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WO1999009986A1 - Derives de 4-aminoquinazoline - Google Patents

Derives de 4-aminoquinazoline Download PDF

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Publication number
WO1999009986A1
WO1999009986A1 PCT/JP1998/003711 JP9803711W WO9909986A1 WO 1999009986 A1 WO1999009986 A1 WO 1999009986A1 JP 9803711 W JP9803711 W JP 9803711W WO 9909986 A1 WO9909986 A1 WO 9909986A1
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WIPO (PCT)
Prior art keywords
substituted
unsubstituted
lower alkyl
mmol
compound
Prior art date
Application number
PCT/JP1998/003711
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English (en)
Japanese (ja)
Inventor
Kimihisa Ueno
Yuji Nomoto
Kotaro Takasaki
Miho Yoshida
Hideaki Kusaka
Hiroshi Yano
Satoshi Nakanishi
Yuzuru Matsuda
Noriaki Uesaka
Chiharu Suzuki
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
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Publication date
Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to AU87487/98A priority Critical patent/AU8748798A/en
Publication of WO1999009986A1 publication Critical patent/WO1999009986A1/fr

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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

Definitions

  • the present invention relates to an insulin secretagogue and a therapeutic agent for diabetes containing a 4-aminoquinazoline derivative as an active ingredient.
  • the present invention also relates to a 4-aminoquinazoline derivative having a glucose concentration-dependent promoting action on insulin secretion and a suitable hypoglycemic action, and being useful as a therapeutic agent for diabetes.
  • Diabetes is a condition characterized by inappropriately elevated blood sugar levels, abnormal insulin secretion and various metabolic and vascular abnormalities, in which various treatments are ineffective or ineffective. If left untreated-severe complications may occur due to arterial and neurological disorders caused by hyperglycemia. For this reason, measures for lowering blood glucose have been studied for a very long time.
  • glycemic control can be performed by a combination of exercise therapy and drugs that lower blood glucose levels.
  • an insulin secretagogue is currently widely used in clinical practice as one of the oral hypoglycemic agents.
  • currently available insulin secretagogues induce insulin secretion independent of the concentration of dalcos, so that wrong doses can cause severe hypoglycemia or It is unsatisfactory because it can only improve the blood sugar control to the extent that it cannot be performed.Therefore, there is a danger of causing hypoglycemia by inducing insulin according to the blood glucose level. Few as insulin secretagogues What is effective for blood sugar management of diabetic patients is desired.
  • R la represents hydrogen, halogen, lower alkyl or lower an alkoxy
  • R 2a represents hydrogen, lower alkyl, etc.
  • R 3a represents a full Weniru etc.
  • R 4a, 1 5 & Oyobi 1 6 £ 1 represents hydrogen, halogen, nitro, etc.
  • JP-A-47-22927 discloses that the following compounds and their acid addition salts are useful as anti-inflammatory agents.
  • R lb represents hydrogen, lower alkyl, lower alkoxy, etc.
  • R 2b and R 3b are the same or different and represent hydrogen, lower alkyl, hydroxy lower alkyl, etc.
  • R 4b is hydrogen, halogen, lower Alkyl Or represents lower alkoxy
  • An object of the present invention is to provide an insulin secretagogue and a therapeutic agent for diabetes, which comprise a 4-aminoquinazoline derivative as an active ingredient.
  • the present invention provides a compound of the formula (I)
  • R 1A and R 1 B are the same or different and each is hydrogen, lower alkyl, lower alkoxy, halogen, two collected by filtration, - NR 3 4 (wherein, R 3 Contact and R 4 are hydrogen or the same or different , — NHCOR 5 (where R 5 represents lower alkyl), — NHS ⁇ 2 R 6 (where R fi represents lower alkyl), — CONR 7 R 8 (wherein, R 7 and R 8 are the same or different and each is hydrogen, lower alkyl or represents Ararukiru), lower alkoxycarbonyl, or carboxy or is a lower Arukanoiru or become R 1B guard ⁇ adjacent to the R 1A - Represents (CH 2 ) n 0-(where n represents 1 or 2), Cy represents a substituted or unsubstituted aryl, and R 2 represents hydrogen or substituted or unsubstituted.
  • the present invention also relates to a therapeutic agent for diabetes comprising Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for preventing or treating diabetes comprising administering an effective amount of compound (I) or a pharmacologically acceptable salt thereof, and insulin secretion deficiency or insulin secretion.
  • the present invention relates to a method for preventing or treating a disease state caused by a decrease in susceptibility.
  • the present invention also relates to a method for preventing or treating diabetes and the production of a pharmacological composition useful for preventing or treating a condition caused by insulin secretion deficiency or reduced insulin sensitivity.
  • a pharmacological composition useful for preventing or treating a condition caused by insulin secretion deficiency or reduced insulin sensitivity.
