WO1999035142A1 - Derives de 4-(3-indolyl)imidazole - Google Patents

Derives de 4-(3-indolyl)imidazole Download PDF

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Publication number
WO1999035142A1
WO1999035142A1 PCT/JP1998/005985 JP9805985W WO9935142A1 WO 1999035142 A1 WO1999035142 A1 WO 1999035142A1 JP 9805985 W JP9805985 W JP 9805985W WO 9935142 A1 WO9935142 A1 WO 9935142A1
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WO
WIPO (PCT)
Prior art keywords
group
imidazole
lower alkyl
salt
phenyl
Prior art date
Application number
PCT/JP1998/005985
Other languages
English (en)
Japanese (ja)
Inventor
Tomomi Ota
Misa Nakanishi
Kazuyuki Tomisawa
Takeo Kobori
Yuriko Hatanaka
Original Assignee
Taisho Pharmaceutical Co., Ltd.
Sagami Chemical Research Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co., Ltd., Sagami Chemical Research Center filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to AU16917/99A priority Critical patent/AU1691799A/en
Publication of WO1999035142A1 publication Critical patent/WO1999035142A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a 4— (3-indolinyl) imidazole derivative and a salt thereof, which have a Ca—calmodulin-dependent phosphodiesterase (PDEI) inhibitory action.
  • PDEI Ca—calmodulin-dependent phosphodiesterase
  • Japanese Patent Application Laid-Open No. 188585/1992 discloses a 4- (3-indolinyl) imidazole derivative in which an aryl group such as a 3-fluorophenyl group is imidazole.
  • a compound having a ring at the 2-position is disclosed, but the compound described in the present invention has not been reported. Disclosure of the invention
  • the present inventors have conducted intensive studies on compounds having a Ca—calmodulin-dependent phosphodiesterase (PDEI) inhibitory action, and as a result, have found that a certain 41- (3-indryl) imidazole skeleton has been developed. Possession The inventors have found that the compound satisfies the above purpose, and have further completed the present invention based on the knowledge.
  • PDEI Ca—calmodulin-dependent phosphodiesterase
  • R 1 is the formula
  • R 2 represents a lower alkoxy group.
  • R 3 represents a lower alkyl group, a nitro group, a chenyl group, an alkoxycarbonyl group or a halogen atom, and R 4 represents a lower alkyl group, a phenyl group, a hydroxy group, a phenoxy group, a cyano group.
  • a lower alkyl group means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group.
  • examples include a pill group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, and an isohexyl group.
  • Alkoxycarbonyl group means a linear or branched alkoxycarbonyl group having 2 to 7 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group. , Isopropoxycarbonyl, butoxycanolebonyl, isobutoxycanolebonyl, sec-butoxycanolebonyl, tert-butoxycanoleboninole, pentinoleoxycanoleboninole, hexyloxycarbo And a benzyl group.
  • the acylamino group means an aromatic acylamino group or an aliphatic acylamino group having 1 to 6 carbon atoms, such as a benzoylamino group, a naphthoinoinorea group, or an amino group. Examples thereof include a cetamide group, a propionylamino group, a petrylulamino group, and a valerylamino group.
  • the alkylthio group means a linear or branched alkylthio group having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, and iso. Butylthio, sec-butylthio, tert-butylthio, pentynolethio, hexylthio and the like.
  • the lower alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, Butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopene Tiloxy group, hexyloxy group and the like.
  • a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or a iodine atom.
  • the Po Li main switch LES down harbor R 6 and R 7 are together a connexion forming means Po Li main Chi Le emissions group having 2-6, dimethyl Chi Le emissions group, Application Benefits main switch les down Group, tetramethylene group, pentamethylene group, hexamethylene group and the like.
  • the salts may be those that are pharmaceutically enjoyable, for example, inorganic salts such as hydrochloride, hydrobromide, and sulfate, methansulfonate, p-toluene, and the like. Sulfonates such as sulfonates can be used.
  • the imidazole compound of the formula (1) has the following tautomers in the imidazole portion thereof, and these tautomers are also present in the present invention. included in the range of j.
  • the compound of the formula (1) can be produced, for example, by the following production scheme.
  • the compound represented by the formula (3) is condensed in the presence of Lewis acid to obtain the compound represented by the formula (3).
  • reaction temperature is from 0 ° C to the reflux temperature.
  • the compound of the present invention (1) is reacted by reacting the compound of the formula (3) with the compound of the formula (4) in the presence of excess ammonia or ammonium salt.
  • ammonium acetate, ammonium oxalate, ammonium carbonate, or the like can be used as the ammonium salt
  • the reaction solvent such as acetic acid, propionic acid, or the like can be used.
  • Fatty acids, methanol, Ananol such as ethanol, dioxane, ethers such as tetrahydrofuran and the like can be used.
  • the reaction temperature ranges from room temperature to reflux temperature.
  • the compound of the present invention can be converted into an appropriate pharmaceutical composition (tablets, pills, capsules, granules, dry mouth, injections, etc.) using known carriers, diluents and the like. It can be used orally or parenterally with adjustment. .
  • Solid additives are manufactured using various additives such as excipients, disintegrants, binders, lubricants, and coating bases, using agitation granulation, fluidized bed granulation, and crushing. It can be manufactured by the granulation method.
  • an antioxidant if necessary, an antioxidant, a coating agent, a coloring agent, a flavoring agent, a surfactant, a plasticizer, and the like can be added.
  • the dosage of the active ingredient of the medicament of the present invention varies depending on the age, body weight, administration form and the like, but it is usually 0.1 to 100 mgz / day for an adult, which may be taken once a day or once a day. Administer several divided doses. Industrial availability
  • the compound of the present invention has a Ca—calmodulin-dependent phosphodiesterase (PDEI) inhibitory effect, and by increasing the concentration of cAMP and cGMP in cells, Exhibits pharmacological action.
  • PDEI Ca—calmodulin-dependent phosphodiesterase
  • cAMP and cGMP a Ca—calmodulin-dependent phosphodiesterase
  • Exhibits pharmacological action PDEI is abundant in vascular smooth muscle and brain, and PDEI inhibitors have cerebral vasodilatory and central nervous system improving functions, so central dysfunction after cerebral vascular occlusion, cerebrovascular dementia, senile dementia It is useful for improving cerebral circulation or central function for diseases such as dysfunction, memory and learning dysfunction. Best mode for applying the invention Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.
  • Table 1 shows the structural formulas of the compounds produced according to Examples 1 to 38. Here, the compound number indicates the example number. Table 1
  • PDEI was prepared from bovine cerebrum and used in a two-step method (Bioche m. Biophys. Res. Commun., 169, 315-322).
  • the concentration of each substance in the reaction mixture was adjusted to a final concentration of 2501, and the final concentration of DMS0 was adjusted to 1%.
  • the reaction was stopped by transferring the test tube into a boiling water bath and heating for 5 minutes, then transferred into ice water and cooled.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés de 4-(3-indolyl)imidazole représentés par la formule générale (1), y compris les sels pharmaceutiquement acceptables de ces dérivés. Dans ladite formule, R1 est un groupe représenté par l'une des deux formules générales (a) ou (b). R2 est alcoxy inférieur; R3 est alkyle inférieur, nitro, thiényle, alcoxycarbonyle, ou halogéno, R4 est alkyle inférieur, phényle, hydroxy, phénoxy, cyano, alcoxycarbonyle, acylamino, alkylthio, carboxy, NR6R7, O(CF¿2)mR?8, ou O(CH¿2?)nR?9; R5¿ est hydrogène, alkyle inférieur, alcoxy inférieur, ou halogéno; R6 et R7 sont identiques ou différents, et chacun est alkyle inférieur, ou bien les deux ensembles forment un groupe polyméthylène; R8 est hydrogène ou halogéno; R9 est phényle ou naphtyle; et m et n sont chacun un entier valant de 1 à 4.
PCT/JP1998/005985 1998-01-05 1998-12-28 Derives de 4-(3-indolyl)imidazole WO1999035142A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU16917/99A AU1691799A (en) 1998-01-05 1998-12-28 4-(3-indolyl)imidazole derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP10/354 1998-01-05
JP35598 1998-01-05
JP10/355 1998-01-05
JP35498 1998-01-05

