CN103864658A - 氮杂环丁酮衍生物及其制备方法与应用 - Google Patents
氮杂环丁酮衍生物及其制备方法与应用 Download PDFInfo
- Publication number
- CN103864658A CN103864658A CN201410081252.1A CN201410081252A CN103864658A CN 103864658 A CN103864658 A CN 103864658A CN 201410081252 A CN201410081252 A CN 201410081252A CN 103864658 A CN103864658 A CN 103864658A
- Authority
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- China
- Prior art keywords
- azetidinone
- propyl
- methylphenyl
- trifluoromethoxybenzenesulfonamido
- nitrophenyl
- 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
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- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title abstract description 56
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 34
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- -1 Hydrogen Chemical class 0.000 claims description 67
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000001475 halogen functional group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- BZHINKIFBHBISO-UHFFFAOYSA-N methyl 2-carbonochloridoylbutanoate Chemical compound CCC(C(Cl)=O)C(=O)OC BZHINKIFBHBISO-UHFFFAOYSA-N 0.000 claims description 5
- VNAARIBPAIJLEO-CLJLJLNGSA-N 4-ethyl-N-[3-[(2S,3R)-1-(4-methylphenyl)-2-(4-nitrophenyl)-4-oxoazetidin-3-yl]propyl]benzenesulfonamide Chemical compound C1=CC(CC)=CC=C1S(=O)(=O)NCCC[C@H]1C(=O)N(C=2C=CC(C)=CC=2)[C@@H]1C1=CC=C([N+]([O-])=O)C=C1 VNAARIBPAIJLEO-CLJLJLNGSA-N 0.000 claims description 4
- UAIOEXAAQGAQLG-KAYWLYCHSA-N 4-ethyl-N-[3-[(2S,3R)-2-[4-(methanesulfonamido)phenyl]-1-(4-methylphenyl)-4-oxoazetidin-3-yl]propyl]benzenesulfonamide Chemical compound C1=CC(CC)=CC=C1S(=O)(=O)NCCC[C@H]1C(=O)N(C=2C=CC(C)=CC=2)[C@@H]1C1=CC=C(NS(C)(=O)=O)C=C1 UAIOEXAAQGAQLG-KAYWLYCHSA-N 0.000 claims description 4
- HDHUVJBMSIQOHY-FIRIVFDPSA-N 4-methyl-N-[4-[(2S,3R)-1-(4-methylphenyl)-4-oxo-3-[3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]propyl]azetidin-2-yl]phenyl]benzenesulfonamide Chemical compound C1=CC(C)=CC=C1N1C(=O)[C@H](CCCNS(=O)(=O)C=2C=CC(OC(F)(F)F)=CC=2)[C@H]1C(C=C1)=CC=C1NS(=O)(=O)C1=CC=C(C)C=C1 HDHUVJBMSIQOHY-FIRIVFDPSA-N 0.000 claims description 4
- GRXIWANCLZBVCX-DNQXCXABSA-N N-[3-[(2S,3R)-1-(4-methylphenyl)-2-(4-nitrophenyl)-4-oxoazetidin-3-yl]propyl]-4-(trifluoromethoxy)benzenesulfonamide Chemical compound C1=CC(C)=CC=C1N1C(=O)[C@H](CCCNS(=O)(=O)C=2C=CC(OC(F)(F)F)=CC=2)[C@H]1C1=CC=C([N+]([O-])=O)C=C1 GRXIWANCLZBVCX-DNQXCXABSA-N 0.000 claims description 4
- UFDDJNXJKQPECR-IFMALSPDSA-N N-[3-[(2S,3R)-1-(4-methylphenyl)-2-(4-nitrophenyl)-4-oxoazetidin-3-yl]propyl]thiophene-2-sulfonamide Chemical compound C1=CC(C)=CC=C1N1C(=O)[C@H](CCCNS(=O)(=O)C=2SC=CC=2)[C@H]1C1=CC=C([N+]([O-])=O)C=C1 UFDDJNXJKQPECR-IFMALSPDSA-N 0.000 claims description 4
- BPQBVTFHIHPXKR-JWQCQUIFSA-N N-[3-[(2S,3R)-2-[4-(methanesulfonamido)phenyl]-1-(4-methylphenyl)-4-oxoazetidin-3-yl]propyl]-4-(trifluoromethoxy)benzenesulfonamide Chemical compound C1=CC(C)=CC=C1N1C(=O)[C@H](CCCNS(=O)(=O)C=2C=CC(OC(F)(F)F)=CC=2)[C@H]1C1=CC=C(NS(C)(=O)=O)C=C1 BPQBVTFHIHPXKR-JWQCQUIFSA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- QDMNNMIOWVJVLY-MRVPVSSYSA-N (4s)-4-phenyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@H]1C1=CC=CC=C1 QDMNNMIOWVJVLY-MRVPVSSYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
