CN105254695A - Nucleoside phosphoramidate ramification and application thereof - Google Patents
Nucleoside phosphoramidate ramification and application thereof Download PDFInfo
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Oc1ccccc1 Chemical compound Oc1ccccc1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- QDQVXVRZVCTVHE-YFKPBYRVSA-N CC(C)OC([C@H](C)N)=O Chemical compound CC(C)OC([C@H](C)N)=O QDQVXVRZVCTVHE-YFKPBYRVSA-N 0.000 description 1
- VJHHGWFJYRMRNH-LURJTMIESA-N CC(C)OC([C@H](C)N=C)=O Chemical compound CC(C)OC([C@H](C)N=C)=O VJHHGWFJYRMRNH-LURJTMIESA-N 0.000 description 1
- 0 CC1(C(N(C=CC(N2)=O)C2=O)OC(COP(C)=[Cn])C1OC(C(Cc1c[nH]c2ccccc12)N)=O)F Chemical compound CC1(C(N(C=CC(N2)=O)C2=O)OC(COP(C)=[Cn])C1OC(C(Cc1c[nH]c2ccccc12)N)=O)F 0.000 description 1
- WZXCFKOUZAEMAJ-FMZQPVNHSA-N C[C@@H](C(O[C@H]([C@@H](COc1ccccc1)O[C@H]1N(C=CC(N2)=O)C2=O)[C@@]1(C)F)=O)NC(OCc1ccccc1)=O Chemical compound C[C@@H](C(O[C@H]([C@@H](COc1ccccc1)O[C@H]1N(C=CC(N2)=O)C2=O)[C@@]1(C)F)=O)NC(OCc1ccccc1)=O WZXCFKOUZAEMAJ-FMZQPVNHSA-N 0.000 description 1
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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Abstract
The invention provides a nucleoside phosphoramidate ramification and application thereof. The nucleoside phosphoramidate ramification is specifically taken as the compound with formula I or pharmacy acceptable acidic salt, solvate or aquo-complex thereof, wherein R1 is C1-4 alkyl group; R2 is the phenyl group or naphthyl capable of being arbitrarily replaced and the substituent group is selected from C1-4 alkyl group and C1-4 alkoxy; R3 is acylamino acid or polypeptide acyl group. The compound provided by the invention can be used for preparing the medicines for preventing or treating the infectious diseases of mammals, especially the medicines for preventing or treating hepatitis c, cirrhosis and liver cancer. The formula I is as shown in the specification.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, more particularly, relate to a kind of novel nucleoside phosphoramidate derivative, the acceptable acid salt of pharmacy, solvate or hydrate, and they for the preparation of mammalian infections disease, prevention or treatment hepatitis C, liver cirrhosis, liver cancer medicine in purposes.
Background technology
It is serious health problem that hepatitis C virus (HCV) infects, and it causes chronic hepatic diseases in a large amount of infected individual, and then develops into liver cirrhosis and liver cancer.According to World Health Organization's statistics, there is the infected individual more than 200,000,000 in the whole world, has at least 3 to 4 million peoples infected every year.Once after infected, the people of about 20% can remove this virus, but remaining people may carry HCV in their remaining years.The chronic infection individuality of 10% to 20% finally develops into the destructive sclerosis of liver or cancer.The current medicine for HCV infection has recombinant interferon, separately or the therapy combined with nucleoside analogue ribavirin and the sofosbuvir of Gerald listing.And sofosbuvir has nearly 90% metabolism in vivo for not having activated meta-bolites.Therefore, bioavailability is high, and liver selective is good, and the HCV infection medicine that drug effect is high is still clinical active demand.
Summary of the invention
The object of this invention is to provide a kind of novel nucleoside phosphoramidate derivative with resisting mammal viral infection activity.
Second object of the present invention is to provide the pharmaceutical composition comprising above-mentioned nucleoside phosphoramidate derivative.
3rd object of the present invention is to provide above-mentioned nucleoside phosphoramidate derivative or pharmaceutical composition is preventing or in treatment mammalian infections disease, particularly preventing or treat the purposes of hepatitis C, liver cirrhosis, liver cancer relative disease aspect.