Publications (1)

Publication Number Publication Date
WO1999035142A1 true WO1999035142A1 (fr) 1999-07-15

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/005985 WO1999035142A1 (fr) 1998-01-05 1998-12-28 Derives de 4-(3-indolyl)imidazole

Country Status (2)

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AU (1) AU1691799A (fr)
WO (1) WO1999035142A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10314820B2 (en) 2014-12-04 2019-06-11 Procomcure Biotech Gmbh Imidazole-based heterocyclic compounds
US10322110B2 (en) 2014-12-04 2019-06-18 Procomcure Biotech Gmbh Imidazole-based antimicrobial agents

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02188579A (ja) * 1989-01-13 1990-07-24 Taisho Pharmaceut Co Ltd インドリルイミダゾール誘導体
JPH07126255A (ja) * 1993-09-10 1995-05-16 Eisai Co Ltd キナゾリン系化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02188579A (ja) * 1989-01-13 1990-07-24 Taisho Pharmaceut Co Ltd インドリルイミダゾール誘導体
JPH07126255A (ja) * 1993-09-10 1995-05-16 Eisai Co Ltd キナゾリン系化合物

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10314820B2 (en) 2014-12-04 2019-06-11 Procomcure Biotech Gmbh Imidazole-based heterocyclic compounds
US10322110B2 (en) 2014-12-04 2019-06-18 Procomcure Biotech Gmbh Imidazole-based antimicrobial agents
US10456379B2 (en) 2014-12-04 2019-10-29 Procomcure Biotech Gmbh Imidazole-based antimicrobial agents

Also Published As

Publication number Publication date
AU1691799A (en) 1999-07-26

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