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- 239000002552 dosage form Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- BJEZAHLXDGEQSU-CZNDPXEESA-N N-[4-[(2S,3R)-3-[3-[(4-ethylphenyl)sulfonylamino]propyl]-1-(4-methylphenyl)-4-oxoazetidin-2-yl]phenyl]-4-methylbenzenesulfonamide Chemical compound C1=CC(CC)=CC=C1S(=O)(=O)NCCC[C@H]1C(=O)N(C=2C=CC(C)=CC=2)[C@@H]1C(C=C1)=CC=C1NS(=O)(=O)C1=CC=C(C)C=C1 BJEZAHLXDGEQSU-CZNDPXEESA-N 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
- 150000003934 aromatic aldehydes Chemical class 0.000 claims description 2
- 150000004982 aromatic amines Chemical class 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
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- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims 1
- 229940124530 sulfonamide Drugs 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
- 238000006243 chemical reaction Methods 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000007787 solid Substances 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 235000012000 cholesterol Nutrition 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
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- ZVTWZSXLLMNMQC-UHFFFAOYSA-N 4-phenylmethoxybenzaldehyde Chemical compound C1=CC(C=O)=CC=C1OCC1=CC=CC=C1 ZVTWZSXLLMNMQC-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- JTVILUUAQWQWBK-UHFFFAOYSA-N 2-n-(4-aminocyclohexyl)-6-n-benzyl-9-cyclopentylpurine-2,6-diamine Chemical compound C1CC(N)CCC1NC1=NC(NCC=2C=CC=CC=2)=C(N=CN2C3CCCC3)C2=N1 JTVILUUAQWQWBK-UHFFFAOYSA-N 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 5
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- 238000002156 mixing Methods 0.000 description 1
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- GSOZSSDYIVFJRF-UHFFFAOYSA-N n-(4-methylphenyl)-1-(4-nitrophenyl)methanimine Chemical compound C1=CC(C)=CC=C1N=CC1=CC=C([N+]([O-])=O)C=C1 GSOZSSDYIVFJRF-UHFFFAOYSA-N 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- PXDRFTPXHTVDFR-UHFFFAOYSA-N propane;titanium(4+) Chemical compound [Ti+4].C[CH-]C.C[CH-]C.C[CH-]C.C[CH-]C PXDRFTPXHTVDFR-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明公开了一种氮杂环丁酮衍生物,它是由通式(I)表示的化合物及其可药用盐。本发明还公开了上述氮杂环丁酮衍生物的制备方法和应用。本发明的氮杂环丁酮衍生物可以应用于治疗或预防动脉粥样硬化或降低血浆胆固醇水平,其降血浆胆固醇活性更强,市场前景更广阔。
Description
技术领域
本发明涉及在治疗和预防动脉粥样硬化、肝硬化、高血压中用作降低血浆总胆固醇药物的氮杂环丁酮衍生物及其制备方法与应用。
背景技术
心脑血管疾病是当今危害人类生命健康的第一大杀手,由血脂代谢紊乱所引起的高血脂症是引发动脉粥样硬化、肝硬化、高血压等心脑血管疾病的重要原因之一。目前临床上所使用的降胆固醇药物主要有他汀类药物、贝特类药物、烟酸衍生物及胆酸螯合剂,但这些药物的副作用也很明显,特别是他汀类药物中的西立伐他汀由于横纹肌溶解的副作用造成多例临床死亡病例。(3R,4S)-1-(4-氟苯基)-3-[(3S)-3-(4-氟苯基)-3-羟丙基]-4-(4-羟苯基)-2-氮杂环丁酮(依泽替米贝,Ezetimibe,ZetiaTM)是Merck/Schering-Plough公司研制的新型胆固醇吸收抑制剂,于2002年11月在德国上市,同期在美国上市。该药选择性地抑制了胆固醇在肠道内的吸收,从而达到降低血清中胆固醇的目的,发挥降血脂的作用。依泽替米贝是目前唯一上市的胆固醇吸收抑制剂,但其不能有效地逆转动脉粥样硬化、有潜在的安全性风险等问题,因此寻求降胆固醇活性更强的胆固醇吸收抑制剂具有重要研究意义和应用前景。
发明内容
本发明所要解决的技术问题在于提供一类新型的胆固醇吸收抑制剂——氮杂环丁酮衍生物,其降血浆胆固醇活性更强,市场前景更广阔。
本发明还要解决的技术问题是提供上述氮杂环丁酮衍生物的制备方法。
本发明最后要解决的技术问题是提供上述氮杂环丁酮衍生物的应用。
为解决上述技术问题,本发明采用的技术方案如下:
一种氮杂环丁酮衍生物,它是由通式(I)表示的化合物及其可药用盐:
其中,
Ar代表R3-取代的芳基;
R1-、R2-和R3-代表1~5个取代基,它们独立选自包括:-OR4,-O(CO)R4,-O(CO)OR4,-O(CH2)1-5OR4,-O(CH2)1-2O-,-O(CO)NR4R5,-NR4R5,-NR4(CO)R5,-NR4(CO)OR5,-NR4(CO)NR5R6,-NR4SO2-低级烷基,-NR4SO2-芳基,-CONR4R5,-COR4,-SO2NR4R5,S(O)0-2-烷基,S(O)0-2-芳基,-O(CH2)1-10-COOR4,-O(CH2)1-10CONR4R5,氢,邻-卤代,间-卤代,对-卤代,邻-低级烷基,间-低级烷基,对-低级烷基,芳基,-NO2,-OCF3,-CF3,-(低级亚烷基)-COOR4或-CH=CH-COOR4;
R4、R5和R6独立选自:氢,低级烷基,芳基,芳基取代的低级烷基;
所述的低级烷基为C1-C6直链烷基或C1-C6带支链的烷基,例如甲基、乙基、正丙基、异丙基、叔丁基、正戊基或正己基。优选C1-C3直链烷基或C1-C3带支链的烷基。更优选是甲基、乙基或正丙基。
