CN101691367B - Piperazine and <2,1-a> isoquinoline compounds with antifungal activity and salts thereof - Google Patents
Piperazine and <2,1-a> isoquinoline compounds with antifungal activity and salts thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicaments, and discloses compounds with antifungal activity. The compound is shown in a structural general formula, wherein R1 represents H, OH, CH3O, NO2 or F; R2 represents H, OH, CH3O, NO2 or F; R3 represents H, OH, CH3O, NO2 or F; R4 represents H, OH, CH3O, NO2 or F; R5 represents H, C1 to C20 linear or branched alkyl, C1 to C20 linear or branched alkenyl, benzyl or aromatic substituted benzyl; R6 is equal to O or H; and HX represents HC1 or HBr. The compounds have stable chemical properties, can inhibit the growth of fungal cells, and can be used for preparing antifungal medicaments.
Description
Technical field:
The present invention relates to medical technical field, be about a class piperazine also [2,1-a] isoquinoline compound have the particular chemical structure of anti-mycotic activity
Background technology:
Fungi infestation is life-time service Broad spectrum antibiotics, intubation catheter and tumor chemoradiotherapy clinically thereupon, the destruction of causing human body normal microflora symbiotic relationship, serious threat human life health at present.Serious day by day along with drug resistance and toxic side effect makes that clinical demand to antifungal drug constantly increases at present.The antifungal drug of seeking efficient, wide spectrum and safety is a very urgent problem.
Lanosterol 14 α demethylases (CYP51) are key enzymes in the fungal cell membrane biosynthetic process.Azole antifungals is unique class CYP51 inhibitor of present clinical treatment fungi infestation, also is most widely used antifungal drug.Yet the nitrogen azole drug exists resistance and liver toxicity two big class problems, makes its clinical application be subjected to developing very big restriction.Therefore, the contriver studies crucial amino residue in the active chamber based on enzymatic structure, adopts the computer aided molecular design technology, designs the non-nitrogen azole inhibitor of a class brand new type of brand-new binding pattern, new mechanism of action.This provides new structure type for antifungal drug, and also the appropriate design for the efficient antifungal medicine provides the basis, and more the development of antifungal drug provides a new direction and new research path.
Summary of the invention:
The contriver is according to the binding site property analysis to CYP51 target enzymic activity chamber, in conjunction with the structure of lead compound, by the computer aided molecular design technology, avoid can with nitrogen azole drug bonded protoheme prothetic group Fe atom, with aminoacid functional residue in the active chamber is the medicine binding site, the N-that has designed a class new texture type replaces-2,3,4,6,7,11b-six hydrogen-1H-piperazine is antimycotic inhibitor of [2,1-a] iloquinoline derivative or pharmacy acceptable salt class also.The general structure of novel anti fungistat of the present invention is:
R1 represents H, OH, CH in the formula
3O, NO
2Perhaps F;
R
2Expression H, OH, CH
3O, NO
2Perhaps F;
R
3Expression H, OH, CH
3O, NO
2Perhaps F;
R
4Expression H, OH, CH
3O, NO
2Perhaps F;
R
5Be expressed as H, C
1-C
20Straight or branched alkyl, C
1-C
20Straight or branched thiazolinyl, benzyl or aromatic ring on substituted benzyl
R
6For :=O, H
HX represents HCl, HBr.
The present invention synthetic and be proved have anti-mycotic activity the part piperazine also the chemical structure of [2,1-a] isoquinoline compound or its esters see Table 1.