  • compound (I) or a pharmaceutically acceptable salt thereof for use of compound (I) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a compound (I) or a pharmacologically active compound thereof for the prevention or treatment of diabetes and the prevention or treatment of a condition caused by insulin secretion deficiency or decreased insulin sensitivity.
  • a compound (I) or a pharmacologically active compound thereof for the prevention or treatment of diabetes and the prevention or treatment of a condition caused by insulin secretion deficiency or decreased insulin sensitivity.
  • the present invention provides a compound of the formula (IA) R 2X , n 'A X
  • R 1AX and R 1Bx the same or different and each is hydrogen, lower alk kill, lower alkoxy, Nono androgenic, two collected by filtration, - NR 3 R 4 (wherein, R 3 and R 4 are each as defined above Yes), — NHC 0 R 5
  • C y represents substituted or unsubstituted aryl
  • R 2X represents hydrogen or substituted or unsubstituted lower alkyl
  • a x represents hydrogen, substituted or unsubstituted lower alkyl, substituted Unsubstituted or substituted cycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl
  • substituted Re represents an unsubstituted or unsubstituted heterocyclic group, a substituted or unsubstituted heterocyclic lower alkyl or a substituted or unsubstituted unsaturated heterocyclic lower alkyl
  • R 2X and A x together with the adjacent nitrogen atom represent a substituted or unsubstituted heterocyclic group
  • R 1AX and R 1Bx Do both represent hydrogen, or R 1AX is hydrogen and R 1Bx lower alkyl, lower alkoxy, halogen, two collected by filtration or - NR 3 R 4 (wherein, R 3 and R 4 are Is as defined above):
  • R 2 X represents hydrogen or substituted or unsubstituted lower alkyl
  • a x is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkyl lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic lower alkyl or Represents a substituted or unsubstituted unsaturated heterocyclic lower alkyl, or R 2 X and A x together with an adjacent nitrogen atom represent a substituted or unsubstituted heterocyclic group;
  • Cy is substituted or unsubstituted phenyl (the substituted phenyl is the same or different from unsubstituted lower alkyl, unsubstituted lower alkoxy, halogen, nitro, hydroxy and amino) 3)
  • R 2 X represents hydrogen or substituted or unsubstituted lower alkyl
  • a x is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl, substituted aralkyl, substituted Or an unsubstituted heterocyclic group or a substituted or unsubstituted unsaturated heterocyclic lower alkyl]] or a pharmacologically acceptable salt thereof.
  • the lower alkyl moiety of lower alkyl, lower alkoxy, lower alkylthio, lower alkoxycarbonyl, cycloalkyl lower alkyl, heterocyclic lower alkyl and unsaturated heterocyclic lower alkyl examples include linear or branched C 1 -C 8 carbon atoms such as methyl, ethyl, propyl, and isoprene.
  • Mouth pill butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc.
  • the alkylene of aralkyl represents a group obtained by removing a hydrogen atom from the lower alkyl moiety described above
  • Lower alkanols include straight-chain or branched-chain C 1 to C 9, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, norrelyl, isono, relinole, pino'royl, hexanoyl. , Heptanyl, octanoyl, nonanoyl and the like.
  • Examples of the cycloalkyl moiety of cycloalkyl and cycloalkyl lower alkyl include a carbon ring having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • Nodrogens include fluorine, chlorine, bromine and iodine atoms.
  • the aryl portions of aryl and aralkyl include phenyl, naphthyl and anthryl.
  • Examples of the heterocyclic group and the heterocyclic group portion of the heterocyclic lower alkyl include an aromatic heterocyclic group and an alicyclic heterocyclic group.
  • Examples of the aromatic heterocyclic group include pyridyl and pyrazinyl. , Pyrimidinyl, biridazinyl, benzimidazolyl, indazolyl, indolyl, isoindril, prenyl, quinolyl.
  • Triazolyl Triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenyl and the like.
  • alicyclic heterocyclic group include, for example, pyrrolidinyl, thiazolidinyl, oxazolidinyl, piperidyl, and the like.
  • heterocyclic group bonded to the adjacent nitrogen atom examples include pyrrolidinyl, thiazolidinyl, oxazolidinyl, piperidino, piperazinyl, homopiperazinyl, morpholino, thiomorpholino, and tetrahydrin.
  • the lower alkyl, cycloalkyl, cycloalkyl lower alkyl, alkylene portion of aralkyl and lower alkoxy have the same or the same or same substituents as those having 1 to 3 substituents, such as lower alkoxy, halogen, hydroxy, lower alkoxycarbonyl, carboxy, Mono or di-lower alkylamino may, for example, be mentioned.
  • the lower alkyl portion of the mono- or di-lower alkylamino has the same meaning as the lower alkyl
  • the lower alkoxy, halogen and lower alkoxycarbonyl have the same meanings as above.
  • the substituents on the aryl portion of the aryl and aralkyl and the heterocyclic portion of the heterocyclic group, the heterocyclic lower alkyl and the unsaturated heterocyclic lower alkyl may be the same or the same having 1 to 3 substituents.
