前苏联专利SU1442076A3 Method of producing nucleoside or its pharmaceutically acceptable salts

专利PDF首页>>前苏联专利

专利附录

专利说明

权利要求

类似技术

同族专利

引用文献

法律状态

优先权

专利摘要:
The invention provides novel nucleosides and novel 2,2-difluoro-2-desoxycarbohydrates useful in the preparation of such nucleosides.
公开号:SU1442076A3
申请号:SU843710351
申请日:1984-03-07
公开日:1988-11-30
发明作者:Вейн Хертел Ларри
申请人:Эли Лилли Энд Компани (Фирма)；
IPC主号:

专利说明:

Sl1
This invention relates to a process for the production of new nucleosides.
formulas
: NON |; HE
where R is the base of one of the formulas
About HN o N where R is hydrogen, methyl, fluorine or
iodine,
or their pharmaceutically acceptable salts possessing antiviral activity.
The purpose of the invention is to obtain new nucleosides with greater activity than the known structural analogue, vidarabine (Ara-A).
Example 1. 1- (5-Metsh1g2,4-dioxo-1H, 3N-pyrimidin-1-yl) -1,2-deoxy-2,2-difluoriribose.
Under a nitrogen atmosphere, 2.59 g of 3,5-β-bis (tert-butyldimethylsiloxy) -1-methanesulfonyloxy-2-deoxan-2,2-di-. Fluorobibose is added with 1.60 g of 5-methyl-2,4-bis- (trimethyloxylyloxy) pyrimidine and 45 ml of C37IC1., 2-dihpor-ethane. Then, 1.45 g of trifluoromethanesulphonyloxime-tsilsilane is added to this mixture and the clear solution is stirred at reflux for 2-3 hours. Then the reaction products are cooled to room temperature, 1.35 ml of methanol is added and stirred the resulting suspension for 30 minutes The precipitate is filtered, and the filtrate is reduced to half of its volume under vacuum and diluted with dichloromethane in the same manner. The solution is then washed with an aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solution is filtered and the filtrate is saturated with anhydrous hydrogen bromide. The reaction mixture is stirred for 30 minutes and then condensed under vacuum. The residue is dissolved in methanol and grown
0
the thief is evaporated to dryness under vacuum. The residue is dissolved in water and the solution is extracted twice.
diethyl ether. The aqueous layer is evaporated. The residue is taken up in ethanol and re-evaporated until complete dehydration. 1 g of crude product is obtained, which is chromatographed on 30 g of Woelm silica gel (70-150 mesh), with elution with ethyl acetate, in a yield of 0.76 g of the desired product. This product is further purified by re-crystallization from ethyl 5, acetate, with a yield of 0.37 g of white, crystalline product.
NMRCCDjOD, 90 MHz), f: 1.93 (S, ZN), 3.5-4.67 (t series, 4H) 4.88 (bS, ZN); 6.3 t, J 9 Hz, 1H) i 7.47
0 (m, 1H)} mass spectrum; m / e 278 source.
Dirmere 2. 1- (4-Amino-2-ox-so-1H-pyrimidin-1-yl) -2-deoxy-2,2-β-difluororibose.
Under nitrogen, 5.0 g of β-bis (tert-butyldimethylsiloxy) -1-methane of ulfonyloxy-2-deoxy-2,2-difluorooribose in 1 ml of dry 1,2-dichloroethane are added to 4 g , 68 g of bis-trimethylsilylacetylcytosine and then 3.96 g of trifluoromethanesulfonyloxymethylsilane. The solution is heated to reflux in the range of 3-15 hours. The reaction mixture is cooled to room temperature, 2 ml of methanol are introduced and the suspension is stirred for 30 minutes. The residue is filtered, and the filtrate is concentrated in vacuo to complete dehydration. Remaining: The current is dissolved in methylene chloride, saturated with anhydrous HBr and stirred at room temperature for
45 min. The resulting mixture is concentrated to dryness in vacuo, absorbed by methanolic ammonium and stirred for 15 minutes at room temperature. The solution is then concentrated until completely dried in a vacuum, diluted three times with water and aqueous.
0 a soluble portion is introduced into the column on silica gel with a reverse phase to obtain 100 mg of the desired product by eluting with water.

