JPH04243888A - Imidazo(1,2-a)pyridine derivative, production thereof and alpha-haloketone derivative as intermediate - Google Patents
Imidazo(1,2-a)pyridine derivative, production thereof and alpha-haloketone derivative as intermediateInfo
- Publication number
- JPH04243888A JPH04243888A JP8714391A JP8714391A JPH04243888A JP H04243888 A JPH04243888 A JP H04243888A JP 8714391 A JP8714391 A JP 8714391A JP 8714391 A JP8714391 A JP 8714391A JP H04243888 A JPH04243888 A JP H04243888A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- lower alkyl
- imidazo
- derivative
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
- 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 125000005843 halogen group Chemical group 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 13
- 230000002140 halogenating effect Effects 0.000 abstract description 8
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 239000012442 inert solvent Substances 0.000 abstract description 4
- 238000010992 reflux Methods 0.000 abstract description 3
- NYWUXWTYRPOTAX-UHFFFAOYSA-N 6-bromo-2-[4-(diethoxyphosphorylmethyl)phenyl]imidazo[1,2-a]pyridine Chemical compound C1=CC(CP(=O)(OCC)OCC)=CC=C1C1=CN(C=C(Br)C=C2)C2=N1 NYWUXWTYRPOTAX-UHFFFAOYSA-N 0.000 abstract description 2
- 150000003927 aminopyridines Chemical class 0.000 abstract description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 230000000302 ischemic effect Effects 0.000 abstract 1
- 230000010410 reperfusion Effects 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- -1 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy Chemical group 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 206010063837 Reperfusion injury Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- PRXNKYBFWAWBNZ-UHFFFAOYSA-N trimethylphenylammonium tribromide Chemical compound Br[Br-]Br.C[N+](C)(C)C1=CC=CC=C1 PRXNKYBFWAWBNZ-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CYNUDAYTCFRGQT-UHFFFAOYSA-N 1-[4-(diethoxyphosphorylmethyl)phenyl]ethanone Chemical compound CCOP(=O)(OCC)CC1=CC=C(C(C)=O)C=C1 CYNUDAYTCFRGQT-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- 239000004342 Benzoyl peroxide Substances 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000010446 mirabilite Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- SFLXUZPXEWWQNH-UHFFFAOYSA-K tetrabutylazanium;tribromide Chemical compound [Br-].[Br-].[Br-].CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC SFLXUZPXEWWQNH-UHFFFAOYSA-K 0.000 description 2
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 2
- DTLTUUJDCNTTSN-UHFFFAOYSA-N 1,4-dioxane;molecular bromine Chemical compound BrBr.C1COCCO1 DTLTUUJDCNTTSN-UHFFFAOYSA-N 0.000 description 1
- HARITLZHGNEHDS-UHFFFAOYSA-N 1-[4-(bromomethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=C(CBr)C=C1 HARITLZHGNEHDS-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- STNUMTOOSHSJCR-UHFFFAOYSA-N 2-bromo-1-[4-(diethoxyphosphorylmethyl)phenyl]ethanone Chemical compound CCOP(=O)(OCC)CC1=CC=C(C(=O)CBr)C=C1 STNUMTOOSHSJCR-UHFFFAOYSA-N 0.000 description 1
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000013824 Acidemia Diseases 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 238000005377 adsorption chromatography Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- NSBNSZAXNUGWDJ-UHFFFAOYSA-O monopyridin-1-ium tribromide Chemical compound Br[Br-]Br.C1=CC=[NH+]C=C1 NSBNSZAXNUGWDJ-UHFFFAOYSA-O 0.000 description 1
- 125000005246 nonafluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Abstract
Description
【０００１】0001
【産業上の利用分野】本発明は新規なイミダゾ［１，２
−ａ］ピリジン誘導体、その製造方法及びその中間体と
してのα−ハロケトン誘導体に関する。[Industrial Application Field] The present invention provides a novel imidazo [1,2
-a] Pyridine derivatives, methods for producing the same, and α-haloketone derivatives as intermediates thereof.
