Nghien CLFU - Ky thuat
«* r
Khao sat tac dung khang viem cua cac dan chat
r
1,5- diarylimidazol tren chuot nhat
Le Thj Tuyet Phuang, Truang Ngoc Tuyen, Vo Phiing Nguyen Khoa Duac, Trudng dgi hoc YDuac TP.HCM.
Dat van de
Dj vdng imidazol ty lau dd dygc biit din vdi cdc tde dung dugc ly ddng chii y nhy: khdng khuin, khdng nim, khdng viem, khdng histamin H2, D'C che bam proton trong dieu tri lodt da ddy...nhyng eho den nay hoat tinh khdng viem eiia din chit t h i 1,5-imidazol chua dygc de edp rndt cdch rdng rdi'^'.
Trong nhiing ndm gan ddy, ngdy cdng ed nhieu nhd khoa hpc quan tdm nghien cd'u tim cdc dan chit mdi ed heat tinh khdng viem d'c che chpn lpc COX-2, ddc bidt Id 1,5-diarylimidazol'^"^'.
Ddn chat 1,5-diarylimidazol cd c i u triie ba vdng tu'ang ty nhy cdc chat d'c che chpn Ipc COX-2, da dygc tong hgp vd nghidn ciiu ve tde dung dygc ly trdn te bdo RAW 264.7 eho thiy hiu hit cdc din chat 1,5-diarylimidazol vdi nhdm t h i sulfon/sulfonamid ed hoat tinh lie c h i sinh tong hgp PGEz'^l
Trong nghidn cu-u ndy, chiing tdi khao sdt tde dung khdng viem cap tinh vdi md hinh gdy viem tren ehupt nhdt bdng carrageenin eua cdc dan chit 1,5-diarylimidazpl vdi nhdm the sulfon, dygc tong hgp tai bd mdn Hda Hit-u Ca - Khoa Dygc - Trydng dai hpe Y Dygc Thdnh phe Hp Chi Minh.
Doi tu'O'ng va Phu'O'ng phap nghien
CLFU
Ddi tu'ang nghien cii'u Dgng vat thie nghiem
Chudt nhdt trdng tryang thdnh khdng ke gidi tinh, chiing Swiss albino, ndng tu' 22-25 g, khoe manh do Vien Vaccin vd Sinh pham y te Nha Trang cung cip. Chudt dugc nudi cho quen vdi mdi trydng 2 ngdy trydc khi tien hdnh thii nghi0m. Trong suit qud trinh thy nghidm, chudt dygc cung c i p day dii thyc dn vd nude uong.
Chit dii chiiu:
Celeeoxib 6' dang djeh tree dung dudng uong.
Chit thir nghidm: Cdc d i n chat sulfon cua 1,5-diarylimidazol dygc tong hgp'^' gom: 1-(3- fluorophenyl)-5-(4-methylsulfonylphenyl)imidazol (1MD01), 1-(2,5-difluorophenyl)-5-(4-methylsulfonyl phenyl)imidazol (IMD02), 1-(2-fluorophenyl)-5- (4-methylsulfonylphenyl)midazol (IMD03).
SO2CH3
Chat thir1-(3-fluorophenyl)-5-(4-methylsulfonylphenyl)imidazol
1-(2,5-difluorophenyl)-5-(4-methylsulfonylphenyl)imidazol
1 -(2-fluorophenyl)-5-(4-methylsulfonylphenyl) imidazol
Ky hi^u
IMD01
IMD02
IMD03
Cau true R1
H
F
F
R2
F
F
H
Hinh 1: Ciu triic cdc dan chat sulfon cua 1,5-diarylimidazol Phu'O'ng phap nghien
CLFUVe tong hap chat thip nghiem
Cdc chat thi> nghifem dugc nghi§n ciiu tong hgp theo sa do sau:
16 TAP CHI DUQC HQC - 6/2010 (SO 410 NAM 50)
Nghien CLFU - Ky thuat
^=J< "2
HjCS Ethanol
Rp R2=H,NH2
H3CS
CH- / ^
'N ^ ^ R, IMOl-03
H3C
o
S02CH2NC MeOH:DME K.2C03 IMDOlIMD02 IMD03
R|
H F F
R2
F F H
IMDOl-03
Hinh 2: Sa do dieu che Quy trinh chung dieu ehe cdc c h i t IMOl-03:
Cho dung djeh chda d i n x u i t anilin trong ethanol vdo dung djeh 4-methylthiobenzaldehyd trong ethanol d nhiet dp phdng. Kiem tra phan ung bdng sde ky Idp mdng, khi phan dng xay ra hodn todn, lpc tiia roi k i t tinh lai trong ethanol tuydt doi. S i y d nhiet dd 60°C.