Table 1 compound structure
| Compound | R 1 | R 2 | R 3 | R 4 | R 5 | R 6 | HX |
| 1 | H | H | H | H | (CH 2) 3CH 3 | ＝O | HCl |
| 2 | H | H | H | H | (CH 2) 7CH 3 | ＝O | HCl |
| 3 | H | H | H | H | (CH 2) 8CH 3 | ＝O | HCl |
| 4 | H | H | H | H | (CH 2) 11CH 3 | ＝O | HCl |
| 5 | H | OCH 3 | OCH 3 | H | (CH 2) 3CH 3 | ＝O | HCl |
| 6 | H | OCH 3 | OCH 3 | H | (CH 2) 7CH 3 | ＝O | HCl |
| 7 | H | OCH 3 | OCH 3 | H | (CH 2) 8CH 3 | ＝O | HCl |
| 8 | H | OCH 3 | OCH 3 | H | (CH 2) 11CH 3 | ＝O | HCl |
| 9 | H | H | F | H | (CH 2) 3CH 3 | ＝O | HCl |
| 10 | H | H | F | H | (CH 2) 7CH 3 | ＝O | HCl |
| 11 | H | H | F | H | (CH 2) 8CH 3 | ＝O | HCl |
| 12 | H | H | F | H | (CH 2) 11CH 3 | ＝O | HCl |
| 13 | H | H | H | H | (CH 2) 3CH 3 | H | 2HCl |
| 14 | H | H | H | H | (CH 2) 7CH 3 | H | 2HCl |
| 15 | H | H | H | H | (CH 2) 8CH 3 | H | 2HCl |
| 16 | H | OCH 3 | OCH 3 | H | (CH 2) 3CH 3 | H | 2HCl |
| 17 | H | OCH 3 | OCH 3 | H | (CH 2) 7CH 3 | H | 2HCl |
| 18 | H | OCH 3 | OCH 3 | H | (CH 2) 8CH 3 | H | 2HCl |
| 19 | H | OCH 3 | OCH 3 | H | (CH 2) 11CH 3 | H | 2HCl |
| 20 | H | H | F | H | (CH 2) 3CH 3 | H | 2HCl |
| 21 | H | H | F | H | (CH 2) 7CH 3 | H | 2HCl |
| 22 | H | H | F | H | (CH 2) 8CH 3 | H | 2HCl |
| 23 | H | H | F | H | (CH 2) 11CH 3 | H | 2HCl |
| 24 | H | OH | OH | H | (CH 2) 3CH 3 | H | 2HBr |
| 25 | H | OH | OH | H | (CH 2) 7CH 3 | H | 2HBr |
| 26 | H | OH | OH | H | (CH 2) 8CH 3 | H | 2HBr |
| 27 | H | OH | OH | H | (CH 2) 11CH 3 | H | 2HBr |
| 28 | H | H | H | H | CH 2C 6H 4-p-F | ＝O | HCl |
| 29 | H | H | H | H | CH 2C 6H 3-2，4-Cl | ＝O | HCl |
| 31 | H | OCH 3 | OCH 3 | H | CH 2C 6H 4-p-F | ＝O | HCl |
| 32 | H | OCH 3 | OCH 3 | H | CH 2C 6H 3-2，4-Cl | ＝O | HCl |
| 33 | H | H | F | H | CH 2C 6H 4-p-F | ＝O | HCl |
| 34 | H | H | F | H | CH 2C 6H 3-2，4-Cl | ＝O | HCl |
| 35 | H | H | F | H | CH 2C 6H 4-p-F | H | 2HCl |
| 36 | H | H | F | H | CH 2C 6H 3-2，4-Cl | H | 2HCl |
| 37 | H | OCH 3 | OCH 3 | H | CH 2-CH＝CH 2 | ＝O | HCl |
| 38 | H | H | H | H | CH 2-CH＝CH 2 | ＝O | HCl |
The hydrogen spectrum of table 2 compound, mass-spectrometric data
| 47～3.54，3.61～3.68(dd，2H，CH 2)；4.74～4. 92(t，2H，CH 2)；5.34～5.43(t，1H，CH)；7.12 ～7.28(m，4H，Ar-H)； | ||||
| 5 | C 18H 26N 2O 3·HCl | 354.87 | 0.98～1.02(t，J＝6，3H，CH 3)；1.24～1.47(m， 4H，CH 2)；1.70～1.83(m，2H，CH 2)；2.62～2. 72(m，2H，CH 2)；3.04～3.54(m，4H，CH 2)；3 .86(s，6H，OCH 3)；4.19～4.37(m，2H，CH 2)； 4.85～4.99(m，2H，CH 2)；5.746～5.777(dd， J＝9.3，1H，CH)；6.63(s，1H，Ar-H)； 6.69(s，1H，Ar-H)； | C60.92％；H，7.67 ％；N，7.89％ |
| 6 | C 22H 34N 2O 3·HCl | 410.98 | 0.836～0.880(t，J＝6.2，3H，CH 3)；1.260～1. 289(m，J＝8.7，10H，CH 2)；1.70～1.85(m，2 H，CH 2)；2.60～2.76(t，2H，CH 2)；3.04～3.54 (t，4H，CH 2)；3.726(s，3H，OCH 3)；3.756(s， 3H，OCH 3)；3.97～4.04(m，2H，CH 2)；4.34～ 4.68(t，2H，CH 2)；5.16～5.28(t，1H，CH)；6.7 9(s，1H，Ar-H)；6.93(s，1H，Ar-H)； | C64.29％；H，8.58 ％；N，6.82％； |
| 7 | C 23H 36N 2O 3·HCl | 425.00 | 0.894～0.938(t，J＝6.2，3H，CH 3)；1.23～1.4 3(m，12H，CH 2)；1.88～2.15(m，2H，CH 2)；2 .88～2.96(t，2H，CH 2)；3.34～3.56(t，4H，CH 2)；3.879(s，3H，OCH 3)；3.891(s，3H，OCH 3 )；4.05～4.09，4.22～4.28(m，2H，CH 2)；4.85 ～4.92(m，2H，CH 2)；5.74～5.83(m，1H，CH) ；7.61(s，1H，Ar-H)；7.68(s，1H，Ar-H)； | C65.00％；H，8.77 ％；N，6.59％ |
| 8 | C 26H 42N 2O 3·HCl | 467.08 | 0.822～0.865(t，J＝6.3，3H，CH 3)；1.240～1. 287(m，J＝14.1，16H，CH 2)；1.88～2.15(m，2 H，CH 2)；2.38～2.45(m，2H，CH 2)；3.08～3.1 6(m，2H，CH 2)；3.34～3.56(m，4H，CH 2)；3. 726(s，3H，OCH 3)；3.756(s，3H，OCH 3)；3.9 5～4.09(m，2H，CH 2)；4.65～4.72(m，2H，C H 2)；5.14～5.27(m，1H，CH)；6.81(s，1H，Ar- H)；6.91(s，1H，Ar-H)； | C66.68％；H，9.28 ％；N，6.00％ |
| 9 | C 16H 21FN 2O·HCl | 312.81 | 0.987～1.032(t，J＝6.5，3H，CH 3)；1.37～1.9 4(m，4H，CH 2)；2.84～2.98(t，2H，CH 2)；3.0 4～3.09(m，2H，CH 2)；3.14～3.28(t，2H，CH 2 )；3.42～4.08(m，2H，CH 2)；4.22～4.28，4.71 | C，61.43％；H，7.09 ％；N，8.96％ |