【０００２】0002
【従来の技術】本発明のイミダゾ［１，２−ａ］ピリジ
ン誘導体及びその中間体としてのα−ハロケトン誘導体
は、いずれも文献未載の新規化合物である。BACKGROUND OF THE INVENTION The imidazo[1,2-a]pyridine derivative of the present invention and the α-haloketone derivative as an intermediate therefor are both new compounds that have not been described in any literature.
【０００３】0003
【発明が解決しようとする課題】本発明は後記するよう
に医薬品として有用な化合物及びその製造用中間体とし
ての化合物を提供することを目的とする。OBJECTS OF THE INVENTION As described below, the object of the present invention is to provide a compound useful as a pharmaceutical and a compound as an intermediate for its production.
【０００４】0004
【課題を解決するための手段】本発明によれば、一般式
（１）[Means for Solving the Problems] According to the present invention, general formula (1)
【０００５】[0005]
【化５】
で表わされるイミダゾ［１，２−ａ］ピリジン誘導体が
提供される。An imidazo[1,2-a]pyridine derivative represented by the following formula is provided.
【０００６】上記一般式（１）中、Ｒ１及びＲ２はそれ
ぞれ水素原子、低級アルキル基、ハロゲン原子、ニトロ
基、フェニル低級アルコキシ基、低級アルコキシカルボ
ニル基又はハロゲン置換低級アルキル基を示し、Ｒ３は
水素原子、低級アルキル基又はフェニル基を、Ｒ４は低
級アルキル基をそれぞれ示す。In the above general formula (1), R1 and R2 each represent a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a phenyl lower alkoxy group, a lower alkoxycarbonyl group, or a halogen-substituted lower alkyl group, and R3 represents hydrogen. R4 represents an atom, a lower alkyl group or a phenyl group, and R4 represents a lower alkyl group.
【０００７】また本発明によれば、一般式（２）According to the present invention, general formula (2)
【００
０８】00
08]
【化６】
［式中Ｒ３及びＲ４は上記に同じ。Ｘはハロゲン原子を
示す。］で表わされる化合物と一般式（３）embedded image [In the formula, R3 and R4 are the same as above. X represents a halogen atom. ] and general formula (3)
【０００９
】0009
]
【化７】
［式中Ｒ１及びＲ２は上記に同じ。］で表わされる化合
物とを縮合反応させることによる上記一般式（１）で表
わされるイミダゾ［１，２−ａ］ピリジン誘導体の製造
方法が提供される。embedded image [In the formula, R1 and R2 are the same as above. ] A method for producing an imidazo[1,2-a]pyridine derivative represented by the above general formula (1) by carrying out a condensation reaction with a compound represented by the following is provided.
【００１０】更に本発明によれば、上記一般式（１）で
表わされるイミダゾ［１，２−ａ］ピリジン誘導体の製
造に用いられる上記一般式（２）で表わされるα−ハロ
ケトン誘導体が提供される。Further, according to the present invention, there is provided an α-haloketone derivative represented by the above general formula (2), which is used in the production of an imidazo[1,2-a]pyridine derivative represented by the above general formula (1). Ru.
