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WO1998006724A1 - Agonistes du recepteur du glutamate metabotropique - Google Patents

Agonistes du recepteur du glutamate metabotropique Download PDF

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Publication number
WO1998006724A1
WO1998006724A1 PCT/JP1997/002748 JP9702748W WO9806724A1 WO 1998006724 A1 WO1998006724 A1 WO 1998006724A1 JP 9702748 W JP9702748 W JP 9702748W WO 9806724 A1 WO9806724 A1 WO 9806724A1
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WIPO (PCT)
Prior art keywords
group
lower alkyl
alkyl group
amino
phenylimidazo
Prior art date
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PCT/JP1997/002748
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English (en)
Japanese (ja)
Inventor
Satoshi Hayashibe
Hirotsune Itahana
Kiyoshi Yahiro
Shin-Ichi Tsukamoto
Masamichi Okada
Hiroshi Yamashita
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU37834/97A priority Critical patent/AU3783497A/en
Publication of WO1998006724A1 publication Critical patent/WO1998006724A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems

Definitions

  • the present invention relates to a metabolic port pick-up receptor receptor agonist (ligand) containing an imidazobenzothiazole derivative or a pharmaceutically acceptable salt thereof, and use of the compound for producing the agonist.
  • the present invention relates to a method for treating the disease, which comprises administering an effective amount of the compound to a patient having the disease requiring the agent.
  • the present invention also relates to a novel imidazobenzothiazole derivative or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a pharmaceutical composition comprising the above-mentioned novel imidazobenzothiazole derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Glutamate acts as a neurotransmitter in the mammalian central nervous system (Mayer M. L. and Westbrook G. L., Prog. Ncurobiol., 28 (1987) 197-276). Recent studies have revealed the importance of glutamate in higher cranial nerve function. Glutamate is released from nerve terminals and regulates neuronal activity or neurotransmitter release via glutamate receptors located in the postsynaptic membrane or nerve terminals. Glutamate receptors are currently classified into two broad categories based on various pharmacological and physiological studies. One is an ion channel built-in type, and the other is a metabolically regulated receptor (Hollmann M. and Heinemann S., Annu. Rev. Neurosci., 17 (1994) 31-108).
  • mG1uR metabolic glutamate receptor
  • mG] u R agonist (IS, 3R) -11-aminocyclopentane-1,3-dicarboxylic acid [hereafter (1S, 3R) -ACPD] causes epilepsy Is induced [Tizzano J. et al., Neurosci. Lett., 162 (1993) 12-16; McDonald W. et al., J. Neurosci., 13 (1993) 4445-4455]. Furthermore, m G 1 u R
  • (S) —4-carboxy-13-hydroxy glycine (hereinafter referred to as (S) —CHPG), an antagonist of mG 1 uR2 and an agonist of mG 1 uR2, is effective in various epilepsy models. It has been reported [Daiby NO & Thomsen CJ Pharmacol. Exp. Ther., 276 (1996) 516-522].
  • a compound acting on mG1uR1 may have epilepsy, pain, neurodegenerative disease (cerebral insufficiency after cardiac bypass surgery and transplantation, seizures, cerebral ischemia, spinal cord injury, head trauma , Alzheimer's disease, Huntington's chorea, amyotrophic sclerosis, AIDS-induced dementia, perinatal hypoxia, cardiac arrest, hypoglycemic neuron damage, visual impairment and retinopathy, idiopathic and drugs Induced Parkinson's disease), indicating that benzodiazepine withdrawal syndrome is useful.
  • compounds acting on mG1uRl are caused by impaired neurotransmission due to glumic acid, seizures, migraine, urinary incontinence, mental illness, opiate tolerance and withdrawal symptoms, cocaine withdrawal symptoms, anxiety It may also be useful for vomiting, cerebral edema, chronic pain, and secondary dyskinesis.
  • compounds having an action of metabotropic glutamate receptor include compounds having an amino acid or peptide structure (see JP-A-07-267908) and compounds having a thieno [2,3-b] indole structure (although the imidazo [2,1-b] benzothiazole compound, which is the active ingredient of the drug provided by the present invention, has a structure similar to that of Make a difference.
  • various compounds have been known as imidazo [2,1-b] benzothiazol derivatives. That is, 2-phenylimidazo [2,1—b] benzothiazole derivatives include: (1)
  • Japanese Unexamined Patent Publication No. 57-040492 Japanese Patent Publication No. 1-38971
  • the group, carboxy group, lower alkoxycarbonyl group, nitro group, amino group, mono- or di-lower alkylamino group may have 1 to 3 acylamino groups,
  • halogen atom lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylsulfur
  • X is an oxygen atom, a hydroxyamino group, an imino group or a lower alkylamino group.
  • Y represent a hydrogen atom, a hydroxyl group, an alkoxy group, an amino group, a lower alkyl group, an acylamino group, a mono- or di-lower alkylamino group, or a tetrazo-1-ylamino group, provided that X and Y are integrally nitrogen.
  • Halogen atom hydroxyl group, nitro group, nitroso group, amino group, thiocyanato group, lower alkyl group, hydroxy lower alkyl group, lower Alkoxy group, carboxy lower alkoxy group, lower alkoxycarbonyl lower alkoxy group, acyloxy group, lower alkylthio group, lower alkylsulfinyl ⁇ , lower alkylsulfonyl group, mono- or di-lower alkylamino group, acylamino group or 2-position substitution Or it may have 1 to 3 substituents of the same group as the unsubstituted phenyl group
  • the phenyl group When a substituted or unsubstituted phenyl group is bonded to the 2-position, the phenyl group includes a halogen atom, a hydroxyl group, a lower alkanoyloxy group, an alkoxy group, a nitroso group, a nitro group, and an amino group.
  • An acylamino group, a mono- or di-lower alkylamino group, or one or two substituents of C ( X) -Y described below,
  • the 3-position or other position of the condensed benzene ring ⁇ is halogen, lower alkyl, alkoxy, hydroxyl, nitroso, nitro, amino, acylamino, mono- or di-lower alkyl.
  • 2-phenylimidazo [2,1b] benzothiazole derivatives include:
  • the present inventors have keenly aimed at providing a metabotropic glutamate receptor agonist, particularly a therapeutic drug for the indication of seizures, epilepsy, pain, Parkinson's disease or cerebrovascular disorder, and sequelae due to head trauma.
  • imidazo [2,1-b] benzothiazol derivatives represented by the following formula (I) exhibit potent metabotropic glutamate receptor action, and completed the present invention. .
  • the present invention relates to an agent acting on a metaborate pick glutamate receptor comprising, as an active ingredient, an imidazobenzothiazole derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof. Further, the present invention provides the compound (I) or a pharmaceutically acceptable salt thereof for producing a medicament for administering an effective amount to a patient who needs to act on metabotropic glutamate receptor. Or use Administering an effective amount of the compound (I) or a pharmaceutically acceptable salt thereof to a patient who needs to act on the glutamate receptor.
  • the present invention relates to a remedy, a use, or a method for treating convulsions, epilepsy, pain, Parkinson's disease or cerebral hemorrhage, and head injury due to head injury.
  • a ring (1) 1 to 3 aryls optionally having 3 substituents,
  • bicyclic heterocyclic group in which a benzene ring is fused to the heterocyclic ring, wherein the bicyclic heterocyclic group may have 1 to 3 substituents.
  • R a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group or a lower alkoxy group.
  • RR 3 , R 4 and R 5 same or different, hydrogen atom, halogen atom, lower alkyl group, cyano group, nitro group or formula
  • ⁇ 1 and ⁇ 3 bond or lower alkylene group.
  • R 6 and R 7 identical say yes is different, a hydrogen atom, a lower alkyl group, C 3 8 Shi A cycloalkyl group, an aryl group optionally substituted by 1 to 3 i-substituents, or a phenyl lower alkyl group
  • Ring B (1) A 5-aza having one or two hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom is a 6-membered heterocyclic group, wherein the heterocyclic group is 1 to May have three substituents, or
  • bicyclic hetero ring in which a benzene ring is fused to the hetero ring, wherein the bicyclic hetero ring group may have 1 to 3 substituents.
  • all aryl groups, monocyclic heterocyclic groups and bicyclic heterocyclic groups are preferred.
  • the substituents that may be present include a halogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, an amino lower alkyl group, and mono Or G-lower alkylamino lower alkyl group, hydroxy lower alkylamino lower alkyl group, lower alkoxy lower alkylamino lower alkyl group, lower alkoxycarbonyl lower alkylamino lower alkyl group, mono- or di-acylamino lower alkyl group N-lower alkyl-N-acylamino lower alkyl group, hydride Xyl group, lower alkoxy group,
  • a ring and R 1 have the above-mentioned meanings, and other symbols have the following meanings.
  • R 8 , R 9 , length ⁇ and! ⁇ 1 ' same or different, hydrogen atom, halogen atom, lower alkyl group, cyano group, nitro group or formula
  • R 12 is a lower ⁇ alkyl group, C 3 - 8 A cycloalkyl group, an aryl group optionally having 1 to 3 substituents or a phenyl lower alkyl group), and
  • ring A is a phenyl or furyl group which may be S-substituted by a lower alkyl group or a dinitro group, it is an unsubstituted benzofuryl group
  • any one of R 8 , R 9 , R 1 ⁇ and R 11 is It means ⁇ other than a hydrogen atom or a halogen atom.
  • R 13 is hydroxymethyl 3 ⁇ 4, 2-hydroxyhydryl group, 3-hydroxypropyl group, 2-hydroxypropyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, cyano group, methylcarbamoyl Or a dimethylcarbamoyl group.
  • these compounds (III) of the present invention or a pharmaceutically acceptable salt thereof include unsubstituted 2- and 3-substituted phenyl groups of imidazo [2,1-b] benzothiazoyl ring and fused benzene. It is characterized by its chemical structure in that it is selected as having a specific substituent bonded only to the 7-position of the ring.
  • Japanese Patent Publication No. 11-38971 There is no specific disclosure in Japanese Patent Application Laid-Open No. 56-138196 or Japanese Patent Application Laid-Open No. 57-149288, and it is also specifically disclosed in documents other than these known documents.
  • the compound (III) of the present invention or a pharmaceutically acceptable compound thereof The characteristic of pharmacological I. is that the resulting salt exhibits a mesotrophic glutamate receptor action which is completely different from the drug action described in the above literature.
  • the above compound (II) or (III), or azalea is a pharmaceutical composition comprising a pharmaceutically acceptable carrier, especially a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for treating a metabotropic dal receptor receptor agonist in particular, seizures, epilepsy, pain, Parkinson's disease, cerebrovascular disease, and sequelae due to head trauma.
  • the active ingredients of the medicament of the present invention also include known compounds. Therefore, the compound (I) includes not only the above-mentioned novel compounds (II) and (III) but also the conventionally known imidazobenzo [2,1-b] thiazo. One compound is included.
