  • the base used in the above reaction is not particularly limited as long as it is a base used in a usual reaction.
  • sodium hydride, metal hydride such as hydrogen hydride, sodium metal hydroxide, sodium hydroxide
  • Metal hydroxides such as water-soluble hydroxides, metal carbonates such as lithium carbonate and lithium carbonate, metal bicarbonates such as sodium hydrogen carbonate and hydrogen carbonate, pyridine, triethylamine, triisopropylamine , Diso: ° mouth pyrethylamine, dicyclohexylamine, N-methylpiperidine, picoline, 4-dimethylaminopyridine, 1,4-diazabicyclo [4.3.0] octane, 1,8-diazabicyclo [5.4.0] — Organic amines such as 7-indene, preferably organic amines or metal hydrides.
  • the reaction temperature varies depending on the type of the starting compound, the inert solvent used and the base, but is usually from 78 ° C to 100 ° C (preferably from 0 ° C to room temperature).
  • the reaction time varies depending on the starting compound, the inert solvent used, the type of base and the reaction temperature, but is usually from 5 minutes to 48 hours (preferably from 15 minutes to 1 hour).
  • the target compound (XIV) of the reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off.
  • Step E2 is a step for producing a compound having the general formula (XV), ⁇
  • compound (XIV) is borated using a borating reagent, followed by oxidative treatment.
  • the inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • aromatic hydrocarbons such as benzene, toluene, and xylene. Hydrogens, methylene chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, etc., hydrogenated hydrocarbons, hexane, heptane, lignin, aliphatics such as petroleum ether Hydrocarbons, ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glyco-1, / resin methinole and tenor, and preferably ethers.
  • the boration reagent used in the above reaction is not particularly limited as long as it is used as a boration reagent in a normal reaction.
  • borane-dimethylsulfide complex borane-tetrahydrofuran complex
  • 9-borabicyclo 3.3. 1] a borating reagent such as nonane (9-BBN), and preferably 9_borabicyclo [3.3.1] nonane (9-BBN).
  • the oxidative treatment of the above reaction can be carried out by a method known in the art of ordinary organic synthesis. For example, as described in Org. Syn: Coll. Vol. VII.259, sodium hydrogen peroxide Can be performed.
  • the reaction temperature varies depending on the starting compound, the inert solvent used, and the borating reagent, but is usually from 180 ° C to 100 ° C (preferably from 0 ° C to room temperature).
  • the reaction time varies depending on the starting compound, the inert solvent used, the boration reagent and the reaction temperature, but is usually from 5 minutes to 48 hours (preferably from 15 minutes to 24 hours).
  • the target compound (XV) of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. After washing with water, anhydrous magnesium sulfate, anhydrous sodium sulfate And dried over anhydrous sodium hydrogen carbonate, and then the solvent is distilled off.
  • Step E3 is a step for producing a compound having the general formula (XVII), and in the presence or absence (preferably in the presence) of an inert solvent, compound (XV) in the presence of a base, It is carried out by reacting with a compound having the formula (XVI).
  • the inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • aromatic solvents such as benzene, toluene, and xylene Hydrogens, methylene chloride, chloroform, carbon tetrachloride, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, dichlorobenzene, hexane, heptane, lignin, petroleum ether Aliphatic hydrocarbons, ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, ethers such as diethylene glycol dimethyl ether, organic bases such as pyridine, triethylamine, formamide, ⁇ , ⁇ -dimethyl Such as formamide, ⁇ , ⁇ -dimethylacetamide A Mi earth, preferably a C port Gen hydrocarbon
  • the base used in the above reaction is not particularly limited as long as it is a base used in a usual reaction, and examples thereof include the same bases as those in the above-mentioned Method 1st step, preferably an organic amine. kind.
  • the reaction temperature varies depending on the starting compound, the inert solvent used, and the type of compound (XVI), but is usually from 78 ° C to 100 ° C (preferably from 0 ° C to room temperature). It is.
  • the reaction time varies depending on the starting compound, the inert solvent used, the compound (XV 1) and the reaction temperature, but is usually from 5 minutes to 48 hours (preferably from 15 minutes to 3 hours).
  • the target compound (XVII) of the reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration.
  • an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is added. It is obtained by separating, washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the target compound obtained may be appropriately combined with a conventional method, for example, recrystallization, reprecipitation, or the like, which is commonly used for the separation and purification of organic compounds, and then applied to a mouth chromatography to obtain an appropriate compound. Separation and purification can be performed by eluting with an eluent.
  • Step E4 is a process for producing a compound having the compound (Vila).
  • the compound (XVII) is reacted with the compound (VI) or an acid addition salt thereof (for example, hydrochloric acid) in an inert solvent in the presence of a base.
  • This step can be carried out in the same manner as in the above-mentioned Method A, Step A2.