【００１１】上記一般式（１）〜（３）において示され
る各基としては、具体的にはそれぞれ以下の各基を例示
できる。即ち、低級アルキル基としては、例えばメチル
、エチル、プロピル、イソプロピル、ブチル、イソブチ
ル、ｔｅｒｔ−ブチル、ペンチル、ヘキシル基等の直鎖
又は分岐鎖状の低級アルキル基を例示できる。フェニル
低級アルコキシ基としては、例えばベンジルオキシ、１
−フェニルエトキシ、２−フェニルエトキシ、３−フェ
ニルプロポキシ、４−フェニルブトキシ、２−フェニル
プロポキシ基等を例示できる。低級アルコキシカルボニ
ル基としては、例えばメトキシカルボニル、エトキシカ
ルボニル、プロポキシカルボニル、イソプロポキシカル
ボニル、ブトキシカルボニル、ｔｅｒｔ一ブトキシカル
ボニル基等を例示できる。ハロゲン置換低級アルキル基
としては、例えばトリフルオロメチル、ペンタフルオロ
エチル、ヘプタフルオロプロピル、ノナフルオロブチル
、ウンデカフルオロペンチル、トリデカフルオロヘキシ
ル基等を例示できる。またハロゲン原子には、弗素原子
、塩素原子、臭素原子、沃素原子が包含される。Specific examples of the groups represented by the above general formulas (1) to (3) include the following groups. That is, examples of lower alkyl groups include linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups. Examples of the phenyl lower alkoxy group include benzyloxy, 1
Examples include -phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, and 2-phenylpropoxy groups. Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and tert-butoxycarbonyl. Examples of the halogen-substituted lower alkyl group include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, nonafluorobutyl, undecafluoropentyl, and tridecafluorohexyl groups. Further, the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
【００１２】上記一般式（１）で表わされる本発明誘導
体は、優れた脂質低下作用及び虚血再灌流障害改善作用
を有しており、高脂質血症治療剤及び虚血再灌流障害改
善剤として、例えば高コレステロール血症、高トリグリ
セリド血症、高リン脂質血症、高遊離脂肪酸血症等の各
種疾患（高脂質血症）の、また虚血再灌流障害の治療及
び予防に有用である。The derivative of the present invention represented by the above general formula (1) has an excellent lipid lowering effect and an ischemia reperfusion injury improving effect, and is useful as a hyperlipidemia therapeutic agent and an ischemia reperfusion injury improving agent. It is useful for the treatment and prevention of various diseases (hyperlipidemia) such as hypercholesterolemia, hypertriglyceridemia, hyperphospholipidemia, and hyperfree fatty acidemia, as well as for the treatment and prevention of ischemia-reperfusion injury. .
【００１３】本発明のイミダゾ［１，２−ａ］ピリジン
誘導体は、各種の方法により製造することができる。そ
の具体例を下記反応工程式−１に示す。
反応工程式−１The imidazo[1,2-a]pyridine derivative of the present invention can be produced by various methods. A specific example thereof is shown in Reaction Scheme-1 below. Reaction scheme-1
【００１４】[0014]
【化８】
［各式中Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＸは前記に同じ。
］上記反応工程式に示すα−ハロケトン誘導体（２）と
アミノピリジン誘導体（３）との反応は、反応に悪影響
を及ぼさない不活性溶媒、例えば低級アルコール類、芳
香族炭化水素類、１，２−ジメトキシエタン、１，４−
ジオキサン等の鎖状乃至環状エーテル類、アセトニトリ
ル等の溶媒中で行なわれる。化合物（２）と化合物（３
）との使用割合は、特に限定されないが、通常前者に対
して後者を等モル量〜過剰量用いるのがよい。
反応は好ましくは上記溶媒の還流温度条件下で行なわれ
、用いる化合物（２）及び（３）の種類により異なるが
、一般に約１〜２０時間程度で終了し、かくして目的化
合物（１）を収得できる。embedded image [In each formula, R1, R2, R3, R4 and X are the same as above. ] The reaction between the α-haloketone derivative (2) and the aminopyridine derivative (3) shown in the above reaction scheme can be carried out using an inert solvent that does not adversely affect the reaction, such as lower alcohols, aromatic hydrocarbons, 1,2 -dimethoxyethane, 1,4-
It is carried out in a linear or cyclic ether such as dioxane or a solvent such as acetonitrile. Compound (2) and compound (3
) is not particularly limited, but it is usually preferable to use an equimolar amount to an excess amount of the latter to the former. The reaction is preferably carried out under the reflux temperature condition of the above-mentioned solvent, and although it varies depending on the types of compounds (2) and (3) used, it is generally completed in about 1 to 20 hours, and thus the target compound (1) can be obtained. .