  • lower alkyl, lower alkoxy, halogen, lower alkoxycarbonyl, mono- or di-lower alkylamino, aryl, aralkyl and heterocyclic group are as defined above.
  • the substituents of lower alkyl and lower alkoxy may be the same or different and have 1 to 3 substituents, such as lower alkoxy, halogen, hydroxy, lower alkoxycarbonyl, carboxy, mono- or di-lower alkylamino, and alicyclic heterocyclic.
  • Lower alkoxy, nodogen, lower alkoxycarbonyl, mono- or di-lower alkylamino and alicyclic heterocyclic group are as defined above.
  • the substituents of aryl are the same or different and have 1 to 3 substituents such as lower alkyl, lower alkoxy, halogen, nitro, hydroxy, lower alkoxycarbonyl, carboxy, mono- or di-lower alkylamino, complex
  • a lower alkyl, a lower alkoxy, a halogen, a lower alkoxycarbonyl, a mono- or di-lower alkylamino, and a heterocyclic group are as defined above.
  • Examples of the substituent of the substituted heterocyclic group include the same or different substituted or unsubstituted lower alkyl having 1 to 3 substituents, substituted or unsubstituted lower alkoxy, nodogen, and nitrogen.
  • Lower alkyl and Examples of the substituent of the lower alkoxy include lower alkoxy, halogen, hydroxy, lower alkoxycarbonyl, carboxy, mono- or di-lower alkylamino, alicyclic heterocyclic group, and the like.
  • Lower alkoxy, nodogen, lower Alkoxycarbonyl, mono- or di-lower alkylamino and alicyclic heterocyclic group have the same meanings as above.
  • Substituents for aryl and heterocyclic groups include lower alkyl, lower alkoxy, nodogen, nitro, hydroxy, lower alkoxycarbonyl, carboxy, mono- or di-lower alkylamino, and complex ring groups.
  • the lower alkyl, halogen, lower alkoxy, lower alkoxycarbonyl, mono- or di-lower alkylamino and heterocyclic groups are as defined above.
  • lower alkyl, lower alkoxy, halogen, lower alkoxycarbonyl, mono- or di-lower alkylamino, aryl, aralkyl and heterocyclic group are the same as defined above for lower alkyl and lower alkoxy.
  • lower alkoxy, halogen, lower alkoxycarbonyl mono- or di-lower alkylamino And alicyclic heterocyclic groups are as defined above.
  • Aryl and heterocyclic group substituents Lower alkyl, lower alkoxy, nodogen, nitro, hydroxy, lower alkoxycarbonyl, carboxy, mono- or di-lower alkylamino, heterocyclic group, etc., and lower alkyl, halogen, lower alkoxy, lower alkoxycarbonyl,
  • the mono- or di-lower alkylamino and the heterocyclic group are as defined above.
  • a non-toxic, water-soluble salt is preferred, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc.
  • acid addition salts such as organic acid salts such as tartrate, alkali metal salts such as sodium salts and calcium salts, alkaline earth metal salts such as magnesium salts and calcium salts, ammonium salts And ammonium salts such as tetramethylammonium and the like, and organic amine addition salts such as morpholine addition salt and piperidine addition salt.
  • Compound (I) can be produced by a series of reactions shown below.
  • Compound (I) can be produced according to the following reaction steps.
  • the compound (X) is a 2-styryl-4-quinazolinone derivative
  • the compound (I) is prepared by converting the compound (X) with 1 equivalent to an excess amount of the amine (XI) to a lower alcohol such as ethanol or isoprononol, tetrahydrofuran, N, N-dimethylformamide or the like. Reaction in an organic solvent, if necessary, in the presence of a base such as N, N-diisop-piruethylamine at a temperature between room temperature and the boiling point of the solvent used, for several hours to several days, preferably 5 to 48 hours Can be obtained.
  • a base such as N, N-diisop-piruethylamine
  • 2-Styryl_4-monoquinazolinone derivative (IX) is a compound
  • Compound (IX) can be prepared by using a compound (II) described in US Pat. No. 3,970,648 or the like as an aldehyde which is commercially available or can be produced by a known method.
  • (V) is dissolved in a solvent such as acetic anhydride, acetic acid, or trifluoroacetic acid, in the presence of 1 to 10 equivalents of ammonium acetate, sodium acetate, or the like, or an alcohol, N, N— Metallic alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or organic amines such as pyridin in a solvent such as dimethylformamide It can be obtained by reacting at a temperature between 100 and 200 ° C.
  • compound (IX) is the same as compound (II) and 2 Reacting ⁇ 5 equivalents of compound (V) with acetic acid in the presence of 2-5 equivalents of ammonium acetate at a temperature between 100 ° C. and the boiling point of acetic acid for 1-48 hours Can be obtained.
