CN105254695B - Nucleoside phosphoramidate derivative and its application - Google Patents
Nucleoside phosphoramidate derivative and its application Download PDFInfo
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- CN105254695B CN105254695B CN201510755269.5A CN201510755269A CN105254695B CN 105254695 B CN105254695 B CN 105254695B CN 201510755269 A CN201510755269 A CN 201510755269A CN 105254695 B CN105254695 B CN 105254695B
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- pharmaceutically acceptable
- acid salt
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- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012087 reference standard solution Substances 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of nucleoside phosphoramidate derivative and its applications, are specially compound of formula I or its pharmaceutically acceptable acid salt, solvate or hydrate;Wherein: R1For C1~4Alkyl;R2For the phenyl or naphthyl arbitrarily replaced, substituent group is selected from C1~4Alkyl, C1~4Alkoxy;R3For amino acid acyl or polypeptide acyl group.The compound of the present invention can be used for preparing prevention or treatment mammalian infections disease medicament, be especially used to prepare prevention or treat hepatitis C, cirrhosis, liver cancer drug in.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, spread out more specifically to a kind of novel nucleoside phosphoramidate
Biological, pharmaceutically acceptable acid salt, solvate or hydrate and they preparation be used for mammalian infections disease
Purposes in disease, the drug for preventing or treating hepatitis C, cirrhosis, liver cancer.
Background technique
Hepatitis C Virus (HCV) infection is serious health problem, is caused in a large amount of infected individual chronic
Liver diseases, and then develop into cirrhosis and liver cancer.According to the statistics of the World Health Organization, the whole world has more than 200,000,000 and is felt root
Dye individual, at least 3 to 4 million peoples are infected every year.After infected, about 20% people can remove the virus, still
Remaining people may carry HCV in their remaining years.10% to 20% chronic infection individual is eventually developed to liver destruction
The hardening or cancer of property.Be currently used in HCV infection therapeutic agent have recombinant interferon, individually or with nucleoside analog Li Bawei
The sofosbuvir for therapy and the Gerald listing that forest form combines.And sofosbuvir has nearly 90% to be metabolized as not have in vivo
Active metabolite.Therefore, bioavilability is high, and liver selective is good, and the high HCV infection therapeutic agent of drug effect is still to face
The urgent need of bed.
Summary of the invention
Novel there is the active nucleosides amino phosphorus of resisting mammal viral infection the object of the present invention is to provide a kind of
Acid ester derivant.
A second object of the present invention is to provide the pharmaceutical compositions comprising above-mentioned nucleoside phosphoramidate derivative.
Third object of the present invention is to provide above-mentioned nucleoside phosphoramidate derivative or pharmaceutical compositions in prevention or
In terms for the treatment of mammalian infections disease, in terms of especially preventing or treating hepatitis C, cirrhosis, liver cancer related disease
Purposes.
Specifically, the present invention provides a kind of nucleoside phosphoramidate derivative, such as compounds of formula I or its medicine
Acceptable acid salt, solvate or hydrate on:
Wherein:
R1For C1~4Alkyl;
R2For the phenyl or naphthyl arbitrarily replaced, substituent group is selected from C1~4Alkyl, C1~4Alkoxy;
R3For amino acid acyl or polypeptide acyl group.
R in a kind of preferred embodiment of the invention, in formula Compound I1For methyl, ethyl or isopropyl
Base;Further preferred isopropyl.
R in a kind of preferred embodiment of the invention, in formula Compound I2For phenyl or naphthyl;Further
It is preferred that phenyl.
R in a kind of preferred embodiment of the invention, in formula Compound I3For natural amino acid acyl group, non-
Natural amino acid acyl group or two acyltransferase polypeptides.
R in a kind of preferred embodiment of the invention, in formula Compound I3For natural amino acid acyl group.