Quy trinh chung dieu che cdc c h i t 1MD01'- 03': hda tan 1M01-03 trong hon hgp methanol (MeOH) vd 1,2-dimethoxyethan (DME), eho tiep p-tolylsulfonylmethylisoeyanid vd kali earbonat vdo, phan u'ng dugc thyc hi$n trong mdi trydng khi argon vd khan d nhiet dp phdng, kiem tra phan U'ng bdng sde ky ldp mong. Sau phan yng, bay hai dung mdi bdng mdy ed quay, chiet san pham bdng cloroform, k i t tinh lai trong ethyl acetat. S i y d nhiet dp 60°C.
Quy trinh chung dieu ehe cdc c h i t IMD01-03:
eho ty tu" dung djeh oxon trong nyde vdo dung djeh IMDOl'-03' trong tetrahydrofuran (THF) d - 5 °C, sau dd cho phan u-ng 6' nhi^t dd phdng, kiem tra phan iing bdng sde ky ldp mong. Sau phan yng, diing ethyl acetat de chiit imidazol, bdc hai dung mdi roi k i t tinh lai trong ethyl acetat.
Ve thif tac dung khang viem cap tinh:
Chit gdy vidm: Carrageenin dugc cung c i p bdi Sigma Aldrieh. Dung djeh carrageenin 1 % pha trong dung djeh sinh ly dygc chuan bj trydc khi thu nghiem 2 gid de carrageenin tryang nd'.
Dung cu do thi tich chdn chudt: thiit bj Plethysmometer model 7140, hdng Ugo Basile.
SCH, IMDOl'-03' cdc chit thir nghi$m
Khao sdt tac dung khang viem cap tinh '^' Chudt d y g c gdy vidm bdng cdch tiem vdp gan bdn chdn trdi 0,025 ml dung djeh carrageenin 1%. Do the tieh chdn chudt 3 gid sau khi tidm. Cdc chugt ed the tieh chdn sung phii trdn 50% so vdi binh thudng dugc lya ehpn cho thu' nghiem.
Dp phu chdn chudt dugc tinh theo cdng thyc:
X^
Vn-Vo Vo xlOO X: Dd phii tfnh theo %VQ: the tich chdn chudt trudc khi gay viem (dan vjdo 1/100 ml)
Vn: the tieh chdn ehupt sau khi gdy viem (dan vjdp 1/100 ml)
Chudt dygc chia ngau nhidn thdnh cdc Id:
Cdc 16 thCr d y g c cho uong djeh treo cdc ddn c h i t 1,5-diarylimidazol nong dO 100 mg/kg vd 200 mg/kg edn ndng; Id celeeoxib d y g c eho uong djeh treo celeeoxib nong dO 100 mg/kg; 16 td d y g c dygc eho uong dung m6i Tween 20 0,05% vd CMC 0,5%; 16 chu-ng cho uong nudc cit. Chupt d y g c cho uong theo the tich 0,1ml/10g edn ndng.
Theo d6i the tich syng phii ciia chdn ehuOt m6i ngdy vdo 1 gid nhat djnh trong 6 ngdy lidn tiep.