  • particularly preferred compounds are those in which RR 3 , R 4 and R 5 are the same or different, and are hydrogen, cyano,
  • R S particularly preferred compounds of the present invention compound (II), R S, RR 1 G and R 1 1 are the same or different and, in the definition contained in R 2, RR and R 5 of the compound (I)
  • R S particularly preferred compounds of the present invention compound (II)
  • RR 1 G is the same or different and, in the definition contained in R 2, RR and R 5 of the compound (I)
  • ring A is an aryl group or a benzodioxolyl group which may have a substituent, R 8 , R 9 and R 1 . And at least one of R 1 1
  • ring A is a phenyl or furyl group which may be substituted with a lower alkyl group or a nitro group, when it is unsubstituted benzofuryl, or benzopyranyl which may be substituted with an oxo group.
  • any one of R H , R 9 , R 1 ° and R 11 is a compound meaning a group other than a hydrogen atom or a halogen atom ,
  • R 8 , R 9 , R 1 Q and R 11 are the same or different, and more preferably a hydrogen atom, a cyano group, or a compound represented by the formula
  • RH is a hydrogen atom, a lower alkyl group or an aryl group
  • R 15 and R 16 are the same or A hydrogen atom or a lower alkyl group
  • R 17 -CO- and R 18 -C 0- are the same or different and represent an acyl group.
  • any one of R 8 , R 9 , R 1 Q and R 11 is a compound which tastes a group other than a hydrogen atom or a halogen atom.
  • Compounds not included in compounds (III) and (III) but included only in compound (I) include those in which R 4 is a hydroxyl group, a lower alkoxy group, a lower alkylsulfinyl group, amino tea or mono- or di- a lower alkylamino amino group, with a 3 ⁇ 4 is unsubstituted, and R ', R L ⁇ R 3 and R "' are hydrogen atoms compounds,
  • R 1 is a lower alkoxy lower alkyl group, a hydroxy lower alkoxy lower alkyl group, a lower alkoxy lower alkoxy lower alkoxy group, a carboxy lower alkoxy lower alkoxy group, a lower alkoxy lower alkoxy group or a lower alkoxy lower alkoxy group.
  • compositions are provided.
  • pharmaceutically acceptable salts are provided.
  • Compounds that are not contained in compounds (U) and (III) but are contained only in compound (I) include 7-hydroxy-2-phenylimidazo [2,1—b] benzothiazol and 7-methyl Ethoxy-2—phenylimidazo [2,1—b] benzothiazol, 7-ethoxy—2—phenylimidazo [2,1—b] benzothiazol, 7—methylsulfinyl-2— Phenylimidazo [2,1-b] benzothiazole, 7-amino-2-phenylimidazo [2, 1-b] benzothiazole or 7-methylamino-2-phenylimidazo [2, 1-b] Benzothiazole,
  • Compounds included in the compound (II) include 7-methoxymethyl-2-phenylenediazo [2,1—b] benzothiazol, 7 — [(2-hydroxyethoxy) methyl] 1-2— Phenylimidazo [2, 1 — b] benzothiazol, 7 — [(2-methoxyethoxyquin) methyl] 1-2-phenyl midazo
  • Compounds included in the compound (III) include 7-hydroxymethyl-2-phenylimidazo [2,11-b] benzothiazole, 2- (hydroxyethyl) 1-2-phenylimidazo [2, 1—b] benzothiazole, 7—
  • a aryl group which may have 1 to 3 substituents and "an oxygen atom and a nitrogen which may have 1 to 3 substituents”
  • the substituent of the ⁇ bicyclic heterocyclic group in which a benzene ring is condensed '' is the substituent described above.
  • the IS substituent on the carbon atom includes all the substituents described above, and the substituent on the ring nitrogen atom includes a lower alkyl group, an acyl group, and a carbamoyl group.
  • Mono- or di-lower alkyl rubamoyl group amino group, mono or lower alkyl amino group, hydroxy lower alkyl amino group, lower alkoxy lower alkyl amino group, lower alkoxy carbonyl amino group, mono or diacylamino group
  • the “lower alkyl group” is a straight-chain or branched alkyl group having 1 to 6 carbon atoms (C; (; alkyl group)).
  • the “lower alkylene group” means a linear or branched alkylene group having 1 to 6 carbon atoms (C ⁇ e alkylene group).
  • the "lower alkylene group” specifically, for example, a methylene group, ethylene Group, methylmethylene group, trimethylene group, 1-methylethylene group, 2-methylethylene group, tetramethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group, 3-methyltrimethylene group, 1-ethylethyl Tylene group, 2-ethylethylene group, pentamethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group, 3-methyltetramethylene group, 4-methyltetramethylene group, hexamethylene group and the like.
  • C -! 4 alkylene S among others methylene group, an ethylene group are preferable.
  • C 3 8 consequent opening alkyl group meaning taste cyclic saturated hydrocarbon group having from 3 to 8 carbon atoms, specifically, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group consequent opening, cyclohexylene A butyl group and a cyclooctyl group.
  • cyclo propyl 3 ⁇ 4 cyclopentyl group, C 3, such as a cyclohexyl group - 6 cycloalkyl group, especially a cyclopropyl group is preferred.
  • aryl group optionally having 1 to 3 substituents refers to the aromatic carbon group having 6 to 14 carbon atoms optionally having 1 to 3 substituents.
  • aryl group of the "aryl group optionally having 1 to 3 substituents” means a hydrogen ring group, and specifically includes, for example, a phenyl group, a naphthyl group, an anthryl A phenyl group or a naphthyl group.
  • Phenyl lower alkyl group means ⁇ ⁇ in which a phenyl group is bonded to any hydrogen atom of the above “lower alkyl group”.
  • phenyl lower alkyl group include benzyl group, phenyl group, 1-phenylethyl group, 3-phenylpropyl group, 2-phenylpropyl group, 1-phenylpropyl group, 1-methyl-2-phenylethyl group, 4-phenylbutyl group, 3-phenylbutyl group, 2-phenylbutyl group, 1 1-phenylbutyl group, 2-methyl-3-phenylpropyl group, 5 monophenylpentyl group, 4-phenylpentyl group, 3-phenylpentyl group, 2-phenylpentyl group, 1-phenylpentyl group, 3-methyl-4-phenylbutyl group, 6 —Phenylhexyl group and the like.
  • the “5- or 6-membered heterocyclic group having one or two hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom” which may have a substituent include: Represents a furyl group, a dihydrofuryl group, a tetrahydrofuryl group, a chenyl group, a dihydrochenyl group, a tetrahydrochenyl group, a pyrrolyl group, a pyrrolylyl group, Mouth lysinyl, imidazolyl, imidazolinyl, imidazolidinyl, vilazolyl, vilazolidinyl, pyrazolidinyl, thiazolyl, isothiazolinole, oxazolyl, isoxazolyl, trirazazolyl, tetrazolyl Group, pyridyl group, dihydropyridyl group, t
  • the “bicyclic heterocyclic group in which a benzene ring is fused to the heterocyclic ring” is specifically a benzofuryl group, a benzochenyl group, Indrill group, dihydric indolyl II, isoindolyl II, dihydric isoindolyl group, quinolyl II, dihydric quinolyl II, tetrahydroquinolyl group, isoquinolyl group, dihydric isoquinolyl group And a tetrahydroisoquinolyl group.
  • the bond of these monocyclic and bicyclic heterocyclic groups may be derived from any of the carbon atoms and nitrogen atoms of the heterocyclic ring, and may be derived from the benzene ring for the bicyclic heterocyclic ring. May be. Further, the heterocyclic group or the bicyclic heterocyclic group may have 1 to 3 of the above substituents.
  • halogen atom in the present invention means an atom having an atomic weight of up to 127 in the periodic table VIIa, and specifically includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. .
  • “Lower alkoxy group” means an alkoxy group having 1 to 6 carbon atoms and a straight or branched carbon chain (C, 6 alkoxy group).
  • Specific examples of the “lower alkoxy group” include, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy (amyloxy) group, Pentyloxy (isoamyloxy) group, neopentyloxy group, tert-pentyloxy group, hexyloxy group, isohexyloxy group and the like.
  • “Hydroxy lower alkyl group” means a group in which an arbitrary hydrogen atom of the above “lower alkyl group” is substituted with a hydroxyl group (HO—Ce-alkyl group).
  • hydroxy lower alkyl group examples include, for example, hydroxymethyl group, 1-hydroxyl; ;, 2-hydroxyl group, 1-hydroxypropyl ⁇ , 2-hydroxypropyl group, 3 —Hydroxypropyl group, 1—Hydroxy-1- 1—Methylethyl group, 2-Hydroxy—1—Methylethyl 3 ⁇ 4, 1—Hydroxybutyl group, 2—Hydroxybutyl group, 3—Hydroxybutyl group, 4-Hydroxybutyl group 1-hydroxy-2-methylpropyl group, 2-hydroxy-2-methylpropyl group, 3-hydroxy-2-methylpropyl group, 1-hydroxypropyl 1-methylpropyl group, 2-hydroxyl group Methylpropyl group, 3—hydroxyl 1-methylpropyl group, 2—hydroxyl 1-ethylethyl 3 ⁇ 4, 1-hydroxylpe Methyl group, 2-hydroxypentyl group, 3-hydroxypentyl group, 4-
  • human Doroki sheet C, - 4 alkyl group especially human Dorokishimechiru group, 1 Ichihi Dorokishechiru group, 2-arsenide Dorokishechiru group, a 2-hydroxycarboxylic propyl are preferred.
  • “Lower alkoxy lower alkyl group” means a group (C, _ ( ; alkoxy C, 6 alkyl group)) in which any hydrogen atom of the above “lower alkyl group” is substituted by the above “lower alkoxy group J”.
  • a 4- alkoxy C, ⁇ alkyl group is preferable, and a methoxymethyl group, a methoxethyl group, an ethoxymethyl group, an ethoxyxetoxy group, and a 2-methoxypropyl group are more preferable.
  • the “aryloxy lower alkyl group optionally having 1 to 3 substituents” may be such that the hydroxy hydrogen of the “hydroxy lower alkyl group” may have the above “1 to 3 substituents”.
  • the "aryloxy lower alkyl group” portion of the “aryloxy lower alkyl group optionally having 1 to 3 substituents” may be, for example, a phenyloxy group as a phenyloxy group, such as a phenyloxymethyl group, a 2-phenyloxyethyl group, —Phenoxhetyl group,
  • hydroxymethoxymethyl group 11- (hydroxymethoxy) ethyl group, 2- (hydroxymethoxy) ethyl group, 11- (hydroxymethoxy) propyl group, 2- (hydroxymethoxy) propyl 1- (hydroxymethoxy) butyl group, 2- (hydroxymethoxy) butyl tea, 3- (hydroxymethoxy) butyl group, 4- (hydroxymethoxy) butyl group, 5- (hydroxymethoxy) butyl group Xy) pentyl group, 6- (hydroxymethoxy) hexyl group, (2-hydroxyethoxy) methyl group, (1-hydroxyethoxy) methyl group, 2- (2-hydroxyethoxy) ethyl group, 1- (2-hydroxyloxy) ethyl group, 2- (1-hydroxyloxy) ethyl group, 1- (1-hydroxyloxyxetoxy) Butyl group, 3- (2 - human Dorokishe Bok alkoxy) propyl, 4 one
  • “Lower alkoxy lower alkoxy lower alkyl group” the “lower alkyl group” any been substituted hydrogen atoms in the "lower alkoxy lower alkoxy group” (C i _ 6 alkoxy C i of - 6 alkoxy, -. 6 alkyl Group).
