CN102558067A - 1-arylsulfonyl-1H-benzimidazole derivative and preparation method and application thereof - Google Patents
1-arylsulfonyl-1H-benzimidazole derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN102558067A CN102558067A CN2012100034193A CN201210003419A CN102558067A CN 102558067 A CN102558067 A CN 102558067A CN 2012100034193 A CN2012100034193 A CN 2012100034193A CN 201210003419 A CN201210003419 A CN 201210003419A CN 102558067 A CN102558067 A CN 102558067A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- independently
- arylsulfonyl
- hcv
- preparation
- 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.)
- Pending
Links
- 0 C1/*=C/N=C/CO*1 Chemical compound C1/*=C/N=C/CO*1 0.000 description 2
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a 1-arylsulfonyl-1H-benzimidazole derivative and a preparation method and application thereof, belonging to the field of chemical medicine. The 1-arylsulfonyl-1H-benzimidazole derivative has a structure shown by formula I in the specification. According to the invention, the 1-arylsulfonyl-1H-benzimidazole derivative is obtained based on massive screening, and has anti-HCV activity; and a new option is provided for the development and application of a medicine for resisting chronic hepatitis C.
Description
Technical field
The invention belongs to chemical field of medicaments, particularly 1-arylsulfonyl-1H-benzimidizole derivatives.
Background technology
Chronic hepatitis C is a kind of chronic hepatic diseases that is caused by hepatitis C virus (HCV), is the major cause of liver cirrhosis and liver cancer, also is the first cause of present liver transplantation.Show according to The World Health Organization (WHO) investigation in 1999, the whole world have approximately 3% people (1.7 hundred million people) infected HCV (
J. Viral. Hepat.1999,6:35-47), China infection rate be about 3.2% (4,000 ten thousand people) (
Lancet Infect. Dis.2005. 5:558 – 67), and number of the infected the trend that increases is year by year arranged.These have infected the crowd of HCV, through after the latent period of 10-20, have 80% people will develop into chronic hepatitis C approximately, and 20% people will be further developed into liver cirrhosis, the people of 1%-4% will finally worsen change into liver cancer (
Med. Res. Rev.2007,27:353-73).
The traditional standard scheme of the treatment chronic hepatitis C of FDA approval is combined utilization PEG-interferon-' alpha ' and ribavirin, some problems below this regimen exists: 1.. efficient low; 2.. treatment cycle is long, and medical expense is high; 3.. toxic side effect is comparatively serious.In May, 2011, two kinds of medicine-NS3-4A proteinase inhibitor telaprevir (Vertex Pharmaceuticals) that directly act on viral oneself protein and boceprevir (Merck)-by the FDA approval be used for HCV treatment (
Nature,2011,474, S5), the triple therapy of these two kinds of medicines and ribavirin and PEG-interferon-' alpha ' combined utilization is efficient can bring up to 70% by original 50%.This has explained that on the one hand direct antiviral can improve the efficient of treatment greatly, has demonstrated its good prospects for application.But be exceedingly fast owing to these two kinds of medicine list time spent resistances produce on the other hand, (
Sci. Transl. Med.2010,2,30ra32); Can't break away from based on the traditional treatment medicine of Interferon, rabbit and be used for the treatment of chronic hepatitis C separately; So the toxic side effect that traditional remedies is had can not be eliminated in triple therapy, and possibly introduce new toxic side effects, and on treatment cycle; Triple therapy does not have clear superiority than traditional remedies yet, and medical expense maybe be higher than traditional treatment (
Nature,2011,474, S5).So exploitation has chronic hepatitis C medicine ten minutes necessity of new mechanism of action.
In China; The infection level of HCV is a little more than world average level; But because the HCV infection is very long latent period, developed into liver cirrhosis and liver cancer when most of cases are diagnosed as the chronic hepatitis C patient, the treatment level of state's chronic hepatitis C reaches developed country's level far away still.And the approval that present NS3-4A proteinase inhibitor does not obtain SFDA is used for the treatment of chronic hepatitis C, so the treatment situation of present China chronic hepatitis C is quite severe, presses for the anti-HCV new drug that exploitation has independent intellectual property right.
HCV Nonstructural Protein NS4B is a kind of 4 transmembrane proteins;, HCV can induce the necessary membranaceous network of virus replication to form when duplicating; Therefore very important to duplicating of virus; But because its separation and purification difficulty relatively, at present the investigator to the understanding of NS4B also seldom, thereby to the rare report of anti-HCV medicament that NS4B developed.2005, people such as Chunduru (
WO200505131; Sci. Transl. Med. 2010,2,15ra6) utilize dynamic light scattering method (DLS) to find the compound a nguizole of a kind of NS4B of acting on parents spiral 4BAH2; This compound has good anti-HCV effect under the sub-micro volumetric molar concentration; And not having significant cytotoxicity, this is to report that the NS4B suppressor factor is used for anti-HCV for the first time.2008, people such as Shirit Einav (
Nat. Biotechnol. 2008,26:1019-1027) utilize micro-fluidic technologies; Find that first NS4B passes through parents' spiral 4BAH1 and links to each other with viral strand RNA; And this connection is necessary to duplicating of HCV; Through high flux screening, they filter out clemizole hydrochloride (Clemizole, a kind of histamine H 1 receptor antagonist) from 1280 kinds of compounds can suppress duplicating of virus by specificity inhibition NS4B with being connected of viral strand RNA.Through the inducible resistance sudden change, the replication of clemizole hydrochloride multidrug resistant disease strain descends greatly, this means that the resistance of this type NS4B suppressor factor produces and possibly produce slower than the resistance of proteinase inhibitor such as Boceprevir.In further pharmacology is tested; They have the synergistic effect of height when finding this compound and proteinase inhibitor telaprevir and boceprevir combined utilization; And have additive effect during with medication combined application such as Interferon, rabbit and ribavirins, and can reduce when this compound and boceprevir combined utilization medicament-resistant mutation generation (
J. Infect. Dis.2010; 202:65-74).At present, clemizole hydrochloride has got into clinical b conceptual phase of I phase in nz and Australia.These discoveries; Mean that the NS4B suppressor factor possibly become a kind of anti-chronic hepatitis C medicine that gets a good chance of; The introducing of such suppressor factor also is the innovation of later therapy for hepatitis C strategy, and---breaking away from the regimen that uses Interferon, rabbit and ribavirin in the traditional remedies---brought hope.