  • Compound (IX) is obtained by combining compound (III) or compound (IV) with compound (VI) which is commercially available or can be produced by a known method in a solvent such as pyridine. —Reaction in the presence of dimethylaminoviridine at a temperature between 0 ° C. and room temperature for 1 to 24 hours to obtain compound (VII) or compound (VIII). 0 to 30% sodium hydroxide, hydrating power In an aqueous solution such as room temperature, if necessary, in the presence of an alcohol such as ethanol, between 70 ° C and the boiling point of the solvent used This can be obtained by heating at a temperature for 1 to 24 hours.
  • Compound (I) can also be produced according to the method described in US Pat. No. 4,661,621 or a modification thereof, according to the following reaction steps.
  • the compound (XII) is produced in the same manner as in the production method A, in which the compound (X) is obtained from the compound (IX).
  • the compound (II) can be obtained by treating the compound (II) with a chromating agent.
  • Compound (XIII) can be obtained by reacting compound (XII) with amine (XI) in the same manner as in production method A to obtain compound (I) from compound (X). Can be.
  • compound (I) is a compound
  • a part of the compound (I) obtained here can be used as a synthetic intermediate to further lead to a new derivative (I).
  • a compound R 1A or R 1B is ⁇ Mi Roh among the compounds (I) (la), the compound (I) No Chi R 1A or of the R 1B crab collected by filtration Compound (lb) in acetic acid or concentrated hydrochloric acid or in a mixed solvent of these with an organic solvent such as ethanol, 3 to 10 equivalents, preferably 3 to 5 equivalents of zinc, tin, iron, tin dichloride, etc.
  • 1-5 hours 1-5 atmospheres, preferably 1-2 atmospheres of hydrogen gas, or the compound (lb) in an inert solvent such as tetrahydrofuran.
  • 1 to 24 equivalents preferably 1 to 5 hours at a temperature between 0 ° C and room temperature in the presence of ⁇ 5 equivalents, preferably 1-2 equivalents of a reducing agent such as lithium aluminum hydride Can be obtained by doing so.
  • R 5 has the same meaning as defined above
  • equivalents of carboxylic acid R 5 C 0 2 H acid halide derived from an acid anhydride or mixed acid anhydride 1-2 equivalents of In a solvent such as N, N-dimethylformamide or tetrahydrofuran in the presence of a base such as triethylamine or pyridine, a temperature between 0 ° C and the boiling point of the solvent used is 1 to 24.
  • a base such as pyridin or triethylamine
  • reaction can be carried out at a temperature of about to room temperature for 1 to 24 hours, preferably 1 to 4 hours.
  • Compound (I) No Chi R 1 A or R 1 B gar NHS_ ⁇ 2 R beta (wherein, R 6 has the same meaning as defined above) compound is (I d), the compound
  • (I e) is a compound (I f) in which R 1A or R is 1 C 2 H of the compound (I) in an inert solvent such as dichloromethan or tetrahydrofuran in an amount of from 1 equivalent to 1 equivalent.
  • Acid halide preferably obtained by treating for 1 to 3 hours, or Is the compound (If) and 1 to 2 equivalents of ethyl chlorocarbonate in an inert solvent such as dichloromethane and tetrahydrofuran at a temperature of 0.5 ° C to 0.5 ° C at a temperature between 0 ° C and room temperature.
  • a condensing agent such as 1 to 5 equivalents, preferably 1 to 3 equivalents of N, N-dicyclohexylcarpoimide, 1-ethyl-3_ (3'-dimethylaminopropyl) carpoimide
  • a base such as pyridine or triethylamine
  • the compound (Ig) in which R 1A or R 1B is a lower alkynyl group other than formyl is a compound in which R or R 1B in the compound (I) is halogen, preferably iodine.
  • (Ih) and 1 to 5 equivalents, preferably 1 to 2 equivalents of the corresponding trialkyl (1-alkoxyalkenyl) tin are treated with N, N-dimethylformamide,
  • an inert solvent such as lahydrofuran
  • 0.1 to 1 equivalent, preferably 0.1 to 0.2 equivalent of a catalyst such as dichlorobistriphenylphosphine palladium, between room temperature and the boiling point of the solvent used. It can be obtained by reacting at a temperature for 1 to 12 hours, preferably for 1 to 4 hours.
  • the compound (Ii) having a hydroxymethyl moiety in Cy is a compound (Ij) having a lower alkoxycarbonyl moiety in Cy, and a compound such as tetrahydrofuran. 1 to 10 equivalents, preferably 1 to 3 equivalents, of a reducing agent such as lithium borohydride or lithium aluminum hydride in a solvent such as a ter-based solvent at a temperature between 0 ° C and room temperature. , 1 to 24 hours, preferably 1 to 3 hours.
  • the compound (Ii) is obtained by converting a compound (Ik) having a lower alkoxy moiety in Cy into an inert solvent such as dichloroethane, benzene, cyclohexane, or a Lewis compound such as aluminum chloride or getylaluminum.