Phyang phdp thong ke mo ta d y g c sy dgng de tinh gid trj trung binh cua dO syng phii. Dti lieu d y g c trinh bdy d y d i dang so trung binh + SEM. Sy khde biet giiia ede 16 d y g c phdn tieh
Nghien C^FU - Ky thuat
bdng phyang phdp Kruskal-Wallis, sau dd Id Mann- Whitney vdi p h i n mem Minitab 14.0.
P<0,05 d y g c cho Id ed y nghTa thong ke.
Ket qua nghien
CLPU V§ tong hap3-Fluoro-/\/-(4-methylthiobenzyliden)anilin (IM01): hieu s u i t phan yng 95%, san p h i m Id tinh the mdu vdng nhat, nhiet dp ndng chay 40
°C. • ' H - N M R (200 MHz, CDCI3) 5 8,37 (s, I H , CH-imin); 7,80 (d, J = 8,6 Hz, 2H, Ar-H); 7.39- 7,25 (m, I H , Ar-H); 7,30 (d, J = 8,6 Hz, 2H, Ar- H); 6,99-6,88 (m, 3H, Ar-H); 2,53 (s, 3H, SCH3).
2,5-Difluoro-/\/-(4-methylthiobenzyliden)anilin (1M02): hieu s u i t phan ung 96%, san p h i m la tinh the khdng mdu, nhiet dp ndng chay 78 °C.
^H-NMR (200 MHz, CDCI3) 6 8,42 (s, I H , CH- imin); 7,82 (d, J = 8,6 Hz, 2H, Ar-H); 7,30 (d, J = 8,6 Hz, 2H, Ar-H); 7,14-7,07 (m, I H , Ar-H); 6,90- 6,83 (m, 2H, Ar-H); 2,53 (s, 3H, SCH3).
2-Fluoro-A/-(4-methylthiobenzyliden)anilin (IM03): hieu s u i t phan u'ng 93%, san p h i m Id tinh the khong mdu, nhiet dp ndng chay 62-63
°C. • ' H - N M R (200 MHz. CDCI3) 5 8,40 (s, I H , CH-imin); 7,83 (d, J = 8,2 Hz, 2H. Ar-H); 7,30 (d, J = 8,2 Hz, 2H, Ar-H); 7,27-7,13 (m, 4H, Ar-H);
2,53 (s, 3H, SCH3).
1-(3-Fluorophenyl)-5-(4-methylthiophenyl) imidazol (IM01'): hieu s u i t phan dng 85%, san p h i m Id tinh the khdng mdu, nhiet dp ndng chay 143-144 °C. • ' H - N M R (200 MHz, CDCI3) 5 7,68 (s, 1H, Hj-imidazol); 7,42-7,31 (m, 1H, Ar-H);
7,23 (s, I H , H4-imidazol); 7,16-6,90 (m, 7H, Ar- H); 2,45 (s, 3H, SCH3).
- 1-(2,5-Difluorophenyl)-5-(4-methylthiophenyl) imidazol (1M02'): hieu s u i t phan iing 88%, san p h i m Id tinh the mdu vdng nhat, nhiet dp ndng chay 115-116 °C. ^H-NMR (200 MHz, CDCI3) 5 7,64 (s, IH, H2-imidazol); 7,24 (s, I H , H4-imidazol);
7,17-6,90 (m, 7H, Ar-H); 2,44 (s, 3H, SCH3).
- 1 -(2-Fluorophenyl)-5-(4-methylthiophenyl) imidazol (IM03'): hieu s u i t phan u-ng 63%, san pham Id tinh the khong mdu, nhiet dd ndng
chay 94-95 °C. ' ' H - N M R (200 MHz, CDCI3) 6 7,65 (s, 1H, Hz-imidazpl); 7,41-7,34 (m, I H , Ar-H);
7,22-7,20 (m, 2H, Ar-H), 7,18 (s, I H , H4-imidazol);
7,13-7,01 (m, 5H, Ar-H); 2,43 (s, 3H, SCH3).