R in a kind of preferred embodiment of the invention, in formula Compound I3For glycyl, alanyl
Base, valyl base, leucyl-, isoleucyl-, phenylalanyl, tryptophanyl, tyrosyl, aspartyl, asparagus fern
Amide acyl group, glutamyl, glutaminyl, lysyl-, methionyl, seryl-, Threonyl, cysteinyl
Base, prolyl, histamine acyl group or arginyl-.
R in a kind of preferred embodiment of the invention, in formula Compound I1For methyl, ethyl or isopropyl
Base;R2For phenyl or naphthyl;R3For glycyl, alanyl, valyl base, leucyl-, isoleucyl-, phenylalanyl
Base, tryptophanyl, tyrosyl, aspartyl, asparaginyl-, glutamyl, glutaminyl, lysyl-,
Methionyl, seryl-, Threonyl, cysteinyl-, prolyl, histamine acyl group, arginyl-.
R in a kind of more preferred of the invention, in formula Compound I1For isopropyl;R2For phenyl;
R3For glycyl, alanyl, valyl base, leucyl-, isoleucyl-, phenylalanyl, tryptophanyl, tyrasamine acyl
Base, aspartyl, asparaginyl-, glutamyl, glutaminyl, lysyl-, methionyl, seryl
Base, Threonyl, cysteinyl-, prolyl, histamine acyl group, arginyl-.
In particularly preferred embodiment of the invention, compound provided by the invention in following compound one
Kind or its pharmaceutically acceptable acid salt, solvate or hydrate:
In embodiments of the invention, the derivative provided by the invention includes the enantiomter of compound of formula I and outer
Raceme.
In embodiments of the invention, derivative of the present invention includes compound of formula I or its is pharmaceutically acceptable
Acid salt, including but not limited to compound and it is following acid formed salt: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, winestone
Acid, phosphoric acid, lactic acid, acetic acid, maleic acid, fumaric acid, malic acid, tussol, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, oxalic acid or
Succinic acid.
" C in the present invention1~4Alkyl " refers to the linear chain or branched chain saturated hydrocarbyl containing 1,2,3 or 4 carbon atom, including
But be not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl etc..
" any to replace " in the present invention refers to substituent group or does not have substituent group.
" C in the present invention1~4Alkoxy " refers to the alkyl-substituted of the linear chain or branched chain containing 1,2,3 or 4 carbon atom
Oxygroup, i.e. " C1~4Alkyl-O- ".
" amino acid acyl " in the present invention refers to that the carboxyl in amino acid (NH2-R-C (=O)-OH) lacks-OH institute shape
At group (NH2-R-C (=O) -).Amino acid referred herein includes 20 kinds of natural amino acids, also includes various non-natural ammonia
Base acid, such as: alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylpropyl alcohol
Propylhomoserin (Phe), tryptophan (Trp), methionine (Met), glycine (Gly), serine (Ser), threonine (Thr), half Guang ammonia
Sour (Cys), tyrosine (Tyr), glutamine (Gln), aspartic acid (Asp), glutamic acid (Glu), rely asparagine (Asn)
Propylhomoserin (Lys), arginine (Arg), histidine (His) etc..
" polypeptide acyl group " in the present invention refers to that the carboxyl (- C (=O)-OH) in polypeptide lacks-OH and is formed by group,
Here polypeptide includes being formed by small molecule compound, preferably two by peptide bond with upper amino acid by 2,3 or 4
Peptide, including but not limited to Ganguertai, Glycyl-L-tyrosine, glutamine dipeptide, third group of dipeptides etc..
Second aspect, the present invention provides above-mentioned nucleoside phosphoramidate derivative compound of formula I or its can pharmaceutically connect
By the preparation method of acid salt, solvate or hydrate, including the following steps:
Formula II compound with formula III compound under the conditions of condensing agent or Formula II compound is reacted with formula IV compound, then
Removing amino protecting group obtains compound of formula I
Wherein, the R in Formula II compound, formula III compound and formula IV compound1、R2、R3As determined in compound of formula I
Justice, condensing agent can be carbonyl dimidazoles (CDI), N, N '-diisopropylcarbodiimide (DIC), N, two Asia of N '-dicyclohexyl carbon
Amine (DCC), N- (3- dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (EDCHCl), O- (7- pyridine and three nitrogen
Azoles)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU), benzotriazole-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid
Ester (HBTU), Cbz group are the benzyloxycarbonyl protecting group for protecting amino.