Specifically, the invention provides a kind of nucleoside phosphoramidate derivative, as the compound of general formula I, or its pharmaceutically acceptable acid salt, solvate or hydrate:
Wherein:
R
1for C
1 ~ 4alkyl;
R
2for the phenyl or naphthyl replaced arbitrarily, its substituting group is selected from C
1 ~ 4alkyl, C
1 ~ 4alkoxyl group;
R
3for amino acid acyl or polypeptide acyl group.
In a kind of preferred embodiment of the present invention, the R in formula I
1for methyl, ethyl or sec.-propyl; Preferred sec.-propyl further.
In a kind of preferred embodiment of the present invention, the R in formula I
2for phenyl or naphthyl; Preferred phenyl further.
In a kind of preferred embodiment of the present invention, the R in formula I
3for natural amino acid acyl group, alpha-non-natural amino acid acyl group or two acyltransferase polypeptides.
In a kind of preferred embodiment of the present invention, the R in formula I
3for natural amino acid acyl group.
In a kind of preferred embodiment of the present invention, the R in formula I
3for glycyl, alanyl, valyl, leucyl, isoleucyl, phenylalanyl, tryptophyl, tyrosyl, aspartyl, asparagyl, glutamyl, glutaminyl, lysyl, methionyl, seryl, Threonyl, cysteinyl, prolyl, histidyl or arginyl.
In a kind of preferred embodiment of the present invention, the R in formula I
1for methyl, ethyl or sec.-propyl; R
2for phenyl or naphthyl; R
3for glycyl, alanyl, valyl, leucyl, isoleucyl, phenylalanyl, tryptophyl, tyrosyl, aspartyl, asparagyl, glutamyl, glutaminyl, lysyl, methionyl, seryl, Threonyl, cysteinyl, prolyl, histidyl, arginyl.
In a kind of more preferred of the present invention, the R in formula I
1for sec.-propyl; R
2for phenyl; R
3for glycyl, alanyl, valyl, leucyl, isoleucyl, phenylalanyl, tryptophyl, tyrosyl, aspartyl, asparagyl, glutamyl, glutaminyl, lysyl, methionyl, seryl, Threonyl, cysteinyl, prolyl, histidyl, arginyl.
In particularly preferred embodiment of the present invention, compound provided by the invention is selected from the one in following compound, or its pharmaceutically acceptable acid salt, solvate or hydrate:
in embodiments of the invention, described derivative provided by the invention comprises enantiomer and the racemic modification of formula I.
In embodiments of the invention, derivative of the present invention comprises formula I or its pharmaceutically acceptable acid salt, includes but not limited to the salt that compound and following acid are formed: hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, citric acid, tartrate, phosphoric acid, lactic acid, acetic acid, toxilic acid, fumaric acid, oxysuccinic acid, tussol, methylsulfonic acid, Phenylsulfonic acid, tosic acid, oxalic acid or succsinic acid.
" C in the present invention
1 ~ 4alkyl " refer to and straight or branched saturated hydrocarbyl containing 1,2,3 or 4 carbon atom include but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl etc.
" replacing arbitrarily " in the present invention refers to have substituting group or do not have substituting group.
" C in the present invention
1 ~ 4alkoxyl group " refer to the oxygen base that the alkyl of the straight or branched containing 1,2,3 or 4 carbon atom replaces, i.e. " C
1 ~ 4alkyl-O-".
The carboxyl that " amino acid acyl " in the present invention refers in amino acid (NH2-R-C (=O)-OH) lacks the group (NH2-R-C (=O)-) that-OH is formed.Here the amino acid of indication comprises 20 kinds of natural amino acids, also various alpha-non-natural amino acid is comprised, such as: L-Ala (Ala), α-amino-isovaleric acid (Val), leucine (Leu), Isoleucine (Ile), proline(Pro) (Pro), phenylalanine (Phe), tryptophane (Trp), methionine(Met) (Met), glycine (Gly), Serine (Ser), Threonine (Thr), halfcystine (Cys), tyrosine (Tyr), l-asparagine (Asn), glutamine (Gln), aspartic acid (Asp), L-glutamic acid (Glu), Methionin (Lys), arginine (Arg), Histidine (His) etc.