- 1 -(3-Fluorophenyl)-5-(4-methylsulfonylphenyl) imidazol (1M01): hieu s u i t phan u'ng 97%, san p h i m Id tinh the khdng mdu, nhiet dp ndng chay 157-158 °C. ^H-NMR (200 MHz, CDCI3) S 7,84 (d, J = 8,4 Hz, 2H, Ar-H); 7,75 (s, I H , Hj- imidazol); 7,48-7.36 (m, I H , Ar-H); 7,39 (s, IH, H4-imidazol); 7,31 (d, J = 8,4 Hz, 2H. Ar-H);
7.20-7,11 (m, I H , Ar-H); 7,00-6,92 (m, 2H. Ar- H ) ; 3 , 0 5 ( s , 3H,S02CH3).
- 1-(2,5-Difluorophenyl)-5-(4-methylsulfonylphenyl) imidazol (IM02): hieu s u i t phan d'ng 97%, san p h i m Id tinh the khdng mdu, nhiet dp ndng chay 206-207 °C. • ' H - N M R (200 MHz, CDCI3) 5 7,83 (d, J = 8,4 Hz, 2H, Ar-H); 7,71 (s, I H , Hj- imidazol); 7.39 (s, I H , H4-imidazol); 7,31 (d, J = 8,4 Hz, 2H, Ar-H); 7,20-7,14 (m, 2H, Ar-H); 7,06- 6,98 (m, 1H, Ar-H); 3,30 (s, 3H, SO2CH3).
- 1 -(2-Fluorophenyl)-5-(4-methylsulfonylphenyl) imidazol (IM03): hi$u s u i t phan u'ng 96%, san p h i m Id tinh the khong mdu, nhiet dp ndng chay 219-220 °C. ^H-NMR (200 MHz, CDCI3) 5 7,92- 7,88 (m, 2H, Ar-H); 7,81 (s, I H , Hz-imidazol); 7,57- 7,51 (m, 2H, Ar-H); 7.42 (s, I H , H4-imidazol); 7,38- 7,30 (m, 4H, Ar-H); 3,13 (s, 3H, SO2CH3).
Ve thir tac dgng khang viem cap tinh:
Chupt dygc ehia ngau nhien lam 9 16 nhy sau:
L6 ta dugfc (n=16)
Dung moi Lo Tween20 0,05% ehirng
va CMC 0,5% (n=15)
Nwac cat
Ld celeeoxib (n=17)
celeeoxib 100 mg/kg Fl
(n=9) IMDOl 100 mg/kg F2 (n=9)
IMDOl 200mg/kg F3
(n=8) IIV1D02 100 mg/kg F4 (n=8)
IMD02 200mg/kg F5
(n=8) IMD03 100 mg/kg F6 (n=8)
IMD03 200mg/kg
Bang 1 : Do phii chdn chudt (X%) sau 3 gi& gdy viem bdng carageenin 1% vd sau 6 ngay diiu tri Lo
Chiing Ta du'gc Celeeoxib
Fl F2
3 gia 69,62 ±2,88 68,46 ±2,97 68,66±3,21 72,02±4,11 72,00±3,32
Ngay 1 66,00 ±3,99 69,39 ±3,66 67.38±3.98 73,62±4,61 65,71±4,46
Ngay 2 61,94 ±3,79 67,17 ±4,43 61.22±3.98 74,82±3,74 77,66±6,71
Ngay 3 53,54 ±3,79 56,90 ±4,56 39.76"±2.38 62,89±3,73 66,63±6,22
Ngay 4 49,72 ±3,01 51,27 ±3,38 35.81*±2.35 44,53±4,27 59,41±8,54
Ngay 5 45,09 ±2,36 48,06 ±3,56 30.84**±2.03 38,17±3,42 51,26±8,61
Ngay 6 40,70 ±2,47 44,95 ±3,11 26.87**±1.88 26.55**±3.61 39,68±5,61
18 TAP CHI DU'QC HQC - 6/2010 (SO 410 NAM 50)
• Nghien CLFU - Ky thuat
F3 65,73±3,14 F4 67,41 ±3,64 F5 67,65±4,02 F6 69,80±4,51
64,27±3,61 64,90±3,51 60,24±7,02 65,30±10,51 64,16±6,73 54,30±4,34 54,02*±4,94 44,16**±4,97
58,46±5,55 59,04±11,72
50,29±3,70 40,24*±4,64