The present invention is directed to HCV NS4B; Designed and synthesized hepatitis C virus (HCV) suppressor factor of one type of novel texture; This compounds is analyzed in (HCV Replicon luciferase Assay) and HCV replicon MTT test (HCV Replicon MTT Assay) two tests at HCV replicon luciferase and has been shown the effect of HCV inhibition preferably, has shown lower cytotoxicity simultaneously.
Summary of the invention
First technical problem to be solved by this invention provides one type of new 1-arylsulfonyl-1H-benzimidizole derivatives, and structure is suc as formula shown in the I:
Ⅰ
Wherein, R
1Independently be H, C1~C8 alkyl, C2~C8 naphthenic base, halogen replacement C1~C8 alkyl, hydroxyl replacement C1~C8 alkyl, CF
3,
,
,
Or the epoxy group(ing) that to have substituent ring skeleton be 2~8 C; Substituting group independently is H or C1~C8 alkyl;
R
2~R
6Independently be H, C1~C8 alkyl, C2~C8 naphthenic base, C1~C8 alkoxyl group, OH, CF
3Or OCF
3
R
7~R
10Independently be H, C1~C8 alkyl, C2~C8 naphthenic base, C1~C8 alkoxyl group, OH, CF
3Or OCF
3;
R
11~R
30Independently be H, C2~C8 naphthenic base or C1~C8 alkyl;
w=0~1,x=0~1,y=0~1,z=0~1。
Preferably, R
1Independently be H, C1~C8 alkyl, C2~C8 naphthenic base, halogen replacement C1~C8 alkyl, hydroxyl replacement C1~C8 alkyl, CF
3,
,
,
Or the epoxy group(ing) that to have substituent ring skeleton be 2~8 C; Substituting group independently is H or C1~C8 alkyl;
R
2~R
6Independently be H, C1~C8 alkyl, C1~C8 alkoxyl group, OH, CF
3Or OCF
3
R
7~R
10Independently be H, C1~C8 alkyl, C1~C8 alkoxyl group, OH, CF
3Or OCF
3;
R
11~R
30It independently is H or C1~C8 alkyl;
w=0~1,x=0~1,y=0~1,z=0~1。
Preferably, R
1Independently be H, C1~C8 alkyl, C2~C8 naphthenic base, halogen replacement C1~C8 alkyl, hydroxyl replacement C1~C8 alkyl, CF
3,
,
,
Or the ring skeleton is the epoxy group(ing) of 2~8 C;
R
2~R
6Independently be H, C1~C8 alkyl, C1~C8 alkoxyl group or CF
3
R
7~R
30Be H;
w=x=y=0。
Optimum, R
1Independently be H, C1~C4 alkyl, halogen replacement C1~C4 alkyl, hydroxyl replacement C1~C4 alkyl, CF
3,
,
,
Or the ring skeleton is the epoxy group(ing) of 2~4 C;
R
2~R
6Independently be H, C1~C4 alkyl, C1~C4 alkoxyl group or CF
3
R
7~R
30Be H;
w=x=y=0。
Second technical problem to be solved by this invention provides the 1-arylsulfonyl-1 shown in the above-mentioned formula I
HThe preparation method of-benzimidizole derivatives, synthetic route is as follows:
Prepare through the nitrogen sulfonylation by compound 1 and compound 2.
Reaction solvent is preferably the mixed solvent V/V=1/1 of THF and methylene dichloride.
Room temperature, nitrogen protection be reaction 12h down.
The 3rd technical problem to be solved by this invention provides the 1-arylsulfonyl-1 shown in the above-mentioned formula I
HThe purposes of-benzimidizole derivatives in the anti-chronic hepatitis C medicine of preparation.
The present invention also provides a kind of pharmaceutical composition, is by the 1-arylsulfonyl-1 shown in the above-mentioned formula I
H-benzimidizole derivatives adds that the complementary composition of acceptable pharmaceutically is prepared from.This pharmaceutical composition can be used for preparing anti-chronic hepatitis C medicine.
The present invention obtains 1-arylsulfonyl-1 on the basis of a large amount of screenings
H-benzimidizole derivatives and 9-arylsulfonyl-9
H-purine derivative has anti-HCV activity, for the development and application of anti-chronic hepatitis C medicine provides new selection.