  • the treatment can be carried out for 1 to 48 hours in the presence of an acid or in a strong acid such as trifluoroacetic acid or hydrobromic acid at a temperature between room temperature and the boiling point of the solvent used.
  • the compound (Im) having a mono- or di-lower alkylaminomethyl moiety or a heterocyclic methyl moiety together with an adjacent nitrogen atom in Cy is the compound (Ii) 1 to: L 0 equivalents, preferably 1 to 2 equivalents of methanesulfonyl chloride, p-toluenesulfonyl chloride, etc., and inactive such as methylene chloride, chloroform, N, N-dimethylformamide, tetrahydrofuran, etc.
  • a temperature between 0 ° C and the boiling point of the solvent to be used preferably At a temperature between 0 ° C and room temperature for 1-48 hours, preferably 1
  • a compound (Ii) in which the hydroxyl group is protected by an appropriate leaving group is obtained, and then the obtained protected form is used in an amount of 1 to 10 equivalents, preferably 1 to 5 equivalents.
  • Equivalent amount of the corresponding mono- or di-lower alkylamine or heterocyclic amine in a solvent such as methanol, ethanol, N-methylbilidone, tetrahydrofuran, etc. 1 to 24 hours, preferably 5 to 12 hours, at a temperature between room temperature and 150 ° C using a sealed container (such as a sealed tube) as necessary. It can be obtained by reacting.
  • Compound (I n) of compound (I) having a halogenomethyl moiety in Cy can be obtained by converting compound (I i) without solvent or dichloromethane, tetrahydrofuran, N, N-dimethylformamide 1 to equivalent of solvent in a solvent such as thionyl chloride, at a temperature between 0 ° C and the boiling point of the solvent used, for 1 to 24 hours, preferably 1 to 24 hours. Treat for 10 hours or compound (Ii) in a solvent such as tetrahydrofuran, N, N-dimethylformamide with 1-3 equivalents of lithium halide and 1-3 equivalents.
  • Compound (Im) is prepared by combining compound (In) with 1 to 10 equivalents, preferably:! To 5 equivalents of the corresponding mono- or di-lower alkylamine or heterocyclic amide, In a solvent such as drofuran or N, N-dimethylformamide, 1 to 10 equivalents, preferably 1 to 5 equivalents of a base such as potassium carbonate or N, N-diisopropylethylamine Below. It can also be obtained by reacting at a temperature between room temperature and the boiling point of the solvent used, preferably at room temperature, for 1-24 hours, preferably 3-8 hours. You.
  • the intermediates and the target compound in the above production method are purified by methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and high performance liquid chromatography using silica gel.
  • the intermediate can be subjected to the next reaction without purification.
  • a salt of compound (I) if compound (I) is obtained in the form of a salt, it may be purified as it is, or if compound (I) is obtained in a free form, compound (I) May be dissolved or suspended in a suitable solvent.
  • a salt may be formed by adding a suitable acid or base to isolate.
  • the compound (I) may have various resting holidays: ⁇ : which are all included in the concept of the present invention.
  • Compound (I) and its pharmaceutically acceptable salts may be in the form of adducts with water or various solvents, and these adducts are also included in the present invention. .
  • Table 1 shows specific examples of the compound (I) obtained by the above production method.
  • Ph phenyl n- Bu: n-butyl Table 1 continued
  • Test Example 1 Insulin secretion promoting activity by 5 cultured cells
  • the culture of MIN 6 cells and the insulin secretion test using MIN 6 cells were basically carried out according to the literature (Ishihara et al., Diabethology, Vol. 36, pp. 113-114-145, 1993).
  • the effect of the compound on insulin secretion activity in the presence of 14.5 mM glucose was determined by measuring the amount of insulin in the cell culture supernatant collected as follows.
  • the MIN6 cells cultured in the 24-well plate were added to buffer A containing 2 mM glucose (119 mM sodium chloride, 4.74 mM calcium chloride, 2.54 mM calcium chloride, 1.1 9 mM magnesium sulfate, 1.19 mM lithium dihydrogen phosphate, 10 mM 2— [4- (2-hydroxyshethyl) 1-1—pirazinyl] ethanesulfonic acid, 0.1% After washing twice with 1 ml of bovine serum albumin pH 7.3), the mixture was incubated at 37 ° C. for 45 minutes in buffer A containing 1 ml of 2 mM glucose.
  • the culture supernatant was replaced with a buffer A (0.9 ml) containing various concentrations of the test compound and 2 mM glucose, and further incubated at 37 ° C for 15 minutes.
  • MIN6 cells were stimulated with glucose by adding buffer A (O.lml) containing 127 mM glucose (final glucose concentration: 14.5 mM). After stimulation, the cells were incubated at 37 ° C for 45 minutes, and the culture supernatant was collected.