5SHE (SVZOV, 90 mHz), s: 3.7-4.65
; (series t, 4H) -, 4.83 (bS, 4I); 5.97, (d, J 8 Hz, 1H); 6.24 (t, J 8 Hz, 1H) i 7.88 (d, J 8 Hz, 1H) i mass spectrum: m / e 263 original.
Example 3. 1- (A-Amino-5-iodo--2-oxo-1H-pyrimidin-1-yl) -2-deoxy--2,2-difluororibose.
Under nitrogen, to 1.99 g of 3,5-β-bis (tert-butyldimethylsiloxy) -1-methanesulfonyloxy-2-deoxy-2,2-difluorooribose in 1.35 ml of dry 1,2-dichloro .4 g 3,5-bis (tert-butyldimethylsilyloxy) -1-methanesulfonyloxy-2-deoxy-2,2-difluorooribose and 45.4 g to 5-meethane were added 2.08 g of tris-trimethyl-1-1-5-iodocytosine and 1.11 g of trifluoro U mn-2,4-bis (trimethylsiloxoxy) pyrimimethanesulfonyloxymethylsclan, Rastin is combined and heated in an atmosphere of
the thief is refluxed
in the range of 3-15 hours. The reaction mixture
cooled to room temperature.
re-nitrogen and stirring, for 1 hour and at 150 seconds for 1 hour. After that, the mixture is cooled to
(t, J 8 Hz, 1H) j 7.9 D (d, J 7 Hz, 1H); mass spectrum: m / e 282 source. ;
Example 5. 1- (5-1 etyp-2, A- -dioxy-1H, 3N-pyr imiddin-1-yl) -2-deoxy-2,2-difluororibose.
5.4 g 3,5-bis (tert-butyldimethylsilyloxy) -1-methanesulfonyloxy-2-desoxy-2,2-difluoriribose and 45.4 g 5-measure of nitrogen and agitation, for 1 h and at 150 s within 1 hour. After that the mixture is cooled to
5.0 ml of methanol obtained at room temperature is added, the suspension is diluted and the mixture is stirred with approximately 25 ml of water and 10 ml of methanol. Suspended for 30 min. The residue is filtered and the filtrate is concentrated in vacuo to dryness. The residue is dissolved in methylenium, filtered through a layer of diatomaceous earth and the layer is washed with acetone. The combined filtrates are evaporated with chloride, saturated with anhydrous HBr and ne-20 are under vacuum and 5.3 g are obtained by stirring at room temperature for 45 minutes. The mixture is concentrated to the "tyxoro state" in a vacuum. The residue is saturated three times with water, neutralized. HNSO3 and separated on a column with a liquid are reverse phase phase (MeOH (9: 1), to obtain 26 ml of the desired product.
NMRXCDjOD, 90 MHz), f I, 73 (t series, 4H); 4.9 (bS, 4H) 6.25 (t, J 8 gi, 1H); 8.44 (S, 1H), mass spectrum: m / e 389 source. Example 4. 1- (2,4-dioxo-5l residue). The residue is dissolved in 10 ml of acetone and introduced into a 4.5 s column packed with 80 g of silica gel.
Sch) alumina alumina with a mixture of dichlorum 25 tan: methanol: triethylamine 15: 1: 1.
The first 100 ml of eluent is discarded, and the next 300 ml is evaporated under vacuum and 4.1 g syrupobr are obtained; This product is dissolved in 40 ml of acetone. Hydrogen chloride is bubbled through the solution for 1 hour and then hydrogen bromide is bubbled through for another 1 hour. After that, the solution is evaporated at 62 and
-fluoro-1H, 3H-pyrimidin-1-yl) -2-deoxy-2, 2-difluororibose. 4.4 g of oily dark are obtained.
Under nitrogen to 1.1 g of 3,5-bis-, product. (tert-butyldimets1siloxy) -1-methane-sulfonyloxy-2-deoxy-2,2-difluoro-oribose in 20 ml of dry dichloroethane
This product was dissolved in 10 ml of a warm mixture of dichloromethane: vinegar 3: 1 acid and introduced into the column.
2.88 g of bis-trimethylsilyl-5-40 4.5 cm, packed with 45 g of silica gel are added. For
-fluorouracil and 0.66 g of trifluoromethanesulfonyloxytrimethylsilane. The solution is cooled to room temperature, 1.0 ml of methanol is added and the suspension is stirred for approximately 30 minutes. The residue is filtered and the filtrate is concentrated in vacuo to dryness. The residue is dissolved in methylene chloride, saturated with anhydrous
for the first 1000 ml, a mixture of dichloromethane: acetic acid 3: 1 is used as eluent, after which only acetic acid 45 is used as eluent. Most of the desired product is in 1000 and 1400 ml mezkuda fractions coming out of the column, as shown by thin-layer chromatography on silica gel using HBG and stirred at room temperature by 50 "dichloromethane: methanol 15: 1.
about 45 minutes. The mixture is concentrated to dryness in vacuo. The rest of the trizvda is saturated with HjO, neutralized with NaHCO3 and separated on a reverse-phase silica gel column, eluting with water to give the desired product.
NMR (CD, OD, 90 MHz), tf i 3.5-4.5 (series m, 4H); 4.65. (bS-, ZN) 5.89
at room temperature, diluted with 25 ml of water and 10 ml of methanol. Suspension
Zium is filtered through a filtrate with a layer of kieselguhr and the layer is washed with acetone. The combined filtrates evaporated the residue. The residue was dissolved in 10 ml of acetone and introduced into a 4.5 cm column packed with 80 g of silica gel.
Sch) alumina d alumina with a mixture of dichloromethane 25 tane: methanol: triethylamine 15: 1: 1.
The first 100 ml of eluent is discarded, and the next 300 ml is evaporated under vacuum to obtain 4.1 g of syrup-like; This product is dissolved in 30 ml of acetone. Hydrogen chloride is bubbled through the solution for 1 hour and then hydrogen bromide is bubbled through for another 1 hour. After that, the solution is evaporated at 62 and
product.
This product was dissolved in 10 ml of a warm mixture of dichloromethane: acetic acid 3: 1 and introduced into the column.
for the first 1000 ml, a mixture of dichloromethane: acetic acid 3: 1 is used as eluent, after which only acetic acid 45 is used as eluent. Most of the desired product is in 1000 and 1400 ml mescade fractions leaving the column, as shown by silica gel thin-layer chromatography using. These fractions are combined and evaporated under vacuum, and the residue is dissolved in 15 ml of cold acetone and filtered. The filtrate is evaporated under vacuum to give an oil, which is dissolved in 5 ml of acetone and chromatographed on 20 g of silica gel using a 15: 1 mixture of dichloromethane methanol. Product containing fractions are combined.
evaporated under vacuum: 300 mg of a semi-liquid compound is obtained. This product is dissolved in 5 ml of acetone and filtered, the filtrate is evaporated under vacuum to obtain 230 mg of a light brown semi-solid compound. It is dissolved in 10 ml of a saturated sodium bicarbonate aqueous solution, and the solution is extracted two times in portions of 15 ml of diethyl ether. Thereafter, the aqueous phase is evaporated under vacuum, the residue is suspended in acetone and filtered, the filtrate is evaporated under vacuum, and 1 AO mg of the desired product is obtained in the form of a reddish-brown viscous oil.
Example 6. 1- (5-Methyl-2,4-d-ioxo: -1H J 3N-pyrimidin-1-yl) -2-de 3-hydroxy-2,2-difluoro, oribrosa.
To 80.0 g of 3} 5-bis (tert-butyldimethyleshl1-ILOXI) -1-methanesulfonyloxy-2-deoxy-2,2-difluorobribose -v. nitrogen atmosphere: 1.4 liters of freshly distilled methylene chloride and 49.5 g of 5-methyl-2,4-bis (trimethyl-Silyl oxy) pyrimidine are added. To this mixture, 44.8 g of trifluoromethanesulfonyl-oxitrime-tylsilane was added and the reaction mixture was heated under reflux for approximately 3.25 hours. The reaction mixture was stirred at room temperature overnight and 41.6 ml of methanol was added to it. The resultant mixture was stirred for approximately 30 minutes, the precipitated solid was collected by filtration. The filtrate is concentrated under vacuum at 45 ° C from a dark oil obtained, which is dissolved in 500 ml of methylene chloride saturated with anhydrous hydrogen bromide. The resulting suspension is stirred for approximately 3 hours, after which the volatile compounds are removed under vacuum at 45. The residue is dissolved in 100 ml of 10% sodium bicarbonate solution and 100 ml of diethyl ether. The aqueous layer was separated and concentrated under vacuum at 50 seconds and a residue was obtained, which was dissolved three times with portions of 1 DO ml of hot ethyl acetate. The combined layers are combined, evaporated in vacuo at 45 and a residue is obtained, which is dissolved in 50 ml of water. This solution is chromatographed in 10 ml portions on a Waters Prep 500 C reverse phase column.
nineteen
using a water / methanol mixture (v / v, 9: 1) as eluent, 2.21 g of 1- (5-methyl-2,4-dioxo-1H, 3H-pyrimndin-1-yl) -2 are obtained. dehydroxy-2,2 difluororibose. NMR (, 90 MHz), /: 1.9 (singlet, GN); 3.65 - 4.65 (multiplet, 4H); 34-83 (singlet, 3H) j 6.12 (double doublet, J
7 Hz, 12 Hz, 1H); 7.70 (singlet, 1H); mass spectroscopy t / e. Example 7. 1- (2-Oxo-4-amino--1H-pyrimidin-1-yl) -2-deoxy-2,2 - DI - fluoroxylose.
Under nitrogen atmosphere, 23 g of tris (trimethylsilyl) cytosine and 300 ml of chloride are added to 23 g of 3,5-bis- (tert-butschimetilysilyloxy) -2-methanesulfonyloxy-2-deoxy-2,2-difluoro-xylose under nitrogen. methylene. To this mixture was added 10.84 g of trifluoromethanesulfonyloxy-: trimethylsipane and the mixture was heated under reflux for approximately 16 hours. The mixture is cooled to
room temperature and 20 ml of methanol are added to the mixture. The solution is vigorously stirred for approximately 1 hour at room temperature, and the precipitated solid
the compound is collected by filtration. 100 ml is added to the organic layer; the odes and sustanzia are vigorously stirred for 30 minutes. The organic layer is separated and evaporated.
dry to a reduced
pressure, get 11.2 g of brown oil. The residue is dissolved in 97 ml of methanol, and 33 g of a BiO Rad A.G cation exchange resin is added to the solution.
50X8. The suspension is stirred for approximately 16 hours at room temperature and the resin is collected by filtration. The resin is washed with 50 ml of methanol and vigorously stirred in a solution of 100 ml of methanol and 100 ml of ammonium hydroxide. This operation is repeated two times, the combined filters are con- centrated under a vacuum at 5 ° and 2.09 g of a yellow residue. The suspension is suspended in 25 ml of water and stirred vigorously for 15 minutes. The insoluble precipitate is collected by filtration and 0.25 g of compound A is obtained. The filtrate is concentrated
under vacuum at 50 ° C, 0.86 of Compound B is obtained. Compound A is dissolved in 20 ml of methanol and stirred for 3 days with Bio Rad AG 50WX8 at room temperature.
The resin is filtered and suspended in 30 ml of a 1: 1 (v / v) methanol / ammonium hydroxide solution. The resin is again filtered under vacuum at 50 ° C., and 0.14 g of 1- (2-deoxy-2,2-β-difluoro-p-B-xylofuranosyl) -cytosine is obtained. NMR (CDgOD, 90 MHz), f: 3.72- 4.34 (multiplet, 4H)} 4.78 (singlet 4H) -, 5.86 (doublet, J V Hz, 1H); 6.17 (doublet, J = 15 Hz, 1H); 7.78 (doublet, J = 8 Hz, 1H); mass spectrometry:.
Compound B was chromatographed on a Whatman ODS-3 reverse phase preparative column (50 cm) using water / methanol (v / v, 1: 1) as eluent to give 0.06 g of 1- (2-deoxy-2, 2 di P h ftop-in / -d-xylophyranosyl) cytosine. NMR (CDjOD, 90 MHz), f: 3.53-3.9 (multiplet, 2H) j 4.1-4.57 (guattiplet, 2H); 4.83 (singlet, 4H) j 5.9 (doublet, J 8 Hz, 1H); 6.3 (double J = 7 Hz, 12 Hz, 1H), 7.55 (doublet, J 8 rUf 1H) i mass spectrometer: m / e 263 p.
Example 8. 1- (5-Methyl-2-oxo-4-amino-1H-pyrimidin-1-yl) -2-deoxy-2,2-difluororibose,
In the nitrogen atmosphere, a solution of 1.86 g, 3,5-bis (tert-butyldimethylsilyloxy) -2 -2-methanesulfonyloxy-2-deoxy-2,2-difluoroborobose, 1.87 g of tris-trimethylsilyl-cytosine and 1.34 g of trifluoromethanesulfonyloxytrimethylsilane in 37 ml of dry methylene chloride is refluxed overnight. The reaction mixture is cooled to room temperature and 1 ml of methanol is added to it. The precipitated solid is collected by filtration and the filtrate is evaporated under vacuum at 45 °. The residue is dissolved in approximately 20 ml of water and this solution is concentrated to approximately half of its original volume by evaporation under vacuum at 50 °. The residue is triturated several times in 10 ml portions of warm acetone. The organic extracts are combined, evaporated in vacuo at 45 °): „1.67 g of yellow oil is obtained. This compound is dissolved in 15 ml of methanol / water (v / v, 2: 1) and stirred overnight with 5 g of BiO Rad AG 50WX8, the suspension is closed with anhydrous ammonia and stirred for approximately
420768
for 10 minutes The resin is collected by vacuum filtration and suspended in 30 ml of a mixture of methanol / ammonia (1: 1
g by volume). The suspension is stirred for approximately 10 minutes. The resin is collected by filtration, the main filtrates are combined, concentrated under vacuum at 50 and receive
10 1.5 g, orange oil. The oil is dissolved in 10 MP of water, this solution of chromium is then taken in portions of 2 ml of a preparative (50 cm) reverse phase Whatman partisil ODS-3
15 using water as
eluent and get 0.07 g of 1- (5-metsh-2-oxo-4-amino-1H-pyrimidine-1-yl) -2-deoxy-2,2-difluoriribose. NMR (CDgOD, 90 MHz), /: 1.94 (singlet,
20 MN), 3.53-4.62 (multiplet, 4H); 4.75
(singlet, 4H); 6.17 (triplet, J
8 Hz, 1H) i 7.67 (singlet, 1H); to
mass spectrometry; m / e 277 r.
The antiviral activity of the compounds in accordance with the invention is shown by in vitro tests performed by the following method.
African monkey kidney cells (BSC-1) or He cells; grown in a 25 cm vial produced by Falcon at 37 ° C in medium 199 containing 5% inactivated serum (th 1year embryo (BSC-1),
35 penicillin (150 IU / ml) and streptomycin (150 µg / ml). When merged monolayers were formed, the growth culture medium was drained and 0.3 ml of the corresponding dilution of the indicated
40 viruses are added to each cup. After adsorption for 1 hour at room temperature, the virus that has been introduced into the cell layer has been covered with culture medium containing
45 1 h of ionogram No. 2 and 1 h of medium 199 with doubled concentration, including the shortening of the tel's embryo FS1, penicillin, streptomycin, as well as the test compound at the indicated
50 concentrations expressed in micrograms per milliliter (µg / ml). The bottle, in which there were no test compounds, served as a control. The main solutions of the test compound were made in dimethyl sulfoxide at a concentration of 10 µg / ml. The vials are incubated for 72 hours at 37 ° C. Plaques are visible in those areas where the virus infects and penetrates the cells, i.
Some of the compounds described are evaluated by in vitro analysis of tissue culture. This analysis involves the growth of a layer of cells at the bottom of a tissue culture plate. Cells infected with the Strain of the virus and covered with a continuous layer of nutrient agar. Filter paper discs impregnated with a measured amount of the test compound are then applied to the surface of the agar. The plates are incubated at 37 ° C., and the cells are then fixed with formalin and stained with a tetrachrome dye. The antiviral activity zones of the test compound are then counted in millimeters. The morphology of protective cells is assessed on a scale from 0 to 4; O - completely destroyed cells, 4 - normal cells.
In tab. 6 presents the results of this analysis. Compounds were analyzed at the indicated concentrations. Numbers in brackets corresponding to NHz
where R is hydrogen, methyl, fluorine, or
iodine
or their pharmaceutically acceptable salts, characterized in that the compound of the general formula
50 .
/%
4-i-f
UHF F
55
where Q is a group of CHX, where X is a split group}
J | and
J is independently a hydroxy protecting group,
interacting with protected reaction mixtures with a subsequent base of the formulas described by the removal of protective groups and moreover, in an inert solvent medium, the desired product, either as 1,2-dichloroethane or in chlorine form or as pharmaceutical methylene, at a temperature of ki-ki of an acceptable salt.
72 53
35
99
too
X
98,100
Aaometry1 mixture (i / and |) Anomra configuration only.
Session of an example.
Suppression of bloat formation, Z, pr of definition of conceptual x connect it, ICG / m, e. Using cells in C-1, covered with a layer of agar, SeadobaeoenstA virus (Paeudorabie viru)
100 502520
231815
1 (X
A metric mixture (/ and | gof cation).
Example Compound
Suppression of blistering,%, at certain concentrations of the compound, µg / ml, using BSC-1 cells covered
a layer of agar
100
20
Herpes simplex, type II
- 100 100 83 .28 Virus: polio, type I (Polio virus)
Anomer configuration only,
t and b "c t
12
21
too
eight
31 - 100 100
Tvsl aa 2
12
JO
12-65 - ...
too - 1001001009Т
T a B L I C a 3
100
100
too
/ 3 - anomer configuration. c (- anoner configuration.
/ h - anomer only. - possibly toxic.
Table 5
Table 6
19 (4) 17 (4) U (4)
15
1442076
16 Continuation of table 6
17
1442076