[0021]
| ～4.84(m，2H，CH 2)；5.75～5.87(m，1H，CH) ；6.93～7.09(m，3H，Ar-H)；7.17～7.22(m，2 H，Ar-H)； | ||||
| 10 | C 20H 29FN 2O·HCl | 368.92 | 0.874～0.914(t，J＝6，3H，CH 3)；1.27～1.44( m，10H，CH 2)；1.84～2.08(t，2H，CH 2)；2.84 ～2.92(m，2H，CH 2)；3.14～3.28(t，2H，CH 2) ；3.42～4.04(m，2H，CH 2)；4.18～4.26，4.74～ 4.84(m，2H，CH 2)；5.79～5.86(m，1H，CH)； 6.89～7.03(t，3H，Ar-H)；7.17～7.22(t，2H， Ar-H)； | C，65.11％；H，8.20 ％；N，7.59％ |
| 11 | C 21H 31FN 2O·HCl | 382.94 | 0.868～0.914(t，J＝6.1，3H，CH 3)；1.17～1.4 0(m，12H，CH 2)；1.84～2.08(t，2H，CH 2)；2. 76～2.92(m，2H，CH 2)；3.10～3.22(t，2H，C H 2)；3.40～4.04(m，2H，CH 2)；4.18～4.26，4. 74～4.84(m，2H，CH 2)；5.78～5.90(m，1H，C H)；6.90～7.02(t，3H，Ar-H)；7.17～7.23(t，2 H，Ar-H)； | C，65.86％；H，8.42 ％；N，7.32％； |
| 12 | C 24H 39FN 2O·HCl | 425.02 | 0.865～0.912(t，J＝6.1，3H，CH 3)；1.19～1.4 2(m，18H，CH 2)；1.82～2.08(m，2H，CH 2)；2 .78～2.96(m，2H，CH 2)；3.10～3.22(t，2H，C H 2)；3.38～4.02(m，2H，CH 2)；4.16～4.24，4. 78～4.87(m，2H，CH 2)；5.78～5.90(m，1H，C H)；6.91～7.04(t，3H，Ar-H)；7.17～7.20(t，2 H，Ar-H)； | C，67.82％；H，9.01 ％；N，6.59％ |
| 13 | C 16H 24N 2·2HCl | 317.3 | 0.897～0.946(t，J＝6.1，3H，CH 3)；1.301～1. 374(m，J＝21.9，2H，CH 2)；1.74～1.85(m，2 H，CH 2)；3.14～3.20(m，4H，CH 2)；3.61～3.8 9(m，8H，CH 2)；3.90～3.94(m，1H，CH)；7.2 1～7.48(m，4H，Ar-H)； | C，60.57％；H，8.26 ％；N，8.83％ |
| 14 | C 20H 32N 2·2HCl | 373.4 | 0.837～0.876(t，J＝6.1，3H，CH 3)；1.262～1. 288(m，J＝6.2，10H，CH 2)；1.74～1.85(m，2 H，CH 2)；3.14～3.20(t，4H，CH 2)；3.51～3.53 (m，8H，CH 2)；3.62～3.67(t，1H，CH)；7.21～ 7.48(m，4H，Ar-H)； | C，64.33％；H，9.18 ％；N，7.50％ |
| 15 | C 21H 34N 2·2HCl | 387.43 | 0.831～0.875(t，J＝6.2，3H，CH 3)；1.03～1.4 4(m，12H，CH 2)；1.74～1.85(m，2H，CH 2)；3 | C，65.10％；H，9.37 ％；N，7.23％ |
[0022]
| .14～3.20(m，4H，CH 2)；3.51～3.53(m，8H， CH 2)；3.96～4.05(t，1H，CH)；7.20～7.45(m， 4H，Ar-H)； | ||||
| 16 | C 18H 28N 2O 2·2HCl | 377.35 | 0.900～0.949(t，J＝6.1，3H，CH 3)；1.302～1. 378(m，J＝22.8，2H，CH 2)；1.64～1.80(m，2 H，CH 2)；3.14～3.20(t，4H，CH 2)；3.71～3.7 9(m，8H，CH 2)；3.80～3.82(m，1H，CH)；3.7 33(s，3H，OCH 3)；3.759(s，3H，OCH 3)；6.80 7(m，2H，Ar-H)；6.852(m，2H，Ar-H)； | C，57.29％；H，8.01 ％；N，7.42％ |
| 17 | C 22H 36N 2O 2·2HCl | 433.36 | 0.889～0.931(t，J＝6.2，3H，CH 3)；1.265～1. 326(m，J＝18.3，10H，CH 2)；1.84～2.08(m，2 H，CH 2)；2.84～3.08(m，4H，CH 2)；3.51～3.5 3(m，8H，CH 2)；3.84(s，6H，OCH 3)；5.35～5. 55(m，1H，CH)；6.66(s，2H，Ar-H)； | C，60.96％；H，8.84 ％；N，6.46％ |
| 18 | C 23H 38N 2O 2·2HCl | 447.48 | 0.861～0.904(t，J＝6.3，3H，CH 3)；1.264～1. 351(m，J＝26.1，12H，CH 2)；1.84～2.06(m，2 H，CH 2)；2.84～3.08(m，4H，CH 2)；3.51～3.5 3(m，8H，CH 2)；3.78(s，6H，OCH 3)；5.32～5. 48(m，1H，CH)；6.66(s，2H，Ar-H)； | C，61.73％；H，9.01 ％；N，6.26％ |
| 19 | C 26H 44N 2O 2·2HCl | 489.56 | 0.820～0.864(t，J＝6.2，3H，CH 3)；1.017～1. 064(m，J＝14.1，16H，CH 2)；1.74～1.86(m，2 H，CH 2)；3.04～3.18(m，4H，CH 2)；3.739(s， 3H，OCH 3)；3.763(s，3H，OCH 3)；3.52～3.6 3(m，8H，CH 2)；5.32～5.48(m，1H，CH)；6.8 30(s，1H，Ar-H)；6.872(s，1H，Ar-H)； | C，63.79％；H，9.47 ％；N，5.72％ |
| 20 | C 16H 23FN 2·2HCl | 335.29 | 0.973～1.022(t，J＝6.4，3H，CH 3)；1.391～1. 465(m，J＝22.2，2H，CH 2)；1.84～2.07(m，2 H，CH 2)；2.64～2.86(t，4H，CH 2)；3.14～3.28 (t，6H，CH 2)；4.22～4.28，4.71～4.84(m，2H， CH 2)；4.20～4.32(m，1H，CH)；6.86～6.94( m，2H，Ar-H)；7.12～7.19(t，1H，Ar-H) | C，57.32％；H，7.52 ％；N，8.63％ |
| 21 | C 20H 31FN 2·2HCl | 391.39 | 0.869～0.913(t，J＝6.2，3H，CH 3)；1.281～1. 313(m，J＝9.6，10H，CH 2)；1.84～2.04(m，2 H，CH 2)；2.84～3.32(t，4H，CH 2)；3.54～4.46 (m，6H，CH 2)；4.22～4.31(m，2H，CH2)；5.4 0～5.60(m，1H，CH)；6.86～6.94(m，2H，Ar- | C，61.37％；H，8.50 ％；N，7.16％ |
[0023]
| H)；7.14～7.27(t，1H，Ar-H) | ||||
| 22 | C 21H 33FN 2·2HCl | 405.42 | 0.898～0.943(t，J＝6.2，3H，CH 3)；1.28～1.4 4(m，12H，CH 2)；1.84～2.07(m，2H，CH 2)；2 .94～3.06(t，4H，CH 2)；3.54～3.88(t，6H，CH 2)；4.22～4.84(m，2H，CH 2)；5.50～5.82(t，1 H，CH)；6.89～7.04(m，2H，Ar-H)；7.12～7.1 8(t，1H，Ar-H) | C，62.21；H，8.70％； N.6.91％ |
