CN1681814A - 通过1h-咪唑并[4,5-c]喹啉-4-邻苯二甲酰亚胺类中间体制备1h-咪唑并[4,5-c]喹啉-4-胺类化合物 - Google Patents
通过1h-咪唑并[4,5-c]喹啉-4-邻苯二甲酰亚胺类中间体制备1h-咪唑并[4,5-c]喹啉-4-胺类化合物 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims description 26
- HQBUPOAKJGJGCD-UHFFFAOYSA-N 3h-imidazo[4,5-c]quinolin-4-amine Chemical class NC1=NC2=CC=CC=C2C2=C1N=CN2 HQBUPOAKJGJGCD-UHFFFAOYSA-N 0.000 title abstract description 4
- 239000000543 intermediate Substances 0.000 title abstract 4
- OJLIXSLFKYPKRR-UHFFFAOYSA-N 4-(3h-imidazo[4,5-c]quinolin-4-yl)isoindole-1,3-dione Chemical compound O=C1NC(=O)C2=C1C=CC=C2C1=NC2=CC=CC=C2C2=C1NC=N2 OJLIXSLFKYPKRR-UHFFFAOYSA-N 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 41
- 125000004432 carbon atom Chemical group C* 0.000 claims description 80
- 125000000217 alkyl group Chemical group 0.000 claims description 60
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- -1 (phenyl) ethyl Chemical group 0.000 claims description 41
- 150000001875 compounds Chemical class 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- GLGSZERYOLHNML-UHFFFAOYSA-N $l^{1}-oxidanyl(phenyl)methanone Chemical compound [O]C(=O)C1=CC=CC=C1 GLGSZERYOLHNML-UHFFFAOYSA-N 0.000 claims description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 6
- 150000001336 alkenes Chemical class 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- BWDBEAQIHAEVLV-UHFFFAOYSA-N 6-methylheptan-1-ol Chemical compound CC(C)CCCCCO BWDBEAQIHAEVLV-UHFFFAOYSA-N 0.000 claims description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 3
- IIFFFBSAXDNJHX-UHFFFAOYSA-N 2-methyl-n,n-bis(2-methylpropyl)propan-1-amine Chemical compound CC(C)CN(CC(C)C)CC(C)C IIFFFBSAXDNJHX-UHFFFAOYSA-N 0.000 claims description 2
- 150000001266 acyl halides Chemical class 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 abstract description 17
- 229960002751 imiquimod Drugs 0.000 abstract description 14
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- KSILMCDYDAKOJD-UHFFFAOYSA-N 2-aminoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(N)C(=O)C2=C1 KSILMCDYDAKOJD-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 4
- CXYOCSTZCULCAE-UHFFFAOYSA-N 1-(2-methylpropyl)imidazo[4,5-c]quinoline Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=CN=C21 CXYOCSTZCULCAE-UHFFFAOYSA-N 0.000 description 3
- VPAHUZBYWPFYAH-UHFFFAOYSA-N 4-(2-methylpropyl)quinolin-3-amine Chemical compound C1=CC=C2C(CC(C)C)=C(N)C=NC2=C1 VPAHUZBYWPFYAH-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 238000010531 catalytic reduction reaction Methods 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- TXXCAJBAEQEWTD-UHFFFAOYSA-N 4-(2-methylpropyl)-3-nitroquinoline Chemical compound C1=CC=C2C(CC(C)C)=C([N+]([O-])=O)C=NC2=C1 TXXCAJBAEQEWTD-UHFFFAOYSA-N 0.000 description 2
- FQYRLEXKXQRZDH-UHFFFAOYSA-N 4-aminoquinoline Chemical compound C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000370738 Chlorion Species 0.000 description 2