The carboxyl (-C (=O)-OH) that " polypeptide acyl group " in the present invention refers in polypeptide lacks the group that-OH is formed; here polypeptide comprises by 2,3 or 4 micromolecular compounds formed by peptide bond with upper amino acid; be preferably dipeptides, include but not limited to Ganguertai, Glycyl-L-tyrosine, glutamine dipeptide, third group of dipeptides etc.
Second aspect, the invention provides the preparation method of above-mentioned nucleoside phosphoramidate derivative formula I or its pharmaceutical acceptable acid formula salt, solvate or hydrate, comprises the following steps:
Formula II compound and formula III compound under condensing agent condition or formula II compound and formula IV compound react, then remove amino protecting group and obtain formula I
Wherein, the R in formula II compound, formula III compound and formula IV compound
1, R
2, R
3defined such as formula in I; condensing agent can be carbonyl dimidazoles (CDI), N; N '-DIC (DIC), N; N '-dicyclohexylcarbodiimide (DCC), N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (EDCHCl), O-(7-nitrogen benzotriazole)-N; N; N '; N '-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N; N; N '; N '-tetramethyl-urea phosphofluoric acid ester (HBTU), Cbz group is the benzyloxycarbonyl protecting group of protection amino.
As the preferred embodiment of one, the invention provides the preparation method of above-mentioned nucleoside phosphoramidate derivative formula I or its pharmaceutically acceptable acid salt, solvate or hydrate, described method comprises and is dissolved in organic solvent by formula II compound or its salt, add alkali under cooling in batches, then react with formula IV compound, remove Cbz protecting group by catalytic hydrogenation again, obtain formula I; Or formula III compound and condensing agent are reacted; add alkali, then react with the organic solvent of formula II compound or its salt, then remove Cbz protecting group by catalytic hydrogenation; obtain formula I, can be further purified by ordinary method such as recrystallization, column chromatography etc. if necessary.Here, described alkali can be mineral alkali or organic bases, can be selected from sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine or DIPEA etc.The organic solvent solution of formula I and acid or the aqueous solution proportionally salify obtain the acid salt of formula I.
Especially, for R such as such as MJ10707, MJ10708, MJ10710, MJ10711, MJ10713, MJ10714, MJ10715, MJ10716, MJ10717, MJ10718, MJ10719, MJ10720 in the present invention
3there is in group the compound of extra easily reactive functionality, add corresponding side chain protected, after condensation reaction, add deprotection steps.
The third aspect, present invention also offers and comprise the treatment aforementioned nucleoside phosphoramidate derivative formula I of significant quantity or the pharmaceutical composition of its acid salt pharmaceutically accepted, solvate or hydrate, this pharmaceutical composition can also comprise pharmaceutically acceptable carrier or thinner, this pharmaceutical composition can also comprise other activeconstituentss, to form the composition of drug combination or to have the composition of synergy.This pharmaceutical composition is by intravenous administration, organize administration, Intraperitoneal medication, oral administration or intranasal administration by being injected into.This pharmaceutical composition can have the form being selected from solution, dispersion, suspension, powder, capsule, tablet, pill, time-release capsules, time release tablet and time release pill.The dosage of this pharmaceutical composition is 5-5000mg/ day.
Fourth aspect, the invention provides acid salt, solvate or hydrate that above-mentioned nucleoside phosphoramidate derivative pharmaceutically accepts such as formula I or its for the preparation of prevention or treatment mammalian infections disease medicament, in the medicine especially for preparation prevention or treatment hepatitis C, liver cirrhosis, liver cancer.
Compared with prior art, novel nucleoside phosphoramidate derivative of the present invention has significant anti-HCV activity, and the concentration of the key index liver active metabolite of its anti-HCV activity is even apparently higher than sofosbuvir.
Accompanying drawing explanation
Fig. 1 SD rat oral gavage gives the concentration (ng/g) of liver active metabolite GS-461203 after the compounds of this invention of 80mg/kg and sofosbuvir.
Embodiment
Carry out exemplary illustration embodiment of the present invention by the following examples, for the ordinary skill in the art, under the teachings of the present invention, according to prior art, to the improvement that embodiment of the present invention is carried out, still belong in protection scope of the present invention.
The source of the raw materials of compound used in embodiment is: all reagent is bought by Reagent Company, and formula II compound synthesizes with reference to the method for J.Org.Chem.2011,76,8311-8319 containing sofosbuvir.