  • Specific examples of “lower alkoxy lower alkoxy lower alkyl group” include “lower alkoxy lower alkyl group” as methoxymethyl group, ethoxymethyl group, methoxyxyl group, ethoxyxeti group. For example, methoxymethoxymethyl group, ethoxymethoxymethyl group
  • propoxymethoxymethyl group isopropoxymethoxymethyl group, butoxymethoxymethyl3 ⁇ 4, (2-methoxyethoxy) methyl group, (2-ethoxyquinoxy) methyl3 ⁇ 4, (2-propoxyethoxy) methyl group, (2-isopropoxy) (Ethoxy) methyl group, (2-butoxyethoxy) methyl ffi, 2- (methoxymethoxy) ethyl group, 2- (ethoxymethoxy) ethyl group, 2- (propoxymethoxy) ethyl group, 2- (isopropoxyme Ethoxy, ethyl, 2- (butoxymethoxy) ethyl, 2- (2-methoxyethoxy) ethyl, 2 (2-ethoxyethoxy) ethyl, 2- (2-propoxyethoxy) ethyl, 2- (2-isopropoxyethoxy) ethyl group, 2- (2-butoxyethoxy)
  • “Ashiru group” means a carboxylic acid, especially lower alkanecarboxylic acids, C 3 8 cycloalk cans carboxylic acid, ⁇ Li one Rukarubon acid, the acid residue of the full We alkenyl carboxylic acids.
  • lower alkanoyl groups such as formyl group, acetyl group, propanol group, butyryl group, isoptyryl group, valeryl group, isovaleryl group, and bivaloyl group, cyclopropylcarbonyl group, cyclobutylcarbonyl group, cycloalkyl pentyl group, hexyl group cycloheteroalkyl, Puchinore force Honoré Boniru group cycloheteroalkyl, C 3.
  • lower alkanoyl groups such as formyl group, acetyl group, propanol group, butyryl group, isoptyryl group, valeryl group, isovaleryl group, and bivaloyl group, cyclopropylcarbonyl group, cyclobutylcarbonyl group, cycloalkyl pentyl group, hexyl group cycloheteroalkyl, Puchinore force Honoré Boniru group cycl
  • acyloxy lower alkyl group means a group (acyl-0-C,-. Alkyl group) in which the hydroxyl group of the above “hydroxy lower alkyl group” is substituted with an acyloxy group. This “acyloxy lower alkyl group” is used as the lower alkylene group.
  • Examples of the methylene group and ethylene group and the lower alkenyl group as the acyl group include formyloxymethyl, acetoxymethyl, propionyloxymethyl, ptyryloxymethyl, isoptyryloxymethyl, Valeryloxymethyl group, isovaleryloxymethyl group, bivaloyloxymethyl group, formyloxyl group, acetoxyl, propionyloxyl group, butyryloxetyl group, isobutyryloxyl group, pa'relylo Examples include a xicetyl group, an isovaleryloxethyl group, and a bivaloyloxethyl group.
  • the “lower alkoxycarbonyl group” is formed as an ester with a carboxyl group and a linear or branched lower alcohol having 1 to 6 carbon atoms (C, fi alcohol), and the hydroxyl group of the carboxyl group is the above “lower alkoxy group”. [C.sub.r, alkoxy) carbonyl group].
  • lower alkoxycarbonyl examples include, for example, a methoxycarbonyl (carboxy) group, an ethoxycarbonyl (carbethoxy) group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, Butoxycarbonyl group, sec—butoxycarbonyl group, tert-butoxycarbonyl (B oc) group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert—pentyloxycarbonyl group And a hexyloxycarbonyl group, an isohexyloxycarbonyl group and the like.
  • an (alkoxy) carbonyl group especially a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group are preferred.
  • Carboxy lower alkyl group can be any group in which a hydrogen atom is substituted with a carboxyl group of the "lower alkyl group” (H 0 ⁇ C - C, - fi alkyl group) means a. Specifically, carboxymethyl group, 1-carboxyethyl group, 2-carboxyethyl group , Carboxypropyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxy] -methylethyl, 2-carboxy-1 monomethylethyl, 1 carboxybutyl, 2-carboxybutyl Group, 3-carboxybutyl, 4-carboxybutyl, 1-carboxy-2-methylpropyl, 2-carboxy-2-methylpropyl, 3-carboxy-2-methylpropyl, 1-carboxy-1-methyl Propyl group, 2-carboxy-1-methylpropyl group, 3-carboxy-1-methylpropyl group, 2-carboxy-1-ethylethyl group
  • “Lower alkoxycarbonyl lower alkyl group” means a group in which any hydrogen atom of the above “lower alkyl group” is substituted with a lower alkoxycarbonyl group [(C i ._ 6 alkoxy) carbonyl group].
  • C l 4 alkoxycarbonyl C Bok 4 alkyl group especially main Bok alkoxycarbonylmethyl group, main Bok Kishikarubo two Ruechi group, ethoxycarbonylmethyl group, ethoxycarbonyl E chill group.
  • Carboxy-lower alkoxy lower alkyl group the “lower alkyl group” group in which a hydrogen atom of the arbitrary is substituted by "carboxy lower alkoxy group” (HOOC - C, - f; alkoxy C e alkyl group) means a .
  • Specific examples of the "carboxy lower alkoxy lower alkyl group” include, for example, carboxymethoxymethyl group, 1.1- (carboxymethoxy) ethyl group, 2 .— (carboxymethoxy) ethyl group, and 11- (carboxymethoxy) ethyl group.
  • Methoxy) propyl group 2- (carboxymethoxy) propyl group, 1- (carboxymethoxy) butyl group, 2- (carboxymethoxy) butyl group, 3- (carboxymethoxy) butyl group, 4- (carboxymethoxy) butyl group (Carboxymethoxy) butyl, 5- (carboxymethoxy) pentyl, 6- (carboxymethoxy) hexyl, (2-carboxyethoxy) methyl, (1-carboxyethoxy) methyl, 2- (2-carboxyethoxy) ethyl 3 ⁇ 4, 1- (2-carboxyethoxy) ethyl group, 2- (1-carboxyethoxy) ethyl group Xy) ethyl group, 1- (1-carboxyethoxy) ethyl group, 3- (2-carboxyethoxy) propyl group, 4- (2-carboxyethoxy) butyl group, (3-car
  • lower alkoxycarbonyl lower alkoxy lower alkyl group When the "lower alkoxycarbonyl lower alkoxy lower alkyl group" is exemplified as the above “lower alkoxy lower alkyl group” by a methoxymethyl group, an ethoxymethyl group, a methoxethyl group or an ethoxyquinethyl group, methoxycarbonyl methoxymethyl is exemplified.
  • “Lower alkylthio group” means a mercapto group group in which a hydrogen atom is substituted with the lower alkyl group (thiol group) (C, _ 6 alkylthio groups). Specifically, for example, methylthio group, ethylthio group, propylthio group, isopropylthio group, Examples include a tylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, neopentylthio group, tert-pentylthio group, hexylthio group, and isohexylthio group. Particularly, a C, 4 alkylthio group, and at most a methylthio group and an ethylthio group are preferred.
  • the “lower alkylsulfinyl group” refers to a group in which the lower alkylthio group is oxidized with an equimolar amount of an oxidizing group.
  • a C 4 alkylsulfinyl group is particularly preferable, and
  • the lower alkylsulfonyl group J means a group in which the lower alkylthio group is oxidized with twice the molar amount of an oxidizing agent or a group in which the lower alkylsulfinyl group is oxidized with an equimolar amount of an oxidizing agent.
  • “Lower alkylsulfonyl O alkoxy group” human Dorokishiru group and from 1 to 6 linear or branched lower alkanoic acid (C] fi alkanesulfonic acid) and de sulfonate formed group carbon atoms (C, -6 alkylsulfonyloxy group).
  • the “lower alkylsulfonyloxy lower alkyl group” is a compound in which the “hydroxy lower alkyl group” is a sulfonic acid ester formed with a lower alkanesulfonic acid, and the hydrogen atom of the hydroxyl xyl group is the above “lower alkylsulfonyl group”.
  • 3 ⁇ 4 which is K conversion with 3 ⁇ 4 "(C, _ f; alkylsulfonyl O carboxymethyl C, (;..
  • Suruhoniruokishi lower alkyl group "specifically Tatoebameyun Sulfonyloxymethyl group, 2-methanesulfonyloxyshetyl group, 3—methanesulfonyloxypropyl group, 2—methanesulfonyloxy1-1-methylethyl group, 4-methansulfonyloxybutyl group, benzenesulfonyloxymethyl &, 2 —ethanesulfonyloxystyl group, 3 —ethanesulfonyloxypropyl group, 2 —ethanesulfonyl
  • Preferable examples include an alkoxy-11-methylethyl group and a 4-ethanesulfonyloxybutyl group.
  • ⁇ arylsulfonyloxy lower alkyl group optionally having one to three substituents '' refers to the above-mentioned ⁇ hydroxy lower alkyl group '' having one to three substituents. It means a group (arylsulfonyloxy C, — 6 alkyl group) formed by sulfonic acid ester with arylsulfonic acid.
  • a benzenesulfonyloxymethyl group a benzenesulfonyloxyl group, a benzenesulfonyloxypropyl group, a benzenesulfonyloxybutyl group, a p-toluenesulfonyloxymethyl group, a p-toluenesulfonyloxymethyl group
  • Suitable groups include a p-toluenesulfonyloxypropyl group, a p-toluenesulfonyloxybutyl group and the like.
  • -CONH 2 is a lower alkyl group in which the amino hydrogen atom is the above-mentioned lower alkyl group, and mono-aza is a di-substituted group (mono- or di-C, _f ; alkyl rubamoyl group).
  • N- C ⁇ 4 alkyl Cal Bamoiru group N, N - are preferred di (C Medicine 4 alkyl) force Rubamoiru group, among, N - methylcarbamoyl group, N- E Ji-carbamoyl, N, N-Dimethyl carbamoyl and N, N-getylcarbamoyl are preferred.
  • Power Rubamoiru lower alkoxy lower alkyl group can be any radicals substituted hydrogen atom is "force Rubamoiru lower alkoxy group” (H 2 NC 0- C of the "lower alkyl group", - 6 alkoxy C t _ 6 alkyl Group).