所述的低级亚烷基为C1-C6亚烷基,如亚甲基、1,2-亚乙基、1,3-亚丙基、1,4-亚丁基、1,5-亚戊基或1,6-亚己基等。
上述氮杂环丁酮衍生物中进一步优选的化合物为以下任一化合物及其可药用盐:
(3R,4S)-1-(4-甲基苯基)-3-(3-苯磺酰胺基丙基)-4-(4-硝基苯基)-2-氮杂环丁酮(I1);
(3R,4S)-1-(4-甲基苯基)-3-(3-苯磺酰胺基丙基)-4-(4-甲磺酰胺基苯基)-2-氮杂环丁酮(I2);
(3R,4S)-1-(4-甲基苯基)-3-(3-苯磺酰胺基丙基)-4-[4-(4-甲基苯磺酰胺基)苯基]-2-氮杂环丁酮(I3);
(3R,4S)-1-(4-甲基苯基)-3-[3-(4-乙基苯磺酰胺基)丙基]-4-(4-硝基苯基)-2-氮杂环丁酮(I4);
(3R,4S)-1-(4-甲基苯基)-3-[3-(4-乙基苯磺酰胺基)丙基]-4-(4-甲磺酰胺基苯基)-2-氮杂环丁酮(I5);
(3R,4S)-1-(4-甲基苯基)-3-[3-(4-乙基苯磺酰胺基)丙基]-4-[4-(4-甲基苯磺酰胺基)苯基)-2-氮杂环丁酮(I6);
(3R,4S)-1-(4-甲基苯基)-3-[3-(4-三氟甲氧基苯磺酰胺基)丙基]-4-(4-硝基苯基)-2-氮杂环丁酮(I7);
(3R,4S)-1-(4-甲基苯基)-3-[3-(4-三氟甲氧基苯磺酰胺基)丙基]-4-(4-甲磺酰胺基苯基)-2-氮杂环丁酮(I8);
(3R,4S)-1-(4-甲基苯基)-3-[3-(4-三氟甲氧基苯磺酰胺基)丙基]-4-[4-(4-甲基苯磺酰胺基)苯基]-2-氮杂环丁酮(I9);
(3R,4S)-1-(4-甲基苯基)-3-[3-(2-噻吩磺酰胺基)丙基]-4-(4-硝基苯基)-2-氮杂环丁酮(I10);
(3R,4S)-1-(4-甲基苯基)-3-[3-(2-噻吩磺酰胺基)丙基]-4-(4-甲磺酰胺基苯基)-2-氮杂环丁酮(I11);
(3R,4S)-1-(4-甲基苯基)-3-[3-(2-噻吩磺酰胺基)丙基]-4-[4-(4-甲基苯磺酰胺基)苯基)-2-氮杂环丁酮(I12);
(3R,4S)-1-(4-甲基苯基)-3-[3-(3-溴苯磺酰胺基)丙基]-4-(4-硝基苯基)-2-氮杂环丁酮(I13);
(3R,4S)-1-(4-甲基苯基)-3-[3-(2-三氟甲氧基苯磺酰胺基)丙基]-4-(4-硝基苯基)-2-氮杂环丁酮(I14);
(3R,4S)-1-(4-甲基苯基)-3-[3-(2-三氟甲氧基苯磺酰胺基)丙基]-4-(4-甲磺酰胺基苯基)-2-氮杂环丁酮(I15);
(3R,4S)-1-(4-甲基苯基)-3-[3-(2-三氟甲氧基苯磺酰胺基)丙基]-4-[4-(4-甲基苯磺酰胺基)苯基]-2-氮杂环丁酮(I16);
(3R,4S)-1-(4-氟苯基)-3-[3-(4–三氟甲基苯磺酰胺基)丙基]-4-(4-羟基苯基)-2-氮杂环丁酮(I17);
(3R,4S)-1-(4-氟苯基)-3-[3-(4–氟苯磺酰胺基)丙基]-4-(4-羟基苯基)-2-氮杂环丁酮(I18);
(3R,4S)-1-(4-氟苯基)-3-[3-(4–乙基苯磺酰胺基)丙基]-4-(4-羟基苯基)-2-氮杂环丁酮(I19);
(3R,4S)-1-(4-氟苯基)-3-[3-(4–叔丁基苯磺酰胺基)丙基]-4-(4-羟基苯基)-2-氮杂环丁酮(I20);
(3R,4S)-1-(4-氟苯基)-3-[3-(4–三氟甲氧基苯磺酰胺基)丙基]-4-(4-羟基苯基)-2-氮杂环丁酮(I21);
(3R,4S)-1-(4-氟苯基)-3-[3-(2–三氟甲氧基苯磺酰胺基)丙基]-4-(4-羟基苯基)-2-氮杂环丁酮(I22)。
上述优选的化合物,其对应的结构式如下:
其中,
上述氮杂环丁酮衍生物的制备方法,取代芳香醛和取代芳香胺反应生成中间体(Ⅲ),氯甲酰丁酸甲酯与(S)-4-苯基-2-噁唑烷酮反应生成中间体(Ⅱ),中间体(Ⅱ)与中间体(Ⅲ)进行加成反应后生成中间体(Ⅳ),中间体(Ⅳ)在TBAF的氟离子催化下闭环得到中间体(Ⅴ),中间体(Ⅴ)水解后得到中间体(Ⅵ),中间体(Ⅵ)在BH3/THF溶液中还原得到中间体(Ⅶ),中间体(Ⅶ)与TsCl反应后得到中间体(Ⅷ),中间体(Ⅷ)再与芳香磺酰胺反应后最终得到化合物(Ⅰ);
反应路线如下:
其中,关键中间体氯甲酰丁酸甲酯的制备是通过戊二酸酐醇解,再酰氯化获得。具体反应路线如下:
上述氮杂环丁酮衍生物在制备治疗或预防动脉粥样硬化或降低血浆胆固醇水平的药物中的应用。
其中,所述的氮杂环丁酮衍生物为通式(I)表示的化合物或其可药用盐或其药学上可接受的载体。药学上可接受的载体是指一种或几种惰性的,非毒性的固体或液体填充物、稀释剂、助剂等,它们不逆向与活性化合物或病人发生作用。
上述氮杂环丁酮衍生物在药物中使用的剂型是片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂、注射液等药剂学上常用剂型。
口服用药片和胶囊含有传统的赋形剂如填充物、稀释剂、润滑剂、分散剂以及粘合剂。可按照本领域中熟知的方法进行制备。
以上活性化合物的剂量将因配方而异。
一般地,证明有利的量为达到所需结果,每千克体重每24小时给药通式(I)化合物的总量为约0.01-100mg,优选总量约0.1-50mg。如果必要,以几次单剂量的形式给药。然而如果必要,也可以偏离上述用量,即这取决于待治疗的受试者的类型和体重、个体对药物的行为、疾病的性质和严重性、制剂和给药的类型、以及给药时间或间隔。
有益效果:本发明的氮杂环丁酮衍生物可以应用于治疗或预防动脉粥样硬化或降低血浆胆固醇水平,其降血浆胆固醇活性更强,市场前景更广阔。
具体实施方式
根据下述实施例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实施例所描述的内容仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
实施例1:氯甲酰丁酸甲酯的制备。
100g(0.878mol)戊二酸酐溶50mL无水甲醇,加热回流1h后,减压蒸馏,除去未反应的甲醇,反应液冷却至室温,缓缓加入200mL二氯亚砜和6滴DMF,加热回流2h后,水泵减压蒸馏,除去剩余的二氯亚砜后,再用油泵减压蒸馏,收集96℃-98℃/10mmHg的馏分,得淡黄色液体124.2g,收率:86.4%。
实施例2:(S)–5–氧代–5–(2–氧代–4–苯基–噁唑环烷基–3)戊酸甲酯(II)的制备。
250mL三颈瓶中加入(S)–4–苯基–2–噁唑烷酮7.83g(48mmol),DIPEA15mL,无水二氯甲烷144mL,DMF3滴以及DMAP催化量,加热至回流,缓慢滴加氯甲酰丁酸甲酯11.5g(72mmol)。回流反应3小时,TLC显示反应完全后用1M稀盐酸终止反应,饱和碳酸氢钠,饱和食盐水洗涤,无水硫酸钠干燥,浓缩,制砂,最后柱层析分离得纯品9.3g,收率:66.15%,mp:54℃-56℃。
1H-NMR(CDCl3,300Hz):δ=1.94(2H,m,-CH2-),2.35(2H,m,-CH2-),3.00(2H,m,-CH2-),3.65(3H,s,-CH3),4.28(1H,m,-CH2O-),4.69(1H,m,-CH2O-),5.41(1H,m,-CH-),7.29(2H,m,Ar-H),7.36(3H,m,Ar-H);MS(ESI+,m/z):292.1([M+H]+)。
实施例3:N–(4–甲基苯基)–4–硝基苯基亚甲胺(III1)的制备。
250mL圆底烧瓶中加入5.0g(0.047mol)对甲基苯胺,7.1g(0.047mol)4–硝基苯甲醛和110mL异丙醇,油浴加热回流5h,TLC跟踪反应进程。反应结束后,室温冷却即有晶体析出,继续低温析晶。抽滤,滤饼干燥得白色针状晶体9.32g,收率:82.4%。
实施例4:(4R,5S)–5–(4–4–硝基苯基)–5–(4–甲基苯胺基)–4–((S)–2–氧代–4–苯基噁唑环烷基–3–羰基)戊酸甲酯(IV1)的制备。