  • the effect of the compounds on insulin secretion activity in the presence of 5 mM glucose was determined by measuring the amount of insulin in the cell supernatant collected as follows. Cultured on 24 plates MIN6 cells were washed twice with 1 ml of buffer A containing 5 mM glucose, and then replaced with buffer A (0.9 ml) containing various concentrations of the test compound and 5 mM glucose. Thereafter, the cells were incubated at 37 ° C for 45 minutes (final glucose concentration: 5 mM), and the culture supernatant was collected.
  • Antibody-reactive insulin secreted into the culture supernatant is a phosphate buffer containing 1% bovine serum albumin, 0.1% Tween 20, 0.12% EDTA'2Na, and 0.1% sodium azide. After dilution, quantification was performed by enzyme immunoassay or radioimmunoassay. The insulin secretion promoting activity of the test compound was calculated by the following formula. The results were shown as the average value (avg) of 3 to 4 cases. Insulin secretion promoting activity (ng / ml)-Insulin secretion in the presence of test compound-Insulin secretion in the absence of test compound Table 2
  • the compound of the present invention was shown to have insulin secretion activity under high concentration of glucose. In addition, these compounds had no significant secretion promoting activity under low concentration of glucose (5 mM). On the other hand, glibenclamide (Pharma Coserabi, Vol. 5, p. 43, 1985), which was used as a control, had a remarkable secretion promoting activity even under low concentration of glucose.
  • the compound of the present invention did not show an insulin secretion promoting effect even when orally administered to a fasted normal rat (SD male).
  • the inhibitory effect of the compound of the present invention on the increase in blood glucose level is based on a report by Hillaire-Buys et al. (British Journal Journal of Pharmacy, Vol. 109, Vol. 1, pp. 183, 1993). The blood glucose levels before and after administration of the compound of the present invention and before and after the glucose load were tested.
  • Test example (2) Inhibition test of blood sugar increase in glucose load in a diabetic model animal (hypoglycemic effect on blood glucose level after GK rat glucose load)
  • test compound (10 mg / kg) was dissolved in dimethyl acetate After mixing with polyoxy-hardened ethylene castor oil, it was further mixed with physiological saline to obtain a drug solution.
  • Glucose was dissolved in distilled water and adjusted to a concentration of 50% (W / V%).
  • a 12-week-old male GK rat was used for the experiment.
  • the animals were anesthetized by intraperitoneal injection of pentobarbi sodium at a dose of 5 Omg / kg body weight. After fixation in the dorsal position, an incision was made on the analogous part, and a force neura was inserted into the left carotid artery and the left jugular vein. The other end of the force neuron passed under the skin and was fixed outside the body from the back. The patient was fasted for 16 hours postoperatively, but had free access to water for the experiment.
  • heparin was administered at a dose of 1000 U / kg body weight through an intravenous indwelling forcenula.
  • the drug solution was administered via an intravenous force neuron, immediately followed by 0.3 ml of saline from the same force neuron.
  • the solvent used for the drug solution was similarly administered to the control group. Two minutes after drug administration, the glucose solution is
  • Oral administration was performed at a dose of 4 ml / kg body weight. Blood was collected from the urea indwelling in the artery 4 minutes before glucose loading and at 15 330 ⁇ 60 ⁇ 120 ⁇ 180 minutes after sugar loading, and at 300 rpm at 4 ° C. The mixture was centrifuged for 15 minutes, and the concentration of glucose in the supernatant was measured by the glucose oxidase method (Clinini Chemistry, Vol. 6, p. 4666, 1960). The results were shown as the average value of glucose concentration and the standard dose of one case in four cases.
  • Compound (I) and a pharmacologically acceptable salt thereof are useful for the treatment of diabetes because they exhibit an insulin secretion-promoting action in 5 cultured cells and a hypoglycemic action in rats.
  • Compound (I) or a pharmacologically acceptable salt thereof may be a commonly used drug such as tablets, pills, capsules, powders, granules, syrups, injections, drops, suppositories, etc. It can be prepared in a form that can be administered orally or parenterally, such as by intramuscular injection, intravenous injection, infusion, or rectally via suppositories.
  • parenterally such as by intramuscular injection, intravenous injection, infusion, or rectally via suppositories.
  • dosage forms for oral or parenteral administration generally known methods are applied, for example, various excipients, lubricants, binders, disintegrants, suspending agents, etc. It may contain a tonicity agent, an emulsifier and the like.
  • Pharmaceutical carriers to be used include, for example, sucrose, gelatin, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, alginic acid, talc and sodium citrate.
  • the compound (I) and a pharmacologically acceptable salt thereof for the above purpose, it is usually administered systemically or locally in an oral or parenteral form.
  • the dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, and the like.
  • OOO mg / adult per adult, 1 time per person, or per adult It is orally or parenterally administered once to several times a day in the range of 1 to 100 mg per dose, or is continuously administered intravenously for 1 to 24 hours a day.
  • a dose smaller than the above dose may be sufficient, or administration outside the range may be necessary.
  • a tablet having the following composition was prepared by a conventional method.
  • a capsule having the following composition was prepared by a conventional method.