1Su, 720
Idok-suridin
250
78
7.8,100 31.2 10.0
The inhibition in squeaking tissue culture is described.
in tab. . tab. 1 — Inhibiting refers to the ability to inhibit the formation of plaque
18 Continuation of table 7
33 (3)
lOOZe inhibited 59% inhibition 76Z by inhibiting 30% inhibition by 20% inhibition

权利要求:
Claims (1)
[1]
Claim
A method of obtaining a nucleoside of the General formula
Yeah
Acyclovir
7.6
1.74 where R is the base of one of the formulas
Some of the compounds described are evaluated in an in vitro tissue culture assay. This analysis includes the growth of a layer of cells at the bottom of a tissue culture plate. Cells are infected with a strain of the virus and are coated with a continuous layer of nutrient agar. Filter paper disks soaked with a measured amount of the test compound are then applied to the surface of the agar. The cups were incubated at 37 ° C and the cells were then fixed for- where R _t is hydrogen, methyl, fluorine, or iodine or their pharmaceutically acceptable salts, characterized in that the compound of the general formula is raspberry and stained with a tetrachrome dye. The antiviral activity zones inherent in the test compound gg are then counted in millimeters. The morphology of protective cells is evaluated on a scale from 0 to 4: 0 - completely destroyed cells, 4 - normal cells. ₅ 5
In the table. 6 presents the results of this analysis. Compounds were analyzed at the indicated concentrations. The numbers in brackets correspond to 4-4-f bp F where Q is the CHX group, where X is the group we split off, May the group;
J ₄ and
J ₂ is independently hydroxy-protective and
1 2 singing the reaction mixture, followed by removal of the protective groups and isolation of the desired product, in free form or in the form of a pharmaceutically acceptable salt.
reacted with the protected base of the formulas described above in an inert solvent such as 1,2-dichloroethane or methylene chloride at a temperature of table 1
Compound
Depressed blancoobrazaamog, X, at uniformed concentrations of compounds, mcg / md, e NsyaoyaMs- • we breathe cells vz-l is covered: agar layer, Herpes simplex, type 1
an example 100 fifty 25 20 12.5 Ί-- 1 ¹⁰ 1 6.25 3.12 2 J.56 1 0.78 0.39 0.2 1* 96 72 53 - 35 • fifteen 12 - 0 - 8 4 * I **: 99- 99 - 98 - - 21 - 31 - - · g- - '‘Too - 100 - - 100 - too - - 100 / to.
_f * Anometric mixture (</ s) configuration) * Anomer configuration only.
ϊ a b i vpa 2.
Inhibition of plaque formation, 2, at certain concentrations of the compound, μg / m, e. the use of cells In C-1, covered with a layer of agar, the virus of pseudoadamism (Pseudorabia virus)
Compound example. ·
100 fifty 25 20 12 10 6 3 2 1 0.2 1*· 23 18 fifteen -. 126 5 - - 2 - - - 100 - 100 . ·. - - 100 100 100
Compound Example
1*
Inhibition of plaque formation,%, at certain concentrations of the compound, μg / ml, using BSC-1 cells coated with an agar layer
20 10 2 1 ABOUT
Herpes simplex, type II. 100 100 ¹ Virus: polio, type • - 100
83, 28 (Polio virus)
100 100 * Anomer configuration only
Compound Example
Inhibition of plaque formation,%, at certain concentrations of compounds, μg / ml, using Hela cells coated with an agar layer, Herpes simplex, type II
U0 20 10 2 1
1 * 100
1**
100 100 * a configuration of the anomer.
D * Y ¹ d is the configuration of the anomer.
Table 5
Compound Example Inhibition of plaque formation,%, at certain concentrations, mg / ml, compounds using Hela cells coated with an agar layer, Herpes simplex, type I 100 20 10 2 1 0.2 1* - 100 100 99 - 99 42 ’ 2 - 100** 100** 100 90 54
* / E - anomer only. ** - possibly TOXIC. '
Compound Example
The concentration of the impregnating solution, μg / ml
5000
Table 6
Dimensions------—PolioIII cell area, mm, the used strain of the virus • Herpes Ann arbor Setnlihi forest - 65 (4) - - 47 (4) 50 (4) 45 (4) 19 (4) 44 (4) ’ 45 (4) 40 (4) 17 (4) 39 (4) 40 (4) 32 (4) 14 (4)
1000
500
250
fifteen
Continuation of Table 6
Compound Example
Impregnation concentration
The size of the cell zone, mm, the used strain of the virus solution, μg / ml
Polio III • Herpes
Ann arbor
Semlihl forest
123 34 (4) 37 (4) 24 (4) 10 (4) 62.5 28 (4) 34 (4) 21 (4) 7 (3) 31.25 15 (4) 30 (4) 16 (4) - 25 ' 15 (4) 27 (4) - - 12.5 14 (3) 24 (4) - - 6.25 9 (1) 20 (4) - - 3.13 - 15 (4) - - 1,56 - 9 (4) - - 78 -. 7 (2) - -
ι 'table 7
¹ Example Test system (virus) Dose, mcg / ml results 1 g 3 4 3 HSV-1 5000 23 (4) *25 15 (1) *12.5 14 (1) * HSV ** „ fifty 100% inhibition Pseudo rabies 20 25% inhibition 7 HSV-1 1.25 100% inhibition (anomer Polio virus Type I 100 92% inhibition Nye mix 8 )HSV-1 20 13% inhibition
100
29% inhibition
1442076 18
Continuation of Table 7
1 2 3 4 6 CCRF-CEM all (human leukemic cells) IC _wo 7 20 Idoxur idin250 33 (3) *78 100% Inhibition7.8 59% inhibition Ara-a100 76% inhibition31,2 30% inhibition • · 10.0 20% inhibition
* 3on inhibition when tissue culture is scripted is described in Table. 6 / ** See tab. 1 - inhibition refers to the ability to inhibit plaque formation.