  • a carbamoyl methoxymethyl group 1- (power rubamoyl methoxy) ethyl group, a 2- (power rubamoyl methoxy) ethyl group, an 11- (power rubamoyl methoxy) propyl group, and a 2- (power rubamoyl methoxy) propyl group, ) Propyl group, 1— (Power rubamoyl methoxy) butyl group, 2— (Power rubamoyl methoxy) butyl group, 3— (Power rubamoyl methoxy) butyl group, 4 -— (Power rubamoyl methoxy) butyl 3 ⁇ 4, 5-( Force rubamoyl methoxy) Pentyl group, 6- (Lubamoylethoxy) hexyl group, (2-Lubamoylethoxy) methyl group, (1 Lubamoylethoxy) methyl group, 2- (2-Lubamoylethoxy)
  • the “mono- or di-lower alkyl lower alkoxy lower alkyl group” is a group in which the hydrogen atom of the amino group of the above “lower lower alkoxy lower alkyl group” is mono- or di-substituted with the above “lower alkyl group” (mono-lower alkyl group). or di - C, - 6 alkyl force Rubamoiru C, - 6 alkoxy C,..
  • N butylcarbamo Mono-lower alkyl groups such as ilmethoxymethyl group, N-isobutylcarbamoylmethoxymethyl group, N-pentylcarbamoylmethoxymethyl group, N-hexylcarbamoylmethoxymethyl group, and N, N-dimethylcarbamoylmethoxymethyl group Xymethyl group, N, N—Getylcarbamoylmethoxymethyl group, N, N—Dipropyl rubamoylmethoxymethyl group, N, N—Dibutyl rubamoylmethoxymethyl group, N—Ethyl—N—Methylcarbamoylmethoxymethyl Group, N—methyl—N—Probyl rubamoyl methoxymethyl group, N—ethyl Symmetric or asymmetric, such as N-propyl rubamoyl methoxymethyl group, N-butyl-N-methyl
  • the "mono- or di-lower alkylamino group” is a mono- or di-substituted (mono- or di-C, _ ⁇ alkylamino group) in which a hydrogen atom of an amino group is mono- or di-substituted by the above-mentioned "lower alkyl group”. means.
  • a mono-lower alkylamino group such as a pentylamino group, a tert-pentylamino group, a hexylamino group, an isohexylamino group, and a dimethylamino group, a acetylamino group, a dipropylamino group, a dibutylamino group, an ethylmethylamino group, a methylpropylamino group;
  • Examples thereof include symmetric or asymmetric di-low
  • N - 4 ⁇ Rukiruami amino group, N, N - is suitable di C Bok 4 Arukiruami amino group is, among others, N Mechiruamino group, N - Echiruami Bruno 3 ⁇ 4, N, N - Jimechiruami amino group, N, N- Getylamino groups are preferred.
  • “Hydroxy lower alkylamino group” means a group in which a hydrogen atom of an amino group is substituted with the above “hydroxy lower alkyl group” [(OH—C 6 alkyl) amino group].
  • Specific examples of the “hydroxy lower alkylamino group” include, for example, a hydroxymethylamino group, a 2-hydroxylamino group, a 1-hydroxylamino group, a 3-hydroxypropylamino group, 2-hydroxypropylamino group, 1-hydroxypropylamino group, 2-hydroxy-1-methylethylamino group, 4-Hydroxybutylamino, 3—Hydroxybutylamino, 2—Hydroxybutylamino, 1-Hydroxybutylamino, 3-Hydroxy-2-methylpropylamino ⁇ , 5-hydroxypentylamino group, 6-hydroxyhexylamino group and the like. Of these, a hydroxy- 4- alkylamino group is preferred
  • N-lower alkyl-N— (hydroxy lower alkyl) amino group is a group in which the hydrogen atom of an amino group is di-substituted by the above “hydroxy lower alkyl group” and the above “lower alkyl group” [ ⁇ — ( 0 ⁇ -C, G alkyl) one N—C,. Alkylamino].
  • a 2-hydroxyl group is exemplified.
  • N-C-alkyl one N - a (human Doroki shea C i-4 alkyl) amino group, more preferably N-C i - 2 alkyl - N i (arsenate Dorokishi C, _ 2 alkyl) Amino group It is.
  • a "lower alkoxy lower alkyl group” a methoxymethyl group, a 2-methoxyl group, an ethoxymethyl group, a 2-ethoxylethyl group may be mentioned, for example, a methoxymethylamino group, a 2-methoxylamino group, E Bok Kishimechiruami amino group, a 2-E Toki Chez chill ⁇ amino 3 ⁇ 4.
  • C had alkoxy C 4 alkylamino 3 ⁇ 4 are preferred, especially main butoxy Mechiruamino group, main Tokishechiruami amino group, ethoxymethyl ⁇ Mi amino group, ethoxy An ethylamino group is preferred.
  • “Mono- or diasilamino” means that the hydrogen atom of the amino group is "Group” means a mono- or di-substituted group. Specifically, for example, a formylamino group, an acetylamino group, a propionylamino group, an isopropionylamino group, a butyrylamino group, an isobutyrylamino group, a sec-butylinylamino group, a tert-butylylamino group, a octylerylamino group, isovalerylamino , A lower alkenyl group such as a bivaloylamino group, a cyclopropylcarbonylamino group, a cyclobutylcarbonylamino group, a cyclopentylcarbonylamino group, a cyclohexylcarbonylamino group, a cycloheptylcarbonylamin
  • N—lower alkyl-N-anlumino group is a group in which a hydrogen atom of an amino group is di-substituted with the above “lower alkyl group” and “acyl group” (N—C 6 alkyl-N—acylamino group) ) Means Specifically, for example, N-methylformylamino group, N-ethylformylamino group, N-propylformylamino group, N-isopropylformylamino group, N-butylformylamino group, N-isobutylformylamino group Group, N-sec—butylhonoleminoleamino group, N—tert—butinolehonoremilamino group, N—pentylformylamino group, N—hexylformylamino group, N-methylacetylamino group, N —Ethyl acetylamino, N —Propy
  • N - C, _ 4 alkyl - N- (C, _ 4 Al force Noiru or C 3 6 cycloalkyl carbonitrile yl) amino group and among them N-CI 2-alkyl one N- (C i _ 3 Al force Noiru Or cyclopropylcarbonyl) amino group is preferred.
  • Amino lower alkyl refers to any group in which a hydrogen atom is substituted with amino group of the "lower alkyl group” - means (H 2 N C i e alkyl group). Specifically, aminoamino, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 1-amino-1-methylethyl, 2-amino-1-methylethyl, 1-aminobutyl, 2-aminobutyl, 3-aminobutyl, 4-aminobutyl Aminobutyl group, 1-amino-2-methylpropyl group, 2-amino-2-methylpropyl group, 3-amino-2-methylpropyl group,
  • Examples thereof include a 3-aminohexyl group, a 4-aminohexyl group, and a 5-aminohexyl group.
  • ⁇ Mi Bruno C - an alkyl group, more preferably Aminome methyl group, aminoethyl ⁇ .
  • the “mono- or di-lower alkylamino lower alkyl group” is a group (mono- or di-substituted) in which the hydrogen atom of the amino group of the above “amino lower alkyl group” is mono- or di-substituted by the above “lower alkyl 3 ⁇ 4”. means one C Bok 6 Arukiruami Bruno C Bok 6 alkyl group).
  • the aminoamino group as the "amino lower alkyl group", N-methylaminomethyl group, N-ethylaminoamino group, N-propylaminomethyl Mono-lower alkylamino lower alkyl groups such as N-isopropylaminomethyl group, N-butylaminomethyl group, N-isobutylaminomethyl group, N-pentylaminomethyl group, N-hexylaminomethyl group, and N, N—dimethylaminomethyl group, N, N—getylaminomethyl group, N, N—dipropylaminomethyl group, N, N—dibutylaminomethyl group, N—ethyl-N-methylaminomethyl group, N—methylyl N—Propylaminomethyl, N—Ethyl-N—Propylaminomethyl, N—Buty
  • “Mono- or dimethylamino lower alkyl” means a group in which the hydrogen atom of the amino group of "amino lower alkyl group” is mono- or di-substituted by the above-mentioned "amino group”.
  • the "mono- or di-acylamino lower alkyl group” may be exemplified by an aminomethyl group as the “amino lower alkyl group” and a lower alkanol group as the "acyl group", for example, N-formylaminomethyl, N-acetylamino.
  • Monomethylaminomethyl such as nomethyl group, N—propanoylaminomethyl ⁇ , N—butyrylaminomethyl group, N—isobutyrylaminomethyl group, N—valerylaminomethyl3 ⁇ 4 group, and N, N—diacetylaminomethyl Group, N, N—the diacylaminomethyl group of dipropanoylaminomethyl.
  • N-formylaminomethyl, N-acetylaminomethyl, N-cyclopropylcarbonylmethyl, N-formylaminoethyl, N-acetylaminoethyl, and N-cyclopropylcarbonylethyl are preferred.
  • N-lower alkyl-N-acylamino lower alkyl group is a group in which the hydrogen atom of the amino group of the above “amino lower alkyl group” is substituted by the above “lower alkyl group” and “acyl group” (N—C , — G alkyl-N —acylamino C alkyl group).
  • “N-lower alkyl-N-acylamino lower alkyl group” is the above-mentioned "amino lower alkyl group” as aminoamino, and the "lower alkyl group” substituted at the N-position is a methyl group, an ethyl group, or an "acyl group”.
  • Examples of a lower alkanoyl group include N-methyl-N-formylaminomethyl group, N-methyl-N-acetylaminomethyl group, N-methyl-N-propanoylaminomethyl group, and N-methyl-N-butylylamino.
  • N-methyl-N-isobutyrylaminomethyl group N-methyl-N-valerylaminomethyl group, N-methyl-N-bivaloylaminomethyl group, N-ethyl-N-formylaminomethyl group, N-ethyl-N Acetylaminomethyl group, N-ethyl-N-propanoylaminomethyl group, N-ethyl-N-butyrylaminome Le group, N - Echiru N- isobutyrylamino aminomethyl group, N one Echiru one N - carbonochloridate Reriruami Nomechiru group, N- Echiru N - Bibaroiruami drink It becomes a tyl group.
  • N-C 4 alkyl-1 N— (C, — 4 alkanol or C 3
  • alkyl groups are preferred, and more preferably N—C or 2 alkyl-N— (C, 3 alkanoyl or cyclopropyl propyl) amino C, _ 2 It is an alkyl group.
  • “Human Dorokishi lower alkylamino-lower-alkyl group” is the “lower alkyl group” group in which a hydrogen atom is substituted with a previous "human Dorokishi lower alkylamino Bruno 3 ⁇ 4" of [(OH one C _ c alkyl) ⁇ Mi Bruno - C; — (; Alkyl «].” Hydroxy lower alkylamino lower alkyl group "is exemplified by hydroxymethylamino3 ⁇ 4, 2-hydroxyoxethylamino group as hydroxy lower alkylamino group.
  • N-lower alkyl-N- (hydroxy lower alkyl) amino lower alkyl group is a compound in which any hydrogen atom of the above “lower alkyl group” is the above “N-lower alkyl-N- (hydroxy lower alkyl) amino group”. It has been substituted with the "[N- (C ie alkyl) Single N- (OH- C, _ 6 alkyl) amino C i-6 alkyl group means a.