Embodiment as one preferred, the present invention provides above-mentioned nucleoside phosphoramidate derivative compound of formula I
Or the preparation method of its pharmaceutically acceptable acid salt, solvate or hydrate, the method includes by Formula II compound
Or its salt is dissolved in organic solvent, and alkali is added portionwise under cooling, then reacts with formula IV compound, then removed with catalytic hydrogenation
Cbz protecting group, obtains compound of formula I;Or formula III compound is reacted with condensing agent, be added alkali, then with Formula II compound or
The organic solvent of its salt reacts, then removes Cbz protecting group with catalytic hydrogenation, obtains compound of formula I, can pass through if necessary
Conventional method for example recrystallizes, column chromatography etc. is further purified.Here, the alkali can be inorganic base or organic base, optional
From sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, triethylamine or N, N- diisopropylethylamine etc..Compound of formula I and acid
Organic solvent solution or aqueous solution proportionally obtain the acid salt of compound of formula I at salt.
Particularly, for such as MJ10707, MJ10708 in the present invention, MJ10710, MJ10711, MJ10713,
The R such as MJ10714, MJ10715, MJ10716, MJ10717, MJ10718, MJ10719, MJ107203Have in group additional easily anti-
The compound for answering functional group is added corresponding side chain protection, deprotection steps is added after condensation reaction.
The third aspect, the present invention also provides the aforementioned nucleoside phosphoramidate derivative Formulas I comprising therapeutically effective amount
The pharmaceutical composition of object or its acid salt pharmaceutically received, solvate or hydrate is closed, which can be also
Comprising pharmaceutical acceptable carrier or diluent, which can also include other active components, to form the group of drug combination
Close object or with synergistic composition.The pharmaceutical composition can by intravenous injection administration, by be injected into tissue to
Medicine, Intraperitoneal medication, oral administration or intranasal administration.The pharmaceutical composition can have selected from solution, dispersion, suspension,
The form of powder, capsule, tablet, pill, time-release capsules, time release tablet and time release pill.The pharmaceutical composition
The dosage of object is 5-5000mg/ days.
Fourth aspect, the present invention provides above-mentioned nucleoside phosphoramidate derivative such as compound of formula I or its pharmaceutically connect
Acid salt, solvate or the hydrate received are used to prepare prevention or treatment mammalian infections disease medicament, especially
Be used to prepare prevention or treat hepatitis C, cirrhosis, liver cancer drug in.
Compared with prior art, novel nucleoside phosphoramidate derivative of the invention has significant anti-HCV activity,
The concentration of the key index liver active metabolite of its anti-HCV activity is even apparently higher than sofosbuvir.
Detailed description of the invention
Fig. 1 SD rat oral gavage gives liver active metabolite GS- after the compounds of this invention and sofosbuvir of 80mg/kg
461203 concentration (ng/g).
Specific embodiment
Carry out exemplary illustration embodiment of the present invention by the following examples, for those of ordinary skill in the art and
Speech still falls within guarantor of the invention to the improvement that embodiment of the present invention carries out according to the prior art under the teachings of the present invention
It protects in range.
The source of raw materials of compound used in embodiment is: all reagents are bought by Reagent Company, Formula II compound
It is synthesized containing sofosbuvir with reference to the method for J.Org.Chem.2011,76,8311-8319.
Hydrogen nuclear magnetic resonance modal data is acquired and is handled by Bruker AV-300 nuclear magnetic resonance chemical analyser.