  • the starting compounds (X), (X1), (XIII) and (XVI) are known compounds or are easily produced according to known methods or methods similar thereto. [For example, J. Org. Chem., 6, 489 (1941); Chem. Ber., 1199 (1989), etc.] Effect of the Invention
  • the benzhydrinole derivative having the above general formula (I) or (II), its pharmaceutically acceptable salt, its ester or other derivative according to the present invention is an excellent IL-4 and / or IL-10 derivative.
  • Th1 selective immunosuppressant eg, rheumatoid arthritis, which is a chronic inflammatory disease, fl-vessel specific autoimmune disease (eg, diabetes, multiple sclerosis, inflammatory bowel disease (eg, , Ulcerative colitis, Crohn's disease), glomerulonephritis, hepatitis, liver injury, autoimmune hemolytic anemia, leukopenia, thrombocytopenia, allergic encephalitis, demyelinating disease, Hashimoto's thyroiditis, Addison's disease, epithelium Hypothyroidism, pernicious anemia, localized gyrus Enteritis, atrophic gastritis, gluten intolerant enteropathy, Good Pasteur syndrome, streptococcal post-infection
  • the substance has high 7k solubility, high oral absorption, rapid onset of action, high transferability to target organs or cells, low transferability in the brain, side effects (antihistamine action, anti-serotonin action) , Low anti-dopamine action, wide safety margin (difference in efficacy and toxicity), and excellent pharmacokinetics (long plasma half-life, large AUC, low tissue accumulation, etc.) ).
  • a pharmaceutically acceptable salt thereof, estenole or other derivative thereof is used as the therapeutic or prophylactic agent, as such or mixed with appropriate pharmacologically acceptable excipients, diluents, etc., for example, orally, such as tablets, capsules, granules, powders or syrups, or injections or suppositories, etc. Can be administered parenterally.
  • excipients eg, lactose, white bran, glucose, mannitol, sorbitol such as sorbitol; corn starch, potato starch, starch derivatives such as ⁇ -starch, dextrin; Organic excipients such as cellulose gum; arabia gum; dextran; pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate magnesium; calcium hydrogen phosphate; Inorganic excipients such as phosphates, carbonates such as calcium carbonate, sulfates such as calcium sulfate, etc.), lubricants (eg, stearic acid, calcium stearate, mag stearate) Metal stearates such as nesium; talc; colloidal silica; .
  • excipients eg, lactose, white bran, glucose, mannitol, sorbitol such as sorbitol; corn
  • Gum, Gay waxes such as ⁇ ; boric acid; sulfates such as sodium sulfate; adipic acid Dali Chole; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; Can be mentioned.
  • Binders for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients
  • disintegrants for example, cellulose derivatives such as low-substituted hydroxypropylcellulose, phenolic methoxyphenol resin, phenolic phenolic cellulose, internally crosslinked carboxymethylcellulose sodium; Chemically modified starch and celluloses such as xymethyl starch, carboxymethyl starch sodium, cross-linked polybierpi-olidon, etc.), stabilizers (para-benzoic acid ester such as methylparaben and propylparaben).
  • Chloroptanol benzilano Alcohols such as cole and fueruetinole alcohol; benzalco-dum chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.
  • Flavoring agents e.g., commonly used sweeteners, sour agents, flavors, etc.
  • diluents can be produced by known methods.
  • the dosage varies depending on symptoms, age, etc.For oral administration, the lower limit is 0.1 mg (preferably 0.5 mg) and the upper limit is 4000 mg (preferably 400 mg) per dose per day.
  • the lower limit of 0.1 mg (preferably 0.05 mg) and the upper limit of 500 mg (preferably 300 mg) per adult may be 1 to 6 times a day for adults. It is desirable to administer according to. BEST MODE FOR CARRYING OUT THE INVENTION
  • Example 1 Example 1
  • the obtained compound was dissolved in ethyl acetate (10 ml), oxalic acid (41 mg, 0.46 ol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (200 mg, 90%).
  • the obtained compound was dissolved in ethyl acetate, oxalic acid (55 mg, 0.61 mmol) was added, and the mixture was allowed to stand at room temperature for one hour. The precipitated crystals were collected by filtration to give the title compound as white crystals (233 mg, 77%).
  • the obtained compound was dissolved in ethyl acetate, oxalic acid (43 mg, 0.48 ramol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration, 170 mg (7 2%) of the title compound as white crystals was obtained.
  • the obtained compound was dissolved in ethyl acetate, oxalic acid (25 mg, 0.28 mol) was added, and the mixture was allowed to stand at room temperature for one hour. The precipitated crystals were collected by filtration to give the title compound as white crystals (110 mg, 74%).
  • Example (12a) The compound obtained in Example (12a) was dissolved in 10 ml of ethyl acetate, and oxalic acid was added.
  • Example (13a) The compound obtained in Example (13a) was dissolved in 10 ml of ethyl acetate, and oxalic acid was added.
  • Example (14a) The compound obtained in Example (14a) was rapidly dissolved in 10 ml of ethyl acetate, and oxalic acid was added.
  • Example 15a The compound obtained in Example (15a) was dissolved in 10 ml of ethyl acetate, and oxalic acid was added. 91 mg (1.01 nimol) was added, and the mixture was allowed to stand at room temperature. The precipitated crystals were collected by filtration to give 322 mg (60%) of the title compound as white crystals.