  • N-lower alkyl-N-hydroxy lower alkylamino is exemplified by N- (2-hydroxyxethyl) -N-methylamino group, N- (2 —Hydroxitytyl) — N—Methylaminomethyl group, 2 — [[N- (2-Hydroxyshetyl) -1-N—methylamino] ethyl group, 11 — [[N— (2-Hydroxicetyl) —N —Methylamino] ethyl group, 3 — [[N- (2-hydroxyethyl) -N-methylamino] propyl group, 2 — [[N- (2-hydroxylethyl) ) —N-methylamino] propyl group, 1 — [[N— (2-hydroxyhydricyl)
  • N- 4-alkyl one N- ( ⁇ H - C, 4 alkyl) ⁇ Mi amino group are preferred, especially N- (2-arsenate Dorokishechi Le) Single N- methylaminomethyl 3 ⁇ 4, 2- [[N - ( 2-Hydroxityl) 1-N-methylamino] ethyl and 1-[[N- (2-hydroxyxethyl) -1-N-methylamino] ethyl group are preferred.
  • lower alkoxy lower alkylamino lower alkyl S is a group (C 6 alkoxy C, 6 alkyl amido) in which any of the above-mentioned “lower alkyl” is substituted with the above “lower alkoxy lower alkylamino group”.
  • Roh C Bok e an alkyl group 'taste.
  • “Lower alkoxycarbonylamino lower alkyl group” means a group in which any hydrogen atom of the above “lower alkyl group” is substituted with the above “lower alkoxycarbonylamino group”, and specifically, “lower alkoxycarbonylamino group”.
  • Examples of the “alkoxycarbonylamino group” include an ethoxycarbonylamino group, such as an ethoxycarbonylaminomethyl group, a 2- (ethoxycarbonylamino) ethyl group, and a 1— (ethoxycarbonylamino group.
  • C ## alkyl group are preferred, more preferably main butoxycarbonyl ⁇ Mi Nomechiru Sibe, E WINCH alkoxycarbonyl ⁇ Mi Nomechiru 3 ⁇ 4, tert - Bed Bok butoxycarbonyl ⁇ Minomethyl group, 2- (methoxycarbonylamino) ethyl group, 2- (ethoxycarbonylamino) ethyl group, 2- (tert-butoxycarbonylamino) ethyl group, 11- (methoxycarbonylamino) ethyl group Amino) ethyl group, 11- (ethoxycarbonylamino) ethyl group, 11- (tert-butoxycarbonylamino) ethyl group and the like.
  • the compound which is an active ingredient of the medicament of the present invention may form a salt.
  • the present invention also includes pharmaceutically acceptable salts of the compounds (I), (II) and (III).
  • examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and pivalic acid.
  • Organic acids such as, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, citric acid, malic acid, tartaric acid, carbonic acid, methanesulfonic acid, ethanesulfonic acid, glumic acid, and aspartic acid
  • Inorganic bases such as potassium, sodium, magnesium, calcium, and aluminum, such as acid addition salts, such as methylamine, dimethylamine, trimethylamine, ethylamine, getylamine, triethylamine, monoethanolamine, diethanolamine, Trietanolamine, cyclohexylamine, meglumine, lysine, ordinine, altritin
  • Inorganic bases such as potassium, sodium, magnesium, calcium, and aluminum, such as acid addition salts, such as methylamine, dimethylamine, trimethylamine, ethylamine, getylamine, triethylamine, monoethanolamine, diethanolamine, Trietanolamine,
  • the compound of the present invention has an optical isomer based on an asymmetric carbon atom depending on the type of the substituent. Further, depending on the type of the substituent, there are cis or trans isomers, syn or anti isomers, tautomers, and the like. In the present invention, these isomers An isolated product or a mixture thereof is included.
  • the compound of the present invention is isolated as various crystal forms such as hydrates, various solvates, and polymorphs of the product.
  • the present invention also includes these substances. Manufacturing method
  • the compound to be used in the pharmaceutical composition of the present invention can be easily obtained from known compounds by the production method described in the known document.
  • the novel compound can be produced by applying various synthesis methods in consideration of the structural characteristics thereof, or by reacting according to the production method of the above-mentioned known product.
  • an alternative production method will be exemplified as a method for producing compound (I) containing a known compound.
  • the amino group, carboxyl group, hydroxy group, and mercapto group of the intermediate or the object of the present invention must be replaced with an appropriate protecting group, that is, a functional group that can be easily converted to these groups. May be technically effective.
  • protecting groups include, for example, those described in "Protective Groups in Organic Synthesis", 2nd edition, by Greene and Wuts. It can be used as appropriate.
  • protecting functional groups that can be easily converted to carbonyl groups, such as hydroxymethylene groups, and functional groups that can be easily converted to aromatic amino groups, such as aromatic nitro groups Can be used as a base.
  • the elimination of the protecting group can be performed according to a conventional method.
  • the protecting group of the amino group is a substituted or unsubstituted benzyloxycarbonyl group
  • catalytic reduction is usually preferred.
  • Other urethane-type protecting groups such as a tert-butoxycarbonyl group are advantageously treated with an acid such as hydrobromic acid Z-acetic acid, trifluoroacetic acid, hydrochloric acid, hydrochloric acid / acetic acid, or hydrochloric acid / dioxane.
  • the protecting group of the amino group is phthalimide formed integrally with the amino nitrogen
  • a method of treating with hydrazines, ammonia, primary amines and the like described below is advantageously used.
  • Carboxyl When the protecting group is a methyl group or an ethyl group, the above-mentioned acid treatment is applied to the substituted aza when the substituted aza is an unsubstituted benzyl group, and when it is a trimethylsilyl group or the like, it is brought into contact with water. The protecting group can be easily removed.
  • Protecting groups for mercapto and hydroxy groups can be removed by treatment with sodium Z liquid ammonia or hydrofluoric acid, and depending on the type of protecting group (for example, 0-benzyl, 0-benzyloxycarbonyl, S- (p-Nitrobenzyl) By catalytic reduction, the protecting group of the acyl group can be removed by acid or hydrolysis.
  • suitable inert solvents include alcohol solvents such as methanol, ethanol and isopropanol, halogenated hydrocarbon solvents such as methylene chloride, chloroform and dichloroethylene, benzene, toluene and xylene. And aromatic solvents such as ethers, dioxane and tetrahydrofuran (THF), hexane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and acetonitrile.
  • alcohol solvents such as methanol, ethanol and isopropanol
  • halogenated hydrocarbon solvents such as methylene chloride, chloroform and dichloroethylene
  • benzene toluene and xylene.
  • aromatic solvents such as ethers, dioxane and tetrahydrofuran (THF), hexane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and acetonitrile.
  • Suitable condensing agents include carbodidimide derivatives such as N, N'-dicyclohexylcarpoimide [if necessary, 1-hydroxybenzotriazole (H0BT) or N-hydroxysuccinimide ( HOSU), etc.], water-soluble carbodiimide represented by 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diphenylphosphoryl azide, Examples include azo derivatives typified by getyl azodi carboxylate, triphenylphosphine, N, N'-carbonyldiimidazole, benzotriazole-1-1-fluoroquin tris (dimethylamino) phosphonium hexafluorophosphate and the like.
  • carbodidimide derivatives such as N, N'-dicyclohexylcarpoimide [if necessary, 1-hydroxybenzotriazole (H0BT) or N-hydroxysuccinimide (
  • Suitable inorganic bases include sodium hydride, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, hydroxylated water, carbonated water, and the like.
  • Suitable organic bases include pyridine, triethylamine, and the like. , Diisopropylethylamine, N, N'-Dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] pentacar 7-ene, 1,4-diazabicyclo [2.2.2] octane, butyllithium, lithium bis (trimethylsilyl) amido And so on.
  • Suitable acid catalysts include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and toluenesulfonic acid.
  • Suitable metal hydride complexes include sodium borohydride, lithium borohydride, borane, its dimethyl sulfide complex, sodium cyanoborohydride, and sodium hydride. And sodium borohydride.
  • Suitable oxides include pyridinum chromate chromate, pyridinum dichromate, manganese dioxide, potassium permanganate, dimethyl sulfoxide and the like.
  • the compound (I) of the present invention can be produced by a conventional method for producing an imidazo [2,1-b] benzothiazol derivative.
  • a conventional method for producing an imidazo [2,1-b] benzothiazol derivative For example, when the 2-amino benzothiazole derivative of the formula (IV) is used as a raw material, this is used as the ⁇ -locus represented by; ⁇ (V). It can be produced by reacting compounds.
  • examples of the halogen atom represented by X 1 include an iodine atom, a nitrogen atom, a chlorine atom, and the like.
  • the reaction is carried out in a suitable inert solvent (particularly an alcoholic solvent), using an excess amount of one or more of the compounds (IV) and / or (V) in an appropriate amount. It is advantageous to carry out the reaction under normal temperature to heating, preferably at the reflux temperature of the solvent.
  • a ring is as defined above, corresponding to R 2 1, 4's in the R 22, R and R 24 do not participate in the respective reaction RR 2, R 3, R 4 and R 5 Y 1 1 is represented by the formula — Y 1 —, —Y 1 — ⁇ — Y 2 —, — Y 1 — S— Y 2 —, or — Y 1 — N (R 6 ) —Y 3 — based on the (here ⁇ ⁇ 2, ⁇ 3 and R 6 are as defined above), R 25 is a hydrogen atom, human Dorokishiru group or an ester-forming group I do. ]
  • the compound (la) in which a substituent having a hydroxy lower alkyl group or a hydroxy lower alkyl group as its partial structure is substituted with the corresponding carboxylic acid or ester can be produced by reducing the hydride (VI) by a conventional method.
  • the ester-forming group may be any ester-forming group in which the R 25 C 0 group is converted into HOCH 2 ⁇ ⁇ ⁇ by -reduction, and among them, the ester-forming group included in the object of the present invention is particularly preferred.
  • lower alkoxy groups such as ethoxy and ethoxy.
  • the groups R 25 —C 0— Y 11 — and H ⁇ —CH 2 — Y 11 — are described in the form of bonding to any position of the fused benzene ring of the imidazobenzothiazole ring, when a group corresponding to R 1 may be one that binds to Chijimigoi imidazole ring.
  • the iS substituents of the condensed benzene ring are R 2 , R : ⁇ R 4 and R 5 (the same applies to the following substituent conversion method).
  • the reduction is carried out by adding an appropriate metal hydride complex in an appropriate inert solvent (in particular, an alcohol solvent or an ether solvent) and setting appropriate temperature conditions from ice-cooling to reflux temperature.
  • an appropriate inert solvent in particular, an alcohol solvent or an ether solvent
  • a compound (I b) substituted with a hydroxy lower alkyl group and a substituent having a hydroxy lower alkyl group as its partial structure is a corresponding carboxylic acid
  • the ester or aldehyde compound (VII) can be produced by hydride reduction according to a conventional method in the same manner as in method a.
  • reaction method of the substituents on the imidazobenzothiazole ring and the ring A or the ring B can be carried out in the same manner.
  • the reaction of the substituent on the benzothiazole ring is explained, and the description of the applicable reaction on the ring A or the ring B is omitted.