  • Example 4 was obtained from 4-black mouth _ 6, 7-dimethoxy 2-(E)-styrylquinazoline (250 mg, 0.77 mmol) obtained in a. In a similar manner, N, N-diisopropylethylamine
  • the N, N-diisopropylethylethyla was prepared from the 4,7-dichroic mouth-2- (E) -styrylquinazoline (0.24 g, 0.80 mmol) obtained in Reference Example 2b in the same manner as in Example 1.
  • the title compound (77 mg, 25%) was obtained using min (0.14 ml, 0.80 mmol) and 4- (2-aminoethyl) pyridine (0.18 ml, 1.60 mmol).
  • Example 21 2 [2— ( ⁇ )-(4—chloromethylphenyl) vinyl] _6,7—dimethoxy-1-4-piperidinoquinazoline (200 mg, 0.47 mmol) obtained in 1 was converted to N, N—dimethylform The solution was dissolved in amide (5 ml), potassium carbonate (0.32 g, 2.35 mmol) and a 50% aqueous dimethylamine solution (0.06 ml, 1.42 mmol) were added, and the mixture was stirred at room temperature for 7 hours. The solvent was distilled off from the reaction mixture under reduced pressure, and the obtained residue was extracted with chloroform and water.
  • Example 26 7-Ethoxycarbonyl-4- (piperidino-2- (E))-styrylquinazoline (200 mg, 0.52 mmol) obtained in 6 was obtained by adding 10 ml of tetrahydrofuran and 5 ml of tetrahydrofuran. The mixture was dissolved in a mixed solvent, 1N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction solution was washed with ether and separated, the obtained aqueous layer was adjusted to pH 3 with 1N hydrochloric acid. The precipitated crystals were collected by filtration and dried to give the title compound (143 mg, 77%).
  • 6-phenyl-4- 4-piperidino-2- (E) -styryleki obtained by the same method as in Example 1 or according to the method described in German Patent No. 2,135,172.
  • Nazolin (361 mg, 0.82 mmol) is dissolved in N, N-dimethylformamide (5 ml), and triptyl (1-ethoxyvinyl) tin (0.55 ml, 1.64 mmol) and dichlorobistriphenylphosphine are dissolved.
  • Innoradium 58 mg, 0.08 mmol
  • 5% hydrochloric acid (8 ml) was added, and the mixture was stirred at room temperature.
  • Reference Example 2 4 black mouth—6, 7—dimethoxy-1 2—obtained in a
  • Example 4 (4 — tert-butoxycarbonylbiperazine-1-yl)-1, 6, 7-dimethoxy-2-[2-(E)-(4-methoxycarbonyl) obtained in 5 Enyl) vinyl] quinazoline (551 mg, 1.03 mmol) and trifluoroacetic acid (5.0 ml) were obtained in the same manner as in Example 37 to give the title compound (369 mg, 82%).
  • 6,7-Dimethoxy-1-methylquinazoline-1 (3H) -one and 4-trifluoromethoxybenzaldehyde can be obtained by the same method as in Reference Example 1a followed by Reference Example 2a.
  • Black mouth— 2 [21- (E)-(4-trifluoromethoxyphenyl) vinyl] — 6,7—Dimethoxyquinazoline (300 mg, 0.73 mmol), 50% by the same method as in Example 1.
  • the title compound (20 mg, 65%) was obtained using dimethylamine aqueous solution (10 ml, 0.1 lmol).
  • 6,7-Dimethoxy-2-methylquinazoline-l-4 (3H) -one and 2,3-methylenedioxybenzaldehyde can be obtained in the same manner as in Reference Example 1a and then in Reference Example 2a.
  • the title compound (0.25 g, 81%) was obtained by using a 50% aqueous dimethylamine solution (10.0 ml, O.llmol) according to the method described above.
  • the title compound (339 mg, 88%) was prepared using N-diisopropylethylamine (0.15 ml, 0.84 mmol) and 2 — (2-methylaminoethyl) pyridin (() .47 ml, 3.4 mmol). Obtained.
  • the title compound (0.30 g, 98%) was obtained from (300 mg, 0.88 mmol) in the same manner as in Example 1 using a 50% aqueous solution of dimethylamine (10 ml, O.llmol).
  • the obtained crystals were dissolved in methylene chloride (10 ml), trifluoroacetic acid (10 ml) was slowly added at room temperature, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was evaporated under reduced pressure, and the residue was recrystallized from hexane / chloroform to give the title compound (341 mg, 16%).
  • an insulin secretagogue and a therapeutic agent for diabetes containing a 4-aminoquinazoline derivative as an active ingredient it is possible to provide an insulin secretagogue and a therapeutic agent for diabetes containing a 4-aminoquinazoline derivative as an active ingredient.