  • Example (17b) The compound obtained in Example (17b) was dissolved in ethyl acetate (2 ml), oxalic acid (46 mg, 0.51 nimol) was added, and the mixture was allowed to stand at room temperature at room temperature. The precipitated crystals were collected by filtration to give 210 mg (79%) of the title compound as white crystals.
  • Example (18a) The compound obtained in Example (18a) was dissolved in 2 ml of ethyl acetate, and oxalic acid was added.
  • Example (19a) The compound obtained in Example (19a) was dissolved in ethyl acetate, and oxalic acid
  • Example (20a) The compound obtained in Example (20a) was dissolved in ethyl acetate, oxalic acid (46 mg, 051 inniol) dissolved in methanol was added thereto, and the mixture was allowed to stand at room temperature at room temperature. The precipitated crystals were collected by filtration to give the title compound as white crystals (114 mg, 42%).
  • Example (2 la) The compound obtained in Example (2 la) was dissolved in 2 ml of ethyl acetate, and oxalic acid was added.
  • Example (22b) 8- ⁇ 2-[(3,4,5-) fluorophenyl) phenylmethoxy 1-ethyl 1-oxa-3,18-diazaspiro J4,5] decane-2-one oxalate
  • the compound obtained in Example (22a) was dissolved in 20 ml of ethyl acetate, and oxalic acid was added.
  • Example (23a) The compound obtained in Example (23a) was dissolved in 2 ml of ethyl acetate, and oxalic acid was added.
  • Example (24a) The compound obtained in Example (24a) was dissolved in 2 ml of ethyl acetate, and oxalic acid was dissolved.
  • Example (25a) The compound obtained in Example (25a) was dissolved in 2 ml of ethyl acetate, and oxalic acid was dissolved.
  • Example 26 8- ⁇ 2- [bis- (3,4-difluorophenyl) methoxy] ethynole ⁇ -1-oxa-3,8-diazaspiro [4,5] synthesized in Example 12
  • the reaction was carried out using 90 mg (0.19 mmol) of decane-2-one and 580 ⁇ m of methane, to obtain 54 mg (50%) of the title compound as white crystals.
  • Example 23 8- ⁇ 3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl ⁇ -1-oxa-3,8-diazaspiro synthesized in Example 23 in the same manner as in Example 26.
  • the reaction was carried out using 150 mg (0.32 nmol) of [4,5] decane-2-one and 140 ⁇ m of methane, to obtain 126 mg (65%) of the title compound as yellow crystals.
  • Example (30a) The compound synthesized in Example (30a) was dissolved in methanol, and oxalic acid was dissolved.
  • Example 26 In the same manner as in Example 26, the reaction was carried out using 170 mg (0.33 mmol) of the compound synthesized in Example (30b) and 140 ⁇ l of dichloromethane, to obtain 192 mg (89%) of the title compound as white crystals.
  • Example 26 8- ⁇ 2- [bis- (4-fluorophenyl) methoxy] ethyloxa- 3,8-diazaspiro [4,5] decane-2-synthesized in Example (31a)
  • the reaction was performed using 90 mg (0.22 mmol) of ON and methane, and 58 mg (48%) of the title compound was obtained as white crystals.
  • Mouse cell clone IL-10 production-inducing effect on D10.G4.1 cells
  • D 10.G4.1 cells were converted from RPMI medium containing 10% fetal calf serum and 5 ⁇ 2 mercaptoethanol. (Life Technologies) to adjust the cell concentration to 2500 cells / 0.2 ml, and dispensed 0.2 ml each into a 96-well flat bottom plate (Corning). At this time, 0.16 g / ml compound was added. After culturing for 24 hours, IL-10 was produced in the culture supernatant. IL-10 in the culture supernatant was
  • the compound of the present invention exhibited an excellent IL-10 production inducing action.
  • Murine T cell clone D10.G4.1 cells were transformed with RPMI medium containing 10% fetal calf serum and 5 mM 2 mercaptoethanol ( Life Technologies Co., Ltd.) and adjusted to a cell concentration of 25000 cells / 0.2 ml, and dispensed 0.2 ml each into a 96-well flat bottom plate (Corning). At this time, 0.16 ⁇ g / ml compound was added. After culturing for 24 hours, IL-4 was produced in the culture supernatant. IL-4 in culture supernatant is ELISAKIT
  • the compound of the present invention showed an excellent IL-4 production inducing action.
  • G4.1 cells were cultured in RPMI 1640 medium (manufactured by Life Technologies) containing 10 ° / 0 fetal bovine serum and 5 ⁇ of 2-mercaptoethanol at 250 000 cells / cell. Each 0.2 ml was dispensed into a 96-well flat bottom plate (Corning). At this time, a predetermined concentration of the compound was added.
  • an anti-mouse CD3s antibody (manufactured by BD Biosciences) was adsorbed to a 96-well flat-bottom plate at a final concentration of 0.4 zg / ml.
  • the cells were dispensed at 25,000 cells / 0.2 ml. After culturing for 24 hours, IL-10 was produced in the culture supernatant. IL-10 in the culture supernatant was measured by ELISA KIT (Genzyrae Techne).
  • Example 250 From the above results, it is clear that the compound of the present invention has an excellent IL-10 production inducing action.
  • Test example 4
  • the mouse T cell clone D10.G4.1 cells were transformed into 250,000 cells / 0,000 in RPMI 1640 medium (Life Technologies) containing 10% fetal calf serum and 5 M 2-mercaptoethanol. Each 2 ml was dispensed into a 96-well flat bottom plate (Corning). At this time, a predetermined concentration of the compound was added.
  • an anti-mouse CD3e antibody (manufactured by BD Biosciences) was adsorbed to a 96-well flat bottom plate at a final concentration of 0.4 / g / ml, and D10.G4.
  • One cell was dispensed at 25,000 cells / 0.2 ml. After 24 hours of culture, IL-4 was produced in the culture supernatant. IL-4 in the culture supernatant was measured by ELISA KIT (Genzyme Techne).
  • Example 25 036 From the above results, it is clear that the compound of the present invention has an excellent IL-4 production inducing effect.