47,043,47 51,56+9,51 44,68±3,79 39,20±4,44
42,52±3,39 46,02±9,23 43,63±2,98 36,15'*±2,87
33,37*±2,95 43,21±8,15 41,63±2,83 34,15*#±2,28
- CELECOXJB - rm'iNG - TA DipC
Ngiy 2 Ngdy 3 Ng&y 4 Ngdy 5 Ngiy 6
Hinh 3: D0 phu chdn chudt (X%) sau 3 gi&
gdy vidm vd sau 6 ngdy diiu tn & cdc Id ehirng, Id td duac. Id celeeoxib vd Id thir F1, F3 vd F5
& ndng dd 100mg/kg
Ghi chii: *.' p<0,05, **; p<0,01: khac co y nghTa thong ke so v&i Id ehirng.
#: p<0,05: khae CO y nghTa thong ke so v&i Id celeeoxib.
syng phu giam khde nhau ed nghTa thong kd so vdi 16 chung d ngdy thii 6, lieu 200 mg/kg (F2) cd dp syng phii giam khde nhau khdng ed y nghTa thing k§ SP vdi 16 chd'ng treng suit qud trinh thu nghiem. Tde dpng khdng viem eiia Fl xuit hien chdm, tuang dyang vdi celeeoxib d ngdy thy 6. F2 khdng ed tde dpng khdng viem.
-1-(2,5-difluomphenyl)-5-(4-methylsulfonylphenyl) imidazol (IMD02): d liiu 100 mg/kg (F3) ed dd syng phu giam khde nhau cd nghTa thing ke so vdi 16 ehiyng 6' ngdy thu' 6, lieu 200 mg/kg (F4) ed dd sung phii giam khde nhau khong cd y nghTa thong kd so vdi 16 chung trong suit qud trinh thy nghidm. Tde dung khdng viem ciia F3 xuit hidn chdm, tyang dyang vdi celeeoxib d ngdy thy 6. F4 khdng ed tde dpng khdng vidm.
-1-(2-fluorophenyl)-5-(4-methylsulfonylphenyl) imidazol (IMD03): d lieu 100 mg/kg (F5) cd dd sung phu giam khde nhau khdng ed nghTa thong ke so vdi 16 chd'ng trong suit qud trinh thy nghiem, lieu 200 mg/kg (F6) co dd sung phii giam khde nhau ed y nghTa thong ke so vdi Id chd'ng 6' ngdy thii 1, 2, 3, 5, 6. F5 khdng ed tde dung khdng viem. Tde dung khdng viem ciia F6 nhanh vd manh han celeeoxib 6' ngdy 1, 2;
tyang dyang celeeoxib d ngdy 3. 5; y i u han celeeoxib d ngdy thu' 6.
Ban luan
Cdc k i t qua thy nghidm thu dugc tu- ede dan chit sulfon 1,5- diarylimidazol trong md hinh khao sdt tde dung khdng viem cip tinh in vivo tren chdn chu6t tuang doi phu hgp vdi ede kit qua khao sdt tde dung khdng viem /n-wW^' nhyng ed sy khde biet giiia ede chit thi> d lieu SLK dung. Trong thy nghiem in-vitro, ede ddn chit sulfon ciia 1.5-diarylimidazol IMDOl;
1MD02; IMD03 deu eho tde dung khdng viem rit tot (>90%) tuang dyang vdi celeeoxib. Trong thy nghiem in-vitro, IMDOl vd IMD02 eho tde dung khdng viem chdm han celeeoxib vd ed tde dpng khdng viem d lieu 100 mg/kg; IMD03 eho tde dung khdng viem nhanh han celeeoxib d lieu 200 mg/kg.