100mL两颈瓶中加入20mL无水二氯甲烷,液氮降温至-10℃~-20℃,反应体系隔水隔氧。加入四氯化钛1mL,四异丙基钛0.2mL,搅拌,缓慢滴加(S)–5–氧代–5–(2–氧代–4–苯基–噁唑环烷基–3)戊酸甲酯(II)2.66g(9.14mmol)的无水二氯甲烷溶液10mL,反应5min,再滴加DIPEA3.6mL,维持内温-10℃~-20℃反应1h,继续滴加N–(4–甲基苯基)–4–硝基苯基亚甲胺2.53g(10.51mmol)的无水二氯甲烷溶液10mL,保温反应4h。加入冰醋酸的无水二氯甲烷溶液(2.6mL+5mL)终止反应,然后升至室温,滴加1mol/L的硫酸,搅拌1h至亚胺完全分解。最后以饱和食盐水洗涤,无水硫酸钠干燥,甲醇重结晶得纯品1.85g,收率38%。
1H-NMR(CDCl3,300Hz):δ=1.76(1H,m,-CH2-),2.18(2H,m,-CH2-),2.23(3H,s,-PhCH3),2.31(1H,m,-CH2-),3.61(3H,s,-OCH3-),4.22(1H,m,-CH-),4.46(1H,m,-CHN-),4.70(1H,m,-CH2O-),4.70(1H,m,-CH2O-),4.87(1H,m,-CH2O-),5.43(1H,m,-CH-),6.21(2H,d,Ar-H),6.85(2H,d,Ar-H),6.93(4H,m,Ar-H),7.13(1H,m,Ar-H),7.54(2H,d,Ar-H),8.03(2H,d,Ar-H);MS(ESI+,m/z):532.3([M+H]+)。
实施例5:(3R,4S)–3–[2–氧代–4–(4–硝基苯基)–1–(4–甲基苯基)–2–氮杂环丁
酮基]丙酸甲酯(V1)的制备。
50mL两颈瓶中加入(4R,5S)–5–(4–4–硝基苯基)–5–(4–甲基苯胺基)–4–((S)–2–氧代–4–苯基噁唑环烷基–3–羰基)戊酸甲酯1.7g(3.2mmol)、甲苯25mL,加热至外温为60℃~70℃,加入BSA2.6mL。0.5h后加入TBAF催化量,保温反应3h~3.5h。TLC显示反应完全后,将反应液冷却至室温,加入甲醇3.5mL。转至分液漏斗,补加乙酸乙酯40mL,以1M稀盐酸,饱和碳酸氢钠,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,制砂,柱层析得产品0.72g,收率61%。
1H-NMR(CDCl3,300Hz):δ=2.23(2H,m,-CH2-),2.25(3H,s,-CH3),2.63(2H,m,-CH2-),3.11(1H,m,-CH-),3.67(3H,s,-CH3),4.82(1H,s,-CHN-),7.08(4H,m,Ar-H),7.52(2H,m,Ar-H),8.23(2H,m,Ar-H);MS(ESI+,m/z):368.5([M+H]+)。
实施例6:(3R,4S)–3–[2–氧代–4–(4–硝基苯基)–1–(4–甲基苯基)–2–氮杂环丁酮基]丙酸(VI1)的制备。
2.76g(7.5mmol)(3R,4S)–3–[2–氧代–4–(4–硝基苯基)–1–(4–甲基苯基)–2–氮杂环丁酮基]丙酸甲酯,溶于30mL四氢呋喃中,加入1M氢氧化锂水溶液40mL,室温搅拌2h,加入1mol/L盐酸溶液,调PH至6.0,EtOAc萃取分液,有机相以水,饱和食盐水洗,无水硫酸钠干燥,减压蒸去溶剂,得产物2.36g,收率:89%。
实施例7:(3R,4S)–1–(4–甲基苯基)–3–(3–羟基正丙基)–4–(4–硝基苯基)–2–氮杂环丁酮(VII1)的制备。
100mL圆底烧瓶中投入2.16g(6.1mmol)(3R,4S)–3–[2–氧代–4–(4–硝基苯基)–1–(4–甲基苯基)–2–氮杂环丁基]丙酸,用30mL无水THF溶解,冰水浴冷却,缓慢加入14.64mmol硼烷二甲硫醚的THF溶液。反应8小时,TLC(PE:EtOAc=2:1)显示反应基本完成。将反应液冰水浴中冷却,加1M盐酸终止反应,转移至旋转蒸发仪蒸去大部分THF,再用乙酸乙酯萃取,除去水层,有机层用饱和食盐水洗两次,无水Na2SO4干燥,柱层析得纯品0.94g,收率为45%。
1H-NMR(CDCl3,300Hz):δ=1.79(2H,m,-CH2-),2.06(2H,m,-CH2-),3.27(3H,s,-PhCH3),3.12(1H,m,-CH-),3.71(2H,m,-OCH2-),4.76(1H,d,-NCH-),7.06(2H,d,Ar-H),7.12(2H,d,Ar-H),7.52(2H,d,Ar-H),8.24(2H,d,Ar-H);MS(ESI+,m/z):341.3([M+H]+)
实施例8:(3R,4S)–1–(4–甲基苯基)–3–(3–对甲苯磺酸酯基正丙基)–4–(4–硝基苯基)–2–氮杂环丁酮(VIII1)制备。
在100mL圆底烧瓶中加入0.42g(1.23mmol)(3R,4S)–1–(4–甲基苯基)–3–(3–羟基正丙基)–4–(4–硝基苯基)–2–氮杂环丁酮,20mLDCM,0.28g对甲苯磺酰氯,室温搅拌5min。0.24mL三乙胺溶于10mL二氯甲烷中,缓慢滴加到反应液中,反应6h。TLC(PE:EtOAc=3:1)显示反应基本完成。反应液用100mL二氯甲烷稀释,用饱和食盐水水洗三次,无水硫酸钠干燥,浓缩制砂,柱层析得纯品0.56g,收率91.6%。
1H-NMR(CDCl3,300Hz):δ=1.91(2H,m,-CH2-),2.01(2H,m,-CH2-),2.27(3H,s,-PhCH3),2.44(3H,s,-PhCH3),3.03(1H,m,-CH-),4.08(2H,m,-OCH2-),4.74(1H,d,-NCH-),7.07(4H,m,Ar-H),7.34(2H,d,Ar-H),7.50(2H,d,Ar-H),7.76(2H,d,Ar-H),8.22(2H,d,Ar-H);MS(ESI+,m/z):495.3([M+H]+)。
实施例9:(3R,4S)–1–(4–甲基苯基)–3–(3–苯磺酰胺基丙基)–4–(4–硝基苯基)–2–氮杂环丁酮(I1)的制备。
在25mL圆底烧瓶中加入0.34g(0.69mmol)(3R,4S)–1–(4–甲基苯基)–3–(3–对甲苯磺酸酯基正丙基)–4–(4–硝基苯基)–2–氮杂环丁酮,5mL乙腈,0.19g碳酸钾和0.216g苯磺酰胺,混合物90℃加热12h。TLC(PE:EtOAc=3:1)显示反应基本完成。冷却到室温后,将乙腈旋掉,加入12mL水和7.2mLDCM,水相再用7.2mLDCM萃取三次,合并有机相后7.2mL水洗两次,再用3mol/LNaOH洗四次,每次4.8mL再水洗一次,无水硫酸钠干燥,浓缩制砂,柱层析得白色固体0.26g,收率80%,mp:57℃-59℃。1H-NMR(CDCl3,500Hz):δ=1.75(2H,m,-CH2-),2.01(2H,m,-CH2-),2.27(3H,s,-PhCH3),3.01(1H,s,-CH-),3.03(2H,d,-NHCH2-),4.71(1H,d,-NCH-),4.74(1H,s,-NHCH2-),7.07(4H,m,Ar-H),7.52(5H,m,Ar-H),7.85(2H,d,Ar-H),8.23(2H,d,Ar-H);MS(ESI+,m/z):480.2([M+H]+)。
实施例10:(3R,4S)–1–(4–甲基苯基)–3–(3–苯磺酰胺基丙基)–4–(4–甲磺酰胺基苯基)–2–氮杂环丁酮(I2)的制备。
在25mL圆底烧瓶中加入0.29g(I1),用12mL的甲醇溶解后加入催化量Pd/C,加氢气球,置换圆底烧瓶中的空气3次,室温搅拌20min。TLC(PE:EtOAc=2:1),显示反应基本完成。反应液过滤,用6mL甲醇洗涤一次。减压蒸去溶剂,得产物白色固体0.23g,收率83%。