Description of drawings
Fig. 1 compound 2-chloromethyl-1-p-toluenesulfonyl-1
H-benzoglyoxaline, 2-chloromethyl-1-(4-anisole alkylsulfonyl)-1
H-benzoglyoxaline anti-HCV activity test result.
Fig. 2 compound 2-chloromethyl-1-(4-isopropoxy benzenesulfonyl)-1
H-benzoglyoxaline, 2-chloromethyl-1-(4-tert.-butylbenzene alkylsulfonyl)-1
H-benzoglyoxaline anti-HCV activity test result.
Embodiment
The preparation method of compound 1 is:
1, R
1Independently be H, C1~C8 alkyl, C1~C8 naphthenic base, halogen replacement C1~C8 alkyl, hydroxyl replacement C1~C8 alkyl, CF
3,
,
,
Or the epoxy group(ing) that to have substituent ring skeleton be 1~8 C; When substituting group independently was H or C1~C8 alkyl, synthetic route was following:
Compound 3 prepares with compound 4 dehydration condensations.
K is a halogen.
Reaction solvent is organic alcohol below 8 carbon, the excellent ethanol of electing as.Temperature of reaction is a reflux temperature.
Below in conjunction with embodiment the present invention is done further elaboration.Embodiment only is used to explain the present invention, rather than limits the present invention by any way.
Synthesizing of embodiment 1 2-chloromethyl benzimidazole
Synthetic route is as follows:
O-Phenylene Diamine (20.01 g, 184.95 mmol) and Mono Chloro Acetic Acid (22.72 g, 240.43 mmol) add in the 250 mL there-necked flasks, then to wherein adding 4 mol/L hydrochloric acid, 150 mL; Stirring at normal temperature 3h under the nitrogen protection is warming up to 110 ℃, backflow 6h then; Stopped reaction, with in the reaction solution impouring 300 mL cold water, being neutralized to pH with weak ammonia (5 mol/L) under the vigorous stirring is 8 while hot; Suction filtration is with cold wash twice, dry cake; Ethanol is solvent recrystallization, gets product 25.12 g, productive rate 81.08%.Purity (HPLC) >=95%.
1H-NMR?(400MHz,?DMSO-D6)?δ:4.93(s,?2H,?-CH
2-),?7.22(m,?2H),?7.59(m,?2H),?12.21(s,?1H).
Synthesizing of embodiment 2 2-tolimidazoles
Synthetic route is as follows:
Press the preparation method of midbody 2-chloromethyl benzimidazole, raw material is replaced with O-Phenylene Diamine and Glacial acetic acid min. 99.5, directly obtain 2-tolimidazole, productive rate 85.50% after the filtration.Purity (HPLC) >=95%.
1H-NMR?(400MHz,?DMSO-D6)?δ:?2.51(s,?3H,?-CH
3),?7.12(m,?2H),?7.47(m,?2H),?12.18(s,?1H).
Synthesizing of embodiment 3 2-trifluoro methyl benzimidazoles
Synthetic route is as follows:
Press the preparation method of midbody 2-chloromethyl benzimidazole, raw material is replaced with O-Phenylene Diamine and trifluoroacetic acid, directly obtain 2-tolimidazole, productive rate 87.92% after the filtration.Purity (HPLC) >=98%.
1H-NMR?(400MHz,?DMSO-D6)?δ:?7.58(m,?2H),?7.84(m,?2H),?12.89(s,?1H).
Synthetic route is as follows:
Press the preparation method of midbody 2-chloromethyl benzimidazole, raw material is replaced with O-Phenylene Diamine and trifluoroacetic acid, directly obtain 2-tolimidazole, productive rate 78.83% after the filtration.Purity (HPLC) >=96%.
1H-NMR?(400MHz,?DMSO-D6)?δ:?1.50(d,?3H,?-CH
3),?4.92(m,?1H,?-CH-),?5.77(d,?1H,?-OH),?7.12(m,?2H),?7.42(d,?1H),?7.54(d,?1H),?12.24(s,?1H).
Synthesizing of embodiment 5 midbody 2-vinyl benzo imidazoles
Synthetic route is as follows:
O-Phenylene Diamine (5.41 g, 50 mmol) and 3-bromo-propionic acid (9.18 g, 60 mmol) add in the 100mL there-necked flask; To wherein adding polyphosphoric acid (PPA) 30 mL, stir 6 h, stopped reaction in 110 ℃ under the nitrogen protection then; While hot with in the reaction solution impouring 150 mL cold water; Being neutralized to pH with weak ammonia (5 mol/L) under the vigorous stirring is 8, and the back is with ETHYLE ACETATE and water extraction, and ethyl acetate layer is water (50 ml * 2), saturated sodium bicarbonate solution (50 ml * 2), saturated aqueous common salt (50 ml * 2) washing respectively; Anhydrous magnesium sulfate drying; Product is used recrystallization from ethyl acetate/petroleum ether after removing solvent under reduced pressure, gets product 4.06 g, productive rate 56.39%.Purity (HPLC) >=97%.
1H-NMR?(400MHz,?DMSO-D6)?δ:5.65(s,?1H,?=CH
2),?6.25(s,?1H,?=CH
2),?6.77(m,?1H,?=CH-),?7.17(m,?2H),?7.46(d,?1H),?7.59(d,?1H),?12.58(s,?1H).