" \ ^ - • — CEI-KCOXIB
\ . T -o— CHONO
T \ ^ \ " ' ' " " ^ • ^ ^ - ^ ^ ^
• .
> - » - TADIOC - a - H2
• \ ^ ^ -T - • — f4
^ > s . ; + - o - F6
Ngdy 2 Ngdy 3 Ngdy 4 Ngdy 5
Hinh 4: Dd phii chdn chudt (X%) sau 3 gi&
gdy vidm vd sau 6 ngdy diiu td & cdc Id ehirng.
Id td duac, Id celeeoxib, cdc Id thir F2, F4 vd F6
& ndng do 200mg/kg
Nhdn xdt: So sdnh dp phii chdn chupt sau 6 ngdy dieu tri d cdc Id chiing, 16 td dygc, 16 celeeoxib vd cdc 16 thi> nhdn thiy:
- Ld td duac: dp syng phu giam khde nhau khong ed y nghTa thong kd so vdi 16 chung trong suit qud trinh thy nghiem. Dung mdi 0,05%
Tween 20 vd 0,5%) CMC sy dung pha djeh treo khdng cho tde dung khdng viem cung nhy khdng Idm tdng qud trinh syng viem gdy ra bdi carrageenin tren chdn ehupt.
- Celeeoxib 100 mg/kg: dO sung phii giam khde nhau ed y nghTa thong ke so vdi 16 chung d ngdy thy 3, tde dung ndy kdo ddi den hit dgt diiu trj.
- 1-(3-fluon3phenyl)-5-(4-methylsulfonylphenyl)
imidazol (IMD01): a lieu 100mg/kg (Ft) ed dp
Nghien CLFU - Ky thuat
Khi flupr hda vj tri 2 hpdc/vd vj tri 5 tren nhdm 1-aryl eua d i n c h i t sulfon 1,5- diarylimidazol cd the Idm thay doi hoat tinh khdng vidm. Hoat tinh khdng viem e i p tinh eua IMD03 (fluor hda a vi tri 2-aryl), cho tde dung khdng vidm nhanh han celeeoxib ed the do fluor hut di^n ty manh; IMD02 (difluor hda 2,5-aryl) 1dm chdm tde dung khdng viem ciia d i n chit sulfon 1,5- diarylimidazol, ed le sy difluor hda dd 1dm cho eau true phdn tii cOa cae chit cong kenh, 1dm giam kha nang h i p thu cua d i n chit d i di den dugc nai viem. IMDOl (fluor hda d vi tri 3-aryl) eung Idm chdm tde dung khdng viem eiia d i n chit sulfon 1,5- diarylimidazol cd the do kha ndng hiit didn tu yeu han khi fluor hda d vj tri 2-aryl.
Tde dgng khdng vidm a lieu t h i p 100 mg/kg eao han so vdi lieu cao 200 mg/kg ngoai try 1- (2-fluon3phenyl)-5- (4-methylsulfonylphenyl) imidazol lieu 200 mg/kg nhanh vd manh han lieu 100 mg/kg.
K§t luan
K i t qua thu d y g c t y cdc ddn c h i t sulfon 1,5- diarylimidazol sau khi khao sdt hoat tinh khdng vidm c i p tinh bdng dudng uong vdi mo hinh gdy viem bdng carrageenin 1 % ggi y rdng nhdm sulfon cd vai trd quan trpng trong tae dung khdng vidm eiia dan c h i t 1,5- diarylimidazol.
Fluor hda vdng 1-aryl eiia dan chat sulfon 1,5- diarylimidazol cd the Idm thay doi hoat tinh khdng viem. 1-(2-fluorophenyl)-5- (4- methylsulfonylphenyl) imidazol lieu 200 mg/kg cho tde dung khdng viem nhanh han celeeoxib.