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- LURYMYITPCOQAU-UHFFFAOYSA-N benzoyl isocyanate Chemical compound O=C=NC(=O)C1=CC=CC=C1 LURYMYITPCOQAU-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- GZWDAJUBJJZHPZ-UHFFFAOYSA-N 1-(2-methylpropyl)-1-oxidoimidazo[4,5-c]quinolin-1-ium Chemical class C1=CC=CC2=C3[N+](CC(C)C)([O-])C=NC3=CN=C21 GZWDAJUBJJZHPZ-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZRFUZDDJSQVQBY-UHFFFAOYSA-N 4-chloro-3-nitroquinoline Chemical compound C1=CC=CC2=C(Cl)C([N+](=O)[O-])=CN=C21 ZRFUZDDJSQVQBY-UHFFFAOYSA-N 0.000 description 1
- 206010059313 Anogenital warts Diseases 0.000 description 1
- 208000000907 Condylomata Acuminata Diseases 0.000 description 1
- 241001635574 Sabatia angularis Species 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 208000025009 anogenital human papillomavirus infection Diseases 0.000 description 1
- 201000004201 anogenital venereal wart Diseases 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
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- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Virology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了1H-咪唑并[4,5-C]喹啉-4-邻苯二甲酰亚胺类中间体,该类中间体可用于1H-咪唑并[4,5-C]喹啉-4-胺类化合物的合成,尤其是咪喹莫特的合成。本发明还提供了该类中间体的制备方法和由该类中间体制备1H-咪唑并[4,5-C]喹啉-4-胺类化合物的方法。
Description
相关申请的交叉参考
本申请要求于2002年7月23日提交的临时申请序列号60/397,607的权利,该临时申请的内容通过引用而结合到本文中。
发明领域
本发明涉及一种合成1H-咪唑并[4,5-C]喹啉-4-邻苯二甲酰亚胺类中间体的方法,该类中间体用于制备1H-咪唑并[4,5-C]喹啉-4-胺类化合物,涉及一种用该类中间体制备1H-咪唑并[4,5-C]喹啉-4-胺类化合物的方法;并且涉及1H-咪唑并[4,5-C]喹啉-4-邻苯二甲酰亚胺类中间体。更详细地讲,本发明涉及一种制备1-异丁基-1H-咪唑并[4,5-C]喹啉-4-胺(咪喹莫特)的新方法,所述方法经1-异丁基-1H-咪唑并[4.5-c]喹啉-4-邻苯二甲酰亚胺中间体在1-异丁基-1H-咪唑并[4.5-c]喹啉-4-胺的4位引入氨基基团,并涉及1-异丁基-1H-咪唑并[4.5-c]喹啉-4-邻苯二甲酰亚胺中间体。
发明背景
咪喹莫特,1-异丁基-1H-咪唑并[4,5-C]喹啉-4-胺是免疫反应调节剂,用于治疗病毒感染,如生殖器疣。咪喹莫特在美国专利4,689,338和5,238,944中公开并具有以下结构:
已知在本领域有几种制备包括咪喹莫特在内的1H-咪唑并[4,5-C]喹啉-4-胺类化合物的方法。4位上的氨基引入主要有三种方法:第一种用氨、二苄基胺或叠氮基对离去基团如氯离子、三氟甲磺酸根等亲核取代;第二种通过在0-5℃下,1-异丁基-1H-咪唑并[4,5-C]喹啉-N-氧化物在甲苯磺酰氯存在下与氢氧化铵或铵盐反应;和第三种通过1-异丁基-1H-咪唑并[4,5-C]喹啉-N-氧化物与异氰酸苯甲酰酯反应。
亲核取代反应已在例如以下专利中公开:WO 97/48704,WO92/06093,美国专利5,395,937,5,756,747,4,988,815,5,602256,5,578,727,4,698,348,4,689,388,欧洲专利EP 145340,EP 0385630,EP310950和JP 04193866。具体地说,在WO 97/48704中通过4-氯衍生物与叠氮化钠反应引入氨基得到四唑部分。四唑部分与三苯基膦反应得到4-氨基衍生物。在美国专利5,395,937中,4-三氟甲磺酸酯(盐)衍生物与二苄胺反应。4-二苄基氨基衍生物的催化还原反应使得在4位上置入一个氨基。美国专利5,756,474公开了用氨在4-氯衍生物上的亲核取代,通过1-异丁基-1H-咪唑并[4,5-C]喹啉-N-氧化物的异构化得到4-羟基衍生物,然后和三氯氧磷反应。以下专利均公开了在高温、高压下用氨在1-异丁基-1H-咪唑并[4,5-C]喹啉-4-氯上的亲核取代:4,988,815,5,602256,5,578,727,4,698,348,4,689,388,EP145340,JP04193866,EP0385630和EP310950。
WO 92/06093公开了在0-5℃下1-异丁基-1H-咪唑并[4,5-C]喹啉-N-氧化物在对甲苯磺酰氯存在下与氢氧化铵或铵盐反应。
WO 92/15581公开了1-异丁基-1H-咪唑并[4,5-C]喹啉-N-氧化物与异氰酸苯甲酰酯的反应。
然而,在本领域仍对不需要高温或高压条件而以高纯度和高得率制备1H-咪唑并[4,5-C]喹啉-4-胺类化合物、尤其是咪喹莫特存在需求。
发明概述
一方面,本发明涉及式(II)化合物:
其中
R1选自:氢;1个至约10个碳原子的直链或支链烷基,任选被选自低级烷基、3个至约6个碳原子的环烷基的取代基取代,其中所述环烷基任选被低级烷基取代;2个至约10个碳原子的直链或支链烯基,其中所述烯基的烯不饱和键间隔1-氮至少一个碳原子,且其中所述直链或支链烷基任选被选自低级烷基、3个至约6个碳原子的环烷基的取代基取代,其中所述环烷基任选被低级烷基取代;1个至约6个碳原子的羟烷基;酰氧基烷基,其中所述酰氧基部分为2个至约4个碳原子的烷酰基氧基或苯甲酰基氧基,且所述烷基部分含有1个至约6个碳原子;苄基;(苯基)乙基;和苯基,其中所述苄基、(苯基)乙基和苯基取代基的苯环上任选被1个或2个独立选自低级烷基、低级烷氧基和卤素的部分取代,条件是当所述苯环被两个这类部分取代时,则所述部分共同含有6个以上的碳原子;