Synthesizing of embodiment 6 midbody 2-morpholine methyl benzoglyoxalines
Synthetic route is as follows:
Weighing midbody 2-chloromethyl benzimidazole 5g (30mmol) adds ethanol 40mL in the 100mL round-bottomed flask, stirs entirely and dissolves; Morpholine 5.23mL (density is 1g/ml for 60mmol, 5.2290g) is dissolved in the 10ml ethanol; Add round-bottomed flask behind the mixing, be warming up to 85 ℃, backflow is spent the night.The point plate revolves dried solvent after confirming to react completely, and smashs solid to pieces, and add water and stir, suction filtration, it is inferior to give a baby a bath on the third day after its birth with cold water, gets product 9.0529g, productive rate 90.01%, purity (HPLC) >=95%.
1H-NMR?(400MHz,?DMSO-D6)?δ:2.52(s,?4H,?O(CH
2)
2),?3.59(s,?4H,?-N(CH
2)
2),?3.78(s,?2H,?=NCH
2-),?7.12(m,?2H),?7.47(m,?2H),?12.32(s,?1H).
Synthesizing of embodiment 7 midbody 2-(N, the N-diallyl is amino) tolimidazole
Synthetic route is as follows:
Press the preparation method of midbody 2-morpholine methyl benzoglyoxaline, raw material is replaced with 2-chloromethyl benzimidazole and NSC 20948, reaction after scouring, filtration directly obtain 2-tolimidazole, productive rate 82.21%.Purity (HPLC) >=93%.
1H-NMR?(400MHz,?DMSO-D6)?δ:3.14(d,?4H,?N(CH
2)
2),?3.78(s,?2H,?=NCH
2-),?5.16(d,?1H,?=CH
2),?5.23(d,?1H,?=CH
2),?5.88(m,?2H,?=CH-),?7.12(m,?2H),?7.44(d,?1H),?7.54(d,?1H),?12.21(s,?1H).
Synthesizing of embodiment 8 title product 2-chloromethyls-1-p-toluenesulfonyl-1H-benzoglyoxaline
Midbody 2-chloromethyl benzimidazole (0.5 g, 3 mmol) adds methylene dichloride and each 10ml of THF in the 50ml round-bottomed flask; Triethylamine (0.83 ml, 6 mmol), the back is to wherein adding Tosyl chloride (1.15 g; 6 mmol) with 4-Dimethylamino pyridine (DMAP) (0.036 g, 0.3 mmol, 10% Mol); Decompression steams solvent after stirring 12 h under the room temperature, and the back is stirred 2h to wherein adding the unsaturated carbonate potassium solution under the room temperature; With methylene dichloride/water extraction, dichloromethane layer is used saturated sodium bicarbonate solution (30 ml * 2), saturated aqueous common salt (30 ml * 2) washing, anhydrous magnesium sulfate drying respectively then.Back organic layer is mixed appearance and is crossed post (moving phase: petrol ether/ethyl acetate=12/1), get product 0.548 g, productive rate 56.99%, purity (HPLC) >=98%
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.40(s,?3H,?-CH
3),?5.17(s,?2H,?-CH
2-),?7.31?(d,
?J=8.4Hz,2H),?7.35-7.43(m,?2H),?7.74(d,
?J=8.0Hz,?1H),?7.95(d,?
J=8.8Hz,?1H),?7.97(d,?
J=8.8Hz,?2H).
ESI-MS?(m/z,?%):?(M+H)
+?321.03.
Synthesizing of embodiment 9 title product 2-chloromethyl-1-(4-anisole alkylsulfonyl)-1H-benzoglyoxaline
Press the preparation method of embodiment 8, raw material is replaced with 2-chloromethyl benzimidazole and corresponding SULPHURYL CHLORIDE, mix and get product 0.643 g, productive rate 63.69%, purity (HPLC) >=99% after appearance is crossed post.
1H-NMR?(400?MHz,?CDCl
3)?δ:?3.84(s,?3H,?-CH
3),?5.19(s,?2H,?-CH
2-),?6.96?(d,
?J=9.2Hz,?2H),?7.39(m,?2H),?7.74(d,
?J=7.2Hz,?1H),?7.95(d,
?J=8.0Hz?1H),?8.05(d,
?J=8.8Hz,?2H).
ESI-MS?(m/z,?%):?(M+H)
+?337.05.
Synthesizing of embodiment 10 title product 2-chloromethyl-1-(3-trifluoromethyl benzenesulfonyl)-1H-benzoglyoxaline
Press the preparation method of embodiment 8, raw material is replaced with 2-chloromethyl benzimidazole and corresponding SULPHURYL CHLORIDE, mix and get product 0.587 g, productive rate 52.21%, purity (HPLC) >=97% after appearance is crossed post.
1H-NMR?(400?MHz,?CDCl
3)?δ:?5.19(s,?2H,?-CH
2-),?7.39-7.49?(m,?2H),?7.70(t,
?J=8.0Hz?1H),?7.76(d,
?J=7.2Hz,?1H),?7.91(d,
?J=7.6Hz,?1H),?7.95(d,
?J=8.0Hz,?1H),?8.30(d,
?J=8.0Hz,?1H),?8.46(s,?1H).
ESI-MS?(m/z,?%):?(M+H)
+?374.99.