Ddy Id chat cd trien vpng trpng qud trinh tim k i i m cdc c h i t khdng viem lie che chpn Ipc COX-2 it tde dung phu , tde dyng khdng vidm manh cd y nghTa treng dieu trj.
Summary
A new type of 1-aryl-5-(4-methylsulfonylphenyl) imidazoles were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors with in vivo anti-inflammatory activity. Of the tested compounds, 1-(2-fluotDphenyl)-5-(4- methylsulfonylphenyl) imidazole showed very good anti-inflammatory activity compared to celeeoxib in the camageenan-induced mice paw edema assay.
The results were discussed in terms of structure- activity relationships (SARs) of these compounds.
Tai lieu tham khao
1. Tuyen, T. N.. Synthesis and antiinflammatory activity of 1,5-diarylimidazoles- Design and Synthesis of Furofuran Lignans, Kangwon National University (2005).
2. Almansa C, Alfdn J, et al. Synthesis and structure-activity relationship of a new series of COX- 2 elective inhibitor: 1,5-diarylimidazoles. J. Med.
Chem. (2003), 46 (16): 3463-75.
3. Khanna IK, Yu Y, et al. Selective cyclooygenase-2 inhibitors: heteroaryl modified 1,2- diarylimidazoles are potent, orally active antiinflammatory agents. J Med. Chem. (2000), 43 (16): 3168-85.
4. Navidpour, L., Hooman Shadnia, et al.. Design, synthesis, and biological evaluation of substituted 2- alkylthio-1,5-diarylimidazoles as selective COX-2 inhibitors. Bioorg. & Medical Chemistry (2007), 15 (5):
1976-1982.
5. Tuyen TN, Sin KS, et al. Synthesis and antiinflammatory activity of 1,5-diarylimidazoles. Arch.
Phami. Res. (2005), 28 (9): 1013-8.
6. Winter C A, Risley E A, et at. Carrageenin-induced edema In hind paw of the rat as an assay for antiinflammatory drugs. Biol. Med. (1962), 111: 544-547.
T o n g h c y p . . . (Tiip trang 52)
Summary
Synthesis of 6,7-dimethoxy-2-methyl-3,5,8- trioxo-2,3,5,8-tetrahydroisoquinoline (2) from 7- hydroxy-6-methoxy-3,4-dihydroisoquinoline (4) and 6,7-dimethoxy-isoquinoline (3) was achieved. Copper-acetate catalyzed the oxydation of (7) gave 7,8-dioxo derivatives (8a, b). Treatment of 8a, b with sulfuric acid, followed by diazomethane gave p-quinone (10a, b). Reductive acetylation of 10a, b with zinc-acetic acid and acetic anhydride yielded 5,8-diacetoxyisoquinolines (11a, b). Treatment of methyl iodide (12a, b) with silver oxide gave 2.
Tai lieu tham khao
1. Aral T., Yazawa K., Mikami Y., Kubo A. and Takahashi K., Isolation and Characterization of Satellite Antibiotics, Mimosamycin and Chlorocarcins from Streptomyces lavendulae. Streptothricin Source, J. Antibiot (Tokyo) (1976), 29 (4), p. 398.
2. Fukumi H., Kurihara H., Hata T., Tamura T, Mishima H., Kubo A. and Aral T, Mimosamycine, A Novel Antibiotic Produced by Streptomyces lavendulae N°.314 Structure and Synthesis,
Tetrahedron Lett.. (1977) p. 3825.
3. Mishima H., Fukumi H. and Kurihara H., Synthesis of Mimosamycin, Heterocycles. (1977) 6. p. 1652.
4. Mc. Killop A. and Brown S. P., A two step synthesis of mimosamycin. Synthetic communication (1987)17(6), p. 657.
20 TAP CHi DUQC HQC - 6/2010 (SO 410 NAM 50)