R2选自:氢;含1个至约8个碳原子的直链或支链烷基;苄基;(苯基)乙基;和苯基,其中所述苄基、(苯基)乙基和苯基取代基的苯环上任选被1个或2个独立选自低级烷基、低级烷氧基和卤素的部分取代,条件是当所述苯环被两个这类部分取代时,则所述部分共同含有6个以上的碳原子;
R独立选自:1个至约4个碳原子的烷氧基;1个至约4个碳原子的烷基;和卤素;且
n为0-2的整数,条件是如果n为2,则所述基团共同含有不大于6个的碳原子。
在一个优选的实施方案中,R1为异丁基,R2为氢,n为0。
另一方面,本发明涉及一种制备式(II)的1H-咪唑并[4,5-C]喹啉-4-邻苯二甲酰亚胺的方法,所述方法包括式(III)的化合物在合适的有机溶剂中与邻苯二甲酰亚胺反应,其中R、R1、R2和n如上述定义。
另一方面,本发明涉及一种制备式(I)的化合物的方法,所述方法包括式(II)的化合物在合适的溶剂中与水合肼反应,其中R、R1、R2和n如上述定义。
现在,本发明这些方面以及其它方面将通过以下的发明详述进行更详细的说明。
发明详述
一方面,本发明涉及一种制备式(I)的1H-咪唑并[4,5-C]喹啉-4-胺类化合物的方法。优选的1H-咪唑并[4,5-C]喹啉-4-胺为咪喹莫特。然而,本发明方法可用于制备在式(I)范围内的任何化合物,包括在以下专利中公开的那些化合物:美国专利5,756,747,5,395,937,4,689,338,EP 385630,WO 97/48704,WO 92/06093和WO 92/15581,所有这些专利通过引用而整体结合至本文中。
本发明也涉及新的式(II)的1H-咪唑并[4,5-C]喹啉-4-邻苯二甲酰亚胺类中间体以及一种制备式(II)的中间体的方法,该类中间体用于制备式(I)的1H-咪唑并[4,5-C]喹啉-4-胺类化合物。
式(II)的1H-咪唑并[4,5-C]喹啉-4-邻苯二甲酰亚胺类中间体通过式(III)的1H-咪唑并[4,5-C]喹啉-N-氧化物与邻苯二甲酰亚胺制备。该反应在溶剂和碱存在下实施。优选的溶剂包括二氯甲烷和乙酸乙酯。优选的碱包括三-正-丁基胺、三乙胺和三异丁基胺。最优选的混合物为乙酸乙酯和三-正-丁基胺。优选该反应在苯甲酰氯存在下实施。优选该反应在约0-10℃之间的温度下实施,反应约一个小时。
式(III)的1H-咪唑并[4,5-C]喹啉-N-氧化物可通过本领域已知的任何方法获得,包括在美国专利5,756,747、WO92/06093和WO 92/15581中公开的那些方法,所有这些专利通过引用而整体结合至本文中。
然后,式(II)的1H-咪唑并[4,5-C]喹啉-4-邻苯二甲酰亚胺类中间体在合适的溶剂中与水合肼反应生成(I)的1H-咪唑并[4,5-C]喹啉-4-胺类化合物。优选的溶剂为水。优选加入异辛醇以避免产生泡沫。优选该反应在约94-95℃之间的温度下实施,反应约4-5个小时。
可用于制备式(I)的1H-咪唑并[4,5-C]喹啉-4-胺类化合物的一个反应流程如下所示:
本发明通过以下非限制性实施例进行更详细的说明。
实施例1
4-异丁基-3-硝基喹啉的制备
在-10℃和+15℃之间、在三乙胺(TEA)存在并无水的条件下,4-氯-3-硝基喹啉在甲苯中与异丁基胺反应。经洗涤和相分离后,有机溶液准备用于下一步骤。
实施例2
4-异丁基-3-氨基喹啉的制备
以甲苯为溶剂、5%的披钯碳(水分50%)为催化剂,于40-45℃和常压下催化还原实施例1中制得的4-异丁基-3-硝基喹啉上的硝基,得到4-异丁基-3-氨基喹啉。反应的速度依赖于搅拌的效率。滤去催化剂,溶液准备用于下一步骤。
实施例3
1-异丁基-1H-咪唑并[4,5-C]喹啉的制备
将实施例2中制得的4-异丁基-3-氨基喹啉在甲苯中、102-110℃下,用TEOF(原甲酸三乙酯)环化制备1-异丁基-1H-咪唑并[4,5-C]喹啉,并加入20%摩尔的甲酸加快反应速度。在加入TEOF之前,为了防止其水解,有必要通过共沸蒸馏除去在催化还原中形成的水。反应期间通过蒸馏乙醇和甲苯的混合物来维持反应内温在102-110℃。
实施例4
1-异丁基-1H-咪唑并[4,5-C]喹啉N-氧化物的制备
将实施例3中制得的1-异丁基-1H-咪唑并[4,5-C]喹啉在甲苯中以过乙酸为氧化剂,于40-45℃下氧化得到1-异丁基-1H-咪唑并[4,5-C]喹啉N-氧化物。加入硫酸钠溶液和氢氧化铵后过滤分离出产物。
实施例5
1-异丁基-1H-咪唑并[4,5-C]喹啉-4-邻苯二甲酰亚胺的制备
将93ml二氯甲烷和1 5g 1-异丁基-1H-咪唑并[4,5-C]喹啉N-氧化物(HPLC=95%)加入到250ml三颈圆底烧瓶中。然后在氮气和搅拌下,往烧瓶中加入24.55g三-正丁基胺(98%)和10.06g邻苯二甲酰亚胺(99%)。将形成的悬浮液冷却到0℃并在一小时内滴加入以下溶液:12.7g苯甲酰氯(98%)的二氯甲烷(13ml)溶液,同时温度保持在0-10℃之间。该混和物在室温下搅拌30分钟并取样。HPLC分析显示含有0.32%的起始原料、87.72%的目标产物和0.43%的4-羟基衍生物。过滤溶液并用10ml二氯甲烷洗涤滤饼三次。将湿的滤饼于25℃重新悬浮在100ml甲醇中至少7小时。经过再悬浮后过滤该溶液,滤饼用10ml甲醇洗涤两次。第二次过滤之前,HPLC显示有≤0.4%的起始原料和≤0.05%的4-羟基衍生物。所得固体在50℃下真空干燥15小时。干燥的固体重18g。HPLC显示该固体的纯度为98.98%,基于起始原料(1-异丁基-1H-咪唑并[4,5-C]喹啉N-氧化物)的得率为81.52%。
实施例6
1-异丁基-1H-咪唑并[4,5-C]喹啉-4-胺的制备
在250ml的反应瓶中,将72ml水和18g 1-异丁基-1H-咪唑并[4,5-C]喹啉-4-邻苯二甲酰亚胺(HPLC=98.98%)加热至70℃。在连续搅拌下往反应瓶中滴加入4.8g水合肼,然后加入2ml异辛醇。反应混合物于94-95℃加热4小时后取样。HPLC分析显示含有6.16%的起始原料和94%的目标产物。为了使起始原料完全转化,再继续反应一小时。反应混合物在60℃下冷却并加入180ml甲醇。将该混合物加热回流15分钟,然后于室温下冷却。将该溶液过滤,滤饼用15ml 3.5∶1的甲醇-水混合物洗涤三次。得到的固体湿重22.4g。HPLC分析显示其纯度为98.23%(无邻苯二甲酰肼)。该湿固体用180ml水和5.2g 37%的盐酸于90-93℃处理30分钟。将热悬浮液过滤,滤饼用15ml水洗涤三次。该固体为邻苯二甲酰肼,重4.5g。热溶液于90-93℃用0.115gNa2S2O4和0.576g活性炭处理。30分钟后滤除活性炭,滤饼用10ml水洗涤两次。滤液冷却至70-75℃,加入10g 30%的氢氧化钠至PH11.54,这时有固体沉淀析出。将混合物冷却至室温,一小时后过滤固体,滤饼用10ml水洗涤三次。得到15.1g湿的咪喹莫特粗品(淡粉红色)。咪喹莫特干燥后重10.57g。HPLC显示其纯度为98.12%。含有1.55%的邻苯二甲酰肼。
实施例7
1-异丁基-1H-咪唑并[4,5-C]喹啉-4-胺的纯化