Synthesizing of embodiment 11 title product 2-chloromethyl-1-(4-isopropoxy benzenesulfonyl)-1H-benzoglyoxaline
Press the preparation method of embodiment 8, raw material is replaced with 2-chloromethyl benzimidazole and corresponding SULPHURYL CHLORIDE, mix and get product 0.612 g, productive rate 55.91%, purity (HPLC) >=97% after appearance is crossed post.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.33(d,
?J=6.0Hz,?6H,?-CH
3),?4.59(t,
?J=6.0Hz,?1H,?-CH-),?5.18(s,?2H,?-CH
2-),?6.92?(d,
?J=9.2Hz,?2H),?7.35-7.43(m,?2H),?7.73(d,
?J=8.0Hz,?1H),?7.95(d,
?J=7.6Hz,?1H),?8.02(d,
?J=8.8Hz,?2H).
ESI-MS?(m/z,?%):?(M+Na)
+?387.18.
Synthesizing of embodiment 12 title product 2-chloromethyl-1-(4-tert.-butylbenzene alkylsulfonyl)-1H-benzoglyoxaline
Press the preparation method of embodiment 8, raw material is replaced with 2-chloromethyl benzimidazole and corresponding SULPHURYL CHLORIDE, mix and get product 0.539 g, productive rate 49.51%, purity (HPLC) >=98% after appearance is crossed post.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.29(s,?9H,?-CH
3),?5.18(s,?2H,?-CH
2-),?7.36-7.45(m,?2H),?7.53(d,
?J=8.4Hz,?2H),?7.74(d,
?J=7.6Hz,?1H),?7.98(d,
?J=8.0Hz?1H),?8.02(d,
?J=8.8Hz,?2H).
ESI-MS?(m/z,?%):?(M+Na)
+?385.13.
(1-p-toluenesulfonyl-1-H-benzimidazolyl-2 radicals-yl) alcoholic acid is synthetic for embodiment 13 title product 1-
Press the preparation method of embodiment 8, raw material is replaced with 1-(1
H-benzimidazolyl-2 radicals-yl) ethanol and corresponding SULPHURYL CHLORIDE, mix appearance cross behind the post product 0.436 g, productive rate 45.94%, purity (HPLC)>=98%.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.77(d,
?J=6.8Hz,?3H,?-CH
3),?2.37(s,?1H,?-OH),?5.51(q,
?J=6.0Hz,?1H,?-CH-),?7.28(d,
?J=8.8Hz,?2H),?7.33-7.39(m,?2H),?7.70-7.72(m,?1H),?7.84(d,
?J=8.4Hz,?2H),?7.96-7.98(m,?1H).
ESI-MS?(m/z,?%):?(M+H)
+?317.04.
Synthesizing of embodiment 14 title product 2-methyl isophthalic acid-p-toluenesulfonyl-1H-benzoglyoxalines
Press the preparation method of embodiment 8, raw material is replaced with 2-tolimidazole and corresponding SULPHURYL CHLORIDE, mix and get product 0.598 g, productive rate 69.61%, purity (HPLC) >=98% after appearance is crossed post.
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.40(s,?3H,?-CH
3),?2.81(s,?3H,?-CH
3),?7.28-7.37(m,?4H),?7.62(d,
?J=6.8Hz,?1H),?7.81(d,
?J=8.0Hz,?2H),?8.02(d,
?J=7.6Hz,?1H).
ESI-MS?(m/z,?%):?(M+Na)
+?309.11.
Synthesizing of embodiment 15 title product 2-Trifluoromethyl-1-p-toluenesulfonyl-1H-benzoglyoxalines
Press the preparation method of embodiment 8, raw material is replaced with 2-trifluoro methyl benzimidazole and corresponding SULPHURYL CHLORIDE, mix and get product 0.621 g, productive rate 60.83%, purity (HPLC) >=98% after appearance is crossed post.
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.40(s,?3H,?-CH
3),?7.31(d,
?J=7.6Hz,?2H),?7.45(t,
?J=7.6Hz,?1H),?7.56(t,
?J=7.6Hz,?1H),?7.85(d,
?J=8.4Hz,?1H),?7.93(d,
?J=8.0Hz,?2H),?8.15(d,
?J=8.0Hz,?1H).
ESI-MS?(m/z,?%):?(M+H)
+?341.03.
Synthesizing of embodiment 16 title product 1-p-toluenesulfonyls-2-vinyl-1H-benzoglyoxaline
Press the preparation method of embodiment 8, raw material is replaced with 2-vinyl benzo imidazoles and corresponding SULPHURYL CHLORIDE, mix and get product 0.487 g, productive rate 54.41%, purity (HPLC) >=98% after appearance is crossed post.
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.37(s,?3H,?-CH
3),?5.78(dd,
?J=1.6Hz,
?J=11.2Hz,?1H,?=CH
2),?6.55(dd,
?J=1.6Hz,
?J=16.8Hz,?1H,?=CH
2),?7.25(d,
?J=6.8Hz,?2H),?7.33-7.39(m,?2H),?7.48-5.55(m,?1H),?7.67-7.70(m,?1H),?7.78(d,
?J=8.4Hz,?2H),?8.06-8.08(m,?1H).
ESI-MS?(m/z,?%):?(M+H)
+?299.10.