Hydrogen nuclear magnetic resonance modal data is gathered by BrukerAV-300 nuclear magnetic resonance spectrometer and processes.
The synthesis of embodiment 1MJ10701
(1) synthesis of intermediate M1
By Cbz-Gly-OH (209mg, 1mmol) with 2mlN, dinethylformamide (DMF) dissolves, be cooled to-5 DEG C, DIC (63.1mg is added under stirring, 0.5mmol), 30min is reacted under room temperature, continue to be cooled to-5 DEG C, add S1 (265mg successively, 2mlDMF solution 0.5mmol), triethylamine (60.7mg, 0.6mmol), catalytic amount DMAP (DMAP), room temperature reaction 4h, reaction end is poured in 10ml water, with 10ml extraction into ethyl acetate 3 times, merge organic layer, anhydrous sodium sulfate drying, be spin-dried for solvent, obtain yellow solid, be separated with silica gel column chromatography, obtain off-white powder (M1) 217mg, yield 60.1%.MS(m/z)：721.2[M+1]
+。
(2) synthesis of MJ10701
By M1 (360mg, 0.5mmol) 3ml dissolve with methanol, add 5%Pd/C360mg, under hydrogen, react 20min, after reaction terminates, filter out Pd/C, filtrate is spin-dried for solvent, be separated with silica gel column chromatography, obtain white powder (MJ10701) 118mg, yield 40.2%.MS(m/z)：587.2[M+1]
+；
1H-NMR(DMSO-d6)δ：0.89-1.36(m,12H),3.31-3.34(m,2H),3.77-3.83(m,2H),4.00-4.08(m,1H),4.22-4.30(m,2H),4.84-4.89(m,1H),5.33-5.48(m,1H),5.64-5.67(m,2H),6.01-6.11(m,2H),7.16-7.22(m,3H),7.35-7.40(m,2H),7.70-7.75(m,1H),7.96(s,1H)。
The synthesis of embodiment 2MJ10702
(1) synthesis of intermediate M2
By Cbz-Ala-OH (223mg, 1mmol) with 2mlN, dinethylformamide (DMF) dissolves, be cooled to-5 DEG C, DIC (63.1mg is added under stirring, 0.5mmol), 30min is reacted under room temperature, continue to be cooled to-5 DEG C, add S1 (265mg successively, 2mlDMF solution 0.5mmol), triethylamine (60.7mg, 0.6mmol), catalytic amount DMAP (DMAP), room temperature reaction 4h, reaction end is poured in 10ml water, with 10ml extraction into ethyl acetate 3 times, merge organic layer, anhydrous sodium sulfate drying, be spin-dried for solvent, obtain yellow solid, be separated with silica gel column chromatography, obtain off-white powder (M2) 214mg, yield 58.3%.MS(m/z)：735.2[M+1]
+。
(2) synthesis of MJ10702
By M2 (368mg, 0.5mmol) 3ml dissolve with methanol, add 5%Pd/C360mg, under hydrogen, react 20min, after reaction terminates, filter out Pd/C, filtrate is spin-dried for solvent, be separated with silica gel column chromatography, obtain white powder (MJ10702) 137mg, yield 45.8%.MS(m/z)：601.2[M+1]
+；
1H-NMR(DMSO-d6)δ：0.88-1.37(m,15H),3.22-3.24(m,1H),3.76-3.82(m,2H),3.99-4.08(m,1H),4.21-4.29(m,2H),4.83-4.90(m,1H),5.32-5.49(m,1H),5.62-5.66(m,2H),6.01-6.09(m,2H),7.15-7.22(m,3H),7.35-7.41(m,2H),7.71-7.73(m,1H),7.99(s,1H)。
The synthesis of embodiment 3MJ10703
(1) synthesis of intermediate M3
By Cbz-Val-OH (251mg, 1mmol) with 2mlN, dinethylformamide (DMF) dissolves, be cooled to-5 DEG C, DIC (63.1mg is added under stirring, 0.5mmol), 30min is reacted under room temperature, continue to be cooled to-5 DEG C, add S1 (265mg successively, 2mlDMF solution 0.5mmol), triethylamine (60.7mg, 0.6mmol), catalytic amount DMAP (DMAP), room temperature reaction 4h, reaction end is poured in 10ml water, with 10ml extraction into ethyl acetate 3 times, merge organic layer, anhydrous sodium sulfate drying, be spin-dried for solvent, obtain yellow solid, be separated with silica gel column chromatography, obtain off-white powder (M3) 193mg, yield 50.6%.MS(m/z)：763.3[M+1]