The synthesis of 1 MJ10701 of embodiment
(1) synthesis of intermediate M1
Cbz-Gly-OH (209mg, 1mmol) is dissolved with 2ml n,N-Dimethylformamide (DMF), is cooled to -5 DEG C,
It is added with stirring DIC (63.1mg, 0.5mmol), reacts 30min at room temperature, continues to be cooled to -5 DEG C, sequentially adds S1
The 2ml DMF solution of (265mg, 0.5mmol), triethylamine (60.7mg, 0.6mmol), catalytic amount 4-dimethylaminopyridine
(DMAP), 4h is reacted at room temperature, reaction terminates to pour into 10ml water, be extracted 3 times with 10ml ethyl acetate, merges organic layer, anhydrous
Sodium sulphate is dry, is spin-dried for solvent, obtains yellow solid, separated with silica gel column chromatography, obtains off-white powder (M1) 217mg, yield
60.1%.MS (m/z): 721.2 [M+1]+。
(2) synthesis of MJ10701
M1 (360mg, 0.5mmol) is dissolved with 3ml methanol, 5%Pd/C 360mg is added, reacts 20min under hydrogen, instead
After answering, Pd/C is filtered out, filtrate is spin-dried for solvent, is separated with silica gel column chromatography, white powder (MJ10701) 118mg is obtained,
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 2 MJ10702 of embodiment
(1) synthesis of intermediate M2
Cbz-Ala-OH (223mg, 1mmol) is dissolved with 2ml n,N-Dimethylformamide (DMF), is cooled to -5 DEG C,
It is added with stirring DIC (63.1mg, 0.5mmol), reacts 30min at room temperature, continues to be cooled to -5 DEG C, sequentially adds S1
The 2ml DMF solution of (265mg, 0.5mmol), triethylamine (60.7mg, 0.6mmol), catalytic amount 4-dimethylaminopyridine
(DMAP), 4h is reacted at room temperature, reaction terminates to pour into 10ml water, be extracted 3 times with 10ml ethyl acetate, merges organic layer, anhydrous
Sodium sulphate is dry, is spin-dried for solvent, obtains yellow solid, separated with silica gel column chromatography, obtains off-white powder (M2) 214mg, yield
58.3%.MS (m/z): 735.2 [M+1]+。
(2) synthesis of MJ10702
M2 (368mg, 0.5mmol) is dissolved with 3ml methanol, 5%Pd/C 360mg is added, reacts 20min under hydrogen, instead
After answering, Pd/C is filtered out, filtrate is spin-dried for solvent, is separated with silica gel column chromatography, white powder (MJ10702) 137mg is obtained,
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 3 MJ10703 of embodiment
(1) synthesis of intermediate M3
Cbz-Val-OH (251mg, 1mmol) is dissolved with 2ml n,N-Dimethylformamide (DMF), is cooled to -5 DEG C,
It is added with stirring DIC (63.1mg, 0.5mmol), reacts 30min at room temperature, continues to be cooled to -5 DEG C, sequentially adds S1
The 2ml DMF solution of (265mg, 0.5mmol), triethylamine (60.7mg, 0.6mmol), catalytic amount 4-dimethylaminopyridine
(DMAP), 4h is reacted at room temperature, reaction terminates to pour into 10ml water, be extracted 3 times with 10ml ethyl acetate, merges organic layer, anhydrous
Sodium sulphate is dry, is spin-dried for solvent, obtains yellow solid, separated with silica gel column chromatography, obtains off-white powder (M3) 193mg, yield
50.6%.MS (m/z): 763.3 [M+1]+。
(2) synthesis of MJ10703
M3 (381mg, 0.5mmol) is dissolved with 3ml methanol, 5%Pd/C 360mg is added, 20min, reaction knot are reacted under hydrogen
Shu Hou filters out Pd/C, and filtrate is spin-dried for solvent, is separated with silica gel column chromatography, obtains 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 4 MJ10704 of embodiment
Using the leucine of benzyloxycarbonyl group protection amino as starting material, with the method for embodiment 3, target compound is made,
Yield 51.3%.MS (m/z): 643.2 [M+1]+。
The synthesis of 5 MJ10705 of embodiment
Using the isoleucine of benzyloxycarbonyl group protection amino as starting material, with the method for embodiment 3, target chemical combination is made