Synthesizing of embodiment 17 title product 2-(oxyethane-2-yl)-1-p-toluenesulfonyl-1H-benzoglyoxaline
Compound 1-p-toluenesulfonyl-2-vinyl-1H-benzoglyoxaline (0.600 g; 2 mmol) be dissolved in the 10ml methylene dichloride; The back is to wherein adding metachloroperbenzoic acid (mCPBA) (1.003 g, 85%, 5 mmol) and sodium hydrogencarbonate (0.420 g; 5 mmol); Under the normal temperature after the stirred overnight to wherein adding each 20 ml of entry and methylene dichloride, extraction back organic layer is used saturated sodium bicarbonate solution (15 ml * 2), saturated aqueous common salt (15 ml * 2) washing, anhydrous magnesium sulfate drying successively.Back organic layer is mixed appearance and is crossed post (moving phase: petrol ether/ethyl acetate=6/1), get product 0.186 g, productive rate 29.62%, purity (HPLC) >=98%.
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.39(s,?3H,?-CH
3),?3.29-3.32(m,?1H,?-CH
2),?3.41-3.43(m,?1H,?-CH
2),?4.72(q,
?J=2.8Hz,
?J=4.0Hz,?1H,?-CH),?7.32(d,
?J=8.4Hz,?2H),?7.33-7.43(m,?1H), 7.69(d,
?J=8.0Hz,?1H),?7.95(d,
?J=8.4Hz,?2H),?8.01(d,
?J=8.0Hz,?1H).
ESI-MS?(m/z,?%):?(M+H)
+?315.08.
Embodiment 18 title product N, N-diallyl-N-((1-p-toluenesulfonyl-1H-benzimidazolyl-2 radicals-yl) methyl) amine synthetic
Press the preparation method of embodiment 8, raw material is replaced with 2-(N, the N-diallyl is amino) tolimidazole and corresponding SULPHURYL CHLORIDE, mix and get product 0.571 g, productive rate 49.90%, purity (HPLC) >=99% after appearance is crossed post.
1H-NMR?(400MHz,?CDCl
3)?δ:?2.39(s,?3H,?-CH
3),?3.28(sbr,?4H,?N(CH
2)
2),?4.20(sbr,?2H,?=NCH
2-),?5.15(t,?4H,?=CH
2),?5.83(sbr,?2H,?=CH-),?7.27(d,?
J?=9.6Hz,?2H),?7.35(m,?2H),?7.70(dd,
?J?=1.6Hz,
?J?=6.8Hz,?1H),?8.01(t,?3H).
ESI-MS?(m/z,?%):?(M+H)
+?382.20.
Synthesizing of embodiment 19 title product 2-morpholine methyls-1-p-toluenesulfonyl-1H-benzoglyoxaline
Press the preparation method of embodiment 8, raw material is replaced with 2-morpholine methyl benzoglyoxaline and corresponding SULPHURYL CHLORIDE, mix and get product 0.623 g, productive rate 55.90%, purity (HPLC) >=98% after appearance is crossed post.
1H-NMR?(400MHz,?CDCl
3)?δ:?2.40(s,?3H,?-CH
3),?2.64(s,?4H,?O(CH
2)
2),?3.63(s,?4H,?-N(CH
2)
2),?4.08(s,?2H,?=NCH
2-),?7.30(d,
?J?=8.0Hz,?2H),?7.35(m,?2H),?7.70(d,
?J?=8.0Hz,?2H),?7.95(d,
?J?=8.0Hz,?2H),?8.16(d,
?J?=8.0Hz,?2H).
ESI-MS?(m/z,?%):?(M+H)
+?372.23.
The pharmacodynamic experiment part
The external HCV Replicon of Test Example compound luciferase Assay and HCV Replicon MTT Assay.
HCV Replicon luciferase Assay utilizes resorcinolphthalein enzyme process test compounds anti-HCV activity.Its principle is that the subgene group of the HCV NS3-NS5 encoding sox that contains genotype 1b and luciferase encoding sox are merged and the external replicon system that infects of formation; Behind electroporation technology infection Huh7.0 cell; This replicon system can duplicate in born of the same parents, thereby can confirm that through uciferase activity in the test cell HCV replicon is active.
The latter then be through MTT method test viable cell number compound of reaction under different concns to the toxic effect of Huh7.0 cell.MTT is the hydrionic yellow dyes of a kind of acceptance; Can act on the respiratory chain in the viable cell plastosome, the tetrazole ring cracking generates blue first a ceremonial jade-ladle, used in libation crystallization under the effect of succinodehydrogenase and Lrax; First a ceremonial jade-ladle, used in libation crystalline growing amount only is directly proportional with the viable cell number; The first a ceremonial jade-ladle, used in libation crystallization that generates is dissolved in methyl-sulphoxide (DMSO), utilizes ELIASA to measure the optical density(OD) OD value at 570nm place, can reflect the viable cell number.
Cell medium lethal dose(LD&-{50}) CC50 that two tests obtain and the ratio of HCV half-inhibition concentration IC50 are the safety index of compound, and the big more explanation compound of this ratio is safe more, can explain that also compound is not to come from its cytotoxicity to the restraining effect of HCV.
Table 1 is part of compounds HCV Replicon luciferase Assay and HCV Replicon MTT Assay result:
Table 1 part of compounds HCV Replicon luciferase Assay and HCV Replicon MTT Assay result
Annotate: * literature value: IC50=23 μ M, CC50=40 μ M;
* CSA (ciclosporin A) is a kind of immunomodulator, has anti-preferably HCV effect, during test with this as positive control, this result is within the normal range.