【００１５】尚、上記に示すα−ハロケトン誘導体（２
）は、文献未載の新規化合物であり、例えば下記反応工
程式−２に示す方法により製造できる。
反応工程式−２[0015] The above α-haloketone derivative (2)
) is a new compound that has not been described in any literature, and can be produced, for example, by the method shown in Reaction Scheme-2 below. Reaction scheme-2
【００１６】[0016]
【化９】
［各式中Ｒ３、Ｒ４及びＸは前記に同じ。Ｙはハロゲン
原子を示す。］上記において、化合物（４）のハロゲン
化反応は、ベンゼン、四塩化炭素等の不活性溶媒中、過
酸化ベンゾイル、アゾビスイソブチロニトリル、ｔ−ブ
チルハイドロパーオキシド等の触媒の存在下、Ｎ−プロ
ムコハク酸イミド、Ｎ−クロルコハク酸イミド、臭素等
のハロゲン化剤と処理することにより行なわれる。ハロ
ゲン化剤の使用量は化合物（４）に対して等モル量〜小
過剰モル量程度とするのが好ましい。反応は約５０℃〜
溶媒の沸点の範囲の加熱条件下に実施され、一般に５〜
２０時間程度で完結する。embedded image [In each formula, R3, R4 and X are the same as above. Y represents a halogen atom. ] In the above, the halogenation reaction of compound (4) is carried out in an inert solvent such as benzene or carbon tetrachloride in the presence of a catalyst such as benzoyl peroxide, azobisisobutyronitrile, or t-butyl hydroperoxide, This is carried out by treatment with a halogenating agent such as N-promsuccinimide, N-chlorosuccinimide, or bromine. The amount of the halogenating agent used is preferably about an equimolar amount to a small excess molar amount relative to compound (4). The reaction is about 50℃~
It is carried out under heating conditions ranging from the boiling point of the solvent, generally from 5 to
It will be completed in about 20 hours.
【００１７】次に、上記ハロゲン化反応により得られる
化合物（５）をトリアルキルホスファイト（６）と反応
させることにより化合物（７）を収得できる。該反応は
無溶媒で又はエタノール、ベンゼン、Ｎ，Ｎ−ジメチル
ホルムアミド等の不活性溶媒中で、化合物（６）を化合
物（５）に対して１〜５倍モル量程度用いて行なわれる
。反応温度は無溶媒の場合は１３０〜１８０℃程度、溶
媒を用いる場合は溶媒の沸点温度程度とするのがよく、
通常０．５〜３時間程度で反応は終了する。Next, compound (7) can be obtained by reacting compound (5) obtained by the above halogenation reaction with trialkyl phosphite (6). The reaction is carried out without a solvent or in an inert solvent such as ethanol, benzene, N,N-dimethylformamide, etc., using compound (6) in an amount of about 1 to 5 times the molar amount of compound (5). The reaction temperature is preferably about 130 to 180°C when no solvent is used, and about the boiling point temperature of the solvent when a solvent is used.
The reaction usually ends in about 0.5 to 3 hours.
【００１８】続いて、上記により得られた化合物（７）
をハロゲン化することにより、化合物（４）を収得でき
る。ここでハロゲン化剤としては従来公知の各種のもの
を広く使用でき、これには具体的には臭素、塩素、塩化
スルフリル、塩化銅（ＩＩ）、臭化銅（ＩＩ）、Ｎ−ク
ロロ琥珀酸イミド、Ｎ−ブロモ琥珀酸イミド、ジオキサ
ンジブロミド、テトラブチルアンモニウムトリブロミド
、フェニルトリメチルアンモニウムトリブロミド、ピリ
ジニウムヒドロブロミドペルブロミド、ピリドンヒドロ
トリブロミド等が包含される。之等の内では、テトラブ
チルアンモニウムトリブロミド、フェニルトリメチルア
ンモニウムトリブロミド等が有利に用いられる。之等ハ
ロゲン化剤の使用量は、化合物（７）に対して等モル量
〜少過剰量の範囲から選ばれるのが好ましい。反応溶媒
としては、用いるハロゲン化剤の種類により異なるが、
通常、水、メタノール、ジクロロメタン、クロロホルム
、四塩化炭素、ジエチルエーテル、テトラヒドロフラン
、酢酸等を用いるのがよい。反応は、冷却下、室温下及
び加熱下のいずれでも進行するが、通常０℃〜室温の温
度条件を採用するのがよく、一般に０．５〜２０時間程
度で終了し、かくして目的化合物（２）を収得できる。[0018] Subsequently, the compound (7) obtained above
Compound (4) can be obtained by halogenating. Here, a wide variety of conventionally known halogenating agents can be used, including bromine, chlorine, sulfuryl chloride, copper(II) chloride, copper(II) bromide, and N-chlorosuccinic acid. imide, N-bromosuccinimide, dioxane dibromide, tetrabutylammonium tribromide, phenyltrimethylammonium tribromide, pyridinium hydrobromide perbromide, pyridone hydrotribromide, and the like. Among these, tetrabutylammonium tribromide, phenyltrimethylammonium tribromide and the like are advantageously used. The amount of the halogenating agent to be used is preferably selected from the range of equimolar to a small excess amount relative to compound (7). The reaction solvent varies depending on the type of halogenating agent used, but
Usually, water, methanol, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, acetic acid, etc. are preferably used. The reaction proceeds either under cooling, at room temperature, or under heating, but it is usually best to adopt temperature conditions of 0°C to room temperature, and it generally completes in about 0.5 to 20 hours, thus producing the target compound (2 ) can be obtained.