再将0.23g白色固体加入到25mL圆底烧瓶中,用4mLDCM溶解后,加入0.062g三乙胺,0.013gDMAP,室温下滴入2mL0.088g MsCl的DCM溶液,室温搅16h。TLC(PE:EtOAc=2:1),显示反应基本完成。反应液用25mL二氯甲烷稀释,用饱和食盐水水洗三次,无水硫酸钠干燥,浓缩制砂,柱层析得纯品0.22g,收率82%;mp:68℃-70℃。
1H-NMR(CDCl3,300Hz):δ=1.72(2H,m,-CH2-),1.92(2H,m,-CH2-),2.27(3H,s,-PhCH3),2.99(1H,s,-CH-),3.01(2H,d,-NHCH2-),3.02(3H,s,-SO2CH3-),4.58(1H,d,-NCH-),4.98(1H,d,-NHCH2-),6.75(1H,s,-NHSO2-),7.05(2H,d,Ar-H),7.13(2H,d,Ar-H),7.22(2H,d,Ar-H),7.31(3H,m,Ar-H),7.54(3H,m,Ar-H),7.86(2H,d,Ar-H);MS(ESI+,m/z):528.3([M+H]+)。
实施例11:(3R,4S)–1–(4–甲基苯基)–3–(3–苯磺酰胺基丙基)–4–[4–(4–甲基苯磺酰胺基)苯基]–2–氮杂环丁酮(I3)的制备。
在25mL圆底烧瓶中加入0.13g(I1),用5mL的甲醇溶解后加入催化量Pd/C,加氢气球,置换圆底烧瓶中的空气3次,室温搅拌20min。TLC(PE:EtOAc=2:1),显示反应基本完成。反应液过滤,用2mL甲醇洗涤一次。减压蒸去溶剂,得产物白色固体0.1g,收率83%。再将0.1g白色固体加入到25mL圆底烧瓶中,用2mLDCM溶解后,加入0.03g三乙胺,0.006gDMAP,将0.051gTsCl用1mLDCM溶解后,用1mL注射器缓慢注入,室温搅拌16h。TLC(PE:EtOAc=2:1),显示反应基本完成。反应液用20mL二氯甲烷稀释,用饱和食盐水水洗三次,无水硫酸钠干燥,浓缩制砂,柱层析得纯品0.08g,收率60%;mp:148℃-150℃。
1H-NMR(CDCl3,300Hz):δ=1.70(2H,m,-CH2-),1.89(2H,m,-CH2-),2.27(3H,s,-PhCH3),2.27(3H,s,-PhCH3),2.38(3H,s,-PhCH3),2.93(1H,m,-CH-),2.99(2H,m,-NHCH2-),2.99(2H,m,-NHCH2-),4.50(1H,d,-NCH-),4.87(1H,m,-NHCH2-),6.65(1H,s,-NHSO2-),7.04(6H,m,Ar-H),7.21(4H,m,Ar-H),7.51(3H,m,Ar-H),7.65(2H,d,Ar-H),7.84(2H,d,Ar-H);MS(ESI+,m/z):604.4([M+H]+)。
实施例12:(3R,4S)–1–(4–甲基苯基)–3–[3–(4–乙基苯磺酰胺基)丙基]–4–(4–硝基苯基)–2–氮杂环丁酮(I4)的制备。
参照I1的制备方法,以4–硝基苯甲醛和对甲基苯胺为原料,得白色固体0.24g,收率:68%,mp:57℃-59℃。
1H-NMR(CDCl3,300Hz)δ:1.26(3H,m,-CH2CH3-),1.74(2H,m,-CH2-),1.99(2H,m,-CH2-),2.27(3H,s,-PhCH3),2.71(2H,m,-CH2CH3-),3.00(1H,m,-CH-),3.04(2H,m,-NHCH2-),4.72(1H,s,-NCH-),4.73(1H,s,-NHCH2-),7.07(4H,m,Ar-H),7.32(2H,d,Ar-H),7.50(2H,d,Ar-H),7.75(2H,d,Ar-H),8.22(2H,d,Ar-H);MS(ESI+,m/z):508.3([M+H]+)。
实施例13:(3R,4S)–1–(4–甲基苯基)–3–[3–(4–乙基苯磺酰胺基)丙基]–4–(4–甲磺酰胺基苯基)–2–氮杂环丁酮(I5)的制备。
参照I2的制备方法,以4–硝基苯甲醛和对甲基苯胺为原料,得白色固体0.12g,收率:70%,mp:64℃-66℃。
1H-NMR(CDCl3,500Hz):δ=1.25(3H,m,-CH2CH3-),1.72(2H,m,-CH2-),1.92(2H,m,-CH2-),2.26(3H,s,-PhCH3),2.71(2H,m,-CH2CH3-),2.98(1H,d,-CH-),2.99(2H,d,-NHCH2-),3.03(3H,s,-SO2CH3-),4.58(1H,s,-NCH-),4.96(1H,s,-NHCH2-),6.87(1H,s,-NHSO2-),7.03(2H,d,Ar-H),7.12(2H,d,Ar-H),7.22(2H,d,Ar-H),7.29(4H,m,Ar-H),7.75(2H,d,Ar-H);MS(ESI+,m/z):554.3([M-H]-)。
实施例14:(3R,4S)–1–(4–甲基苯基)–3–[3–(4–乙基苯磺酰胺基)丙基]–4–[4–(4–甲基苯磺酰胺基)苯基]–2–氮杂环丁酮(I6)的制备。
参照I3的制备方法,以4–硝基苯甲醛和对甲基苯胺为原料,得白色固体0.07g,收率:60%,mp:106℃-108℃。
1H-NMR(CDCl3,300Hz):δ=1.25(3H,m,-CH2CH3-),1.68(2H,m,-CH2-),1.90(2H,m,-CH2-),2.26(3H,s,-PhCH3),2.38(3H,s,-PhCH3),2.71(2H,m,-CH2CH3-),2.92(1H,d,-CH-),2.95(2H,d,-NHCH2-),4.51(1H,s,-NCH-),4.78(1H,s,-NHCH2-),6.67(1H,s,-NHSO2-),7.04(6H,m,Ar-H),7.20(4H,m,Ar-H),7.31(2H,d,Ar-H),7.65(2H,d,Ar-H),7.74(2H,d,Ar-H);MS(ESI+,m/z):632.4([M+H]+)。
实施例15:(3R,4S)–1–(4–甲基苯基)–3–[3–(4–三氟甲氧基苯磺酰胺基)丙基]–4–(4–硝基苯基)–2–氮杂环丁酮(I7)的制备。
参照I1的制备方法,以4–硝基苯甲醛和对甲基苯胺为原料,得白色固体0.4g,收率:78%,mp:56℃-58℃。
1H-NMR(CDCl3,300Hz):δ=1.78(2H,m,-CH2-),2.01(2H,m,-CH2-),2.28(3H,s,-PhCH3),3.03(1H,m,-CH-),3.06(2H,m,-NHCH2-),4.73(1H,d,-NCH-),5.04(1H,m,-NHCH2-),7.08(4H,m,Ar-H),7.33(2H,d,Ar-H),7.50(2H,d,Ar-H),7.91(2H,d,Ar-H),8.23(2H,d,Ar-H);MS(ESI+,m/z):564.3([M+H]+)。
实施例16:(3R,4S)–1–(4–甲基苯基)–3–[3–(4–三氟甲氧基苯磺酰胺基)丙基]–4–(4–甲磺酰胺基苯基)–2–氮杂环丁酮(I8)的制备。
参照I2的制备方法,以4–硝基苯甲醛和对甲基苯胺为原料,得白色固体0.105g,收率:74%,mp:68℃-70℃。
1H-NMR(CDCl3,500Hz):δ=1.73(2H,m,-CH2-),1.93(2H,m,-CH2-),2.26(3H,s,-PhCH3),3.01(1Hs,-CH-),3.02(2H,s,-NHCH2-),3.03(3H,s,-SO2CH3-),4.59(1H,s,-NCH-),5.34(1H,m,-NHCH2-),7.00(1H,s,-NHSO2-),7.03(2H,d,Ar-H),7.12(2H,d,Ar-H),7.22(2H,d,Ar-H),7.31(5H,m,Ar-H),7.91(2H,d,Ar-H);MS(ESI+,m/z):610.3([M-H]-)。