+。
(2) synthesis of MJ10703
by M3 (381mg, 0.5mmol) 3ml dissolve with methanol, add 5%Pd/C360mg, under hydrogen, react 20min, after reaction terminates, filter out Pd/C, filtrate is spin-dried for solvent, be separated with silica gel column chromatography, obtain white powder (MJ10703) 159mg, yield 50.6%.MS(m/z)：629.2[M+1]
+；
1H-NMR(DMSO-d6)δ：0.89-1.36(m,18H),1.85-1.91(m,1H),3.23-3.25(m,1H),3.77-3.83(m,2H),3.99-4.07(m,1H),4.22-4.29(m,2H),4.82-4.90(m,1H),5.33-5.50(m,1H),5.64-5.67(m,2H),6.02-6.10(m,2H),7.16-7.22(m,3H),7.35-7.40(m,2H),7.70-7.73(m,1H),7.95(s,1H)。
The synthesis of embodiment 4MJ10704
With the leucine of carbobenzoxy-(Cbz) protection amino for starting raw material, with the method for embodiment 3, obtained target compound, yield 51.3%.MS(m/z)：643.2[M+1]
+。
The synthesis of embodiment 5MJ10705
With the Isoleucine of carbobenzoxy-(Cbz) protection amino for starting raw material, with the method for embodiment 3, obtained target compound, yield 41.1%.MS(m/z)：643.2[M+1]
+。
The synthesis of embodiment 6MJ10706
With the phenylalanine of carbobenzoxy-(Cbz) protection amino for starting raw material, with the method for embodiment 3, obtained target compound, yield 40.7%.MS(m/z)：677.2[M+1]
+。
The synthesis of embodiment 7MJ10709
With the l-asparagine of carbobenzoxy-(Cbz) protection amino for starting raw material, with the method for embodiment 3, obtained target compound, yield 52.7%.MS(m/z)：644.2[M+1]
+。
The synthesis of embodiment 8MJ10712
With the glutamine of carbobenzoxy-(Cbz) protection amino for starting raw material, with the method for embodiment 3, obtained target compound, yield 45.2%.MS(m/z)：658.2[M+1]
+。
The synthesis of embodiment 9MJ10718
With the proline(Pro) of carbobenzoxy-(Cbz) protection amino for starting raw material, with the method for embodiment 3, obtained target compound, yield 41.1%.MS(m/z)：627.2[M+1]
+。
The synthesis of embodiment 10MJ10707
(1) synthesis of intermediate M7
By Cbz-Trp (Boc)-OH (438mg, 1mmol) with 2mlN, dinethylformamide (DMF) dissolves, be cooled to-5 DEG C, DIC (63.1mg is added under stirring, 0.5mmol), 30min is reacted under room temperature, continue to be cooled to-5 DEG C, add S1 (265mg successively, 2mlDMF solution 0.5mmol), triethylamine (60.7mg, 0.6mmol), catalytic amount DMAP (DMAP), room temperature reaction 4h, reaction end is poured in 10ml water, with 10ml extraction into ethyl acetate 3 times, merge organic layer, anhydrous sodium sulfate drying, be spin-dried for solvent, obtain white solid, be separated with silica gel column chromatography, obtain white powder (M7) 300mg, yield 63.2%.MS(m/z)：950.3[M+1]
+。
(2) synthesis of MJ10707
By M7 (475mg, 0.5mmol) 10ml dissolve with methanol, pass into hydrogen chloride gas, after reaction terminates, add 5%Pd/C300mg, under hydrogen, react 20min, after reaction terminates, filter out Pd/C, use saturated sodium bicarbonate solution cancellation, be spin-dried for solvent, be separated with silica gel column chromatography, obtain white powder (MJ10707) 109mg, yield 30.5%.MS(m/z)：716.2[M+1]
+。
The synthesis of embodiment 11MJ10708
With the tyrosine of carbobenzoxy-(Cbz) protection amino, benzyl protection phenolic hydroxyl group for starting raw material, with the method for embodiment 3, obtained target compound, yield 38.1%.MS(m/z)：693.2[M+1]
+。
The synthesis of embodiment 12MJ10710