【００１９】上記各工程における目的化合物は、通常の
分離手段により容易に単離精製することができる。該分
離手段としては、例えば溶媒抽出、再結晶、吸着クロマ
トグラフィー、プレパラティブ薄層クロマトグラフィー
等を例示できる。The target compounds in each of the above steps can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, recrystallization, adsorption chromatography, and preparative thin layer chromatography.
【００２０】[0020]
【実施例】以下、本発明を更に詳しく説明するため実施
例を挙げる。[Examples] Examples will be given below to explain the present invention in more detail.
【００２１】[0021]
【実施例１】２−ブロモ−４′−ジエトキシホスホリル
メチルアセトフェノンの製造
４′−メチルアセトフェノン７４ｇ（０．５５モル）、
Ｎ−ブロムコハク酸イミド９７．９ｇ（０．５５モル）
及び過酸化ベンゾイル０．０５ｇをベンゼン４００ｍｌ
に加えて１５時間加熱還流した。反応混合液に水を加え
、クロロホルムで抽出し、有機層を無水硫酸マグネシウ
ムで乾燥した後、溶媒を留去して、粗製の４′−ブロム
メチルアセトフェノンを得た。次に、これを亜リン酸ト
リエチル２００ｍｌ（１．５モル）と共に、１６０℃で
１時間加熱攪拌した。反応終了後、過剰の亜リン酸トリ
エチルを減圧留去し、残渣をシリカゲルカラムクロマト
グラフィー（クロロホルム：酢酸エチル＝１：１で溶出
）で精製して、油状の４′−ジエトキシホスホリルメチ
ルアセトフェノン９７ｇを得た。[Example 1] Production of 2-bromo-4'-diethoxyphosphorylmethylacetophenone 74 g (0.55 mol) of 4'-methylacetophenone,
N-bromosuccinimide 97.9g (0.55 mol)
and 0.05 g of benzoyl peroxide in 400 ml of benzene.
In addition, the mixture was heated under reflux for 15 hours. Water was added to the reaction mixture, extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain crude 4'-bromomethylacetophenone. Next, this was heated and stirred at 160° C. for 1 hour with 200 ml (1.5 mol) of triethyl phosphite. After the reaction, excess triethyl phosphite was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with chloroform:ethyl acetate = 1:1) to obtain 97 g of oily 4'-diethoxyphosphorylmethylacetophenone. I got it.