实施例17:(3R,4S)–1–(4–甲基苯基)–3–[3–(4–三氟甲氧基苯磺酰胺基)丙基]–4–[4–(4–甲基苯磺酰胺基)苯基]–2–氮杂环丁酮(I9)的制备。
参照I3的制备方法,以4–硝基苯甲醛和对甲基苯胺为原料,得白色固体0.085g,收率:65%,mp:77℃-79℃。
1H-NMR(CDCl3,300Hz):δ=1.74(2H,m,-CH2-),1.94(2H,m,-CH2-),2.29(3H,s,-PhCH3),2.41(3H,s,-PhCH3),2.98(1H,m,-CH-),3.06(2H,m,-NHCH2-),4.54(1H,d,-NCH-),5.11(1H,s,-NHCH2-),6.66(1H,s,-NHSO2-),7.07(6H,m,Ar-H),7.23(4H,m,Ar-H),7.34(2H,d,Ar-H),7.68(2H,d,Ar-H),7.92(2H,m,Ar-H);MS(ESI+,m/z):688.4([M+H]+)。
实施例18:(3R,4S)–1–(4–甲基苯基)–3–[3–(2–噻吩磺酰胺基)丙基]–4–(4–硝基苯基)–2–氮杂环丁酮(I10)的制备。
参照I1的制备方法,以4–硝基苯甲醛和对甲基苯胺为原料,得白色固体0.38g,收率:80%,mp:55℃-57℃。
1H-NMR(CDCl3,300Hz):δ=1.78(2H,m,-CH2-),2.01(2H,m,-CH2-),2.27(3H,s,-PhCH3),3.06(1H,m,-CH-),3.12(2H,m,-NHCH2-),4.74(1H,s,-NCH-),4.88(1H,m,-NHCH2-),7.07(5H,m,Ar-H),7.50(2H,d,Ar-H),7.58(2H,m,Ar-H),8.23(2H,d,Ar-H);MS(ESI+,m/z):486.2([M+H]+)。
实施例19:(3R,4S)–1–(4–甲基苯基)–3–[3–(2–噻吩磺酰胺基)丙基]–4–(4–甲磺酰胺基苯基)–2–氮杂环丁酮(I11)的制备。
参照I2的制备方法,以4–硝基苯甲醛和对甲基苯胺为原料,得白色固体0.088g,收率:75%,mp:60℃-62℃。
1H-NMR(CDCl3,500Hz):δ=1.75(2H,m,-CH2-),1.94(2H,d,-CH2-),2.26(3H,s,-PhCH3),3.01(1H,m,-CH-),3.03(3H,s,-SO2CH3-),3.09(2H,m,-NHCH2-),4.60(1H,s,-NCH-),5.14(1H,s,-NHCH2-),6.87(1H,s,-NHSO2-),7.06(3H,m,Ar-H),7.13(2H,d,Ar-H),7.22(2H,d,Ar-H),7.31(2H,d,Ar-H),7.56(1H,d,Ar-H),7.59(1H,d,Ar-H);MS(ESI+,m/z):532.2([M-H]-)。
实施例20:(3R,4S)–1–(4–甲基苯基)–3–[3–(2–噻吩磺酰胺基)丙基]–4–[4–(4–甲基苯磺酰胺基)苯基]–2–氮杂环丁酮(I12)制备。
参照I3的制备方法,以4–硝基苯甲醛和对甲基苯胺为原料,得白色固体0.09g,收率:71%,mp:135℃-137℃。
1H-NMR(CDCl3,300Hz):δ=1.75(2H,m,-CH2-),1.92(2H,m,-CH2-),2.26(3H,s,-PhCH3),2.38(3H,s,-PhCH3),2.96(1H,m,-CH-),3.09(2H,m,-NHCH2-),4.52(1H,d,-NCH-),4.91(1H,d,-NHCH2-),6.50(1H,s,-NHSO2-),7.05(7H,m,Ar-H),7.21(4H,m,Ar-H),7.56(2H,m,Ar-H),7.64(2H,d,Ar-H);MS(ESI+,m/z):610.3([M+H]+)。
实施例21:(3R,4S)–1–(4–甲基苯基)–3–[3–(3–溴苯磺酰胺基)丙基]–4–(4–硝基苯基)–2–氮杂环丁酮(I13)的制备。
参照I1的制备方法,以4–硝基苯甲醛和对甲基苯胺为原料,得白色固体0.42g,收率:84%,mp:58℃-60℃。
1H-NMR(CDCl3,300Hz):δ=1.77(2H,m,-CH2-),1.99(2H,m,-CH2-),2.28(3H,s,-PhCH3),3.03(1H,d,-CH-),3.07(2H,m,-NHCH2-),4.71(1H,s,-NCH-),4.87(1H,m,-NHCH2-),7.08(4H,m,Ar-H),7.39(1H,m,Ar-H),7.49(2H,d,Ar-H),7.69(1H,d,Ar-H),7.78(1H,m,Ar-H),8.00(1H,s,Ar-H),8.24(2H,d,Ar-H);MS(ESI+,m/z):560.2([M+H]+)。
实施例22:(3R,4S)–1–(4–甲基苯基)–3–[3–(2–三氟甲氧基苯磺酰胺基)丙基]–4–(4–硝基苯基)–2–氮杂环丁酮(I14)的制备。
参照I1的制备方法,以4–硝基苯甲醛和对甲基苯胺为原料,得白色固体0.4g,收率:82%,mp:52℃-54℃。
1H-NMR(CDCl3,300Hz):δ=1.77(2H,m,-CH2-),2.00(2H,m,-CH2-),2.27(3H,s,-PhCH3),3.01(1H,m,-CH-),3.06(2H,m,-NHCH2-),4.73(1H,d,-NCH-),5.02(1H,m,-NHCH2-),7.08(4H,m,Ar-H),7.40(2H,m,Ar-H),7.50(2H,d,Ar-H),7.62(1H,m,Ar-H),8.01(1H,m,Ar-H),8.23(2H,d,Ar-H);MS(ESI+,m/z):564.3([M+H]+)。
实施例23:(3R,4S)–1–(4–甲基苯基)–3–[3–(2–三氟甲氧基苯磺酰胺基)丙基]–4–(4–甲磺酰胺基苯基)–2–氮杂环丁酮(I15)的制备。
参照I2的制备方法,以4–硝基苯甲醛和对甲基苯胺为原料,得白色固体0.12g,收率:76%,mp:67℃-68℃。
1H-NMR(CDCl3,500Hz):δ=1.73(2H,m,-CH2-),1.94(2H,m,-CH2-),2.26(3H,s,-PhCH3),2.99(1Hd,-CH-),3.03(2H,s,-NHCH2-),3.06(3H,s,-SO2CH3-),4.58(1H,d,-NCH-),5.09(1H,m,-NHCH2-),6.76(1H,s,-NHSO2-),7.04(2H,d,Ar-H),7.12(2H,d,Ar-H),7.21(2H,d,Ar-H),7.31(2H,d,Ar-H),7.40(2H,m,Ar-H),7.61(1H,m,Ar-H),8.01(1H,m,Ar-H);MS(ESI+,m/z):612.3([M+H]+)。
实施例24:(3R,4S)–1–(4–甲基苯基)–3–[3–(2–三氟甲氧基苯磺酰胺基)丙基]–4–[4–(4–甲基苯磺酰胺基)苯基]–2–氮杂环丁酮(I16)的制备。
参照I3的制备方法,以4–硝基苯甲醛和对甲基苯胺为原料,得白色固体0.11g,收率:68%,mp:72℃-74℃。
1H-NMR(CDCl3,300Hz):δ=1.72(2H,m,-CH2-),1.91(2H,m,-CH2-),2.27(3H,s,-PhCH3),2.39(3H,s,-PhCH3),2.96(1H,m,-CH-),3.03(2H,m,-NHCH2-),4.52(1H,d,-NCH-),5.02(1H,m,-NHCH2-),6.64(1H,s,-NHSO2-),7.06(6H,m,Ar-H),7.22(4H,m,Ar-H),7.39(2H,m,Ar-H),7.63(3H,m,Ar-H),8.00(1H,m,Ar-H);MS(ESI+,m/z):688.4([M+H]+)。