With the Asp side chain carboxyl benzyl ester of carbobenzoxy-(Cbz) protection amino for starting raw material, with the method for embodiment 3, obtained target compound, yield 39.9%.MS(m/z)：645.2[M+1]
+。
The synthesis of embodiment 13MJ10711
With the glutamate side chain carboxyl benzyl ester of carbobenzoxy-(Cbz) protection amino for starting raw material, with the method for embodiment 3, obtained target compound, yield 41.5%.MS(m/z)：659.2[M+1]
+。
The synthesis of embodiment 14MJ10713
With the Methionin of the two protection amino of carbobenzoxy-(Cbz) for starting raw material, with the method for embodiment 3, obtained target compound, yield 53.5%.MS(m/z)：658.2[M+1]
+。
The synthesis of embodiment 15MJ10714
With the methionine(Met) of carbobenzoxy-(Cbz) protection amino for starting raw material, with the method that embodiment 3 is similar, difference is that catalytic hydrogenation uses RaneyNi as catalyzer, obtained target compound, yield 31.3%.MS(m/z)：661.2[M+1]
+。
The synthesis of embodiment 16MJ10715
With the Serine of carbobenzoxy-(Cbz) protection aminobenzyl protection hydroxyl for starting raw material, with the method for embodiment 3, obtained target compound, yield 43.6%.MS(m/z)：617.2[M+1]
+。
The synthesis of embodiment 17MJ10716
With the Threonine of carbobenzoxy-(Cbz) protection aminobenzyl protection hydroxyl for starting raw material, with the method for embodiment 3, obtained target compound, yield 39.1%.MS(m/z)：631.2[M+1]
+。
The synthesis of embodiment 18MJ10717
With the halfcystine of carbobenzoxy-(Cbz) protection aminotrityl protection sulfydryl for starting raw material, with the method that embodiment 10 is similar, difference is that catalytic hydrogenation uses RaneyNi as catalyzer, obtained target compound, yield 23.1%.MS(m/z)：633.2[M+1]
+。
The synthesis of embodiment 19MJ10719
With the Histidine of carbobenzoxy-(Cbz) protection aminotrityl protection side chain heterocyclic nitrogen for starting raw material, with the method for embodiment 10, obtained target compound, yield 27.3%.MS(m/z)：667.2[M+1]
+。
The synthesis of embodiment 20MJ10720
With the arginine of carbobenzoxy-(Cbz) protection aminotrityl protection side chain guanidinium group for starting raw material, with the method for embodiment 10, obtained target compound, yield 29.6%.MS(m/z)：686.2[M+1]
+。
Embodiment 21 rat oral gavage gives the assay of GS-461203 in liver after test compounds
GS-461203 is the active metabolite that anti-third liver medicine Suo Feibuwei (sofosbuvir) is formed in vivo, and it can be incorporated in the RNA of hepatitis C virus by NS5B polysaccharase, as same chain terminator, play antivirus action.After administration, in liver, the content of GS-461203 can reflect the power of the anti-hepatitis C virus effect of this compound.
54 SD rats, be divided into 3 groups, with the dosage of 80mg/kg respectively gavage give the test liquid of sofosbuvir and patents, and respectively at after administration 0.5,1,2,4,8,24 constantly little, by suck sacrificed by carbon dioxide animal (3/per moment/group), liver samples is won appropriate, under putting into-80 DEG C of environment immediately after liver perfusion ice bath physiological saline.
Rat liver sample adds ice bath 70% methanol aqueous solution (containing EDTA etc.), and homogenate is centrifugal, gets supernatant liquor appropriate, volatilizes, dissolve, be need testing solution with the acetonitrile solution containing 0.1% formic acid.