Object, yield 41.1%.MS (m/z): 643.2 [M+1]+。
The synthesis of 6 MJ10706 of embodiment
Using the phenylalanine of benzyloxycarbonyl group protection amino as starting material, with the method for embodiment 3, target chemical combination is made
Object, yield 40.7%.MS (m/z): 677.2 [M+1]+。
The synthesis of 7 MJ10709 of embodiment
Using the asparagine of benzyloxycarbonyl group protection amino as starting material, with the method for embodiment 3, target chemical combination is made
Object, yield 52.7%.MS (m/z): 644.2 [M+1]+。
The synthesis of 8 MJ10712 of embodiment
Using the glutamine of benzyloxycarbonyl group protection amino as starting material, with the method for embodiment 3, target chemical combination is made
Object, yield 45.2%.MS (m/z): 658.2 [M+1]+。
The synthesis of 9 MJ10718 of embodiment
Using the proline of benzyloxycarbonyl group protection amino as starting material, with the method for embodiment 3, target compound is made,
Yield 41.1%.MS (m/z): 627.2 [M+1]+。
The synthesis of 10 MJ10707 of embodiment
(1) synthesis of intermediate M7
Cbz-Trp (Boc)-OH (438mg, 1mmol) is dissolved with 2ml n,N-Dimethylformamide (DMF), be cooled to-
5 DEG C, it is added with stirring DIC (63.1mg, 0.5mmol), reacts 30min at room temperature, continues to be cooled to -5 DEG C, sequentially adds S1
The 2ml DMF solution of (265mg, 0.5mmol), triethylamine (60.7mg, 0.6mmol), catalytic amount 4-dimethylaminopyridine
(DMAP), 4h is reacted at room temperature, reaction terminates to pour into 10ml water, be extracted 3 times with 10ml ethyl acetate, merges organic layer, anhydrous
Sodium sulphate is dry, is spin-dried for solvent, obtains white solid, separated with silica gel column chromatography, obtains white powder (M7) 300mg, yield
63.2%.MS (m/z): 950.3 [M+1]+。
(2) synthesis of MJ10707
M7 (475mg, 0.5mmol) is dissolved with 10ml methanol, is passed through hydrogen chloride gas, after reaction, is added 5%
Pd/C 300mg reacts 20min under hydrogen, after reaction, filters out Pd/C, be quenched with saturated sodium bicarbonate solution, is spin-dried for
Solvent is separated with silica gel column chromatography, obtains white powder (MJ10707) 109mg, yield 30.5%.MS (m/z): 716.2 [M+
1]+。
The synthesis of 11 MJ10708 of embodiment
Using benzyloxycarbonyl group protection amino, benzyl protection phenolic hydroxyl group tyrosine as starting material, with the method for embodiment 3,
Target compound, yield 38.1% is made.MS (m/z): 693.2 [M+1]+。
The synthesis of 12 MJ10710 of embodiment
Using the Asp side chain carboxyl benzyl ester of benzyloxycarbonyl group protection amino as starting material, with the method for embodiment 3, system
Obtain target compound, yield 39.9%.MS (m/z): 645.2 [M+1]+。
The synthesis of 13 MJ10711 of embodiment
Using the glutamate side chain carboxyl benzyl ester of benzyloxycarbonyl group protection amino as starting material, with the method for embodiment 3, it is made
Target compound, yield 41.5%.MS (m/z): 659.2 [M+1]+。
The synthesis of 14 MJ10713 of embodiment
Using the lysine of the double protection amino of benzyloxycarbonyl group as starting material, with the method for embodiment 3, target chemical combination is made
Object, yield 53.5%.MS (m/z): 658.2 [M+1]+。
The synthesis of 15 MJ10714 of embodiment
Using the methionine of benzyloxycarbonyl group protection amino as starting material, the similar method with embodiment 3, difference is to urge
Changing hydrogenation uses Raney Ni as catalyst, and target compound, yield 31.3% is made.MS (m/z): 661.2 [M+1]+。
The synthesis of 16 MJ10715 of embodiment
Using the serine of benzyloxycarbonyl group protection aminobenzyl protection hydroxyl as starting material, with the method for embodiment 3, it is made