【００２２】得られた４′−ジエトキシホスホリルメチ
ルアセトフェノン２４．０ｇ（８８．７ミリモル）をジ
クロロメタン１００ｍｌとメタノール４０ｍｌとの混合
溶媒に溶解させ、これに室温攪拌下にフェニルトリメチ
ルアンモニウムトリブロミド３３．３ｇ（８８．７ミリ
モル）を加えた。室温で２０時間撹拌後、反応混合物中
に水２５０ｍｌを加え、クロロホルムで抽出した。芒硝
上で乾燥し、溶媒を減圧留去した。残渣をシリカゲルカ
ラムクロマトグラフィー（クロロホルム−酢酸エチル＝
１：２で溶出）に付して、油状の標記化合物２４．６ｇ
を得た。このものの１Ｈ−ＮＭＲ分析結果を第２表に示
す。24.0 g (88.7 mmol) of the obtained 4'-diethoxyphosphorylmethylacetophenone was dissolved in a mixed solvent of 100 ml of dichloromethane and 40 ml of methanol, and 33.0 g of phenyltrimethylammonium tribromide was added to the solution while stirring at room temperature. 3 g (88.7 mmol) was added. After stirring at room temperature for 20 hours, 250 ml of water was added to the reaction mixture, and the mixture was extracted with chloroform. It was dried over Glauber's salt and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform-ethyl acetate =
1:2 elution) to give 24.6 g of the title compound as an oil.
I got it. The results of 1H-NMR analysis of this product are shown in Table 2.
【００２３】[0023]
【実施例２及び３】実施例１と同様にして第１表に示す
構造の各化合物を得た。第１表には実施例１の化合物も
併記する。Examples 2 and 3 Compounds having the structures shown in Table 1 were obtained in the same manner as in Example 1. Table 1 also lists the compound of Example 1.
【００２４】また、各化合物の１Ｈ−ＮＭＲ分析結果を
第２表に示す。Table 2 shows the results of 1H-NMR analysis of each compound.
【００２５】[0025]
【表１】[Table 1]
【００２６】[0026]
【表２】[Table 2]
【００２７】[0027]
【実施例４】６−ブロモ−２−（４−ジエトキシホスホ
リルメチルフェニル）イミダゾ［１，２−ａ］ピリジン
の製造
２−アミノ−５−ブロモピリジン１．７３ｇ（１０ミリ
モル）と、実施例１で得た化合物１．７５ｇ（５ミリモ
ル）とを、１，４−ジオキサン３０ｍｌに溶解させ、１
２０℃で１７時間加熱攪拌した。反応混合物に１０％炭
酸カリウム水溶液５０ｍｌを加え、クロロホルムで抽出
した。芒硝上で乾燥し、溶媒を減圧留去した。残渣をシ
リカゲルカラムクロマトグラフィー（クロロホルム−酢
酸エチル＝１：２で溶出）に付して標記化合物を得た。
これをベンゼン−ｎ−ヘキサンより再結晶して、無色結
晶０．７０ｇを得た。融点＝１６０−１６１℃[Example 4] Production of 6-bromo-2-(4-diethoxyphosphorylmethylphenyl)imidazo[1,2-a]pyridine 1.73 g (10 mmol) of 2-amino-5-bromopyridine and Example 1.75 g (5 mmol) of the compound obtained in 1 was dissolved in 30 ml of 1,4-dioxane, and
The mixture was heated and stirred at 20° C. for 17 hours. 50 ml of 10% aqueous potassium carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. It was dried over Glauber's salt and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluted with chloroform-ethyl acetate = 1:2) to obtain the title compound. This was recrystallized from benzene-n-hexane to obtain 0.70 g of colorless crystals. Melting point = 160-161℃
【００２
８】002
8]
【実施例５〜１４】実施例４と同様にして、第３表に示
す構造の各化合物を得た。尚、第３表には実施例４の化
合物も併記する。また該表には性状の項に融点（℃）と
再結晶溶媒の種類を挙げるか又は油状物の場合はその１
Ｈ−ＮＭＲ（ＣＤＣｌ３、内部標準ＴＭＳ）分析結果（
δｐｐｍ値）を挙げる。Examples 5 to 14 Compounds having the structures shown in Table 3 were obtained in the same manner as in Example 4. Note that the compound of Example 4 is also listed in Table 3. The table also lists the melting point (°C) and type of recrystallization solvent in the properties section, or in the case of oily substances, the type of recrystallization solvent.
H-NMR (CDCl3, internal standard TMS) analysis results (
δppm value).