Can find out by last table; Control CSA and Clemizole test result all are in normal range; Can find out that from test data embodiment 8,9,10,11,12,16 all has the ability of HCV inhibition preferably under low micro-molar concentration, but leaf has shown significant cytotoxicity (SI is less than 5); And compound has dose-dependently to the restraining effect of HCV; And embodiment 17 (compound S KLB-HCV-60) is though only just have anti-HCV effect under higher concentration, and its under high density (100 μ M) do not show obvious cytotoxicity, demonstrates its security preferably.
In sum, above-mentioned active compound has stronger restraining effect to HCV, and the part of compounds cytotoxicity is lower, and SI is higher.In addition; Substituted benzimidazole compounds preparation method of the present invention has the reaction conditions gentleness, abundant raw material is easy to get; Operation and advantage such as aftertreatment is simple, overall yield is higher, environmental pollution is less; Therefore, compound of the present invention can be used as the candidate compound of treatment chronic hepatitis C.
Claims (7)
1.1-arylsulfonyl-1H-benzimidizole derivatives, structure is suc as formula shown in the I:
Wherein, R
1Independently be H, C1~C8 alkyl, C2~C8 naphthenic base, halogen replacement C1~C8 alkyl, hydroxyl replacement C1~C8 alkyl, CF
3,
,
,
Or the epoxy group(ing) that to have substituent ring skeleton be 2~8 C; Substituting group independently is H or C1~C8 alkyl;
R
2~R
6Independently be H, C1~C8 alkyl, C2~C8 naphthenic base, C1~C8 alkoxyl group, OH, CF
3Or OCF
3
R
7~R
10Independently be H, C1~C8 alkyl, C2~C8 naphthenic base, C1~C8 alkoxyl group, OH, CF
3Or OCF
3;
R
11~R
30Independently be H, C2~C8 naphthenic base or C1~C8 alkyl;
w=0~1,x=0~1,y=0~1,z=0~1。
2. 1-arylsulfonyl according to claim 1-1H-benzimidizole derivatives is characterized in that: R
1Independently be H, C1~C8 alkyl, C2~C8 naphthenic base, halogen replacement C1~C8 alkyl, hydroxyl replacement C1~C8 alkyl, CF
3,
,
,
or the epoxy group(ing) that to have substituent ring skeleton be 2~8 C; Substituting group independently is H or C1~C8 alkyl;
R
2~R
6Independently be H, C1~C8 alkyl, C1~C8 alkoxyl group, OH, CF
3Or OCF
3
R
7~R
10Independently be H, C1~C8 alkyl, C1~C8 alkoxyl group, OH, CF
3Or OCF
3;
R
11~R
30It independently is H or C1~C8 alkyl;
w=0~1,x=0~1,y=0~1,z=0~1。
3. 1-arylsulfonyl according to claim 2-1H-benzimidizole derivatives is characterized in that: R
1Independently be H, C1~C8 alkyl, C2~C8 naphthenic base, halogen replacement C1~C8 alkyl, hydroxyl replacement C1~C8 alkyl, CF
3,
,
,
Or the ring skeleton is the epoxy group(ing) of 2~8 C;
R
2~R
6Independently be H, C1~C8 alkyl, C1~C8 alkoxyl group or CF
3
R
7~R
30Be H;
w=x=y=0。
4. 1-arylsulfonyl according to claim 3-1H-benzimidizole derivatives is characterized in that: R
1Independently be H, C1~C4 alkyl, halogen replacement C1~C4 alkyl, hydroxyl replacement C1~C4 alkyl, CF
3,
,
,
Or the ring skeleton is the epoxy group(ing) of 2~4 C;
R
2~R
6Independently be H, C1~C4 alkyl, C1~C4 alkoxyl group or CF
3
R
7~R
30Be H;
w=x=y=0。
6. each described 1-arylsulfonyl-1H-benzimidizole derivatives of claim 1~4 is in the purposes of preparation in the anti-hepatitis C medicine.