类似技术:

公开号 | 公开日 | 专利标题

SU1442076A3|1988-11-30|Method of producing nucleoside or its pharmaceutically acceptable salts

US5591722A|1997-01-07|2'-deoxy-4'-thioribonucleosides and their antiviral activity

JP3421335B2|2003-06-30|Enantiomerically pure β-D-|-dioxolane-nucleoside

Tseng et al.1989|Synthesis of 3-deazaneplanocin A, a powerful inhibitor of S-adenosylhomocysteine hydrolase with potent and selective in vitro and in vivo antiviral activities

Robins et al.1983|Nucleic acid related compounds. 39. Efficient conversion of 5-iodo to 5-alkynyl and derived 5-substituted uracil bases and nucleosides

EP0243670B1|1992-07-22|Purine and pyrimidine compounds and their use as anti-viral agents

JP4514242B2|2010-07-28|Antiviral pyrimidine nucleoside analogues

HU203363B|1991-07-29|Process for producing 2',3'-dideoxy-2',2'-difluoronucleosides and pharmaceutical compositions comprising same as active ingredient

Dudycz et al.1984|A simple one-pot method for 6-oxopurine ribonucleoside synthesis: control and mechanism of isomer distribution

Shealy et al.1983|Carbocyclic analogs of 5-substituted uracil nucleosides. Synthesis and antiviral activity

CA2032422A1|1991-06-21|Analogs of oxetanyl purines and pyrimidines

US5744600A|1998-04-28|Phosphonomethoxy carbocyclic nucleosides and nucleotides

US4525299A|1985-06-25|-15-Deoxyspergualin, process for the preparation thereof, and intermediate of the same

US4396623A|1983-08-02|Carbocyclic analogs of uracil nucleosides as antiviral agents

US4728736A|1988-03-01|Carbocyclic analogs of purine ribofuranosides

US4659698A|1987-04-21|Pharmaceutical compositions based on xylosides and lyxosides of purine and pyrimidine bases used in a method of treating viruses

US4188377A|1980-02-12|Carminomycin derivatives, their preparation and use

Whistler et al.1971|4-Thio-D-arabinofuranosylpyrimidine nucleosides

Béres et al.1990|Stereospecific synthesis and antiviral properties of different enantiomerically pure carbocyclic 2'-deoxyribonucleoside analogs derived from common chiral pools:|-|-and |-|-2-oxabicyclo [3.3. 0] oct-6-en-3-one

US4845084A|1989-07-04|Phosphate derivatives of substituted butyl guanines, antiviral compositions containing them, and methods of treating viral infections with them

EP0491793B1|2005-11-30|2'-deoxy-4'-thioribonucleosides as antiviral and anticancer agents

HU196427B|1988-11-28|Process for producing pyrimidine-nukleozide derivatives and pharmaceutical compositions containing them

Shealy et al.1986|Carbocyclic analogs of 5'-amino-5'deoxy-and 3'-amino-3'-deoxythymidines

US3872084A|1975-03-18|Purine nucleoside 3,5-cyclicphosphate compounds

Green et al.1970|The synthesis of oligoribonucleotides—VIII: The preparation of ribonucleoside 2′, 5′-bisketals

同族专利:

公开号 | 公开日

ES530364A0|1985-12-01|

DE19675003I2|2003-05-22|

FI840890A|1984-09-11|

GB2136425A|1984-09-19|

DK162529C|1992-03-30|

EP0122707A1|1984-10-24|

NZ207358A|1987-03-06|

DK190590D0|1990-08-10|

AR243533A1|1993-08-31|

LU88791I2|1996-11-05|

GB2172287B|1987-05-20|

US4692434A|1987-09-08|

GB8610648D0|1986-06-04|

PT78181A|1984-04-01|

JPS59175498A|1984-10-04|

DK190590A|1990-08-10|

AU565856B2|1987-10-01|

CA1223869A|1987-07-07|

US5118820A|1992-06-02|

DE3466224D1|1987-10-22|

JPH06102655B2|1994-12-14|

ES8602840A1|1985-12-01|

AU2537484A|1984-09-13|

JPH0542438B2|1993-06-28|

CY1489A|1989-12-08|

MX9203246A|1992-07-31|

CS246075B2|1986-10-16|

FI77870C|1989-05-10|

FI77870B|1989-01-31|

US4808614A|1989-02-28|

PH23593A|1989-09-11|

PL246601A1|1985-08-13|

PL142437B1|1987-10-31|

HK44989A|1989-06-09|

KR840007883A|1984-12-11|

GB8405805D0|1984-04-11|

EP0122707B1|1987-09-16|

DK114484D0|1984-02-28|

DD216468A5|1984-12-12|

JPH069602A|1994-01-18|

IE57071B1|1992-04-22|

GR81845B|1984-12-12|

PH23240A|1989-06-06|

ZA841605B|1985-10-30|

DK114484A|1984-09-11|

KR860001283B1|1986-09-05|

NL950018I2|1997-03-03|

DK170647B1|1995-11-20|

US5015743A|1991-05-14|

GB2172287A|1986-09-17|

IL71143D0|1984-06-29|

GB2136425B|1987-05-13|

HU193893B|1987-12-28|

AT29726T|1987-10-15|

KE3874A|1989-06-30|

SG21889G|1989-07-14|

US4526988A|1985-07-02|

MY102025A|1992-02-29|

DK162529B|1991-11-11|

IL71143A|1988-07-31|

RO89963A|1986-09-30|

FI840890A0|1984-03-06|

BG40814A3|1987-02-16|

IL80463A|1988-07-31|

UA5955A1|1994-12-29|

IE840584L|1984-09-10|

CA1218647A|1987-03-03|

IL80463D0|1987-01-30|

PT78181B|1986-08-05|

NL950018I1|1995-11-01|

引用文献:

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

US2359208A|1941-03-21|1944-09-26|Lilly Co Eli|beta-substituted-delta alpha,beta-gamma-butyrolactones and beta-substituted-beta-hydroxy-gamma-butyrolactones and the methods of preparing them|

US2359096A|1941-03-21|1944-09-26|Lilly Co Eli|beta-substituted-delta alpha, beta-gamma-butyrolactones and beta-substituted - beta - hydroxy-gamma-butyrolactones and methods of preparing them|

FR1362039A|1963-04-17|1964-05-29|Ct D Etudes Experimentales Et|New process for preparing succinic semi-aldehyde|

US3282921A|1964-06-04|1966-11-01|Syntex Corp|Halo-deoxynucleosides and processes for the preparation thereof|

US3870700A|1973-05-29|1975-03-11|Miles Lab|2-halogeno-2-deoxy-5-uridines|

US4211773A|1978-10-02|1980-07-08|Sloan Kettering Institute For Cancer Research|5-Substituted 1-pyrimidine nucleosides|