  • R 2 1, R 22, R 23, R 24 and ring A have the meanings given above, R 2 "is a lower alkyl group, C 3 - 8 cycloalkyl group, 1 to 3 ⁇ substituents
  • X 2 represents a group represented by the formula —CO—N (R 6 ) — or —N (R 6 ) —CO—
  • Y i 2 represents one Y 1 - or one Y 1 - ⁇ one Y 2 - a group represented by
  • X 3 is Shiki CH 2 - N (R 6) one or one N (R 6) one CH 2 - group represented by (
  • Y ⁇ 2 and R 6 have the above-mentioned meanings.
  • the compound (I c) substituted with a methylamino group or an aminomethyl group which may be substituted with an amino nitrogen, or a substituent having these groups as its partial structure is a compound having the corresponding carbonyl group. It can be produced by subjecting a mino or rudamoyl compound (VIII) to hydride reduction by a conventional method in the same manner as in the reduction method II.
  • the reduction is the same as in Method A, in which the carbonyl group is reduced to a methylene group, and a suitable hydride / gold complex is added in a suitable inert solvent (especially an ether solvent), and then cooled on ice. This is performed by processing under heating.
  • a suitable inert solvent especially an ether solvent
  • R 2 R 2 R 23 , RR 2 C Y 11 and A3 ⁇ 4l have the above-mentioned meaning
  • M is a hydrogen atom or an aluminum atom
  • X 4 is an oxygen atom or a sulfur atom
  • X 5 represents a halogen atom or an organic sulfonate residue.
  • the compound substituted with a substituent having an ether or thioether structure represented by the formula (Ie) is a compound represented by the formula (Id):
  • the starting material is a metal-substituted compound or a compound substituted with a substituent having these groups as its partial structure
  • etherification is carried out by reacting the compound with a halide or a sulfonate represented by the formula (IX).
  • it can be produced by applying a conventional method of thioetherification.
  • organic sulfonic acid residues include alkanesulfonic acid residues such as methanesulfonyloxy, ethanesulfonyloxy, and trifluoromethanesulfonyloxy, benzenesulfonyloxy, and toluenesulfonyloxy (particularly, aromatic sulfonic acid residue such as p-toluenesulfonyloxy group).
  • the reaction is carried out in an inert solvent (especially DMF), using an excess of one of the compounds (Id) and / or (IX) in a reaction-corresponding amount, if the compound (Id) is not a compound substituted with an alkali metal salt. Is carried out at room temperature in the presence of a suitable inorganic base. If necessary, heating can be performed to accelerate the reaction.
  • an inert solvent especially DMF
  • R 2 R2 2, R 23 , R, R 26, Hachiwa, M, X 4, X 5 and Y 1 1 are each as defined above.
  • the compound (Ie) of the present invention may be an alcohol or a phenol represented by the formula (X), which is contrary to the method a).
  • the compound can also be produced by reacting the compound with a metal or a metal-substituted product thereof.
  • reaction is the same as in method a.
  • imidazobenzothiazole compound is a carboxylic acid or an activated derivative thereof
  • R 27 and R 2 s are the same or different and are a hydrogen atom, lower alkyl S, C : , Means an 8- cycloalkyl group, an aryl group optionally having 1 to 3 substituents or a phenyl lower alkyl group, provided that R 27 and R 28 are integrated with an adjacent nitrogen atom 5 to 6 members which may have 1 to 3 substituents, have at least one nitrogen atom, and may additionally have an oxygen atom and Z or a sulfur atom.
  • a nitrogen-containing saturated heterocyclic group may be formed.
  • the compound represented by the formula (Ii) may be a molybmoyl group, a mono- or di-substituted lubamoyl group, or a nitrogen-containing saturated heterocyclic carbonyl group amide-bonded to a carbonyl group and its nitrogen atom.
  • the amide compound substituted with a substituent having a group as its partial structure is a compound (Ih) having a corresponding carboxyl group or its activating group as a raw material, the carboxylic acid or its activating group is used. It can be produced by amidating the compound (Ih) and ammonia represented by the formula (XI) or mono- or di-lower alkylamine by a conventional method (in the case of ammonia, ammonolysis).
  • a 5- to 6-membered nitrogen-containing saturated heterocyclic group which may further have an oxygen atom or a sulfur atom
  • a 5- to 6-membered nitrogen-containing saturated heterocyclic group which may further have an oxygen atom or a sulfur atom
  • 1-pyrrolidinyl group 1-imidazolidinyl group
  • 1-pyrazolidinyl Groups piperidino group, 1-piperazinyl group, morpholino group, thiomorpholino group and the like, which may have 1 to 3 of the above-mentioned ⁇ -converting groups.
  • the carboxyl-activating group include ordinary esters such as methyl ester and ethyl ester, acid halides such as acid chloride and acid bromide, phenolic compounds such as acid azide and ⁇ -nitrophenol.
  • Active esters, symmetrical acid anhydrides, organic acids based on reaction with alkyl esters of halocarboxylic acids, bivaloyl halides, etc. obtained by reacting with ⁇ -hydroxylamine-based compounds such as A mixed acid anhydride, a phosphoric acid-based mixed acid anhydride obtained by reacting diphenylphosphoryl chloride with methyl morpholine.
  • the reaction is carried out in a suitable inert solvent (particularly, an alcoholic solvent or acetic anhydride, etc.), and the compound (Ih) is liberated using a corresponding amount of the compound (Ih) and / or the compound (XI) in excess.
  • a suitable inert solvent particularly, an alcoholic solvent or acetic anhydride, etc.
  • the reaction is preferably carried out in the presence of a suitable condensing agent, preferably in the presence of a suitable inorganic or organic base, usually at room temperature to heating, and, if necessary, in a sealed tube. Is advantageous.
  • R 7 represents a hydrogen atom, a lower alkyl group, C 3 - 8 It means a cycloalkyl group, an aryl group optionally having 1 to 3 substituents, a phenyl lower alkyl group or acyl S. ]
  • the mono- or diacylamino group represented by the formula (I k), the N-substituted N-acylamino group, or the compound substituted with a substituent containing such a group as a partial structure corresponds to
  • the amino compound (I j) when used as a raw material, it can be produced by a conventional amidation reaction of the carboxylic acid represented by the formula (XII) or an activated derivative thereof or an activated form aldehyde.
  • reaction is the same as in method a.
  • R 2 1, R 2 R 2 3, R 2 R 2 9, A ring, X 5 and Y 1 2 have the meanings given above, R 3.
  • R 3 Is a group represented by the formula —R 12 , one Y 2 —OR 12 , one Y 2 —CO—R 12 or —Y 2 —CO—OR 12 (where R 12 and Y 2 are Has meaning).
  • a compound substituted with a substituted amino group represented by the formula (Im) or a substituent having this group as a partial structure thereof can be prepared by using the corresponding amide compound (I 1) as a raw material.
  • reaction is carried out in a suitable inert solvent or in the absence of a solvent, using an excess of the corresponding amount of compound (I 1) and / or compound (XIII) and, if necessary, an inorganic or organic compound suitable as an acid scavenger. It is advantageous to carry out under cooling, at room temperature or under heating, using a suitable organic base with the addition of a base or together with a solvent and an acid scavenger.
  • R 3 1 is hydrogen atom, lower alkyl 3 ⁇ 4, C 8 cycloalkyl group
  • 1 to 3 R 32 is an aryl group, a phenyl lower alkyl group or an acyl group which may have a substituent represented by the formula: R 12 , Y 2 —OR 12 , Y 2 —CO—R 12 or Y 2 —CO—OR 12 means a group represented by R 12 and Y 2 having the same meaning as described above.
  • R 31 and R 32 may be integrated with an adjacent nitrogen atom, may have 1 to 3 substituents, may be condensed with a benzene ring, and have at least 1 nitrogen atom And a 5- or 6-membered nitrogen-containing saturated heterocyclic group which may further have an oxygen atom and / or a sulfur atom.
  • an amine compound represented by the formula (I 0) a nitrogen-containing saturated heterocyclic compound bonded to an alkyl chain at a nitrogen atom site thereof, or a substituent having any of these groups as its partial structure
  • the compound substituted with is reacted with an amine represented by the formula (XIV) in the opposite manner to the method a.
  • reaction is the same as in method a.
  • R 2 1, R 22, R 23, R 2 and ring A have the meanings given above
  • the X 6 is human Dorokishiru group or a halogen atom, ⁇ formula - ⁇ 1 - one Y 1 — 0— Y 2 — or a group represented by Y 1 — N (R 6 ) —Y 2 — (where Y ⁇ 2 and R 6 have the same meaning as above)
  • X 7 is a group represented by the formula one 0 or _ S 0 2 - 0 - a group represented by, R 33 denotes the same group as R 6 or R 7. ]
  • the sulfonic acid ester or ester, or the compound (Iq) having a substituent containing this group as a partial structure may be a corresponding hydroxyl group or its reaction activating group or this group.
  • the compound (I p) having a substituent having a partial structure is used as a raw material, the compound (I p) is produced by reacting the compound with a carboxylic acid or sulfonic acid represented by the formula (XV) or a reaction activated product thereof. it can.
  • a halide in which a hydroxyl group is converted into a halogen atom is used as a reaction activated form of an alcohol component, and an acid halide, an acid ester, an acid anhydride, and the like are used as a reaction activated form of a carboxylic acid.
  • the reaction activated form include sulfonic acid halide.
  • halide is used as the compound (I p).
  • carboxylic acid / sulfonic acid salts can also be used as their activated form.
  • the reaction is carried out in a suitable inert solvent (especially a halogenated hydrocarbon solvent, ether solvent, aromatic hydrocarbon solvent, etc.) depending on the starting compound, especially the activated form thereof.
  • a suitable inert solvent especially a halogenated hydrocarbon solvent, ether solvent, aromatic hydrocarbon solvent, etc.
  • the reaction is carried out under ice-cooling or warming in the presence of organic salt ⁇ , or in the presence of an appropriate acid catalyst, azeotrope by heating and refluxing while removing water generated from the system using a Dean-Stark dehydrator etc. It is useful to apply dehydration.
  • imidazobenzothiazol compound is a carboxylic acid, sulfonic acid or its activated product
  • X 8 is wherein one CO- or - S0 2 - at the indicated
  • an acyloxy group ester
  • a substituted oxysulfonyl group sulfonate
  • a compound (I s) having a substituent containing this group as a partial structure thereof When the corresponding carboxylic acid, sulfonic acid or its activated product (Ir) is used as a raw material, the lower alcohol or its activated product (XVI) Can be produced by reacting
  • reaction activated form of the alcohol component and the reaction activated form such as carboxylic acid are the same as those described above.
  • the esterification reaction is also similar to that of method a, but if the alcohol (XVI) to be reacted can also serve as a solvent, azeotropic distillation in the presence of the above-mentioned appropriate acid catalyst in the alcohol is carried out. A method of dehydration is advantageously used.
  • R 3 4 - C_ ⁇ first and R 3 5 - C ⁇ - means the same or different and Ashiru group.