实施例25:(3R,4S)–1–(4–氟苯基)–3–[3–(4–三氟甲基苯磺酰胺基)丙基]–4–(4–羟基苯基)–2–氮杂环丁酮(I17)的制备。
参照I1的制备方法,以4–苄氧基苯甲醛和对氟苯胺为原料,最后得白色固体0.1g,收率:70%,mp:60.1℃-63.3℃。在25mL圆底烧瓶中加入0.29g上述白色固体,用12mL的甲醇溶解后加入催化量Pd/C,加氢气球,置换圆底烧瓶中的空气3次,室温搅拌3h。TLC(PE:EtOAc=4:1),显示反应基本完成。反应液过滤,用6mL四氢呋喃洗涤一次。减压蒸去溶剂,制砂,过柱得产物白色固体0.17g,收率:70%。
1H-NMR(CDCl3,500Hz):δ=1.74(2H,m,-CH2-),1.92(2H,m,-CH2-),3.02(1H,m,-CH-),3.06(2H,m,-NHCH2-),4.52(1H,d,-NCH-),5.06(1H,m,-NHCH2-),6.83(2H,d,Ar-H),6.93(2H,m,Ar-H),7.21(4H,m,Ar-H),7.67(2H,d,Ar-H),7.98(2H,d,Ar-H);MS(ESI+,m/z):522.3([M+H]+)。
实施例26:(3R,4S)–1–(4–氟苯基)–3–[3–(4–氟苯磺酰胺基)丙基]–4–(4–羟基苯基)–2–氮杂环丁酮(I18)的制备。
参照I17的制备方法,以4–苄氧基苯甲醛和对氟苯胺为原料,得白色固体0.18g,收率:82%,mp:48.3℃-50.3℃。
1H-NMR(CDCl3,300Hz):δ=1.68(2H,m,-CH2-),1.93(2H,m,-CH2-),2.99(1H,d,-CH-),3.03(2H,m,-NHCH2-),4.53(1H,d,-NCH-),4.87(1H,s,-NHCH2-),6.83(2H,d,Ar-H),6.93(2H,m,Ar-H),7.21(6H,m,Ar-H),7.86(2H,m,Ar-H);MS(ESI+,m/z):472.2([M+H]+)。
实施例27:(3R,4S)–1–(4–氟苯基)–3–[3–(4–乙基苯磺酰胺基)丙基]–4–(4–羟基苯基)–2–氮杂环丁酮(I19)的制备。
参照I17的制备方法,以4–苄氧基苯甲醛和对氟苯胺为原料,得白色固体0.15g,收率:63%,mp:48.0℃-56.5℃。
1H-NMR(CDCl3,300Hz):δ=1.24(3H,m,CH3-),1.66(2H,m,-CH2-),1.87(2H,m,-CH2-),2.69(2H,m,-CH2CH3),2.94(1H,s,-CH-),2.96(2H,s,-NHCH2-),4.52(1H,s,-NCH-),5.10(1H,s,-NHCH2-),6.83(2H,d,Ar-H),6.89(2H,m,Ar-H),7.13(2H,d,Ar-H),7.19(2H,m,Ar-H),7.28(2H,m,Ar-H),7.73(2H,d,Ar-H);MS(ESI+,m/z):482.3([M+H]+)。
实施例28:(3R,4S)–1–(4–氟苯基)–3–[3–(4–叔丁基苯磺酰胺基)丙基]–4–(4–羟基苯基)–2–氮杂环丁酮(I20)的制备。
参照I17的制备方法,以4–苄氧基苯甲醛和对氟苯胺为原料,得白色固体0.17g,收率:65%,mp:47.9℃-57.4℃。
1H-NMR(CDCl3,300Hz):δ=1.34(9H,s,(CH3)3-),1.72(2H,m,-CH2-),1.91(2H,m,-CH2-),2.99(1H,d,-CH-),3.03(2H,d,-NHCH2-),4.54(1H,d,-NCH-),4.63(1H,d,-NHCH2-),6.82(2H,d,Ar-H),6.91(2H,m,Ar-H),7.21(4H,m,Ar-H),7.51(2H,d,Ar-H),7.75(2H,d,Ar-H);MS(ESI+,m/z):510.3([M+H]+)。
实施例29:(3R,4S)–1–(4–氟苯基)–3–[3–(4–三氟甲氧基苯磺酰胺基)丙基]–4–(4–羟基苯基)–2–氮杂环丁酮(I21)的制备。
参照I17的制备方法,以4–苄氧基苯甲醛和对氟苯胺为原料,得白色固体0.11g,收率:55%,mp:58.2℃-61.0℃。
1H-NMR(CDCl3,500Hz):δ=1.73(2H,m,-CH2-),1.92(2H,m,-CH2-),3.01(1H,m,-CH-),3.03(2H,m,-NHCH2-),4.53(1H,d,-NCH-),5.10(1H,m,-NHCH2-),6.84(2H,d,Ar-H),6.93(2H,m,Ar-H),7.20(2H,m,Ar-H),7.26(2H,s,Ar-H),7.32(2H,d,Ar-H),7.90(2H,d,Ar-H);MS(ESI+,m/z):538.3([M+H]+)。
实施例30:(3R,4S)–1–(4–氟苯基)–3–[3–(2–三氟甲氧基苯磺酰胺基)丙基]–4–(4–羟基苯基)–2–氮杂环丁酮(I22)的制备。
参照I17的制备方法,以4–苄氧基苯甲醛和对氟苯胺为原料,得白色固体0.18g,收率:73%,mp:36℃-39℃。
1H-NMR(CDCl3,500Hz):δ=1.70(2H,m,-CH2-),1.90(2H,m,-CH2-),2.99(1H,m,-CH-),3.03(2H,m,-NHCH2-),4.53(1H,d,-NCH-),5.02(1H,m,-NHCH2-),6.83(2H,d,Ar-H),6.92(2H,m,Ar-H),7.20(2H,m,Ar-H),7.26(2H,s,Ar-H),7.32(2H,d,Ar-H),7.60(1H,m,Ar-H),8.01(1H,m,Ar-H);MS(ESI+,m/z):538.3([M+H]+)。
实施例31:药理学实验数据。
1、细胞、试剂及仪器
1.1细胞
CaCO-2细胞,订购单位:上海酶联生物科技有限公司
1.2试剂
胆固醇购自sigma life science,货号:C8667-5G
Penicillin-streptomycin solution,购自Hyclone Laboratories,Inc,货号SV30010
DMEM购自gibco by life technology,货号:11995-040
MEM NEAA购自gibco by life technology,货号:11140-050
0.25%Trypsin-EDTA购自gibco by life technology,货号:25200-072
1-油酰基-rac-甘油购自sigma life science,货号:M7765-50mg
Sodium taurocholate hydrate购自sigma life science,货号:86339-1G
BCA蛋白浓度测定试剂盒购自Beyotime,货号:P0012
RIPA裂解液(强)购自Beyotime,货号:P0013B
NaCl购自Biosharp,批号:2012/09
Na2HPO4购自sigma life science,货号:S5136-100G
KCl购自AMRESCO,货号:0395-500G
KH2PO4购自AMRESCO,货号:0781-500G
三氟乙酸(AR)购自国药集团,批号20120608
活性炭购自sigma-Aldrich,货号:C3345-500G
1.3受试药物、阳性药物以及实验过程中用到的试剂的配置
将受试药物以及阳性药物(Ezetimibe)用DMSO配成100mmol/L的溶液。
培养基的配置:20%的去脂FBS,1%双抗,1%非必需氨基酸,DMEM。
胆固醇胶束:在DMEM培养基中加入终浓度为3mmol/L的牛磺胆酸钠,终浓度为30umol/L的油酸单甘油酯,终浓度为2.5mmol/L胆固醇,超声混匀,再经过0.22um的滤膜过滤,保存在4℃的冰箱中待用。
去脂FBS的制备:在50mL的胎牛血清中加入1g的活性炭,震荡均匀,放在4℃冰箱中放置过夜,放在的离心机(4000r,4℃)离心10min,取上层清液,经过0.22um的滤膜过滤即得。