将53.55ml水、23.62ml丁醇、10.57g咪喹莫特粗品和4.77g 37%的盐酸加入到100ml反应瓶内。加热该混合物至55-60℃得到溶液。将该溶液冷却至室温后有白色晶体析出。滤出该固体并用5ml丁醇洗涤两次。得到13.63g咪喹莫特氯化物湿品。HPLC分析显示含有99.89%的咪喹莫特和0.01%的邻苯二甲酰肼。将120ml水和13.36g咪喹莫特氯化物湿品装到250ml反应瓶内并加热至85-90℃。过滤该热溶液,滤饼用5ml热水洗涤。然后加入0.024g Na2S2O4。将该无色溶液冷却至70-75℃,并加入5.3g 30%的氢氧化钠使得PH为9.7,此时有固体沉淀析出。将该悬浮液冷却至20℃并过滤。滤饼用5ml水洗涤三次并用5ml甲醇洗涤两次。洗涤过程中硝酸银检测不到氯离子。固体于50℃下真空干燥8小时。得到8.98g咪喹莫特(灰白色)。HPLC显示纯度为99.94%,基于起始原料(1-异丁基-1H-咪唑并[4,5-C]喹啉N-氧化物)的得率为63.3%。
这样,本发明通过特别优选的实施方案进行了描述并采用实施例进行举例说明,本领域那些技术人员可认识到如所述和举例说明对本发明所做的修改并没有偏离本说明书公开的发明的宗旨和范围。
Claims (22)
1.一种式(II)化合物:
其中
R1选自:氢;1个至约10个碳原子的直链或支链烷基,任选被选自低级烷基、3个至约6个碳原子的环烷基的取代基取代,其中所述环烷基任选被低级烷基取代;2个至约10个碳原子的直链或支链烯基,其中所述烯基的烯不饱和键间隔1-氮至少一个碳原子,且其中所述直链或支链烷基任选被选自低级烷基、3个至约6个碳原子的环烷基的取代基取代,其中所述环烷基任选被低级烷基取代;1个至约6个碳原子的羟烷基;酰氧基烷基,其中所述酰氧基部分为2个至约4个碳原子的烷酰基氧基或苯甲酰基氧基,且所述烷基部分含有1个至约6个碳原子;苄基;(苯基)乙基;和苯基,其中所述苄基、(苯基)乙基和苯基取代基任选在苯环上被1个或2个独立选自低级烷基、低级烷氧基和卤素的部分取代,条件是当所述苯环被两个这类部分取代时,则所述部分共同含有6个以上的碳原子;
R2选自:氢;含1个至约8个碳原子的直链或支链烷基;苄基;(苯基)乙基;和苯基,其中所述苄基、(苯基)乙基和苯基取代基任选在苯环上被1个或2个独立选自低级烷基、低级烷氧基和卤素的部分取代,条件是当所述苯环被两个这类部分取代时,则所述部分共同含有6个以上的碳原子;
R独立选自:1个至约4个碳原子的烷氧基;1个至约4个碳原子的烷基;和卤素;且
n为0-2的整数,条件是如果n为2,则所述基团共同含有不大于6个的碳原子。
2.权利要求1的化合物,其中R1为异丁基,R2为氢,且n为0。
3.一种制备式(II)的1H-咪唑并[4,5-C]喹啉-4-邻苯二甲酰亚胺的方法:
所述方法包括式(III)化合物与邻苯二甲酰亚胺反应,
其中
R1选自:氢;1个至约10个碳原子的直链或支链烷基,任选被选自低级烷基、3个至约6个碳原子的环烷基的取代基取代,其中所述环烷基任选被低级烷基取代;2个至约10个碳原子的直链或支链烯基,其中所述烯基的烯不饱和键间隔1-氮至少一个碳原子,且其中所述直链或支链烷基任选被选自低级烷基、3个至约6个碳原子的环烷基的取代基取代,其中所述环烷基任选被低级烷基取代;1个至约6个碳原子的羟烷基;酰氧基烷基,其中所述酰氧基部分为2个至约4个碳原子的烷酰基氧基或苯甲酰基氧基,且所述烷基部分含有1个至约6个碳原子;苄基;(苯基)乙基;和苯基,其中所述苄基、(苯基)乙基和苯基取代基任选在苯环上被1个或2个独立选自低级烷基、低级烷氧基和卤素的部分取代,条件是当所述苯环被两个这类部分取代时,则所述部分共同含有6个以上的碳原子;
R2选自:氢;含1个至约8个碳原子的直链或支链烷基;苄基;(苯基)乙基;和苯基,其中所述苄基、(苯基)乙基和苯基取代基任选在苯环上被1个或2个独立选自低级烷基、低级烷氧基和卤素的部分取代,条件是当所述苯环被两个这类部分取代时,则所述部分共同含有6个以上的碳原子;
R独立选自:1个至约4个碳原子的烷氧基;1个至约4个碳原子的烷基;和卤素;且
n为0-2的整数,条件是如果n为2,则所述基团共同含有不大于6个的碳原子。
4.权利要求3的方法,其中R1为异丁基,R2为氢,且n为0。
5.权利要求3或权利要求4的方法,其中所述反应在碱和溶剂存在下进行。
6.权利要求5的方法,其中所述溶剂选自二氯甲烷和乙酸乙酯,且所述碱选自三-正丁基胺、三乙胺和三异丁基胺。
7.权利要求6的方法,其中所述溶剂为乙酸乙酯,且所述碱为三-正丁基胺。
8.权利要求5的方法,其中所述反应还在有机酰卤存在下进行。
9.权利要求8的方法,其中所述有机酰卤为苯甲酰氯。
10.权利要求3或权利要求4的方法,其中所述反应在约0℃至约10℃之间进行。
11.权利要求3或权利要求4的方法,其中式(III)化合物与邻苯二甲酰亚胺反应约一小时。
12.一种制备式(I)化合物的方法:
所述方法包括式(II)化合物与水合肼反应,
其中
R1选自:氢;1个至约10个碳原子的直链或支链烷基,任选被选自低级烷基、3个至约6个碳原子的环烷基的取代基取代,其中所述环烷基任选被低级烷基取代;2个至约10个碳原子的直链或支链烯基,其中所述烯基的烯不饱和键间隔1-氮至少一个碳原子,且其中所述直链或支链烷基任选被选自低级烷基、3个至约6个碳原子的环烷基的取代基取代,其中所述环烷基任选被低级烷基取代;1个至约6个碳原子的羟烷基;酰氧基烷基,其中所述酰氧基部分为2个至约4个碳原子的烷酰基氧基或苯甲酰基氧基,且所述烷基部分含有1个至约6个碳原子;苄基;(苯基)乙基;和苯基,其中所述苄基、(苯基)乙基和苯基取代基任选在苯环上被1个或2个独立选自低级烷基、低级烷氧基和卤素的部分取代,条件是当所述苯环被两个这类部分取代时,则所述部分共同含有6个以上的碳原子;
R2选自:氢;含1个至约8个碳原子的直链或支链烷基;苄基;(苯基)乙基;和苯基,其中所述苄基、(苯基)乙基和苯基取代基任选在苯环上被1个或2个独立选自低级烷基、低级烷氧基和卤素的部分取代,条件是当所述苯环被两个这类部分取代时,则所述部分共同含有6个以上的碳原子;
R独立选自:1个至约4个碳原子的烷氧基;1个至约4个碳原子的烷基;和卤素;且
n为0-2的整数,条件是如果n为2,则所述基团共同含有不大于6个的碳原子。
13.权利要求12的方法,其中R1为异丁基,R2为氢,且n为0。
14.权利要求11或权利要求12的方法,其中所述反应在溶剂和异辛醇存在下进行。
15.权利要求14的方法,其中所述溶剂为水。
16.权利要求11或权利要求12的方法,其中所述反应在约94-95℃之间进行。
17.权利要求11或权利要求12的方法,其中式(II)化合物与水合肼反应约4个小时到约5个小时。
18.一种制备式(I)化合物的方法:
所述方法包括:
a)制备式(II)化合物:通过下式(III)的化合物与邻苯二甲酰亚胺反应制备;和
b)将式II化合物转化为式(I)化合物,其中