Measure the content of wherein GS-461203 with LC/MS/MS method, and calculate liver exposed amount (AUC), test compounds liver GS-461203AUC is significantly higher than sofosbuvir group higher than sofosbuvir, MJ10702 group and MJ10703 group, the results are shown in Table 1
The exposed amount (AUC) of GS-461203 in liver after the administration of table 1 rat oral gavage
| Compound | Dosage (mg/kg) | AUC 0-t(ug.h/g) |
| sofosbuvir | 80 | 54.2 |
| MJ10701 | 80 | 65.2 |
| MJ10702 | 80 | 79.1 |
| MJ10703 | 80 | 90.9 |
| MJ10704 | 80 | 67.7 |
| MJ10705 | 80 | 60.4 |
| MJ10706 | 80 | 61.1 |
| MJ10707 | 80 | 70.3 |
| MJ10708 | 80 | 69.9 |
| MJ10709 | 80 | 70.7 |
| MJ10710 | 80 | 59.7 |
| MJ10711 | 80 | 77.3 |
| MJ10712 | 80 | 59.1 |
| MJ10713 | 80 | 75.6 |
| MJ10714 | 80 | 58.1 |
| MJ10715 | 80 | 63.5 |
| MJ10716 | 80 | 70.2 |
| MJ10717 | 80 | 62.1 |
| MJ10718 | 80 | 68.5 |
| MJ10719 | 80 | 71.5 |
| MJ10720 | 80 | 63.1 |
Embodiment 22 rat oral gavage gives the pharmacokinetic of GS-331007 in blood plasma after test compounds
GS-331007 be anti-third liver medicine Suo Feibuwei (sofosbuvir) in vivo metabolism formed nonactive meta-bolites, also be the major metabolite of sofosbuvir, the bioavailability of sofosbuvir in its indirect antimer of existence, it is monophosphate nucleosides that patents also experiences metabolism in vivo, then dephosphorylation is the process of GS-331007, and in test blood plasma, the amount of GS-331007 can reflect invention compound overall absorption situation in vivo.
SD rat, be divided into some groups, often organize 27, with the dosage of 50mg/kg respectively gavage give the test liquid of sofosbuvir and patents, and respectively at after administration 0.5,1,2,3,4,6,8,10,12 constantly little, gather animal plasma (3/per moment/group).
Adopt the concentration of metabolite GS-331007 in Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) analytical procedure quantitative assay rat plasma, by WinNonlin6.2 software, calculate pharmacokinetic parameters by non-compartment model, the results are shown in Table 2
Table 2 rat oral gavage gives the pharmacokinetic parameter of GS-331007 in blood plasma after sofosbuvir and test compounds
| Compound | Dosage (mg/kg) | C max(ng/g) | t 1/2(hr) | AUC last(hr*ng/g) |
| sofosbuvir | 50 | 1653 | 2.56 | 6987 |
| MJ10702 | 50 | 1865 | 3.12 | 8567 |
| MJ10703 | 50 | 1743 | 2.37 | 7359 |
| MJ10704 | 50 | 1712 | 3.21 | 7132 |
| MJ10705 | 50 | 1663 | 2.43 | 7764 |
| MJ10706 | 50 | 1581 | 3.11 | 7931 |
| MJ10715 | 50 | 1547 | 3.47 | 7513 |
| MJ10716 | 50 | 1639 | 2.38 | 7079 |
| MJ10718 | 50 | 1987 | 2.33 | 8832 |
Embodiment 23 solubility test
Sofosbuvir cannot salify under acid and alkaline condition, dissolves hardly in neutral aqueous solution, and patents can with sour salify, increase its solubleness in water, preparation provide facility.
The preparation of patents hydrochloride: by the free base acetic acid ethyl dissolution of patents, drips Hydrochloride/ethyl acetate, stirs 10min, add sherwood oil, separate out precipitation, precipitation petroleum ether 3 times, removal of solvent under reduced pressure, obtains the hydrochloride of product.
The preparation of reference standard solution: respectively by the hydrochloride of sofosbuvir, patents, with dissolve with methanol, is made into the solution of 0.5mg/ml.
By testing sample water dissolution, have Precipitation to bottom, filter, with determined by ultraviolet spectrophotometry specific absorbance, calculation sample concentration, the solubleness of test display patents is greater than 6mg/ml, MJ10702 and MJ10703 the results are shown in Table 4.
Table 4 invention compound solubility
| Compound | sofosbuvir | MJ10702 hydrochloride | MJ10703 hydrochloride |
| Solubleness | <2mg/ml | >10mg/ml | >15mg/ml |
Claims (10)
1. formula I, or the acceptable acid salt of its pharmacy, solvate or hydrate:
Wherein:
R
1for C
1 ~ 4alkyl;
R
2for the phenyl or naphthyl replaced arbitrarily, its substituting group is selected from C
1 ~ 4alkyl, C
1 ~ 4alkoxyl group;
R
3for amino acid acyl or polypeptide acyl group.