US4352795A|1981-01-29|1982-10-05|Warner-Lambert Company|7-β-D-Arabinofuranosyl-7H-pyrrolo[2,3-d]pyrimidine compounds and methods for their production|

FI832884A|1982-08-17|1984-02-18|Sandoz Ag|DESOXYURIDINDERIVAT, DERAS FRAMSTAELLNINGSFOERFARANDEN OCH ANVAENDNING SOM PHARMACEUTISKA MEDEL|

US4526988A|1983-03-10|1985-07-02|Eli Lilly And Company|Difluoro antivirals and intermediate therefor|

US4625020A|1983-11-18|1986-11-25|Bristol-Myers Company|Nucleoside process|

CA1295998C|1985-07-29|1992-02-18|Sai P. Sunkara|Nucleosides and their use as antineoplastic agents|US4526988A|1983-03-10|1985-07-02|Eli Lilly And Company|Difluoro antivirals and intermediate therefor|

DE3587500T2|1984-12-04|1993-12-16|Lilly Co Eli|Tumor treatment in mammals.|

ZA859008B|1984-12-04|1987-07-29|Lilly Co Eli|The treatment of tumors in mammals|

CA1295998C|1985-07-29|1992-02-18|Sai P. Sunkara|Nucleosides and their use as antineoplastic agents|

US4681873A|1985-07-29|1987-07-21|Warner-Lambert Company|4-amino-3-halo-2-pyridinone nucleoside and nucleotide compounds|

US4814438A|1986-12-24|1989-03-21|Eli Lilly And Company|Immunoglobulin conjugates of 2',2'-difluronucleosides|

IL84842D0|1986-12-24|1988-06-30|Lilly Co Eli|Immunoglobulin conjugates|

US4994558A|1986-12-24|1991-02-19|Eli Lilly And Company|Immunoglobulin conjugates|

EP0277599A3|1987-01-30|1990-05-09|Asahi Glass Company Ltd.|Fluorine containing cyclopentane derivatives and processes for their production|

CA1340645C|1987-04-17|1999-07-13|Victor E. Marquez|Acid stable dideoxynucleosides active against the cytopathic effects of human immunodeficiency virus|

US4965374A|1987-08-28|1990-10-23|Eli Lilly And Company|Process for and intermediates of 2',2'-difluoronucleosides|

DE3856158T2|1987-08-28|1998-08-20|Lilly Co Eli|Process for the preparation of intermediates useful in the preparation of 2 ', 2'-difluoronucleosides|

US5223608A|1987-08-28|1993-06-29|Eli Lilly And Company|Process for and intermediates of 2',2'-difluoronucleosides|

US4914028A|1988-02-10|1990-04-03|Eli Lilly And Company|Method of preparing beta-2',2'-difluoronucleosides|

US4983724A|1988-02-16|1991-01-08|Eli Lilly And Company|Inversion of 2,2-difluororibose to a 2,2-difluoroxylose and intermediates therefor|

US5644043A|1988-02-16|1997-07-01|Eli Lilly And Company|2',3'-dideoxy-2',2'-difluoronucleosides and intermediates|

ES2075040T3|1988-02-16|1995-10-01|Lilly Co Eli|2 ', 3'-DIDEOXI-2', 2'-DIFLUORONUCLEOSIDES.|

EP0364559B1|1988-03-16|1995-09-20|The Scripps Research Institute|Substituted adenine derivatives useful as therapeutic agents|

US5057301A|1988-04-06|1991-10-15|Neorx Corporation|Modified cellular substrates used as linkers for increased cell retention of diagnostic and therapeutic agents|

US4987224A|1988-08-02|1991-01-22|University Of Georgia Research Foundation, Inc.|Method of preparation of 2',3'-dideoxynucleosides|

US5157114A|1988-08-19|1992-10-20|Burroughs Wellcome Co.|2',3'-dideoxy-3'-fluoro-5-ethyngluridine|

US4954623A|1989-03-20|1990-09-04|Eli Lilly And Company|Recovery of difluoro sugar|

CA2012129A1|1989-03-20|1990-09-20|Ramakrishnan Nagarajan|Recovery of difluoro sugar|

US5426183A|1992-06-22|1995-06-20|Eli Lilly And Company|Catalytic stereoselective glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides|

US5256797A|1992-06-22|1993-10-26|Eli Lilly And Company|Process for separating 2-deoxy-2,2-difluoro-D-ribofuranosyl alkylsulfonate anomers|

YU43193A|1992-06-22|1997-01-08|Eli Lilly And Company|2'-DEOXY-2 ', 2'-DIFLUOROPYRIMIDINE NUCLEOSIDS OF ANTIVIRUS AND ANTICANCEROGENIC ACTIVITY AND INTERMEDIATES|

US5371210A|1992-06-22|1994-12-06|Eli Lilly And Company|Stereoselective fusion glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides|

US5256798A|1992-06-22|1993-10-26|Eli Lilly And Company|Process for preparing alpha-anomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl sulfonates|

CZ123493A3|1992-06-22|1994-02-16|Lilly Co Eli|Stereoselective anionic glycosylation process|

US5594124A|1992-06-22|1997-01-14|Eli Lilly And Company|Stereoselective glycosylation process for preparing 2'-Deoxy-2',2'-difluoropyrimidine nucleosides and 2'-deoxy-2'-fluoropyrimidine nucleosides and intermediates thereof|

US5401838A|1992-06-22|1995-03-28|Eli Lilly And Company|Stereoselective fusion glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides|

US5401861A|1992-06-22|1995-03-28|Eli Lilly And Company|Low temperature process for preparing alpha-anomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl sulfonates|

ES2103433T3|1992-06-22|1997-09-16|Lilly Co Eli|PROCEDURE FOR PREPARING DERIVATIVES OF 1-HALO-2-DESOXI-2,2-DIFLUORO-D-RIBOFURANOSILO ENRICHED IN ALPHA ANOMEROUS.|

US5821357A|1992-06-22|1998-10-13|Eli Lilly And Company|Stereoselective glycosylation process for preparing 2'-deoxy-2',2'-difluoropurine and triazole nucleosides|

US5252756A|1992-06-22|1993-10-12|Eli Lilly And Company|Process for preparing beta-anomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl-arylsulfonates|

US5606048A|1992-06-22|1997-02-25|Eli Lilly And Company|Stereoselective glycosylation process for preparing 2'-Deoxy-2', 2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides|

US5424416A|1993-08-25|1995-06-13|Eli Lilly And Company|Process for preparation of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-hydroxy protected-1-alkyl and aryl sulfonates and their use in preparation of 2',2'-difluoro-2'-deoxy nucleosides|

US5480992A|1993-09-16|1996-01-02|Eli Lilly And Company|Anomeric fluororibosyl amines|

US5428176A|1994-04-14|1995-06-27|Eli Lilly And Company|Process for preparing 2,2-difluoroketene silyl O,S-acetals and α,α-difluoro-β-silyloxy-1,3-dioxolane-4-propanoic acid O,S-esters|

US5637688A|1994-12-13|1997-06-10|Eli Lilly And Company|Process for preparing 1--4-aminopyrimidin-2-one hydrochloride|

US5521294A|1995-01-18|1996-05-28|Eli Lilly And Company|2,2-difluoro-3-carbamoyl ribose sulfonate compounds and process for the preparation of beta nucleosides|

US5559222A|1995-02-03|1996-09-24|Eli Lilly And Company|Preparation of 1--cytosine from 2-deoxy-2,2-difluoro-β-D-ribo-pentopyranose|

US5633367A|1995-03-24|1997-05-27|Eli Lilly And Company|Process for the preparation of a 2-substituted 3,3-difluorofuran|

CA2171518A1|1995-03-24|1996-09-25|Douglas Patton Kjell|Process for the preparation of 2,2'-anhydro- and 2' -keto-1- nucleosides|

EP0779275A3|1995-12-13|1997-09-03|Lilly Co Eli|

US5756775A|1995-12-13|1998-05-26|Eli Lilly And Company|Process to make α,α-difluoro-β-hydroxyl thiol esters|

US6001994A|1995-12-13|1999-12-14|Eli Lilly And Company|Process for making gemcitabine hydrochloride|

US5808020A|1996-08-12|1998-09-15|Associated Universities, Inc.|Optical reaction cell and light source for18F! fluoride radiotracer synthesis|

US6013790A|1996-09-25|2000-01-11|Board Of Regents University Of Nebraska-Lincoln|Heavily fluorinated sugar analogs|

EP0994715A4|1997-03-24|2001-08-08|Lilly Co Eli|Difluoronucleoside phosphonic acids and derivatives thereof|