R1选自:氢;1个至约10个碳原子的直链或支链烷基,任选被选自低级烷基、3个至约6个碳原子的环烷基的取代基取代,其中所述环烷基任选被低级烷基取代;2个至约10个碳原子的直链或支链烯基,其中所述烯基的烯不饱和键间隔1-氮至少一个碳原子,且其中所述直链或支链烷基任选被选自低级烷基、3个至约6个碳原子的环烷基的取代基取代,其中所述环烷基任选被低级烷基取代;1个至约6个碳原子的羟烷基;酰氧基烷基,其中所述酰氧基部分为2个至约4个碳原子的烷酰基氧基或苯甲酰基氧基,且所述烷基部分含有1个至约6个碳原子;苄基;(苯基)乙基;和苯基,其中所述苄基、(苯基)乙基和苯基取代基任选在苯环上被1个或2个独立选自低级烷基、低级烷氧基和卤素的部分取代,条件是当所述苯环被两个这类部分取代时,则所述部分共同含有6个以上的碳原子;
R2选自:氢;含1个至约8个碳原子的直链或支链烷基;苄基;(苯基)乙基;和苯基,其中所述苄基、(苯基)乙基和苯基取代基任选在苯环上被1个或2个独立选自低级烷基、低级烷氧基和卤素的部分取代,条件是当所述苯环被两个这类部分取代时,则所述部分共同含有6个以上的碳原子;
R独立选自:1个至约4个碳原子的烷氧基;1个至约4个碳原子的烷基;和卤素;且
n为0-2的整数,条件是如果n为2,则所述基团共同含有不大于6个的碳原子。
19.权利要求18的方法,其中R1为异丁基,R2为氢,且n为0。
20.一种制备式(I)化合物的方法:
所述方法包括:
a)制备式(II)化合物:
和
b)式(II)化合物与水合肼反应生成式(I)化合物,其中
R1选自:氢;1个至约10个碳原子的直链或支链烷基,任选被选自低级烷基、3个至约6个碳原子的环烷基的取代基取代,其中所述环烷基任选被低级烷基取代;2个至约10个碳原子的直链或支链烯基,其中所述烯基的烯不饱和键间隔1-氮至少1个碳原子,且其中所述直链或支链烷基任选被选自低级烷基、3个至约6个碳原子的环烷基的取代基取代,其中所述环烷基任选被低级烷基取代;1个至约6个碳原子的羟烷基;酰氧基烷基,其中所述酰氧基部分为2个至约4个碳原子的烷酰基氧基或苯甲酰基氧基,且所述烷基部分含有1个至约6个碳原子;苄基;(苯基)乙基;和苯基,其中所述苄基、(苯基)乙基和苯基取代基任选在苯环上被1个或2个独立选自低级烷基、低级烷氧基和卤素的部分取代,条件是当所述苯环被两个这类部分取代时,则所述部分共同含有6个以上的碳原子;
R2选自:氢;含1个至约8个碳原子的直链或支链烷基;苄基;(苯基)乙基;和苯基,其中所述苄基、(苯基)乙基和苯基取代基任选在苯环上被1个或2个独立选自低级烷基、低级烷氧基和卤素的部分取代,条件是当所述苯环被两个这类部分取代时,则所述部分共同含有6个以上的碳原子;
R独立选自:1个至约4个碳原子的烷氧基;1个至约4个碳原子的烷基;和卤素;且
n为0-2的整数,条件是如果n为2,则所述基团共同含有不大于6个的碳原子。
21.权利要求20的方法,其中R1为异丁基,R2为氢,且n为0。
22.权利要求1的化合物,所述化合物通过权利要求3的方法制备。
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Families Citing this family (65)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6677347B2 (en) * | 2000-12-08 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamido ether substituted imidazoquinolines |
CA2488801A1 (en) | 2002-06-07 | 2003-12-18 | 3M Innovative Properties Company | Ether substituted imidazopyridines |
US20040265351A1 (en) | 2003-04-10 | 2004-12-30 | Miller Richard L. | Methods and compositions for enhancing immune response |
EP1617845A4 (en) * | 2003-04-28 | 2006-09-20 | 3M Innovative Properties Co | COMPOSITIONS AND METHODS FOR INDUCING OPOID RECEPTORS |
JP2007502293A (ja) * | 2003-08-12 | 2007-02-08 | スリーエム イノベイティブ プロパティズ カンパニー | ヒドロキシルアミン置換イミダゾ含有化合物 |
AU2004266657B2 (en) * | 2003-08-14 | 2009-07-02 | 3M Innovative Properties Company | Lipid-modified immune response modifiers |
EP1658076B1 (en) * | 2003-08-27 | 2013-03-06 | 3M Innovative Properties Company | Aryloxy and arylalkyleneoxy substituted imidazoquinolines |
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US7687628B2 (en) * | 2003-10-01 | 2010-03-30 | Taro Pharmaceuticals U.S.A., Inc. | Method of preparing 4-amino-1H-imidazo(4,5-c)quinolines and acid addition salts thereof |
AR046046A1 (es) | 2003-10-03 | 2005-11-23 | 3M Innovative Properties Co | Imidazoquinolinas alcoxi sustituidas. composiciones farmaceuticas. |
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US20090075980A1 (en) * | 2003-10-03 | 2009-03-19 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridines and Analogs Thereof |
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CA2545825A1 (en) | 2003-11-14 | 2005-06-02 | 3M Innovative Properties Company | Hydroxylamine substituted imidazo ring compounds |
BRPI0416936A (pt) | 2003-11-25 | 2007-01-16 | 3M Innovative Properties Co | sistemas de anel de imidazo substituìdos e métodos |