PBS:8gNaCl、0.2gKCl、0.24gKH2PO4和1.44gNa2HPO4溶于1L的双蒸水,超声均匀,高温灭菌。
1.4仪器
高效液相购自日本岛津公司,型号:LC-20AT。
酶标仪购自Bio-Tek,型号:Synergy HT。
2、方法
培养CaCO-2细胞于6孔板中,实验分为空白对照组、模型组、阳性药组和受试药组。每组6个平行组,当细胞培养到80%时,将含有100umol/L受试药的培养基加入到每孔中,每孔1.5mL,阳性药一样,另外空白组与模型组加纯培养基,一起培养24h。24h后将培养液吸去,用PBS洗2遍,空白组每孔加1mL的DMEM培养24h,模型组、阳性药组和受试药组每孔加入1mL的胆固醇胶束培养24h。吸取胆固醇胶束,用PBS洗2遍,最后破碎细胞,测蛋白含量及细胞内胆固醇的含量。
3、实验结果
表1
表2
以上药理学数据显示,本发明通式(I)化合物具有较强的降低细胞内胆固醇作用。
Claims (6)
1.一种氮杂环丁酮衍生物,它是由通式(I)表示的化合物及其可药用盐:
其中,
Ar代表R3-取代的芳基;
R1-、R2-和R3-代表1~5个取代基,它们独立选自包括:-OR4,-O(CO)R4,-O(CO)OR4,-O(CH2)1-5OR4,-O(CH2)1-2O-,-O(CO)NR4R5,-NR4R5,-NR4(CO)R5,-NR4(CO)OR5,-NR4(CO)NR5R6,-NR4SO2-低级烷基,-NR4SO2-芳基,-CONR4R5,-COR4,-SO2NR4R5,S(O)0-2-烷基,S(O)0-2-芳基,-O(CH2)1-10-COOR4,-O(CH2)1-10CONR4R5,氢,邻-卤代,间-卤代,对-卤代,邻-低级烷基,间-低级烷基,对-低级烷基,芳基,-NO2,-OCF3,-CF3,-(低级亚烷基)-COOR4或-CH=CH-COOR4;
R4、R5和R6独立选自:氢,低级烷基,芳基,芳基取代的低级烷基;
所述的低级烷基为C1-C6直链烷基或C1-C6带支链的烷基;
所述的低级亚烷基为C1-C6亚烷基。
2.根据权利要求1所述的氮杂环丁酮衍生物,其特征在于,其选自以下任一化合物及其可药用盐:
(3R,4S)-1-(4-甲基苯基)-3-(3-苯磺酰胺基丙基)-4-(4-硝基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-(3-苯磺酰胺基丙基)-4-(4-甲磺酰胺基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-(3-苯磺酰胺基丙基)-4-[4-(4-甲基苯磺酰胺基)苯基]-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-[3-(4-乙基苯磺酰胺基)丙基]-4-(4-硝基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-[3-(4-乙基苯磺酰胺基)丙基]-4-(4-甲磺酰胺基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-[3-(4-乙基苯磺酰胺基)丙基]-4-[4-(4-甲基苯磺酰胺基)苯基]-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-[3-(4-三氟甲氧基苯磺酰胺基)丙基]-4-(4-硝基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-[3-(4-三氟甲氧基苯磺酰胺基)丙基]-4-(4-甲磺酰胺基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-[3-(4-三氟甲氧基苯磺酰胺基)丙基]-4-[4-(4-甲基苯磺酰胺基)苯基]-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-[3-(2-噻吩磺酰胺基)丙基]-4-(4-硝基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-[3-(2-噻吩磺酰胺基)丙基]-4-(4-甲磺酰胺基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-[3-(2-噻吩磺酰胺基)丙基]-4-[4-(4-甲基苯磺酰胺基)苯基]-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-[3-(3-溴苯磺酰胺基)丙基]-4-(4-硝基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-[3-(2-三氟甲氧基苯磺酰胺基)丙基]-4-(4-硝基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-[3-(2-三氟甲氧基苯磺酰胺基)丙基]-4-(4-甲磺酰胺基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-甲基苯基)-3-[3-(2-三氟甲氧基苯磺酰胺基)丙基]-4-[4-(4-甲基苯磺酰胺基)苯基]-2-氮杂环丁酮;
(3R,4S)-1-(4-氟苯基)-3-[3-(4–三氟甲基苯磺酰胺基)丙基]-4-(4-羟基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-氟苯基)-3-[3-(4–氟苯磺酰胺基)丙基]-4-(4-羟基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-氟苯基)-3-[3-(4–乙基苯磺酰胺基)丙基]-4-(4-羟基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-氟苯基)-3-[3-(4–叔丁基苯磺酰胺基)丙基]-4-(4-羟基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-氟苯基)-3-[3-(4–三氟甲氧基苯磺酰胺基)丙基]-4-(4-羟基苯基)-2-氮杂环丁酮;
(3R,4S)-1-(4-氟苯基)-3-[3-(2–三氟甲氧基苯磺酰胺基)丙基]-4-(4-羟基苯基)-2-氮杂环丁酮。
4.权利要求1所述的氮杂环丁酮衍生物在制备治疗或预防动脉粥样硬化或降低血浆胆固醇水平的药物中的应用。
5.根据权利要求4所述的应用,其特征在于,所述的氮杂环丁酮衍生物为通式(I)表示的化合物或其可药用盐或其药学上可接受的载体。
6.根据权利要求4所述的应用,其特征在于,药物剂型为片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂或注射液。
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CN104447489A (zh) * | 2014-12-29 | 2015-03-25 | 南京工业大学 | 3,4-二芳基马来酰亚胺衍生物及其制备方法与应用 |
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CN106432039A (zh) * | 2016-09-27 | 2017-02-22 | 南京工业大学 | 3,4‑二芳基马来酰亚胺衍生物及其制备方法与应用 |
CN106432039B (zh) * | 2016-09-27 | 2019-02-22 | 南京工业大学 | 3,4-二芳基马来酰亚胺衍生物及其制备方法与应用 |
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