| 23 | C 24H 41FN 2·2HCl | 447.5 | 0.859～0.903(t，J＝6.2，3H，CH 3)；1.258～1. 355(m，CH 2)；1.90～2.04(m，2H，CH 2)；2.6 4～2.80(t，4H，CH 2)；2.94～3.38(t，6H，CH 2) ；3.52～3.84(m，2H，CH 2)；4.18～4.24(t，1H， CH)；6.79～6.94(m，2H，Ar-H)；7.089～7.1 37(t，J＝14.4，1H，Ar-H) | C，64.41；H，9.23％； N.6.26％ |
| 24 | C 16H 24N 2O 2·2HBr | 438.2 | 0.900～0.948(t，J＝6.4，3H，CH 3)；1.273～1. 346(m，J＝21.9，2H，CH 2)；1.63～1.80(m，2 H，CH 2)；2.72～2.96(t，2H，CH 2)；3.14～3.34 (t，4H，CH 2)；3.66～3.82(s，4H，OCH 3)；4.25 ～4.38(t，3H，CH 2)；6.596(s，1H，Ar-H)；6.65 6(s，1H，Ar-H)；8.88(s，1H，OH)；9.34(s，1H， OH) | C，43.85；H，5.98％； N，6.39％ |
| 25 | C 20H 32N 2O 2·2HBr | 494.3 | 0.839～0.881(t，J＝6.2，3H，CH 3)；1.263～1. 291(m，J＝8.4，10H，CH 2)；1.65～1.80(m，2 H，CH 2)；2.87～3.01(t，2H，CH 2)；3.14～3.34 (t，4H，CH 2)；3.97～4.04(m，4H，CH 2)；3.97 ～4.18(t，3H，CH 2)；6.583(s，1H，Ar-H)；6.64 5(s，1H，Ar-H)；8.88(s，1H，OH)；9.34(s，1H， OH) | C，48.60；H，6.93％； N，5.67％ |
| 26 | C 21H 34N 2O 2·2HBr | 508.33 | 0.831～0.872(t，J＝6.3，3H，CH 3)；1.255～1. 278(m，J＝6.9，12H，CH 2)；1.65～1.80(m，2 H，CH 2)；2.97～3.11(m，2H，CH 2)；3.14～3.3 4(m，4H，CH 2)；3.67～3.86(m，4H，CH 2)；4. 02～4.18(t，3H，CH 2)；6.59(s，1H，Ar-H)；6.6 7(s，1H，Ar-H)；8.98(s，1H，OH)；9.39(s，1H， OH) | C，49.62；H，7.14％； N，5.51％ |
[0024]
| 27 | C 24H 40N 2O 2·2HBr | 550.41 | 0.821～0.865(t，J＝6.2，3H，CH 3)；1.238～1. 286(m，J＝14.4，18H，CH 2)；1.65～1.80(m，2 H，CH 2)；2.98～3.13(m，2H，CH 2)；3.18～3.2 4(m，4H，CH 2)；3.77～3.82(m，4H，CH 2)；4. 42～4.58(t，3H，CH 2)；6.55(s，1H，Ar-H)；6.6 4(s，1H，Ar-H)；9.04(s，1H，OH)；9.39(s，1H， OH) | C，52.37；H，7.69％； N，5.09％ |
| 28 | C 19H 19FN 2O·HCl | 346.83 | 2.81～2.96(m，4H，CH 2)；3.36～3.62(m，2H， CH 2)；3.92～4.09(m，2H，CH 2)；4.11～4.28( m，2H，CH 2)；4.42～4.82(m，2H，CH 2)；5.81 ～5.88(m，1H，CH)；7.11～7.31(m，4H，Ar-H )；7.65～7.78(m，4H，Ar-H)； | C，65.80；H，5.81％； N，8.08％ |
| 29 | C 19H 18Cl 2N 2O·HCl | 397.73 | 2.74～2.86(m，2H，CH 2)；2.96(s，2H，CH 2)； 3.51～4.09(m，2H，CH 2)；4.11～4.28(m，2H， CH 2)；4.42～4.82(m，2H，CH 2)；5.71～5.82( m，1H，CH)；7.11～7.31(m，4H，Ar-H)；7.65 ～7.78(m，2H，Ar-H)；8.217～8.245(m，J＝8. 4，1H，Ar-H) | C，57.38；H，4.82％； N，7.04％ |
| 30 | C 20H 22N 2O·HCl | 342.68 | 2.38(s，3H，CH 3)；2.35～2.42，2.71～2.77(d d，2H，CH 2)；2.88～3.02(m，2H，CH 2)；3.47～ 3.52(m，2H，CH 2)；3.57～3.60(m，2H，CH 2) ；4.74～4.85(m，1H，CH)；6.94(t，3H，Ar-H)； 7.14～7.21(m，3H，Ar-H)；7.34(m，1H，Ar- H) | C，70.06；H，6.76％； N，8.17％ |
| 31 | C 21H 25FN 2O 2·HCl | 406.88 | 2.38～2.42(m，2H，CH 2)；2.82～2.96(m，3H， CH 2)；3.42～3.52(m，3H，CH 2)；3.52～3.55， 3.64～3.71(m，2H，CH 2)；3.82(s，3H，OCH 3 )；3.86(s，3H，3OCH 3)；4.72～4.85(m，1H，C H)；6.490(s.1H，Ar-H)；6.632(s，1H，Ar-H) ；7.015～7.082(t，J1＝2.1，J2＝4.8，2H，Ar-H) ；7.26～7.38(t，J1＝2.1，J2＝4.8，2H，Ar-H) | C，61.99；H，5.95％； N，6.88％ |
| 32 | C 21H 22Cl 2N 2O 3·HCl | 457.78 | 2.68～2.92(m，4H，CH 2)；3.52～3.82(m，2H， CH 2)；3.76(s，6H，OCH 3)；4.42～4.65，(m，2 | C，55.10；H，5.06％； N，6.12％ |
[0025]
| H，CH 2)；4.72～4.85(m，2H，CH)；5.74(m，1 H，CH)；6.64(s.1H，Ar-H)；6.736～6.742(d， J＝1.8，1H，Ar-H)；7.45(s，1H，Ar-H)；7.56(d ，1H，Ar-H)；8.266～8.372(d，J＝1.8，1H，Ar- H) | ||||
| 33 | C 19H 18F 2N 2O·HCl | 364.82 | 2.74～3.02(m，4H，CH 2)；3.32～3.52(m，2H， CH 2)；3.90～4.48，(m，2H，CH 2)；4.72～4.85 (m，2H，CH)；5.84(m，1H，CH)；6.84(s.2H， Ar-H)；6.72(s，1H，Ar-H)；7.15～7.22(m，1 H，Ar-H)；7.26(s，1H，Ar-H)；7.56～7.78(t，2 H，Ar-H) | C，62.55；H，5.25％； N，7.68％ |
| 34 | C 19H 17Cl 2FN 2O·HCl | 415.72 | 2.84～3.02(m，4H，CH 2)；3.48～3.92(m，2H， CH 2)；4.11～4.48(s，2H，CH 2)；4.52～4.75( m，2H，CH)；5.74(m，1H，CH)；6.84(s.2H，A r-H)；6.72(s，1H，Ar-H)；7.15～7.22(m，1H， Ar-H)；7.56(s，1H，Ar-H)；8.18～8.21(t，1H， Ar-H) | C，54.89；H，4.36％； N，6.74％ |
| 35 | C 19H 20F 2N 2·2HCl | 387.29 | 2.74～2.82(m，2H，CH 2)；2.94～3.12(m，2H， CH 2)；3.34～3.68，(t，2H，CH 2)；3.82～3.89( m，1H，CH)；4.04～4.27(m，2H，CH 2)；3.22～ 3.41(m，2H，CH 2)；3.51～3.71(m，2H，CH 2) ；6.78～6.88(s.2H，Ar-H)；7.05～7.22(m，3H ，Ar-H)；7.56～7.78(t，2H，Ar-H) | C，58.92；H，5.73％； N，7.23％； |
| 36 | C 19H 19Cl 2FN 2·2HCl | 438.19 | 2.04～2.32(m，2H，CH 2)；2.54～2.62(m，2H， CH 2)；2.64～2.78，(t，2H，CH 2)；2.82～2.94( m，1H，CH)；3.04～3.17(m，2H，CH 2)；3.22～ 3.41(m，2H，CH 2)；3.51～3.71(m，2H，CH 2) ；6.72(s，1H，Ar-H)；6.82～6.88(d，1H，Ar-H )；7.06～7.09(d，1H，Ar-H)；7.26～7.41(t，2H ，Ar-H)7.44(s.1H，Ar-H)； | C，52.08；H，4.83％； N，6.39％； |