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AU2005228150A1 (en) * | 2004-03-24 | 2005-10-13 | 3M Innovative Properties Company | Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines |
US20080015184A1 (en) * | 2004-06-14 | 2008-01-17 | 3M Innovative Properties Company | Urea Substituted Imidazopyridines, Imidazoquinolines, and Imidazonaphthyridines |
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WO2006038923A2 (en) * | 2004-06-18 | 2006-04-13 | 3M Innovative Properties Company | Aryl substituted imidazonaphthyridines |
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WO2006065280A2 (en) * | 2004-06-18 | 2006-06-22 | 3M Innovative Properties Company | Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and methods |
US20090270443A1 (en) * | 2004-09-02 | 2009-10-29 | Doris Stoermer | 1-amino imidazo-containing compounds and methods |
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WO2006029115A2 (en) | 2004-09-02 | 2006-03-16 | 3M Innovative Properties Company | 2-amino 1h imidazo ring systems and methods |
EP1804583A4 (en) * | 2004-10-08 | 2009-05-20 | 3M Innovative Properties Co | ADJUVANT FOR DNA VACCINE |
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EP1831214A1 (en) * | 2004-12-27 | 2007-09-12 | Usv Limited | A process for preparation of 4-amino-1-isobutyl-1h-imidazo[4,5-c]-quinoline (imiquimod) |
US8436176B2 (en) * | 2004-12-30 | 2013-05-07 | Medicis Pharmaceutical Corporation | Process for preparing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine |
PT1830876E (pt) * | 2004-12-30 | 2015-07-13 | Meda Ab | Utilização de imiquimod para o tratamento de metástases cutâneas derivadas de um tumor cancerígeno da mama |
US8034938B2 (en) | 2004-12-30 | 2011-10-11 | 3M Innovative Properties Company | Substituted chiral fused [1,2]imidazo[4,5-c] ring compounds |
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WO2006073939A2 (en) * | 2004-12-30 | 2006-07-13 | Takeda Pharmaceutical Company Limited | 1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate and 1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine methanesulfonate |
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US20080318998A1 (en) | 2005-02-09 | 2008-12-25 | Coley Pharmaceutical Group, Inc. | Alkyloxy Substituted Thiazoloquinolines and Thiazolonaphthyridines |
US8378102B2 (en) | 2005-02-09 | 2013-02-19 | 3M Innovative Properties Company | Oxime and hydroxylamine substituted thiazolo[4,5-c] ring compounds and methods |
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WO2006091567A2 (en) * | 2005-02-23 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Hydroxyalkyl substituted imidazoquinoline compounds and methods |
WO2006098852A2 (en) * | 2005-02-23 | 2006-09-21 | Coley Pharmaceutical Group, Inc. | Hydroxyalkyl substituted imidazoquinolines |
EP1850849A2 (en) * | 2005-02-23 | 2007-11-07 | Coley Pharmaceutical Group, Inc. | Method of preferentially inducing the biosynthesis of interferon |