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Abstract

L'invention se rapporte à des dérivés benzhydryle représentés par la formule générale (I) ou (II), ou à leurs sels pharmacologiquement acceptables, à des esters ou à d'autres dérivés qui possèdent un excellent effet immunodépresseur sélectif vis-à-vis des cellules Th1. Dans les formules (I) et (II), R1 est phényle portant un substituant arbitraire sélectionné dans le groupe (a) des substituants en position ortho ou méta et pouvant être par ailleurs substitué par un à quatre groupes arbitraires indépendamment sélectionnés dans le groupe (a) de substituants; R2 est phényle ou analogue; R3 est alkyle inférieur; X- est un anion; n est un entier égal à 2 ou 3; et le groupe (a) des substituants est composé de halogéno, alkyle inférieur, alkyle inférieur halogéné, alcoxy inférieur, alkylthio inférieur, hydroxyle, amino, nitro et cyano.
PCT/JP2001/008902 2000-10-10 2001-10-10 Derives benzhydryle WO2002030938A1 (fr)

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AU2001294215A AU2001294215A1 (en) 2000-10-10 2001-10-10 Benzhydryl derivatives

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Citations (3)

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Publication number Priority date Publication date Assignee Title
US3864348A (en) * 1971-10-29 1975-02-04 Science Union & Cie 1-Oxa-3,8-diaza spiro (4,5) decane compounds
US5597819A (en) * 1992-05-25 1997-01-28 Adir Et Compagnie Phenothiazine cytokine inhibitors
JP2001011050A (ja) * 1999-04-30 2001-01-16 Sankyo Co Ltd 含窒素飽和複素環化合物

Patent Citations (3)

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US3864348A (en) * 1971-10-29 1975-02-04 Science Union & Cie 1-Oxa-3,8-diaza spiro (4,5) decane compounds
US5597819A (en) * 1992-05-25 1997-01-28 Adir Et Compagnie Phenothiazine cytokine inhibitors
JP2001011050A (ja) * 1999-04-30 2001-01-16 Sankyo Co Ltd 含窒素飽和複素環化合物

Non-Patent Citations (1)

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Title
REGNIER GILBERT ET AL.: "Oxazolidinones-1. II. Synthese et proprietes pharmacologiques des derives de I'oxa-1 oxo-2 diaza-3,8 spiro(4,5)decane", CHIMIE THERAPEUTIQUE, vol. 4, no. 3, 1969, pages 185 - 194, XP002906376 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

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