2. formula I according to claim 1 or the acceptable acid salt of its pharmacy, solvate or hydrate, wherein, R
1for methyl, ethyl or sec.-propyl.
3. formula I according to claim 1 or the acceptable acid salt of its pharmacy, solvate or hydrate, wherein, R
2for phenyl or naphthyl.
4. formula I according to claim 1 or the acceptable acid salt of its pharmacy, solvate or hydrate, wherein, R
3for natural amino acid acyl group, alpha-non-natural amino acid acyl group or two acyltransferase polypeptides.
5. formula I according to claim 4 or the acceptable acid salt of its pharmacy, solvate or hydrate, wherein, R
3for glycyl, alanyl, valyl, leucyl, isoleucyl, phenylalanyl, tryptophyl, tyrosyl, aspartyl, asparagyl, glutamyl, glutaminyl, lysyl, methionyl, seryl, Threonyl, cysteinyl, prolyl, histidyl, arginyl.
6. formula I according to claim 1 or the acceptable acid salt of its pharmacy, solvate or hydrate, wherein, R
1for methyl, ethyl or sec.-propyl; R
2for phenyl or naphthyl; R
3for glycyl, alanyl, valyl, leucyl, isoleucyl, phenylalanyl, tryptophyl, tyrosyl, aspartyl, asparagyl, glutamyl, glutaminyl, lysyl, methionyl, seryl, Threonyl, cysteinyl, prolyl, histidyl, arginyl.
7. formula I according to claim 1 or the acceptable acid salt of its pharmacy, solvate or hydrate, wherein compound is selected from:
8. a pharmaceutical composition, it comprises formula I according to any one of claim 1 ~ 7 or the acceptable acid salt of its pharmacy, solvate or hydrate.
9. the formula I according to any one of claim 1 ~ 7 or the acceptable acid salt of its pharmacy, solvate or hydrate are for the preparation of prevention or the purposes for the treatment of mammalian virus infection medicine aspect.
10. the formula I according to any one of claim 1 ~ 7 or the acceptable acid salt of its pharmacy, solvate or hydrate are for the preparation of prevention or the purposes for the treatment of hepatitis C, liver cirrhosis or liver-cancer medicine aspect.
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| CN1891710A (en) * | 2005-07-01 | 2007-01-10 | 博瑞生物医药技术(苏州)有限公司 | L-nucleoside prodrug |
| CN101918425A (en) * | 2007-03-30 | 2010-12-15 | 法莫赛特股份有限公司 | Nucleoside phosphoramidate prodrugs |
| CN102686599A (en) * | 2009-09-29 | 2012-09-19 | 杨森产品有限公司 | Phosphoramidate derivatives of nucleosides |
| WO2014209983A1 (en) * | 2013-06-26 | 2014-12-31 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| US20150266918A1 (en) * | 2014-03-19 | 2015-09-24 | Minghong Zhong | Bridged-Cyclo-ProTides as Prodrugs of Therapeutic Nucleosides and Nucleotides |
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| CN1891710A (en) * | 2005-07-01 | 2007-01-10 | 博瑞生物医药技术(苏州)有限公司 | L-nucleoside prodrug |
| CN101918425A (en) * | 2007-03-30 | 2010-12-15 | 法莫赛特股份有限公司 | Nucleoside phosphoramidate prodrugs |
| CN102686599A (en) * | 2009-09-29 | 2012-09-19 | 杨森产品有限公司 | Phosphoramidate derivatives of nucleosides |
| WO2014209983A1 (en) * | 2013-06-26 | 2014-12-31 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| US20150266918A1 (en) * | 2014-03-19 | 2015-09-24 | Minghong Zhong | Bridged-Cyclo-ProTides as Prodrugs of Therapeutic Nucleosides and Nucleotides |
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| WO2019080724A1 (en) * | 2017-10-23 | 2019-05-02 | 四川科伦博泰生物医药股份有限公司 | Nucleoside phosphate compound and preparation method therefor and use thereof |
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