JP2008531568A (ja) | 2005-02-23 | 2008-08-14 | コーリー ファーマシューティカル グループ,インコーポレイテッド | ヒドロキシアルキルで置換されたイミダゾナフチリジン |
CA2602590A1 (en) | 2005-04-01 | 2006-10-12 | Coley Pharmaceutical Group, Inc. | 1-substituted pyrazolo (3,4-c) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases |
US7943610B2 (en) | 2005-04-01 | 2011-05-17 | 3M Innovative Properties Company | Pyrazolopyridine-1,4-diamines and analogs thereof |
EP1874345B1 (en) * | 2005-04-25 | 2012-08-15 | 3M Innovative Properties Company | Immunostimulatory compositions |
ZA200803029B (en) * | 2005-09-09 | 2009-02-25 | Coley Pharm Group Inc | Amide and carbamate derivatives of alkyl substituted /V-[4-(4-amino-1H-imidazo[4,5-c] quinolin-1-yl)butyl] methane-sulfonamides and methods |
AU2006287270A1 (en) * | 2005-09-09 | 2007-03-15 | Coley Pharmaceutical Group, Inc. | Amide and carbamate derivatives of N-{2-[4-amino-2- (ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide and methods |
KR20080083270A (ko) | 2005-11-04 | 2008-09-17 | 콜레이 파마시티컬 그룹, 인코포레이티드 | 하이드록시 및 알콕시 치환된 1에이치 이미다조퀴놀린 및방법 |
WO2007100634A2 (en) | 2006-02-22 | 2007-09-07 | 3M Innovative Properties Company | Immune response modifier conjugates |
WO2007106854A2 (en) * | 2006-03-15 | 2007-09-20 | Coley Pharmaceutical Group, Inc. | Hydroxy and alkoxy substituted 1h-imidazonaphthyridines and methods |
WO2008008432A2 (en) * | 2006-07-12 | 2008-01-17 | Coley Pharmaceutical Group, Inc. | Substituted chiral fused( 1,2) imidazo (4,5-c) ring compounds and methods |
WO2008030511A2 (en) * | 2006-09-06 | 2008-03-13 | Coley Pharmaceuticial Group, Inc. | Substituted 3,4,6,7-tetrahydro-5h, 1,2a,4a,8-tetraazacyclopenta[cd]phenalenes |
WO2008048683A2 (en) * | 2006-10-16 | 2008-04-24 | Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag | Preparation of 1h-imidazo[4,5-c]quinolin-4-amines via 1h-imidazo[4,5-c]quinolin-4-phthalimide intermediates |
US20080149123A1 (en) * | 2006-12-22 | 2008-06-26 | Mckay William D | Particulate material dispensing hairbrush with combination bristles |
ES2943385T3 (es) | 2010-08-17 | 2023-06-12 | 3M Innovative Properties Company | Compuesto modificador de la respuesta inmunitaria lipidada y su uso médico |
US9475804B2 (en) | 2011-06-03 | 2016-10-25 | 3M Innovative Properties Company | Heterobifunctional linkers with polyethylene glycol segments and immune response modifier conjugates made therefrom |
MX355623B (es) | 2011-06-03 | 2018-04-25 | 3M Innovative Properties Co | Hidrazino-1h-imidazoquinolin-4-aminas y conjugados elaborados a partir de las mismas. |
EP3728255B1 (en) | 2017-12-20 | 2022-01-26 | 3M Innovative Properties Company | Amide substituted imidazo[4,5-c]quinoline compounds with a branched chain linking group for use as an immune response modifier |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA848968B (en) | 1983-11-18 | 1986-06-25 | Riker Laboratories Inc | 1h-imidazo(4,5-c)quinolines and 1h-imidazo(4,5-c)quinolin-4-amines |
IL73534A (en) | 1983-11-18 | 1990-12-23 | Riker Laboratories Inc | 1h-imidazo(4,5-c)quinoline-4-amines,their preparation and pharmaceutical compositions containing certain such compounds |