| 37 | C 17H 22N 2O 3·HCl | 338.83 | 2.28～2.68(t，2H，CH 2)；2.81～3.12(t，4H，C H 2)；3.41～3.64，(d，2H，CH 2)；3.85(s，6H，O CH 3)；4.74～4.90(d，2H，CH 2)；5.22～5.37( d，2H，CH 2)；5.81～5.94(m，1H，CH 2)；6.56( s，1H，Ar-H)；6.62(d，1H，Ar-H)； | C，60.26；H，6.84％； N，8.27％ |
| 38 | C 15H 18N 2O·HCl | 278.78 | 2.28～2.72(t，2H，CH 2)；2.84～3.12(t，4H，C | C，64.63；H，6.87％； |
[0026]
| H 2)；3.11～3.18，(d，2H，CH 2)；4.75～4.92(d d，2H，CH 2)；5.24～5.37(m，2H，CH 2)；5.81～ 5.94(m，1H，CH 2)；6.72(s，1H，Ar-H)；6.82～ 6.88(d，1H，Ar-H)；7.06～7.09(d，1H，Ar-H) ；7.26～7.41(t，2H，Ar-H)7.44(s.1H，Ar-H)； | N，10.05％ |
The The compounds of this invention preparation method is as follows:
1, synthetic route
2, specific operation process is:
1. the 2-phenylethylamine (I) that various phenyl ring replace generates N-chloracetyl-2-phenylethylamine (II) that phenyl ring replaces with the chloroacetyl chloride reaction;
2. N-chloracetyl-2-phenylethylamine (II) that various phenyl ring replace generates 2-(2,2-dimethoxy ethylamino)-N-styroyl ethanamide (III) that phenyl ring replaces with the aminoacetaldehyde dimethyl acetal reaction under the toluene condition;
3. 2-(2,2-dimethoxy ethylamino)-N-styroyl ethanamide (III) that various phenyl ring replace in dichloromethane solvent, dense H
2Reaction generates 2,3,6 of phenyl ring replacement under the SO4 condition, and 7-tetrahydrochysene-1H-piperazine is [2,1-a] isoquinoline 99.9-4 (11bH)-ketone (IV) also;
4. various phenyl ring replace 2,3,6,7-tetrahydrochysene-1H-piperazine also [2,1-a] isoquinoline 99.9-4 (11bH)-ketone (IV) at K
2CO
3Generate the ketone (V) of the N replacement of various phenyl ring replacements under the condition with the hydrochloric ether reaction;
5. the ketone (V) that the N that various phenyl ring replace replaces with the Lithium Aluminium Hydride reduction obtain that N that various phenyl ring replace replaces 2,3,4,6,7,11b-six hydrogen-1H-piperazine is [2,1-a] isoquinoline 99.9 (VI) also
Embodiment:
One. synthesizing of compound
Embodiment 1: 2,3,6 of key intermediate phenyl ring replacement, 7-tetrahydrochysene-1H-piperazine is the preparation of [2,1-a] isoquinoline 99.9-4 (11bH)-ketone (IV) also
1. N-chloracetyl-2-phenylethylamine (II) that various phenyl ring replace
Under ice bath 0-5 ℃, 2-phenylethylamine 60.5g and sodium bicarbonate 53g that various phenyl ring are replaced drop in the 500ml methylene dichloride, slowly drip chloroacetyl chloride 48ml, transfer to room temperature after dripping off and react 2 hours down for 10 ℃.React completely, under 0 ℃ of the ice bath, reaction mixture is poured in the water, separate organic layer with 2M salt pickling 2 times, saturated common salt washing 2 times.The evaporated under reduced pressure solvent gets solid with methyl alcohol and water recrystallization, gets N-chloracetyl-2-phenylethylamine 80g that various phenyl ring replace
2. 2-(2,2-dimethoxy ethylamino)-N-styroyl ethanamide (III) that various phenyl ring replace
Get N-chloracetyl-2-phenylethylamine 6.4g and be dissolved in 30ml toluene, drop into aminoacetaldehyde contract glycol 3.6ml and triethylamine 5ml, 110 ℃ were refluxed 2 hours.After reacting completely, stopped reaction, cold filtration.The evaporated under reduced pressure solvent adds the 30ml methylene dichloride, washes 3 times, separates organic layer, uses anhydrous sodium sulfate drying.Filter evaporate to dryness and get crude product 5.4g, add the 30ml ethyl acetate ,-30 ℃ feed hydrogen chloride gas down, stir a large amount of solids, filtering drying, 2-(2,2-dimethoxy ethylamino)-N-styroyl acetamide hydrochloride.