  • R 34 and R 3 5 is meaning taste alkylene or Orutofuweniren group come together, may form a cyclic dicarboxylic San'i Mi de. )
  • the compound (I u) substituted with a dicarboxylic acid imido group or a substituent having the group as a partial structure when the corresponding hydroxyl compound (I t) is used as a raw material, It can be produced by applying the Mitsunobu reaction.
  • the reaction may be carried out, if necessary, in an inert gas atmosphere, in a suitable inert solvent (especially an ether solvent), and reacting the corresponding amounts of compound (It) and compound (XVII), or one of them. It is advantageous to use an excess amount and add dropwise ezodicarboxylate getyl ester or the like to a mixed solution of these starting compounds and triflatin phosphine under ice-cooling and stir with the same warm skin.
  • a suitable inert solvent especially an ether solvent
  • R 2] , R 22 , R 23 , R 2 R ′′ R 35 , A ring and Y 12 have the above-mentioned meanings.
  • the compound (IV) substituted with an amino group or a substituent containing an amino group as a partial structure thereof is obtained from the dicarboxylic acid imide compound (Iu) obtained by the above Mitsunobu reaction as a raw material.
  • the compound (IV) substituted with an amino group or a substituent containing an amino group as a partial structure thereof is obtained from the dicarboxylic acid imide compound (Iu) obtained by the above Mitsunobu reaction as a raw material.
  • it can be produced by amide exchange with a hydrazine or the like described in the removal of the protecting group.
  • the reaction is carried out using a starting compound (Iu) and an amine such as hydrazine monohydrate or methylamine in a suitable inert solvent (particularly an alcoholic solvent) at room temperature or under heating or heating. It can be carried out under reflux.
  • a suitable inert solvent particularly an alcoholic solvent
  • Compound (I X) in the compound of the present invention can also be produced by genating the corresponding ester (I w), contrary to the above esterification.
  • the reaction can be carried out by a conventional method, and it is only necessary to add a suitable inorganic base in a suitable inert solvent and carry out heat treatment.
  • imidazobenzothiazole is used as a starting compound and a compound having an acyloxy group is similarly formed into a compound, a corresponding hydroxyl compound can be obtained.
  • Compound (IX) in the compound of the present invention can also be produced by acid hydrolysis of the corresponding nitril (XVIII).
  • reaction can be carried out by applying a conventional method using a suitable acid catalyst in a suitable inert solvent. i i) Synthesis of amine by hydrolysis of carbamic acid ester
  • R 2 1, R 22, R 23, R 24 and ring A have the meanings given above
  • D ring may have 1 to 3 substituents, the benzene ring condensed with even if well, one nitrogen atom has, and heterocyclic groups other oxygen atom and / or sulfur atom have they also may 5 to 6 ⁇ nitrogen saturated least
  • R 36 is a lower Y 14 represents an alkoxy group
  • Y 14 represents a group represented by the formula: Y 1 — or —C ⁇ 1 (where Y 1 has the meaning described above).
  • the cyclic amine of the formula (I z) or a compound substituted with a substituent having the cyclic amine as a partial structure thereof can be obtained by converting the corresponding cyclic carbamic acid ester (I y) to an acid or It can be produced by a method of hydrolysis under alkaline conditions.
  • the reaction can be carried out in a suitable inert solvent (particularly an alcoholic solvent) by adding a suitable acid catalyst, or a suitable inorganic or organic base, followed by a conventional method for treatment.
  • a suitable inert solvent particularly an alcoholic solvent
  • R 37 is a hydrogen atom, C i_ 5 alkyl group, C 3 - 8 cycloalkyl group, 1 to 3 substituents in the optionally substituted ⁇ Li - group, or Fuweniru C, and means _ 5 alkyl group).
  • the aldehyde or ketone compound represented by the formula (I) can be produced by oxidizing a raw material compound (I ⁇ ) substituted with a corresponding hydroxymethyl group or a substituent having the same as a partial structure.
  • a conventional method in which a suitable oxidizing agent is added in a suitable inert solvent and the reaction is carried out at room temperature or under heating can be applied.
  • the desired sulfinyl compound or sulfonyl compound can be obtained by oxidizing the corresponding thioether compound or sulfinyl compound by a conventional method.
  • R 38 is a lower alkyl group, alkyl-based substituted hetero ring nitrogen to R 39 is Group.
  • the compound (I5) in which the B ring group is a 3-morpholinyl group is the same as the corresponding formyl compound (Ia) and tri-lower alkyl-12-hydroxylethylaminomethyl silicate (XIX) It can also be produced by a cyclization method in which a cyclic amine is reacted, and then rearranged with cesium fluoride.
  • the reaction with the silicide is carried out in a suitable inert solvent (particularly an aromatic hydrocarbon solvent) by applying azeotropic dehydration by heating to reflux while removing water generated from the system using a Dean-Stark dehydrator.
  • a suitable inert solvent particularly an aromatic hydrocarbon solvent
  • Suitable for reaction with cesium fluoride In an inert solvent (especially DMF), preferably under a dry condition under an inert gas atmosphere.
  • R 22 , R 23 and R 24 are the same groups as any of R 2 , R 3 or R 4 , R 4 ° is a lower alkyl group, Me represents a methyl group.
  • a compound substituted at the 3-position with a lower alkoxymethyl group and substituted with a dimethylamino group or a substituent having this group as a partial structure at one of the condensed benzene rings (I is the corresponding unsubstituted 3-position fused compound)
  • a compound (I ⁇ ) substituted with a substituent having an amino group or an amino group in the benzene ring as a partial structure is subjected to heat treatment with an aqueous formaldehyde solution and formic acid to simultaneously carry out hydroxymethylation and alkylation. Reaction, then acid treatment with hydrochloric acid etc.
  • the oxime or aldoxime compound represented by the formula (I) is capable of iminating the starting compound (I7?) Substituted with the corresponding ketone or aldehyde or a substituent having the same as a partial structure. Can be manufactured.
  • the reaction is carried out by a conventional method in which a suitable inert solvent (especially an alcoholic solvent), a starting compound (IT?) And hydroxylamine or 0-substituted hydroxylamine are treated with a suitable acid catalyst or a suitable inorganic or organic base. Can be applied.
  • a suitable inert solvent especially an alcoholic solvent
  • I starting compound
  • hydroxylamine or 0-substituted hydroxylamine are treated with a suitable acid catalyst or a suitable inorganic or organic base.
  • a compound in which R 6 is a group other than a hydrogen atom can be prepared by using a compound in which R 6 is a hydrogen atom in the compound (10) of the present invention as a raw material, using an inert solvent (particularly, It can be produced by a conventional method of 0-alkylation with an alkylating agent such as an alkyl halide in acetone, acetonitrile, THF, DMF) in the presence of a suitable base.
  • an alkylating agent such as an alkyl halide in acetone, acetonitrile, THF, DMF
  • R 4 1 is lower alkyl
  • C 3 - means an 8 cycloalkyl group or Fuweniru lower alkyl group
  • the carbamate compound represented by the formula (I) in the compound of the present invention can be produced by subjecting the corresponding carboxylic acid (I) to Crutius rearrangement.
  • the reaction is carried out using an azide such as diphenyl azide phosphoryl in an appropriate inert solvent (particularly DMF or THF), or is converted to an acid chloride by a conventional method using thionyl chloride or the like, followed by azide such as sodium azide.
  • the alcohol can be converted to an acid azide by using alcohol (XXIII) under heating, or when an alcohol also serves as a solvent, a conventional method of heating in the alcohol can be applied.
  • the amino compound represented by the formula (S) can be produced by subjecting the carbamate compound (I / c) to acid or alkali hydrolysis by the above-mentioned conventional method.
  • the novel compound is also contained in the raw material compound (IV) of the method 1, the compound (IV) can be produced according to a known production method as shown below.
  • R 2 R ⁇ R 5 and M are as defined before ⁇ and, R 4 2 means the same group as R 4 other than a hydrogen atom
  • compound (IV) can be produced by reacting an aniline derivative with thiocyanic acid or an alkali metal salt thereof.
  • the protecting group is introduced and reacted, and then the protecting group is removed. Synthesize by applying the mutual conversion method.
  • the compound in which R 4 is a hydrogen atom can be produced by using a substituent interconversion method.
  • the compound of the present invention thus produced is isolated and purified as it is or as a salt thereof.
  • the salt can be produced by a conventional salt formation reaction.
  • the compound of the present invention may be isolated as various solvates or hydrates.
  • the compound of the present invention may be isolated as a substance having various crystal forms such as those constituting a polymorph.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, drying, and various types of chromatography.
  • Various isomers can be isolated by the ⁇ method using the difference in physicochemical properties K between the isomers.
  • a racemic compound can be converted into a general optically active acid (eg, oxalate) or a diastereomer salt with an optically active salt by a general racemic resolution method, and then subjected to optical resolution. It can lead to a pure isomer.
  • the diastereomer can be separated by a conventional method, for example, fractional crystallization or chromatography.
  • An optically active compound can also be produced as a stereoisomerically pure substance K by reacting with an appropriate photoactive starting material compound.
  • the compound (I), (II), or (II), or a pharmaceutically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention, has a strong effect on receiving metabolic glutamate. .
  • the active ingredient of the present invention is epilepsy, pain, neurodegenerative disease (cerebral insufficiency after cardiac bypass surgery and transplantation surgery, seizure, cerebral ischemia, spinal cord injury, head injury, Alzheimer's disease, Huntington's disease) , Amyotrophic lateral sclerosis, AIDS-induced dementia, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, visual impairment and retinopathy, idiopathic and drug-induced Parkinson's disease), benzodiazepine withdrawal Useful for drug syndrome
  • the action of the active ingredient of the present invention on the mesotrophic glutamate receptor was evaluated and confirmed as follows.
  • mG1uR1 is a receptor cloned as a glutamate receptor that couples to G proteins and promotes inositol-phospholipid turnover [Masu M. et al. al., Nature, 349 (1991) 760-765].
  • mG1uR1 ⁇ one of the subtypes of mG1uR1
  • the concentration increases by a factor of 4 to 10 (Kawabata S. ct al., Nature, submitted).
  • the compound of the present invention was evaluated using such properties.
  • NIG 3T3 cells expressing mG1uR1 were cultured in DMEM containing 10% dialyzed fetal calf serum, 100 units / ml, 0-1 mg / ml streptomycin sulfate. did.
  • the cells were seeded at 1 ⁇ 10 5 cells on a 13.5 mm diameter glass cover slip and used for the next experiment.
  • Fura 2-AM was loaded onto cells at a final concentration of 6 in Balance salt solution (hereinafter referred to as BBS) at room temperature for 1 hour. After washing the cells twice with BBS, the intracellular calcium concentration was measured using a fluorescence spectrophotometer.
  • BBS Balance salt solution
  • Me has the above-mentioned meaning
  • Ph means a phenyl group
  • Et means an ethyl group.
  • the compounds (I), (II) and (III), or the pharmaceutically acceptable salts thereof, which are the active ingredients of the pharmaceutical composition of the present invention are notable metabolites. It has glutamate receptor action (antagonism).