KR100965488B1|1998-02-25|2010-06-24|에모리 유니버시티|2'-Fluoronucleosides|

TW466112B|1998-04-14|2001-12-01|Lilly Co Eli|Novel use of 2'-deoxy-2',2'-difluorocytidine for immunosuppressive therapy and pharmaceutical composition comprising the same|

US6326507B1|1998-06-19|2001-12-04|Trustees Of Dartmouth College|Therapeutic compounds and methods of use|

US20030008841A1|2000-08-30|2003-01-09|Rene Devos|Anti-HCV nucleoside derivatives|

EP1506962B1|2000-10-20|2008-07-02|Eisai R&D Management Co., Ltd.|Nitrogen-containing aromatic heterocycles|

US7435755B2|2000-11-28|2008-10-14|The Trustees Of Dartmouth College|CDDO-compounds and combination therapies thereof|

US8481712B2|2001-01-22|2013-07-09|Merck Sharp & Dohme Corp.|Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase|

WO2003059334A2|2001-10-25|2003-07-24|Eli Lilly And Company|Gemcitabine in the treatment of smallpox|

US7176237B2|2002-01-15|2007-02-13|The Trustees Of Dartmouth College|Tricyclic-bis-enone derivatives and methods of use thereof|

CN1646534A|2002-02-14|2005-07-27|法玛塞特有限公司|Modified fluorinated nucleoside analogues|

US20060034943A1|2003-10-31|2006-02-16|Technology Innovations Llc|Process for treating a biological organism|

US20050249667A1|2004-03-24|2005-11-10|Tuszynski Jack A|Process for treating a biological organism|

US7994159B2|2003-03-10|2011-08-09|Eisai R&D Management Co., Ltd.|c-Kit kinase inhibitor|

CA2525952A1|2003-05-20|2004-12-09|Aronex Pharmaceuticals, Inc.|Combination chemotherapy comprising gemcitabine and a liposomal platinum complex|

CA2525973A1|2003-05-20|2004-12-09|Aronex Pharmaceuticals, Inc.|Combination chemotherapy comprising capecitabine and a liposomal platinum complex|

EP2345661A1|2003-05-30|2011-07-20|Pharmasset, Inc.|Modified fluorinated nucleoside analogues|

CN100450998C|2003-11-11|2009-01-14|卫材R&D管理有限公司|Urea derivative and process for producing the same|

NZ549605A|2004-02-06|2010-01-29|Threshold Pharmaceuticals Inc|Use of glufosfamide to treat chemotherapy-refractory pancreatic cancer|

WO2005087808A2|2004-03-05|2005-09-22|Ludwig Institute For Cancer Research|Growth factor binding constructs materials and methods|

CN101023094B|2004-07-21|2011-05-18|法莫赛特股份有限公司|Preparation of alkyl-substituted 2-deoxy-2-fluoro-d-ribofuranosyl pyrimidines and purines and their derivatives|

KR101236669B1|2004-07-21|2013-02-22|길리어드 파마셋 엘엘씨|Preparation of alkyl-substituted 2-deoxy-2-fluoro-d-ribofuranosyl pyrimidines and purines and their derivatives|

KR100578616B1|2004-07-23|2006-05-10|한미약품 주식회사|Method for the preparation of d-erythro-2,2-difluoro-2-deoxy-1-oxoribose|

CA2574954C|2004-07-29|2010-04-20|Hanmi Pharm. Co., Ltd.|1-.alpha.-halo-2,2-difluoro-2-deoxy-d-ribofuranose derivatives and process for the preparation thereof|

TW200606159A|2004-07-30|2006-02-16|Pharmaessentia Corp|Stereoselective synthesis of β-nucleosides|

SG158136A1|2004-09-14|2010-01-29|Pharmasset Inc|Preparation of 2`-fluoro-2`- alkyl- substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives|

ES2322175T3|2004-09-17|2009-06-17|EISAI R&D MANAGEMENT CO., LTD.|MEDICINAL COMPOSITION WITH IMPROVED STABILITY AND REDUCED GELIFICATION.|

US20060089328A1|2004-10-22|2006-04-27|Edgar Schridde|Ready-to-use gemcitabine solutions|

US7563570B2|2004-10-29|2009-07-21|Pangaea Biotech|Method of determining a chemotherapeutic regimen for non small cell lung cancer based on BRCA1 expression|

TW200634022A|2004-12-08|2006-10-01|Sicor Inc|Difluoronucleosides and process for preparation thereof|

PL1831237T3|2004-12-17|2009-01-30|Lilly Co Eli|Amide prodrug of gemcitabine, compositions and use thereof|

KR101345002B1|2005-01-21|2013-12-31|아스텍스 테라퓨틱스 리미티드|Pharmaceutical compounds|

WO2006119347A1|2005-05-02|2006-11-09|Pharmaessentia Corp.|STEREOSELECTIVE SYNTHESIS OF β-NUCLEOSIDES|

EP1891087A4|2005-06-03|2008-07-30|Scinopharm Taiwan Ltd|Process of making an alpha-anomer enriched 2-deoxy-2,2-diflouro-d-ribofuranosyl sulfonate and use thereof for making a beta nucleoside|

AU2011202539B2|2005-06-03|2012-07-05|Scinopharm Taiwan, Ltd.|Process of making an alpha-anomer enriched 2-deoxy-2,2-difluoro-d-ribofuranosyl sulfonate and use thereof for making a beta nucleoside|

RU2447889C2|2005-07-18|2012-04-20|Бипар Сайенсиз, Инк.|Method of treating cancer |

US20100160442A1|2006-07-18|2010-06-24|Ossovskaya Valeria S|Formulations for cancer treatment|

AT502221A1|2005-07-20|2007-02-15|Pharmacon Forschung & Beratung Gmbh|HOMOGEMIC CITABINE, PROCESS FOR THEIR PRODUCTION AND THEIR USE|

US20100105031A1|2005-08-01|2010-04-29|Esai R & D Management Co., Ltd.|Method for prediction of the efficacy of vascularization inhibitor|

US9006240B2|2005-08-02|2015-04-14|Eisai R&D Management Co., Ltd.|Method for assay on the effect of vascularization inhibitor|

WO2007015257A2|2005-08-04|2007-02-08|Hetero Drugs Limited|A process for the preparation of gemcitabine using novel intermediates|

CN101277720A|2005-09-01|2008-10-01|卫材R&D管理有限公司|Method for preparation of pharmaceutical composition having improved disintegradability|

WO2007049294A1|2005-10-28|2007-05-03|Arch Pharmalabs Limited|An improved process for preparation of gemcitabine hydrochloride.|

US20090053236A1|2005-11-07|2009-02-26|Eisai R & D Management Co., Ltd.|USE OF COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND c-kit KINASE INHIBITOR|

EP1964837A4|2005-11-22|2010-12-22|Eisai R&D Man Co Ltd|Anti-tumor agent for multiple myeloma|

KR101259648B1|2005-12-14|2013-05-09|동아에스티 주식회사|A manufacturing process of 2′,2′-difluoronucloside and intermediate|

AU2007235210A1|2006-02-06|2007-10-18|Dr. Reddy's Laboratories Ltd.|Preparation of gemcitabine|

JP2009526782A|2006-02-07|2009-07-23|ケマジス・リミテッド|Method for producing gemcitabine and related intermediates|

US20070249823A1|2006-04-20|2007-10-25|Chemagis Ltd.|Process for preparing gemcitabine and associated intermediates|

EP2036557B1|2006-05-18|2015-10-21|Eisai R&D Management Co., Ltd.|Antitumor agent for thyroid cancer|

WO2008001956A1|2006-06-29|2008-01-03|Eisai R & D Management Co., Ltd.|Therapeutic agent for liver fibrosis|

KR100741310B1|2006-08-01|2007-08-01| 유일팜테크|Naphthalene 2-carboxylate derivative useful for synthesizing gemcitabine and a method for preparing the same|

US8865737B2|2006-08-28|2014-10-21|Eisai R&D Management Co., Ltd.|Antitumor agent for undifferentiated gastric cancer|

US20080161324A1|2006-09-14|2008-07-03|Johansen Lisa M|Compositions and methods for treatment of viral diseases|

US8883790B2|2006-10-12|2014-11-11|Astex Therapeutics Limited|Pharmaceutical combinations|

WO2008044041A1|2006-10-12|2008-04-17|Astex Therapeutics Limited|Pharmaceutical combinations|

MX2009003938A|2006-10-27|2009-04-24|Genentech Inc|Antibodies and immunoconjugates and uses therefor.|

CA2670099A1|2006-11-17|2008-05-29|Trustees Of Dartmouth College|Synthesis and biological activities of new tricyclic-bis-enones |

US8921340B2|2006-11-17|2014-12-30|Trustees Of Dartmouth College|Methods for using synthetic triterpenoids in the treatment of bone or cartilage diseases or conditions|