3. 3,6 of various phenyl ring replacements, 7-tetrahydrochysene-1H-piperazine is [2,1-a] isoquinoline 99.9-4 (11bH)-ketone (IV) also
Get 2-(2,2-dimethoxy ethylamino)-N-styroyl acetamide hydrochloride 20g, be dissolved in methylene dichloride 280ml, under ice bath 0-5 ℃, drip vitriol oil 37.5ml, transfer to room temperature reaction after dripping off and spend the night.After reacting completely, pour reaction mixture into frozen water, alkalizing to pH with 20% cold sodium hydroxide solution is about 12.With dichloromethane extraction three times, anhydrous sodium sulfate drying, evaporated under reduced pressure, place, 2,3,6,7-tetrahydrochysene-1H-piperazine is [2,1-a] isoquinoline 99.9-4 (11bH)-about 15g of ketone also.
Embodiment 2: target compound 2-normal-butyl-2,3,6,7-tetrahydrochysene-1H-piperazine be [2,1-a] isoquinoline 99.9-4 (11bH)-ketone (compound 1 in the table 1) also
In acetone soln, add K
2CO
30.82g, HI 0.1g, with 2,3,6,7-tetrahydrochysene-1H-piperazine also [2,1-a] isoquinoline 99.9-4 (11bH)-ketone 1g and bromination of n-butane 1.3ml drops into wherein, 70 ℃ were refluxed 8 hours.Stop but answering evaporated under reduced pressure, add 15ml water, water layer Et
2O extracts 3 times, and combined ether layer 1MHCl 3ml places a large amount of solids appearance, filter crude product.With ethanol/ether recrystallization, get target compound 1.4g.
Preparation method with embodiment 2 can prepare following compounds:
(1) with 2,3,6,7-tetrahydrochysene-1H-piperazine also [2,1-a] isoquinoline 99.9-4 (11bH)-ketone respectively with n-octane bromide, the positive nonane of bromo, bromo n-dodecane, to fluorine bromobenzyl, 2,4-dichloro bromobenzyl, can synthesize compound 2,3,4,28,29,30,37 in the table 1 respectively to methyl bromobenzyl, the reaction of 3-bromopropylene.
(2) with 2,3,6,7-tetrahydrochysene-9,10-dimethoxy-1H-piperazine also [2,1-a] isoquinoline 99.9-4 (11bH)-ketone respectively with bromination of n-butane, n-octane bromide, the positive nonane of bromo, bromo n-dodecane, to fluorine bromobenzyl, 2,4-dichloro bromobenzyl, the reaction of 3-bromopropylene can be synthesized compound 5,6,7,8,31,32,38 in the table 1 respectively.
(3) with 2,3,6,7-tetrahydrochysene-10-fluoro-1H-piperazine also [2,1-a] isoquinoline 99.9-4 (11bH)-ketone respectively with bromination of n-butane, n-octane bromide, the positive nonane of bromo, bromo n-dodecane, to fluorine bromobenzyl, 2, the reaction of 4-dichloro bromobenzyl can be synthesized compound 9,10,11,12,33,34 in the table 1 respectively.
Embodiment 3: target compound 2-normal-butyl-2,3,4,6,7,11b-six hydrogen-1H-piperazine be [2,1-a] isoquinoline 99.9 (compound 13 in the table 1) also
1g compound 1 is added in the 20ml anhydrous tetrahydro furan, under the condition of ice bath, divides to add LiAlH in batches
40.6g, reaction 3h.The frozen water cancellation is filtered, and the organic layer evaporated under reduced pressure adds 1MHCl and gets crude product, the methanol recrystallization, target compound 0.8g.
Preparation method with embodiment 3 can prepare following compounds:
Can prepare compound 13～15 respectively by compound 1～3.Can prepare 16～19 respectively by compound 5～8.There is compound 9～12 to prepare 20～23 respectively.Can prepare 35～36 respectively by compound 33～34.
Embodiment 4: target compound 2-butyl-2,3,4,6,7,11b-six hydrogen-9,10-hydroxyl-1H-piperazine are [2,1-a] isoquinoline 99.9 (compound 24 in the table 1) also
Get 40% Hydrogen bromide 10ml and be added in the 1g compound 5 reflux 4h.Evaporated under reduced pressure, the methanol recrystallization, target compound 0.9g.
Preparation method with embodiment 4 can prepare following compounds:
Can prepare compound 25～27 respectively by compound 6～8.
Two, bacteriostatic test
1, experimental strain: this experiment adopts 6 kinds of common deeps and shallow table pathomycete to be the test bacterium.They are respectively: Candida albicans, cryptococcus neoformans, Oidium tropicale, trichophyton, gypsum shape sporidiole bacteria, smoke aspergillus fumigatus (being provided by fungi storehouse, Shanghai Long March Hospital).