  • the 7-substituted 12-phenylimidazo [2,1-b] benzothiazole compound contained in the compound (III) has a mesotopic glutamate receptor action which is different from the pharmacological action described in the above-mentioned known literature. , Is remarkably excellent.
  • the preparations containing the compound (I) provided by the present invention in particular, the compound (III) or (III) or a pharmaceutically acceptable salt thereof may be used in the form of a carrier or excipient used in usual pharmaceutical preparations It is prepared using agents and other additives.
  • Administration is oral, such as tablets, pills, capsules, granules, powders, and liquids, or non-injection, such as intravenous or intramuscular injections, suppositories, transdermals, inhalants, or intravesical injections. Any form of oral administration may be used.
  • the dose is appropriately determined depending on the individual case in consideration of the symptoms, age, sex, etc. of the administration subject.In general, in the case of oral administration, about 1 mg / kg to 100 mg / day of an adult per day, preferably about 50 mg / day / kg to 200mg / kg, which should be administered once or in 2 to 4 divided doses.
  • the dose per adult is about lmgZkg to 100 mg / kg, preferably about 50mg / kg to 200mg / kg, and is administered once or in 2 to 4 divided doses.
  • the dose is usually 1 to multiple times per day for adults in the range of ImgZkg to SO OmgZkg. It is administered intravenously or by intravenous administration for 1 H 1 to 24 hours. Since the dose fluctuates under rare conditions, it is smaller than the above range.] H: may be sufficient.
  • the one or more active substances may comprise at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolid. Don, mixed with magnesium metasilicate aluminate.
  • the composition may contain, in a conventional manner, additives other than inert diluents, for example, lubricating agents such as magnesium stearate, disintegrating agents such as calcium cellulose glycolate, and stabilizing agents such as lactose.
  • Glutamate may contain a solubilizing or solubilizing agent such as aspartic acid.
  • Tablets or pills may be coated with sugar, such as sucrose, gelatin, hydroxypropinoresenolylose, hydroxypropinolemethinoresenole, or sucrose, as needed, or a film of gastric or enteric substance. May be.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified Contains water and ethanol.
  • the composition may contain, in addition to the inert diluent, auxiliaries such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • sterile aqueous ala includes non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 and the like.
  • Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents (eg, lactose), solubilizing or dissolving aids (eg, glutamate, aspartic acid). May be included.
  • These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide or irradiation. They may also be manufactured as sterile solid compositions, prior to use. Can be used by dissolving it in sterile water or a sterile solvent for injection.
  • the starting compounds of the present invention also include novel compounds.
  • the production method of the starting compounds is shown in Reference Examples.
  • mp melting point
  • NMR nuclear magnetic resonance spectrum
  • MS mass spectrum
  • Example 2 The compound of Example 2 was obtained in the same manner as in Example 1. mp: 217-219 ° C
  • Example 24 The compound of Example 24 was obtained in the same manner as in Example 23.
  • Ethanol (15 ml) was added with ice-cooled brick and 60% oily sodium hydride (447 mg) in an argon atmosphere, and the mixture was stirred at room temperature for 15 minutes. Then, to this was added (2-phenylimidazo [2,1-b] benzothiazo-1-yl 7-yl) methyl mesylate (200 mg), and the mixture was heated under reflux for 30 minutes. After cooling to room temperature, water was added, extracted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate.
  • Example 26 The compound of Example 26 was obtained in the same manner as in Example 25.
  • Example 27 The compound of Example 27 was obtained in the same manner as in Example 25.
  • ⁇ -L7Z d ui tsuma-(Sui 6 ) eyes 6 ?: 9: 4 ⁇ - ⁇ —cho '' / ⁇ 3 ⁇ 43 ⁇ 4 ⁇ ⁇ 3 ⁇ 43 ⁇ 4? ⁇ ⁇ ⁇ S ⁇ 3.0 ⁇ ⁇ ' ! 3 ⁇ 4 (! ⁇ 0)) (-["*.
  • N- (2-phenylimidazo [2,1—b] benzothiazolyl-7-yl) acetamide (307 mg) was dissolved in DMF (3 ml) and dissolved in 60% oil. Hydrogen sodium (50 mg) was added and the mixture was stirred at room temperature until hydrogen generation ceased. Next, methyl iodide (2001) was added, and the mixture was stirred at room temperature overnight. DMF was distilled off under reduced pressure, and the residue was dissolved in chloroform, washed with water, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain about 300 mg of a pale yellow solid. This was purified by silica gel column chromatography (form: chloroform, 30: 1) to obtain the desired product (220 mg) as a colorless solid.
  • Example 43 After the same procedure as in Example 1, the compound of Example 43 was obtained by converting into the hydrochloride. m ⁇ : 145-147 ° C
  • Example 46 In the same manner as in Example 1, the compound of Example 46 was obtained as a hydrobromide.
  • Example 51 The following compound of Example 51 was obtained in the same manner as in Example 49.
  • Acetic anhydride (0.5 ml) was added to a solution of 7-hydroxymethyl-2-phenylimidazo [2,11-b] benzothiazol (140 mg) in pyridine (3 ml) at room temperature at room temperature. The mixture was stirred at the same temperature for 2 hours. After completion of the reaction, water was added, extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was respun from getyl ether to obtain the desired product (130 mg) as colorless crystals.
  • Example 57 The following compound of Example 57 was obtained in the same manner as in Example 56.
  • Ethyl 7-methoxymethyl-2- 2-phenylimidazo [2,1—b] benzothiazol-6-carboxylate (170 mg) was dissolved in THF and methanol in a 2: 1 mixed solvent (15 ml), 1 N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, diluted with water, and then neutralized with acetic acid. The precipitate was collected by filtration and washed with water to give the desired product (143 mg) as a pale yellow product.
  • Example 59 In the same manner as in Example 58, the following compound of Example 59 was obtained.
  • Example 61 The following compound of Example 61 was obtained in the same manner as in Example 60.

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Abstract

L'invention porte sur des préparations médicinales contenant des composés représentés par la formule générale suivante (I) ou leurs sels, acceptables du point de vue pharmaceutique, ayant une activité agonistique à l'égard du récepteur du glutamate métabotropique et se révélant ainsi des plus utiles en tant que remèdes ou palliatifs de différentes maladies, notamment l'épilepsie, les algies, la maladie de Parkinson, etc. Cette invention, qui concerne également l'utilisation qui est faite de ces composés pour la production de ces préparations, des méthodes thérapeutiques concernant les maladies susmentionnées par administration desdits composés à des doses efficaces a trait, de surcroît, à des dérivés d'imidazobenzothiazyle (II) et (III) ou à leurs sels acceptables du point de vue pharmaceutique, employés comme remèdes contre les maladies susmentionnées. Dans ces formules, le noyau A représente un aryle, éventuellement substitué, et un groupe hétérocycle monocyclique ou bicyclique, R1 représente H, un halogéno, un alkyle de faible poids moléculaire, un hydroxy (alkyle de faible poids moléculaire), un alcoxy de faible poids moléculaire (alkyle de faible poids moléculaire) ou un alcoxy de faible poids moléculaire, R?2, R3, R4 et R5¿ représentent chacun un substituant choisi dans le groupe constitué par H, par un halogéno, un alkyle de faible poids moléculaire, CN, NO¿2?, par un alcoxy, un thiol, un carboxylate, un sulfonate, un carbamyle, un amine, un alkyle et par des hétérocycles substitués, R?11, R12 et R14¿ représentent les mêmes substituants que R?2, R3, R4 et R5¿, à l'exclusion de substituants spécifiques et de leurs combinaisons, et R13 représente un hydroxyméthyle, etc.
PCT/JP1997/002748 1996-08-09 1997-08-07 Agonistes du recepteur du glutamate metabotropique WO1998006724A1 (fr)

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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0891978A3 (fr) * 1997-07-18 1999-02-03 F. Hoffmann-La Roche Ag Derives de 5h-thiazolo[3,2-a]pyrimidine
WO2000059913A1 (fr) * 1999-04-06 2000-10-12 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives de thiazolobenzimidazole
DE19948434A1 (de) * 1999-10-08 2001-06-07 Gruenenthal Gmbh Substanzbibliothek enthaltend bicyclische Imidazo-5-amine und/oder bicyclische Imidazo-3-amine
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US8883783B2 (en) 2007-09-19 2014-11-11 Ambit Biosciences Corporation Solid forms comprising N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea, compositions thereof, and uses therewith
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
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US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
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US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
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US6455283B1 (en) 1998-03-17 2002-09-24 Genentech, Inc. Nucleic acids encoding vascular endothelial cell growth factor-E (VEGF-E)
US6642264B1 (en) 1999-04-06 2003-11-04 Yamanouchi Pharmaceutical Co., Ltd. Thiazolobenzoimidazole derivatives
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DE19948434A1 (de) * 1999-10-08 2001-06-07 Gruenenthal Gmbh Substanzbibliothek enthaltend bicyclische Imidazo-5-amine und/oder bicyclische Imidazo-3-amine
WO2002062803A1 (fr) * 2001-02-08 2002-08-15 Yamanouchi Pharmaceutical Co., Ltd. Derive de thienopyrimidine
US9266834B2 (en) 2006-03-15 2016-02-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US7820657B2 (en) 2006-03-17 2010-10-26 Ambit Biosciences Corporation Imidazolothiazole compounds for the treatment of disease
US8921546B2 (en) 2006-03-17 2014-12-30 Ambit Biosciences Corporation Imidazolothiazole compounds for the treatment of disease
US8557810B2 (en) 2006-03-17 2013-10-15 Ambit Biosciences Corporation Imidazolothiazole compounds for the treatment of disease
US8129374B2 (en) 2006-03-17 2012-03-06 Ambit Bioscience Corporation Method of using imidazolothiazole compounds for the treatment of disease
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US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US9132122B2 (en) 2007-09-14 2015-09-15 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US8883783B2 (en) 2007-09-19 2014-11-11 Ambit Biosciences Corporation Solid forms comprising N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea, compositions thereof, and uses therewith
US9585892B2 (en) 2007-09-19 2017-03-07 Ambit Biosciences Solid forms comprising N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea, compositions thereof, and uses therewith
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
WO2010092111A3 (fr) * 2009-02-11 2010-11-04 Technische Universität München Composés pour la mesure non vulnérante d'agrégats de peptides amyloïdes
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9737533B2 (en) 2009-05-12 2017-08-22 Janssen Pharmaceuticals. Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
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US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
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JP2015212272A (ja) * 2009-11-05 2015-11-26 アムビト ビオスシエンセス コルポラチオン イミダゾ［２，１−ｂ］［１，３］ベンゾチアゾール誘導体の調製方法
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US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
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JP7360106B2 (ja) 2017-12-28 2023-10-12 小胞体ストレス研究所株式会社 ベンゾチアゾイミダゾリル化合物を含有する小胞体ストレス調節剤
JPWO2019131656A1 (ja) * 2017-12-28 2021-01-21 小胞体ストレス研究所株式会社 ベンゾチアゾイミダゾリル化合物を含有する小胞体ストレス調節剤
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