US8299046B2|2006-11-17|2012-10-30|Trustees Of Dartmouth College|Synthetic triterpenoids and tricyclic-bis-enones for use in stimulating bone and cartilage growth|

CN101616671A|2007-01-19|2009-12-30|卫材R&D管理有限公司|Composition for treatment of pancreatic cancer|

CA2676796C|2007-01-29|2016-02-23|Eisai R & D Management Co., Ltd.|Composition for treatment of undifferentiated gastric cancer|

WO2008117955A1|2007-03-23|2008-10-02|Dongwoo Syntech Co., Ltd.|Process for preparing of 2'-deoxy-2'2'-difluorocytidine|

CN101024667B|2007-03-30|2011-01-26|湖北益泰药业有限公司|Method for preparing gemcitabine hydrochloride|

US7964580B2|2007-03-30|2011-06-21|Pharmasset, Inc.|Nucleoside phosphoramidate prodrugs|

WO2008124691A1|2007-04-05|2008-10-16|Threshold Pharmaceuticals, Inc.|Glufosfamide combination therapy|

US20080262215A1|2007-04-23|2008-10-23|Chemagis Ltd.|Gemcitabine production process|

CN100475832C|2007-05-31|2009-04-08|南京卡文迪许生物工程技术有限公司|Novel highly-solid selectively synthesizing gemcitabine process and intermediate|

US20090162288A1|2007-07-18|2009-06-25|Nanhai Chen|Use of modified vaccinia virus strains in combination with a chemotherapeutic agent for use in therapeutic methods|

US20090048205A1|2007-08-15|2009-02-19|Colin Meyer|Combination therapy with synthetic triterpenoids and gemcitabine|

US20090069354A1|2007-09-12|2009-03-12|Protia, Llc|Deuterium-enriched gemcitabine|

WO2009042064A2|2007-09-21|2009-04-02|Nektar Therapeutics Al, Corporation|Oligomer-nucleoside phosphate conjugates|

JP4253357B1|2007-09-27|2009-04-08|株式会社湯山製作所|Hand-made medicine supply device, medicine hand-making method, and medicine packaging device|

JO2778B1|2007-10-16|2014-03-15|ايساي انك|Certain Compounds, Compositions and Methods|

US8952035B2|2007-11-09|2015-02-10|Eisai R&D Management Co., Ltd.|Combination of anti-angiogenic substance and anti-tumor platinum complex|

DK2219672T3|2007-11-09|2016-05-17|Peregrine Pharmaceuticals Inc|The anti-VEGF antibody compositions and methods|

CA2705417A1|2007-11-12|2009-05-22|Bipar Sciences, Inc.|Treatment of uterine cancer and ovarian cancer with a parp inhibitor alone or in combination with anti-tumor agents|

WO2009096377A1|2008-01-29|2009-08-06|Eisai R & D Management Co., Ltd.|Combined use of angiogenesis inhibitor and taxane|

PT2271658T|2008-04-18|2017-02-13|Reata Pharmaceuticals Inc|Antioxidant inflammation modulators: c-17 homologated oleanolic acid derivatives|

WO2009129545A1|2008-04-18|2009-10-22|Reata Pharmaceuticals, Inc.|Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the c-ring|

US8071632B2|2008-04-18|2011-12-06|Reata Pharmaceuticals, Inc.|Antioxidant inflammation modulators: novel derivatives of oleanolic acid|

DK2276493T3|2008-04-18|2019-01-02|Reata Pharmaceuticals Inc|ANTIOXIDATIVE INFLAMMATION MODULATORS: OLEANOLIC ACID DERIVATIVES WITH AMINO AND OTHER MODIFICATIONS BY C-17|

NZ588708A|2008-04-18|2012-09-28|Reata Pharmaceuticals Inc|2-cyano steroid derivatives including an anti-inflammatory pharmacore|

US8173621B2|2008-06-11|2012-05-08|Gilead Pharmasset Llc|Nucleoside cyclicphosphates|

EP2303906B1|2008-06-12|2016-06-08|ScinoPharm Taiwan, Ltd.|Crystalline polymorphs of gemcitabine base|

JP5758801B2|2008-07-22|2015-08-05|トラスティーズ・オブ・ダートマス・カレッジＴｒｕｓｔｅｅｓｏｆＤａｒｔｍｏｕｔｈＣｏｌｌｅｇｅ|Monocyclic cyanoenone and description of how to use it|

US20110207680A1|2008-08-13|2011-08-25|Curd John G|Administration of Glufosfamide For The Treatment of Cancer|

WO2010049947A2|2008-10-28|2010-05-06|Accrete Pharmaceutical Private Limited|Preparation of gemcitabine and intermediates thereof|

SG172359A1|2008-12-23|2011-07-28|Pharmasset Inc|Nucleoside phosphoramidates|

KR20110104074A|2008-12-23|2011-09-21|파마셋 인코포레이티드|Synthesis of purine nucleosides|

TW201026716A|2008-12-23|2010-07-16|Pharmasset Inc|Nucleoside analogs|

US8609631B2|2009-04-06|2013-12-17|Eisai Inc.|Compositions and methods for treating cancer|

EP2416781B1|2009-04-06|2017-03-08|Otsuka Pharmaceutical Co., Ltd.|Combination of cytidine-based antineoplastic drugs with cytidine deaminase inhibitor and use thereof in the treatment of cancer|

AU2010234641B2|2009-04-06|2016-04-21|Otsuka Pharmaceutical Co., Ltd.|Combination of decitabine with cytidine deaminase inhibitor and use thereof in the treatment of cancer|

AU2010234637B2|2009-04-06|2016-05-12|Otsuka Pharmaceutical Co., Ltd.| -1,3,4, 7-tetrahydro-iazepin-2-0ne derivatives for treating cancer|

US20100273730A1|2009-04-27|2010-10-28|Innopharmax, Inc.|Self-emulsifying pharmaceutical compositions of hydrophilic drugs and preparation thereof|

GB0907551D0|2009-05-01|2009-06-10|Univ Dundee|Treatment or prophylaxis of proliferative conditions|

NZ603232A|2010-03-31|2015-02-27|Gilead Pharmasset Llc|Nucleoside phosphoramidates|

US8618076B2|2009-05-20|2013-12-31|Gilead Pharmasset Llc|Nucleoside phosphoramidates|

WO2011016049A2|2009-07-31|2011-02-10|Astron Research Limited|A stable composition of ready-to-use gemcitabine injection|

EP2473041B1|2009-09-04|2018-03-07|Merck Sharp & Dohme Corp.|Modulators of cell cycle checkpoints and their use in combination with checkpoint kinase inhibitors|

EP2536720A1|2010-02-18|2012-12-26|Centro Nacional de Investigaciones Oncológicas |Triazolo [4, 5 - b]pyridin derivatives|

EP2547359B1|2010-03-15|2016-03-09|The Board of Trustees of the University of Illionis|Inhibitors of beta integrin-g protein alpha subunit binding interactions|

US8563530B2|2010-03-31|2013-10-22|Gilead Pharmassel LLC|Purine nucleoside phosphoramidate|

WO2011143590A1|2010-05-14|2011-11-17|Cornerstone Pharmaceuticals, Inc.|Combination therapy compositions and methods using lipoic acid derivatives and an anti-proliferation agent|

WO2011143593A1|2010-05-14|2011-11-17|Cornerstone Pharmaceuticals, Inc.|Conjugates of a lipoic acid derivative and anti-proliferation agent and medical uses thereof|

EP2586443B1|2010-06-25|2016-03-16|Eisai R&D Management Co., Ltd.|Antitumor agent using compounds having kinase inhibitory effect in combination|

JP6012605B2|2010-09-22|2016-10-25|アリオスバイオファーマインク．|Substituted nucleotide analogs|

WO2012069972A1|2010-11-19|2012-05-31|Piramal Life Sciences Limited|A pharmaceutical combination for the treatment of breast cancer|

WO2012075140A1|2010-11-30|2012-06-07|Pharmasset, Inc.|Compounds|

US9029502B2|2010-12-20|2015-05-12|The Regents Of The University Of Michigan|Inhibitors of the epidermal growth factor receptor-heat shock protein 90 binding interaction|

CN102153602B|2011-02-24|2013-11-06|中国农业大学|Furanosyl modified 1,3,4-thiadiazole derivative and preparation method thereof as well as application of derivative as bactericide|

CN102153601A|2011-02-26|2011-08-17|湖南欧亚生物有限公司|Method for preparing gemcitabine hydrochloride and intermediate thereof with high selectivity|

WO2012123889A1|2011-03-14|2012-09-20|Piramal Healthcare Limited|A synergistic pharmaceutical combination for the treatment of pancreatic cancer|