CA1271477A (en) | 1983-11-18 | 1990-07-10 | John F. Gerster | 1h-imidazo[4,5-c]quinolin-4-amines |
US4689388A (en) | 1985-01-24 | 1987-08-25 | Ajinomoto Co., Inc. | One pack type alicyclic epoxy resin compositions |
WO1989000194A1 (en) * | 1987-07-06 | 1989-01-12 | Louisiana State University Agricultural And Mechan | Inhibition of eucaryotic pathogens and neoplasms and stimulation of fibroblasts and lymphocytes with lytic peptides |
US5238944A (en) | 1988-12-15 | 1993-08-24 | Riker Laboratories, Inc. | Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine |
US5756747A (en) | 1989-02-27 | 1998-05-26 | Riker Laboratories, Inc. | 1H-imidazo 4,5-c!quinolin-4-amines |
DK0385630T3 (da) | 1989-02-27 | 1997-05-12 | Riker Laboratories Inc | 1H-imidazo(4,5-c)quinolin-4-aminer som antivirale midler |
US4988815A (en) | 1989-10-26 | 1991-01-29 | Riker Laboratories, Inc. | 3-Amino or 3-nitro quinoline compounds which are intermediates in preparing 1H-imidazo[4,5-c]quinolines |
DE4005874A1 (de) * | 1990-02-24 | 1991-11-07 | Boehringer Mannheim Gmbh | Traegergebundene rekombinante proteine, verfahren zur herstellung und verwendung als immunogene und vakzine |
CA2093132C (en) * | 1990-10-05 | 2002-02-26 | John F. Gerster | Process for the preparation of imidazo[4,5-c]quinolin-4-amines |
JP2941413B2 (ja) | 1990-11-28 | 1999-08-25 | ライカー ラボラトリース インコーポレーテッド | 1H―イミダゾ[4,5―c]キノリン類の製造方法 |
US5175296A (en) | 1991-03-01 | 1992-12-29 | Minnesota Mining And Manufacturing Company | Imidazo[4,5-c]quinolin-4-amines and processes for their preparation |
SG70625A1 (en) * | 1991-03-01 | 2000-02-22 | Minnesota Mining & Mfg | 1-Substituted 2-substituted 1H-imidazo(4, 5-c) quinolin-4-amines |
US5395937A (en) | 1993-01-29 | 1995-03-07 | Minnesota Mining And Manufacturing Company | Process for preparing quinoline amines |
US5741908A (en) | 1996-06-21 | 1998-04-21 | Minnesota Mining And Manufacturing Company | Process for reparing imidazoquinolinamines |
EP1310096B1 (en) * | 2000-08-16 | 2014-10-08 | The Boeing Company | Method and apparatus for providing bi-directional data services and live television programming to mobile platforms |
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IL166309A (en) | 2010-04-15 |
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ATE338044T1 (de) | 2006-09-15 |
CA2493227A1 (en) | 2004-01-29 |
HRP20050159A2 (en) | 2005-08-31 |
ES2271650T3 (es) | 2007-04-16 |
CN1315828C (zh) | 2007-05-16 |
EP1543002A1 (en) | 2005-06-22 |
EP1543002B1 (en) | 2006-08-30 |
IL166309A0 (en) | 2006-01-15 |
PT1543002E (pt) | 2006-11-30 |
DE60308040D1 (de) | 2006-10-12 |
US6852861B2 (en) | 2005-02-08 |
US20070060755A1 (en) | 2007-03-15 |
JP2006502121A (ja) | 2006-01-19 |
US20040138459A1 (en) | 2004-07-15 |
US7153967B2 (en) | 2006-12-26 |
KR20050028047A (ko) | 2005-03-21 |
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US20050113404A1 (en) | 2005-05-26 |
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