Target compound, yield 43.6%.MS (m/z): 617.2 [M+1]+。
The synthesis of 17 MJ10716 of embodiment
Using the threonine of benzyloxycarbonyl group protection aminobenzyl protection hydroxyl as starting material, with the method for embodiment 3, it is made
Target compound, yield 39.1%.MS (m/z): 631.2 [M+1]+。
The synthesis of 18 MJ10717 of embodiment
It is similar with embodiment 10 using the cysteine of benzyloxycarbonyl group protection aminotrityl protection sulfydryl as starting material
Method, difference is that catalytic hydrogenation use Raney Ni as catalyst, obtained target compound, yield 23.1%.MS(m/
Z): 633.2 [M+1]+。
The synthesis of 19 MJ10719 of embodiment
Using the histidine of benzyloxycarbonyl group protection aminotrityl protection side chain heterocyclic nitrogen as starting material, with embodiment 10
Method, be made target compound, yield 27.3%.MS (m/z): 667.2 [M+1]+。
The synthesis of 20 MJ10720 of embodiment
Using the arginine of benzyloxycarbonyl group protection aminotrityl protection side chain guanidinium group as starting material, with embodiment 10
Target compound, yield 29.6% is made in method.MS (m/z): 686.2 [M+1]+。
21 rat oral gavage of embodiment gives the assay of GS-461203 in liver after test compound
GS-461203 is the active metabolite that anti-hepatitis medicine Suo Feibuwei (sofosbuvir) is formed in vivo, it is logical
Crossing NS5B polymerase can mix into the RNA of hepatitis C virus, play antivirus action as the same chain terminator.After administration
The content of GS-461203 can reflect the power of the anti-hepatitis C virus effect of the compound in liver.
54 SD rats, are divided into 3 groups, and with the dosage of 80mg/kg, sofosbuvir and patent are given in stomach-filling respectively
Close object test liquid, and respectively after administration 0.5,1,2,4,8,24 hour when, by sucking sacrificed by carbon dioxide animal (3/
Per moment/group), it is appropriate to win liver samples after liver perfusion ice bath physiological saline, is immediately placed under -80 DEG C of environment.
70% methanol aqueous solution of rat liver sample bath on the rocks (containing EDTA etc.), is homogenized, and centrifugation takes supernatant appropriate, waves
It is dry, it is dissolved with the acetonitrile solution containing 0.1% formic acid, as test solution.
The content of wherein GS-461203 is measured with LC/MS/MS method, and calculates liver exposed amount (AUC), tests compound
Liver GS-461203AUC is higher than sofosbuvir, and MJ10702 group and MJ10703 group are significantly higher than sofosbuvir group, as a result
It is shown in Table 1
After the administration of 1 rat oral gavage of table in liver GS-461203 exposed amount (AUC)
Compound | Dosage (mg/kg) | AUC0-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 |
22 rat oral gavage of embodiment gives the pharmacokinetic of GS-331007 in blood plasma after test compound
GS-331007 is the nonactive metabolism production that anti-hepatitis medicine Suo Feibuwei (sofosbuvir) is metabolized formation in vivo
The major metabolite of object and sofosbuvir, it there are the bioavilability of sofosbuvir in indirect antimer, patents
Also experience is metabolized as monophosphate nucleosides to compound in vivo, and then dephosphorylation is the process of GS-331007, tests GS- in blood plasma
331007 amount can reflect the overall absorption situation of invention compound in vivo.
SD rat, is divided into several groups, every group 27, with the dosage of 50mg/kg respectively stomach-filling give sofosbuvir,
With the test liquid of patents, and respectively after administration 0.5,1,2,3,4,6,8,10,12 hour when, acquire animal blood plasma (3
Only/per moment/group).