【００２９】[0029]
【表３】[Table 3]
【００３０】[0030]
【表４】[Table 4]
Claims (3)
基、ハロゲン原子、ニトロ基、フェニル低級アルコキシ
基、低級アルコキシカルボニル基又はハロゲン置換低級
アルキル基を示し、Ｒ３は水素原子、低級アルキル基又
はフェニル基を、Ｒ４は低級アルキル基をそれぞれ示す
。］で表わされるイミダゾ［１，２−ａ］ピリジン誘導
体。Claim 1: General formula [Formula 1] [In the formula, R1 and R2 each represent a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a phenyl lower alkoxy group, a lower alkoxycarbonyl group, or a halogen-substituted lower alkyl group, R3 represents a hydrogen atom, a lower alkyl group or a phenyl group, and R4 represents a lower alkyl group. ] An imidazo[1,2-a]pyridine derivative represented by:
示す。］で表わされる化合物と 【化３】 ［式中Ｒ１及びＲ２は上記に同じ。］で表わされる化合
物とを縮合反応させることを特徴とする請求項１に記載
のイミダゾ［１，２−ａ］ピリジン誘導体の製造方法。Claim 2: General formula [Formula 2] [In the formula, R3 and R4 are the same as above. X represents a halogen atom. ] and [Formula 3] [wherein R1 and R2 are the same as above. ] The method for producing an imidazo[1,2-a]pyridine derivative according to claim 1, characterized in that the imidazo[1,2-a]pyridine derivative is subjected to a condensation reaction with a compound represented by the following.
α−ハロケトン誘導体。Claim 3: General formula [Image Omitted] [In the formula, R3, R4 and X are the same as above. ] An α-haloketone derivative represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3087143A JP2549950B2 (en) | 1991-01-24 | 1991-01-24 | Imidazo [1,2-a] pyridine derivative, production method thereof, and α-haloketone derivative as an intermediate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3087143A JP2549950B2 (en) | 1991-01-24 | 1991-01-24 | Imidazo [1,2-a] pyridine derivative, production method thereof, and α-haloketone derivative as an intermediate thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04243888A true JPH04243888A (en) | 1992-08-31 |
| JP2549950B2 JP2549950B2 (en) | 1996-10-30 |
Family
ID=13906760
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3087143A Expired - Fee Related JP2549950B2 (en) | 1991-01-24 | 1991-01-24 | Imidazo [1,2-a] pyridine derivative, production method thereof, and α-haloketone derivative as an intermediate thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2549950B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995000524A1 (en) * | 1993-06-17 | 1995-01-05 | Otsuka Pharmaceutical Factory, Inc. | Phosphonic diester derivative |
| WO1995006051A1 (en) * | 1993-08-20 | 1995-03-02 | Otsuka Pharmaceutical Factory, Inc. | Phosphonic diester derivative |
| WO1998039342A1 (en) * | 1997-03-07 | 1998-09-11 | Metabasis Therapeutics, Inc. | Novel indole and azaindole inhibitors of fructose-1,6-bisphosphatase |
-
1991
- 1991-01-24 JP JP3087143A patent/JP2549950B2/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995000524A1 (en) * | 1993-06-17 | 1995-01-05 | Otsuka Pharmaceutical Factory, Inc. | Phosphonic diester derivative |
| CN1048018C (en) * | 1993-06-17 | 2000-01-05 | 株式会社大塚制药工场 | Phosphonic diester derivative |
| WO1995006051A1 (en) * | 1993-08-20 | 1995-03-02 | Otsuka Pharmaceutical Factory, Inc. | Phosphonic diester derivative |
| US5527786A (en) * | 1993-08-20 | 1996-06-18 | Otsuka Pharmaceutical Factory, Inc. | Phosphonic diester derivatives |
| CN1043897C (en) * | 1993-08-20 | 1999-06-30 | 株式会社大塚制药工场 | Phosphonic diester derivative |
| WO1998039342A1 (en) * | 1997-03-07 | 1998-09-11 | Metabasis Therapeutics, Inc. | Novel indole and azaindole inhibitors of fructose-1,6-bisphosphatase |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2549950B2 (en) | 1996-10-30 |
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