2, bacterium liquid preparation: coccus is cultivated 16h for 35 ℃ at the YEPD liquid nutrient medium, and activation twice with the blood cell counting plate counting, is adjusted bacterial concentration to 1 * 10 with the RPMI1640 nutrient solution
3～5 * 10
3Individual/ml; Thread fungus is seeded to the SDA inclined-plane, and 35 ℃, cultivate a week, activation twice makes bacterial strain cover the SDA inclined-plane, adds an amount of RPMI1640 nutrient solution, blows and beats bacterium colony with suction pipe, and fungal spore is free in the RPMI1640 nutrient solution, filters through four layers of sterile gauze then.Nutrient solution adds the RPMI1640 nutrient solution and adjusts spore concentration to 1 * 10 behind the blood cell counting plate counting
3～5 * 10
3Individual/ml.
3, soup preparation: be subjected to the reagent thing to be made into 6.4gL-1 with DMSO respectively.
4, cultivate and detect: 24 hours measurement results of Candida fungus culture.Survey each hole OD value with enzyme micro-plate reader in 630nm.With the positive control boring ratio, be MIC with the drug level in the minimum concentration hole of OD value decline more than 80%
80(anti-mycotic activity sees Table 3)
Table 3 compound anti-mycotic activity (MIC
80, mgL
-1)
| Compound number | Bai Nian | New latent | The torrid zone | Red hair | Stone is little | The cigarette song |
| 1 | ＞64 | 32 | ＞64 | ＞64 | 64 | ＞64 |
| 2 | ＞64 | 8 | 64 | 16 | 4 | 32 |
| 3 | 16 | 4 | ＞64 | 8 | 2 | 16 |
| 4 | ＞64 | 32 | 32 | 32 | 64 | 64 |
| 5 | ＞64 | 16 | ＞64 | ＞64 | ＞64 | ＞64 |
| 6 | 16 | 8 | 64 | 32 | 16 | 64 |
| 7 | ＞64 | 4 | ＞64 | 32 | 2 | 32 |
| 8 | ＞64 | 32 | ＞64 | ＞64 | ＞64 | ＞64 |
| 9 | ＞64 | 32 | ＞64 | 64 | ＞64 | ＞64 |
| 10 | ＞64 | 16 | ＞64 | 16 | 16 | 32 |
| 11 | 32 | 16 | 64 | 4 | 0.5 | 16 |
| 12 | ＞64 | ＞64 | 64 | 64 | 64 | 32 |
| 13 | ＞64 | 32 | ＞64 | ＞64 | 8 | ＞64 |
| 14 | 16 | 4 | 16 | 8 | 2 | 16 |
| 15 | 8 | 2 | 4 | 4 | 2 | 8 |
| 16 | ＞64 | ＞64 | ＞64 | ＞64 | ＞64 | ＞64 |
| 17 | 32 | 16 | 64 | 16 | 4 | 32 |
[0065]
| 18 | 32 | 4 | 32 | 8 | 2 | ＞64 |
| 19 | ＞64 | 16 | ＞64 | ＞64 | 32 | ＞64 |
| 20 | 64 | ＞64 | ＞64 | ＞64 | 4 | ＞64 |
| 21 | 16 | 4 | 16 | 8 | 4 | 32 |
| 22 | 8 | 4 | 16 | 8 | 2 | 16 |
| 23 | ＞64 | 64 | ＞64 | 64 | 4 | ＞64 |
| 24 | ＞64 | 4 | ＞64 | ＞64 | ＞64 | ＞64 |
| 25 | 16 | 2 | 8 | 16 | 32 | 64 |
| 26 | 8 | 4 | 2 | 8 | 8 | 64 |
| 27 | 64 | 16 | 32 | 16 | 16 | 64 |
| 28 | ＞64 | 64 | 64 | 32 | 32 | 64 |
| 29 | ＞64 | 32 | ＞64 | 32 | 32 | 64 |
| 30 | ＞64 | 32 | ＞64 | 32 | 32 | 64 |
| 31 | ＞64 | 64 | ＞64 | ＞64 | ＞64 | ＞64 |
| 32 | ＞64 | 32 | ＞64 | 32 | 32 | ＞64 |
| 33 | ＞64 | 4 | ＞64 | 32 | 32 | ＞64 |
| 34 | ＞64 | 8 | ＞64 | 32 | 32 | ＞64 |
| 35 | 64 | 64 | 64 | 32 | 16 | ＞64 |
| 36 | 64 | 16 | 64 | 32 | 32 | 32 |
| 37 | ＞64 | ＞64 | ＞64 | ＞64 | ＞64 | ＞64 |
| 38 | ＞64 | ＞64 | ＞64 | ＞64 | ＞64 | ＞64 |
This shows, The compounds of this invention has anti-mycotic activity, N-of the present invention replaces-2,3,4,6,7,11b-six hydrogen-1H-piperazine also [2,1-a] isoquinoline compound is the compound with anti-mycotic activity of a class brand new, and this is that further investigation and developing novel antifungal medicines have been opened up new approach and direction.
Claims (5)
1. have compound or its pharmaceutically acceptable addition salt of anti-mycotic activity, general structure is as follows:
In the formula, HX is expressed as HCl or HBr, and each R group is done following collocation:
(1) R
1～R
3Be H, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(2) R
1, R
2, R
4Be H, R
3Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(3) R
1, R
3, R
4Be H, R
2Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(4) R
2, R
3, R
4Be H, R
1Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(5) R
1, R
2Be H, R
3, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(6) R
1, R
3Be H, R
2, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(7) R
1, R
4Be H, R
2, R
3Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl or C
4～C
20The straight or branched thiazolinyl; R
6The expression H or=O;
(8) R
2, R
3Be H, R
1, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(9) R
2, R
4Be H, R
1, R
3Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(10) R
3, R
4Be H, R
1, R
2Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(11) R
1Be H, R
2, R
3, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(12) R
2Be H, R
1, R
3, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(13) R
3Be H, R
1, R
2, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(14) R
4Be H, R
1, R
2, R
3Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O; Or
(15) R
1, R
2, R
3, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O.