Using metabolin GS- in Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) analysis method quantitative determination rat plasma
331007 concentration calculates pharmacokinetic parameters by non-compartment model, the results are shown in Table 2 by 6.2 software of WinNonlin
2 rat oral gavage of table gives the pharmacokinetics ginseng of sofosbuvir with GS-331007 in blood plasma after test compound
Number
Compound | Dosage (mg/kg) | Cmax(ng/g) | t1/2(hr) | AUClast(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 |
23 solubility test of embodiment
Sofosbuvir can be almost dissolved in neutral aqueous solution at salt under acid and alkaline condition, and patent
Compound can increase its solubility in water, convenience is provided on preparation with acid at salt.
The preparation of patents hydrochloride: the free base of patents is dissolved with ethyl acetate, and chlorination is added dropwise
Hydroacetic acid ethyl ester solution stirs 10min, and petroleum ether is added, and precipitating is precipitated, and precipitating is used petroleum ether 3 times, is removed under reduced pressure molten
Agent obtains the hydrochloride of product.
The preparation of reference standard solution: it respectively by sofosbuvir, the hydrochloride of patents, is dissolved, is matched with methanol
At the solution of 0.5mg/ml.
Sample to be tested is dissolved with water, until Precipitation is arranged at bottom, filtering, with determined by ultraviolet spectrophotometry extinction system
Number, calculates sample concentration, and result of the solubility greater than 6mg/ml, MJ10702 and MJ10703 of test display patents is shown in
Table 4.
4 invention compound solubility of table
Compound | sofosbuvir | MJ10702 hydrochloride | MJ10703 hydrochloride |
Solubility | <2mg/ml | >10mg/ml | >15mg/ml |
Claims (9)
1. compound of formula I or its pharmaceutically acceptable acid salt:
Wherein:
R1For C1~4Alkyl;
R2For the phenyl or naphthyl arbitrarily replaced, substituent group is selected from C1~4Alkyl, C1~4Alkoxy;
R3For natural amino acid acyl group.
2. compound of formula I according to claim 1 or its pharmaceutically acceptable acid salt, wherein R1For methyl, ethyl or
Isopropyl.
3. compound of formula I according to claim 1 or its pharmaceutically acceptable acid salt, wherein R2For phenyl or naphthyl.
4. compound of formula I according to claim 1 or its pharmaceutically acceptable acid salt, wherein R3For glycyl, third
Aminoacyl, valyl base, leucyl-, isoleucyl-, phenylalanyl, tryptophanyl, tyrosyl, aspartyl,
Asparaginyl-, glutamyl, glutaminyl, lysyl-, methionyl, seryl-, Threonyl, half Guang
Aminoacyl, prolyl, histamine acyl group, arginyl-.
5. compound of formula I according to claim 1 or its pharmaceutically acceptable acid salt, wherein R1For methyl, ethyl or
Isopropyl;R2For phenyl or naphthyl;R3For glycyl, alanyl, valyl base, leucyl-, isoleucyl-, phenylpropyl alcohol
Aminoacyl, tryptophanyl, tyrosyl, aspartyl, asparaginyl-, glutamyl, glutaminyl, lysyl
Base, methionyl, seryl-, Threonyl, cysteinyl-, prolyl, histamine acyl group, arginyl-.
6. compound of formula I according to claim 1 or its pharmaceutically acceptable acid salt, wherein compound is selected from:
7. a kind of pharmaceutical composition, it includes compound of formula I according to any one of claims 1 to 6 or its is pharmaceutically acceptable
Acid salt.
8. compound of formula I according to any one of claims 1 to 6 or its pharmaceutically acceptable acid salt be used to prepare prevention or
Treat the purposes in terms of mammalian virus infection medicine.
9. compound of formula I according to any one of claims 1 to 6 or its pharmaceutically acceptable acid salt be used to prepare prevention or
Treat the purposes in terms of hepatitis C, cirrhosis or liver-cancer medicine.
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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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