7. pharmaceutical composition, adding pharmaceutically each described 9-arylsulfonyl-9H-purine derivative of claim 1~4, the complementary composition of acceptable is prepared from.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2012100034193A CN102558067A (en) | 2012-01-07 | 2012-01-07 | 1-arylsulfonyl-1H-benzimidazole derivative and preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2012100034193A CN102558067A (en) | 2012-01-07 | 2012-01-07 | 1-arylsulfonyl-1H-benzimidazole derivative and preparation method and application thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN102558067A true CN102558067A (en) | 2012-07-11 |
Family
ID=46404831
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2012100034193A Pending CN102558067A (en) | 2012-01-07 | 2012-01-07 | 1-arylsulfonyl-1H-benzimidazole derivative and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102558067A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105481775A (en) * | 2014-10-13 | 2016-04-13 | 上海东升新材料有限公司 | 2-diallylaminomethylbenzimidazole and preparation method thereof |
CN105859633A (en) * | 2016-04-07 | 2016-08-17 | 昆明理工大学 | 2-thioacetanilide benzimidazole compound as well as preparation method and application thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1834090A (en) * | 2005-03-18 | 2006-09-20 | 中国科学院上海药物研究所 | Benzimidazole compounds, its prepn. and uses |
-
2012
- 2012-01-07 CN CN2012100034193A patent/CN102558067A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1834090A (en) * | 2005-03-18 | 2006-09-20 | 中国科学院上海药物研究所 | Benzimidazole compounds, its prepn. and uses |
Non-Patent Citations (7)
Title |
---|
《ACS Medicinal Chemistry Letters》 20110805 Pasha M. Khan et al. Identification of Inhibitors of NOD1-Induced Nuclear Factor-kB Activation 780-785页 7 第2卷, * |
《Chemical and Pharmaceutical Bulletin》 20071225 Ayarivan PURATCHIKODY et al. Experimental and QSAR Studies on Antimicrobial Activity of Benzimidazole Derivatives 273-281页 第56卷, 第3期 * |
《Chemical and Pharmaceutical Bulletin》 20071225 Ayarivan PURATCHIKODY et al. Experimental and QSAR Studies on Antimicrobial Activity of Benzimidazole Derivatives 7 第56卷, 第3期 * |
AYARIVAN PURATCHIKODY ET AL.: "Experimental and QSAR Studies on Antimicrobial Activity of Benzimidazole Derivatives", 《CHEMICAL AND PHARMACEUTICAL BULLETIN》, vol. 56, no. 3, 25 December 2007 (2007-12-25), pages 273 - 281 * |
N.NARAYANAN ET AL.: "Organostannyl mediated synthesis of l-alkyl- and 1-sulfonyl-2-trifluoromethylbenzimidazole derivatives", 《JOURNAL OF ORGANOMETALLIC CHEMISTRY》, vol. 423, no. 3, 28 January 1992 (1992-01-28), pages 361 - 366 * |
PASHA M. KHAN ET AL.: "Identification of Inhibitors of NOD1-Induced Nuclear Factor-kB Activation", 《ACS MEDICINAL CHEMISTRY LETTERS》, vol. 2, 5 August 2011 (2011-08-05), pages 780 - 785 * |
RAVI KUMAR CHEEDRALA ET AL.: "Lipase mediated kinetic resolution of benzimidazolyl ethanols", 《TETRAHEDRON: ASYMMETRY》, vol. 19, no. 8, 1 May 2008 (2008-05-01), pages 901 - 905 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105481775A (en) * | 2014-10-13 | 2016-04-13 | 上海东升新材料有限公司 | 2-diallylaminomethylbenzimidazole and preparation method thereof |
CN105481775B (en) * | 2014-10-13 | 2018-03-13 | 上海东升新材料有限公司 | 2 diallyl aminomethyl benzimidazoles and preparation method thereof |
CN105859633A (en) * | 2016-04-07 | 2016-08-17 | 昆明理工大学 | 2-thioacetanilide benzimidazole compound as well as preparation method and application thereof |
CN105859633B (en) * | 2016-04-07 | 2018-10-19 | 昆明理工大学 | A kind of 2- thiacetamides benzimidazoles compound and its preparation method and application |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102295642B (en) | 2-Aryimidazole is [1,2-a] pyridine-3-acetamide, Preparation Method And The Use also | |
JP5250760B2 (en) | Imidazole-5-carboxylic acid derivative, production method and application thereof | |
CN105622525B (en) | The method for being used to prepare antiviral compound | |
KR20100081294A (en) | Imidazopyrazine compounds | |
NO20151329A1 (en) | Novel compounds and compositions for inhibition of fasn | |
CN107759571A (en) | Inhibitors of influenza viruses replication and its application method and purposes | |
CN110950828B (en) | Baicalein or derivatives thereof, preparation method and application | |
CN105884779A (en) | Compound adopted as hepatitis c inhibitor and application thereof in medicine | |
CN105732602B (en) | Benzofuran analogue used as NS4B inhibitor | |
CN106831556A (en) | Sulfamide compound and preparation method thereof and the purposes as lithate transporter inhibitors class medicine | |
CN102558067A (en) | 1-arylsulfonyl-1H-benzimidazole derivative and preparation method and application thereof | |
CN102850355B (en) | 9-sulfonyl-9H-purine derivatives, and preparation method and use thereof | |
CN104334528A (en) | (2-heteroarylamino)succinic acid derivative | |
CN106103417A (en) | Derivant of 1,2 naphthoquinone and preparation method thereof | |
Liu et al. | Synthesis and anti-hepatitis B virus evaluation of novel ethyl 6-hydroxyquinoline-3-carboxylates in vitro | |
CN106117182B (en) | Quinazoline-N- phenethyl tetrahydroisoquinolicompounds compounds and its preparation method and application | |
CN104610272B (en) | Ring-type flavones or isoflavonoid and application thereof | |
CN106083829A (en) | A kind of hepatitis C virus inhibitors, pharmaceutical composition and application thereof | |
CN112107568B (en) | Diaryl amide compound and application thereof | |
JPH01268689A (en) | Novel benzoimidazo(1, 2-c) quinazoline, its production and use | |
CN102617478A (en) | Synthesis of benzimidazole, oxazole and thiazole derivatives and application thereof | |
CN107235994B (en) | Simultaneously [3,2-a] pyrimidine -3- acetamide derivative and the application of 5,7- diphenyl -5H- thiazole | |
CN106188035B (en) | The Preparation method and use of the double-functional group berberinc derivate of 9 substitutions | |
CN103435612A (en) | Compound for treating diabetes mellitus | |
CN104744451A (en) | 1-(3-amino propyl) substituted cyclic amine compound as well as preparation method, pharmaceutical composition and use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120711 |