2. have compound or its pharmaceutically acceptable addition salt of anti-mycotic activity, general structure is as follows:
In the formula, each group is done following collocation:
。
3. compound or its pharmaceutically acceptable addition salt application in the preparation antifungal drug, its general structure is as follows:
In the formula, R
1Expression H, OH, CH
3O, NO
2Perhaps F;
R
2Expression H, OH, CH
3O, NO
2Perhaps F;
R
3Expression H, OH, CH
3O, NO
2Perhaps F;
R
4Expression H, OH, CH
3O, NO
2Perhaps F;
R
5Be expressed as C
1-C
20Straight or branched alkyl, C
1-C
20Straight or branched thiazolinyl or benzyl;
R
6Be expressed as=O or H;
HX is expressed as HCl or HBr.
4. by the described application of claim 3, it is characterized in that in described compound or its pharmaceutically acceptable addition salt, each R group is done following collocation:
(1) R
1～R
3Be H, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(2) R
1, R
2, R
4Be H, R
3Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(3) R
1, R
3, R
4Be H, R
2Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(4) R
2, R
3, R
4Be H, R
1Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(5) R
1, R
2Be H, R
3, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(6) R
1, R
3Be H, R
2, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(7) R
1, R
4Be H, R
2, R
3Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(8) R
2, R
3Be H, R
1, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(9) R
2, R
4Be H, R
1, R
3Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(10) R
3, R
4Be H, R
1, R
2Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(11) R
1Be H, R
2, R
3, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(12) R
2Be H, R
1, R
3, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(13) R
3Be H, R
1, R
2, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O;
(14) R
4Be H, R
1, R
2, R
3Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O; Or
(15) R
1, R
2, R
3, R
4Be OH, OCH
3, NO
2Or F; R
5Expression C
4～C
20Straight or branched alkyl, C
4～C
20Straight or branched thiazolinyl or benzyl; R
6The expression H or=O.
5. compound or its pharmaceutically acceptable addition salt application in the preparation antifungal drug, its structural formula is as follows:
In the formula, each group is done following collocation:
。
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| CN103739601A (en) * | 2013-12-12 | 2014-04-23 | 江苏诚信制药有限公司 | Method for preparing praziquantel |
| CN104710369A (en) * | 2014-11-25 | 2015-06-17 | 山东省立医院 | Quinazolinone antifungal compounds, and synthetic method and application thereof |
| CN114195783B (en) * | 2021-12-29 | 2022-11-25 | 河北嘉一药业有限公司 | Preparation method of levo-praziquantel |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3393195A (en) * | 1964-02-06 | 1968-07-16 | Merck Ag E | 1, 2, 3, 6, 7, 11b-hexahydro-4h-pyrazino-2, 1-a-isoquinolines |
| US3557120A (en) * | 1969-05-21 | 1971-01-19 | Sterling Drug Inc | Hexahydroimidazoisoquinolines |
| US4049659A (en) * | 1975-03-01 | 1977-09-20 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Process for the preparation of 4-oxo-hexahydro-pyrazinoisoquinoline derivatives |
| US4051243A (en) * | 1974-08-28 | 1977-09-27 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Ring substituted pyrazino-isoquinoline derivatives and their preparation |
| US4497952A (en) * | 1982-07-08 | 1985-02-05 | Korea Advanced Institute Of Science And Technology | Process for the production of (±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives |
| CN1412182A (en) * | 2002-11-22 | 2003-04-23 | 中国人民解放军第二军医大学 | Tetrahydroisoquinoline derivative with antifungal activity and its preparation method |
| CN1785978A (en) * | 2005-12-05 | 2006-06-14 | 中国人民解放军第二军医大学 | Tetra hydro iso quinoline compounds possessing anti breed and anti fungus activity and its salt |
-
2009
- 2009-08-31 CN CN 200910194825 patent/CN101691367B/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3393195A (en) * | 1964-02-06 | 1968-07-16 | Merck Ag E | 1, 2, 3, 6, 7, 11b-hexahydro-4h-pyrazino-2, 1-a-isoquinolines |
| US3557120A (en) * | 1969-05-21 | 1971-01-19 | Sterling Drug Inc | Hexahydroimidazoisoquinolines |
| US4051243A (en) * | 1974-08-28 | 1977-09-27 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Ring substituted pyrazino-isoquinoline derivatives and their preparation |
| US4049659A (en) * | 1975-03-01 | 1977-09-20 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Process for the preparation of 4-oxo-hexahydro-pyrazinoisoquinoline derivatives |
| US4497952A (en) * | 1982-07-08 | 1985-02-05 | Korea Advanced Institute Of Science And Technology | Process for the production of (±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives |
| CN1412182A (en) * | 2002-11-22 | 2003-04-23 | 中国人民解放军第二军医大学 | Tetrahydroisoquinoline derivative with antifungal activity and its preparation method |
| CN1785978A (en) * | 2005-12-05 | 2006-06-14 | 中国人民解放军第二军医大学 | Tetra hydro iso quinoline compounds possessing anti breed and anti fungus activity and its salt |
Non-Patent Citations (5)
| Title |
|---|
| ACS.RN 109473-56-5.《STN REGISTRY》.1987,第1-3页. * |
| ACS.RN 133326-68-8.《STN REGISTRY》.1991,第1-3页. * |
| Francisco Yuste, et al..A Short Synthesis of Praziquantel.《J. Heterocyclic Chem.》.1986,第23卷第189-190页. * |
| 胡玉琴等.血吸虫病化学预防药物的研究——吡喹酮类似物的合成.《华西药学杂志》.1996,第11卷(第3期),第129-133页. * |
| 靳立人等.吡喹酮类似物的合成.《药学学报》.1986,第21卷(第3期),第170-176页. * |
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Inventor after: Zhou Youjun Inventor after: Yang Chao Inventor after: Jiang Junhang Inventor after: Tian Wei Inventor after: Tang Hui Inventor after: Zhu Ju Inventor after: Lv Jiaguo Inventor after: Zheng Canhui Inventor after: Li Yanan Inventor after: Zhou Xiaotian Inventor after: Zhou Hao Inventor after: Wang Zhongqing Inventor before: Zhou Youjun Inventor before: Tang Hui Inventor before: Zhu Ju Inventor before: Lv Jiaguo Inventor before: Zheng Canhui Inventor before: Li Yanan |
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