US9150548B2|2011-04-01|2015-10-06|Genentech, Inc.|Combinations of AKT inhibitor compounds and vemurafenib, and methods of use|

US9150603B2|2011-04-13|2015-10-06|Merck Sharp & Dohme Corp.|2′-cyano substituted nucleoside derivatives and methods of use thereof useful for the treatment of viral diseases|

US9061041B2|2011-04-13|2015-06-23|Merck Sharp & Dohme Corp.|2′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases|

EP2697242B1|2011-04-13|2018-10-03|Merck Sharp & Dohme Corp.|2'-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases|

KR101762999B1|2011-04-18|2017-07-28|에자이 알앤드디 매니지먼트 가부시키가이샤|Therapeutic agent for tumor|

EP3444363B1|2011-06-03|2020-11-25|Eisai R&D Management Co., Ltd.|Biomarkers for prediciting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds|

CN102453064B|2011-06-30|2014-07-09|江苏豪森药业股份有限公司|Method for preparing Gemcitabine hydrochloride|

US9408863B2|2011-07-13|2016-08-09|Merck Sharp & Dohme Corp.|5′-substituted nucleoside analogs and methods of use thereof for the treatment of viral diseases|

EP2731434A4|2011-07-13|2014-12-31|Merck Sharp & Dohme|5'-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases|

US8889159B2|2011-11-29|2014-11-18|Gilead Pharmasset Llc|Compositions and methods for treating hepatitis C virus|

EP2750683B2|2011-10-03|2021-01-06|Croda International PLC|Nanoparticles, process for preparation and use thereof as carrier for amphipatic of hydrophobic molecules in fields of medicine including cancer treatment and food related compounds|

CN102417533A|2011-10-28|2012-04-18|江苏正大清江制药有限公司|Synthesis method of gemcitabine hydrochloride|

NO2755614T3|2012-01-03|2018-03-31|

NZ631601A|2012-03-21|2016-06-24|Alios Biopharma Inc|Solid forms of a thiophosphoramidate nucleotide prodrug|

US9012427B2|2012-03-22|2015-04-21|Alios Biopharma, Inc.|Pharmaceutical combinations comprising a thionucleotide analog|

PL2833905T3|2012-04-04|2019-01-31|Halozyme, Inc.|Combination therapy with hyaluronidase and a tumor-targeted taxane|

US8921419B2|2012-05-08|2014-12-30|Trustees Of Dartmouth College|Triterpenoids and compositions containing the same|

WO2013177219A1|2012-05-22|2013-11-28|Idenix Pharmaceuticals, Inc.|D-amino acid compounds for liver disease|

EP2711009A1|2012-09-19|2014-03-26|Institut Univ. de Ciència i Tecnologia, S.A.|Compounds for use in treating or preventing primary and metastatic breast and prostate cancer|

EP2711007A1|2012-09-19|2014-03-26|Institut Univ. de Ciència i Tecnologia, S.A.|4-Aminopyrazolo[3,4-d]pyrimidine for use in treating or preventing primary and metastatic breast and prostate cancer|

EP2711008A1|2012-09-19|2014-03-26|Institut Univ. de Ciència i Tecnologia, S.A.|N6,N6-dimethyladenosine for use in treating or preventing primary and metastatic breast cancer|

AP2015008384A0|2012-10-08|2015-04-30|Univ Montpellier Ct Nat De La Rech Scient|2'-Chloro nucleoside analogs for hcv infection|

US9334239B2|2012-12-21|2016-05-10|Eisai R&D Management Co., Ltd.|Amorphous form of quinoline derivative, and method for producing same|

AR095962A1|2013-04-01|2015-11-25|Moreinx Ab|NANOPARTICLES, STEROL AND SAPONINE COMPOUNDS OF QUILLAJA SAPONARIA MOLINA, PROCESS FOR PREPARATION AND USE OF THE SAME AS CARRIERS FOR AMPHIPATHIC OR HYDROPHOBLE MOLECULES IN THE FIELD OF THE MEDICINE INCLUDING CANCER TREATMENT AND COMPOUNDING|

RU2658601C2|2013-05-14|2018-06-21|Эйсай Ар Энд Ди Менеджмент Ко., Лтд.|Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds|

JP6476591B2|2013-06-05|2019-03-06|セントラル硝子株式会社|Process for producing-2-fluoro-2-C-methyl-D-ribono-γ-lactones|

US20160324885A1|2013-07-10|2016-11-10|Asteriapharma Gmbh|Composition containing modified derivatives of a cytidine antimetabolite for the treatment of susceptible disease|

CN105792845A|2013-07-26|2016-07-20|施瑞修德制药公司|Treatment of pancreatic cancer with a combination of a hypoxia-activated prodrug and a taxane|

MX2016002185A|2013-08-27|2016-06-06|Gilead Pharmasset Llc|Combination formulation of two antiviral compounds.|

EP3063164B1|2013-10-29|2018-12-05|Otsuka Pharmaceutical Co., Ltd.|Synthetic route to 2'-deoxy-2',2'-difluorotetrahydrouridines|

US10080807B2|2014-06-09|2018-09-25|Lipomedix Pharmaceuticals Ltd.|Combination chemotherapy comprising a liposomal prodrug of mitomycin C|

JP2018506301A|2015-01-26|2018-03-08|ザユニバーシティーオブシカゴ|IL13Rα2 binding agents and their use in cancer therapy|

WO2016123143A1|2015-01-26|2016-08-04|The University Of Chicago|CAR T-CELLS RECOGNIZING CANCER-SPECIFIC IL 13Rα2|

JP6792546B2|2015-02-25|2020-11-25|エーザイ・アール・アンド・ディー・マネジメント株式会社|How to suppress bitterness of quinoline derivatives|

CN107295800A|2015-02-25|2017-10-24|配体药物公司|Gemcitabine derivative|

WO2017040766A1|2015-09-02|2017-03-09|Abbvie Inc.|Anti-viral tetrahydrofurane derivatives|

MX2018004137A|2015-10-05|2018-06-13|NuCana plc|Combination therapy.|

AU2017233898A1|2016-03-15|2018-11-01|Oryzon Genomics, S.A.|Combinations of LSD1 inhibitors for use in the treatment of solid tumors|

US11246905B2|2016-08-15|2022-02-15|President And Fellows Of Harvard College|Treating infections using IdsD from Proteus mirabilis|

WO2018094406A1|2016-11-21|2018-05-24|Bexion Pharmaceuticals, Inc.|A combination therapy including sapc-dops for the treatment of pancreatic cancer|

EP3565549B1|2017-01-09|2022-03-09|Shuttle Pharmaceuticals, Inc.|Selective histone deacetylase inhibitors for the treatment of human disease|

EP3606963A1|2017-04-03|2020-02-12|H. Hoffnabb-La Roche Ag|Antibodies binding to steap-1|

BR112019022470A2|2017-04-26|2020-05-12|I. Kalman Thomas|COMPOUND, COMPOSITION, AND, METHOD FOR TREATING AN INDIVIDUAL WITH CANCER.|

TW201912173A|2017-08-07|2019-04-01|美商安進公司|Treatment of triple-negative breast cancer or colorectal cancer with liver metastasis|

US10435429B2|2017-10-03|2019-10-08|Nucorion Pharmaceuticals, Inc.|5-fluorouridine monophosphate cyclic triester compounds|

TW202002952A|2018-03-15|2020-01-16|美商艾伯維有限公司|ABBV-621 in combination with anti-cancer agents for the treatment of pancreatic cancer|

US20190351031A1|2018-05-16|2019-11-21|Halozyme, Inc.|Methods of selecting subjects for combination cancer therapy with a polymer-conjugated soluble ph20|

WO2020044252A1|2018-08-31|2020-03-05|Novartis Ag|Dosage regimes for anti-m-csf antibodies and uses thereof|

EP3669890A1|2018-12-18|2020-06-24|Croda International PLC|Filamentous nanoparticles having vaccine adjuvant effect|

CN113453668A|2019-01-11|2021-09-28|利普麦迪克斯制药有限公司|Liposome composition containing liposome prodrug of mitomycin C and preparation method thereof|

WO2020222668A1|2019-04-30|2020-11-05|Instituto de Medicina Molecular João Lobo Antunes|Rank pathway inhibitors in combination with cdk inhibitors|

CA3140904A1|2019-06-24|2020-12-30|Amgen Inc.|Inhibition of sirp-gamma for cancer treatment|

WO2021209563A1|2020-04-16|2021-10-21|Som Innovation Biotech, S.A.|Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus|

法律状态:

优先权:

申请号 | 申请日 | 专利标题

US06/473,883|US4526988A|1983-03-10|1983-03-10|Difluoro antivirals and intermediate therefor|

[返回顶部]