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Abstract

L'invention se rapporte à des promoteurs de sécrétion d'insuline qui contiennent en tant que principe actif des dérivés de 4-aminoquinazoline représentés par la formule générale (I), ainsi qu'à des sels pharmacologiquement acceptables de ces promoteurs. Dans la formule (I), R?1A et R1B¿ sont identiques ou différents et représentent l'hydrogène, un alkyle inférieur, un alcoxy inférieur, un halogéno, un nitro, -NR?3R4 (où R3 et R4¿ sont identiques ou différents et représentent chacun l'hydrogène ou un alkyle inférieur), etc., ou bien R1A peut former en association avec R1B auquel il est adjacent -O-(CH¿2?)nO- (où n est égal à 1 ou 2); Cy représente un aryle éventuellement substitué; R?2¿ représente l'hydrogène ou un alkyle inférieur éventuellement substitué; et A représente l'hydrogène ou un alkyle inférieur éventuellement substitué, un cycloalkyle éventuellement substitué, etc., ou bien R2 et A peuvent former en association avec l'atome d'azote auquel ils sont adjacents, un hétérocycle éventuellement substitué.
PCT/JP1998/003711 1997-08-22 1998-08-21 Derives de 4-aminoquinazoline WO1999009986A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001072710A1 (fr) * 2000-03-31 2001-10-04 Nippon Shinyaku Co., Ltd. Dérivés et médicaments hétérocycliques
WO2002024667A1 (fr) * 2000-09-20 2002-03-28 Merck Patent Gmbh 4-amino-quinazolines
WO2002036577A1 (fr) * 2000-11-02 2002-05-10 Nippon Shinyaku Co., Ltd. Derives quinazoline et medicaments
WO2002062767A1 (fr) * 2001-02-07 2002-08-15 Sumitomo Pharmaceuticals Company, Limited Nouveaux derives de quinazoline
WO2002024666A3 (fr) * 2000-09-20 2002-09-26 Merck Patent Gmbh 4-amino-quinazolines
WO2004005265A1 (fr) * 2002-07-05 2004-01-15 F. Hoffmann-La Roche Ag Derives de quinazoline
JP2007524637A (ja) * 2003-07-03 2007-08-30 ミリアド ジェネティクス， インコーポレイテッド カスパーゼの活性化因子およびアポトーシスの誘発因子としての４−アリールアミノ−キナゾリン
US7829566B2 (en) 2001-09-17 2010-11-09 Werner Mederski 4-amino-quinazolines
US7989462B2 (en) 2003-07-03 2011-08-02 Myrexis, Inc. 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
US8318730B2 (en) 2003-11-10 2012-11-27 Synta Pharmaceuticals Corporation Fused hetrocyclic compounds
JP2016525570A (ja) * 2013-07-31 2016-08-25 カウンスル オブ サイエンティフィック アンド インダストリアル リサーチ 新規インダゾール化合物とその調製方法

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001072710A1 (fr) * 2000-03-31 2001-10-04 Nippon Shinyaku Co., Ltd. Dérivés et médicaments hétérocycliques
US6794389B2 (en) 2000-03-31 2004-09-21 Nippon Shinyaku Co., Ltd. Quinazoline derivatives and drugs
WO2002024666A3 (fr) * 2000-09-20 2002-09-26 Merck Patent Gmbh 4-amino-quinazolines
WO2002024667A1 (fr) * 2000-09-20 2002-03-28 Merck Patent Gmbh 4-amino-quinazolines
US7220751B2 (en) 2000-11-02 2007-05-22 Nippon Shinyaku Co., Ltd. Quinazoline derivatives and drugs
WO2002036577A1 (fr) * 2000-11-02 2002-05-10 Nippon Shinyaku Co., Ltd. Derives quinazoline et medicaments
WO2002062767A1 (fr) * 2001-02-07 2002-08-15 Sumitomo Pharmaceuticals Company, Limited Nouveaux derives de quinazoline
US7829566B2 (en) 2001-09-17 2010-11-09 Werner Mederski 4-amino-quinazolines
WO2004005265A1 (fr) * 2002-07-05 2004-01-15 F. Hoffmann-La Roche Ag Derives de quinazoline
US7205309B2 (en) 2002-07-05 2007-04-17 Hoffmann-La Roche Inc. Quinazoline derivatives
JP2007524637A (ja) * 2003-07-03 2007-08-30 ミリアド ジェネティクス， インコーポレイテッド カスパーゼの活性化因子およびアポトーシスの誘発因子としての４−アリールアミノ−キナゾリン
US7618975B2 (en) 2003-07-03 2009-11-17 Myriad Pharmaceuticals, Inc. 4-arylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US7989462B2 (en) 2003-07-03 2011-08-02 Myrexis, Inc. 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
US8318730B2 (en) 2003-11-10 2012-11-27 Synta Pharmaceuticals Corporation Fused hetrocyclic compounds
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
JP2016525570A (ja) * 2013-07-31 2016-08-25 カウンスル オブ サイエンティフィック アンド インダストリアル リサーチ 新規インダゾール化合物とその調製方法

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