CN105524049B - Deuterated hepatitis C virus NS 5 A protein on NS inhibitor - Google Patents
Deuterated hepatitis C virus NS 5 A protein on NS inhibitor Download PDFInfo
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- CN105524049B CN105524049B CN201410510406.4A CN201410510406A CN105524049B CN 105524049 B CN105524049 B CN 105524049B CN 201410510406 A CN201410510406 A CN 201410510406A CN 105524049 B CN105524049 B CN 105524049B
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Abstract
The invention belongs to medicinal chemistry arts, and in particular to purposes of deuterated hepatitis C virus NS 5 A protein on NS inhibitor, preparation method, the pharmaceutical composition containing the inhibitor, the inhibitor and its pharmaceutical composition in the drug for preparing treatment infection with hepatitis C virus.The compound of formula I and its pharmaceutically acceptable salt of the present invention has excellent pharmacokinetic property, therefore is suitable as inhibiting the compound of hepatitis C virus NS 5 A protein on NS, and then is suitble to prepare the drug for the treatment of infection with hepatitis C virus.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to deuterated hepatitis C virus NS 5 A protein on NS inhibitor, its system
Preparation Method, the pharmaceutical composition containing the inhibitor, the inhibitor and its pharmaceutical composition are preparing treatment Hepatitis C Virus
Purposes in the drug of infection.
Background technology
Daclatasvir is a kind of new drug for potential treatment hepatitis C developed by Bristol-Myers Squibb Co.,
It is played a role by inhibiting hepatitis C virus NS 5 A protein on NS, granted in Europe at present.Daclatasvir is to HCV's
Several genes type has all reached the inhibitory activity of picomole, wherein optimal with the inhibitory activity to 1a, 1b and 4a.For slow
In the Daclatasvir clinical I phase researchs of property virus type hepatitis C patients, for genotype 1 b HCV, single 100mg agent
Amount can be in the viral decrement for reaching 3.3log10 for 24 hours.
However, there is still a need for exploitations to have inhibitory activity or more preferable pharmacodynamics performance to hepatitis C virus NS 5 A protein on NS for this field
Compound.
Invention content
The present invention provides compound of formula I or its pharmaceutically acceptable salt,
Wherein, R1And R2It may be the same or different, be each independently selected from C1-4Alkyl, which part or whole hydrogen
The C replaced by deuterium (D)1-4Alkyl, on condition that R1Or R2In at least contain there are one deuterium (D) atom, and compound of formula I does not include following
Compound：
In some embodiments, R1And R2C that is identical, being replaced by deuterium (D) selected from which part or whole hydrogen1-4Alkyl.
In some embodiments, R1And R2C that is identical, being replaced by deuterium (D) selected from wherein whole hydrogen1-4Alkyl.Such as R1
And R2It is-CD2CD3、-CD2CD2CD3、-CD(CD3)2、-CD2CD2CD2CD3、-CD2CD(CD3)2、C(CD3)3。
In some embodiments, R1And R2Difference, wherein R1Selected from C1-4Alkyl, R2Selected from which part or whole hydrogen quilts
The C of deuterium (D) substitution1-4Alkyl.
In some embodiments, R1And R2Difference, wherein R1Selected from C1-4Alkyl, R2Selected from wherein whole hydrogen by deuterium (D)
Substituted C1-4Alkyl.
In some embodiments, R1And R2Difference, wherein R1Selected from methyl, R2Replaced by deuterium (D) selected from wherein whole hydrogen
C1-4Alkyl.Such as R2Selected from-CD3、-CD2CD3、-CD2CD2CD3、-CD(CD3)2、-CD2CD2CD2CD3、-CD2CD(CD3)2、C
(CD3)3。
In some embodiments, R1And R2Difference, wherein R1Selected from C1-4Alkyl, R2Selected from wherein whole hydrogen by deuterium (D)
Substituted C1-4Alkyl, and R1And R2Contain identical carbon atom number.
In some embodiments, R1And R2Difference, wherein R1Selected from C1-4Alkyl, R2Selected from wherein whole hydrogen by deuterium (D)
Substituted C1-4Alkyl, and R1And R2Carbon atom number having the same and carbochain construction.Such as R1For-CH (CH3)2, R2For-CD
(CD3)2；R1For-CH2CH(CH3)2, R2For-CD2CD(CD3)2。
In a preferred embodiment of the invention, compound of formula I is selected from following compounds：
" pharmaceutically acceptable salt " refer to the biological efficacy for the free bronsted lowry acids and bases bronsted lowry for remaining specific compound and
There is no the salt of biology ill-effect.The example of pharmaceutically acceptable salt of the present invention include make compound of formula I and organic acid or
Inorganic acid reaction prepare those of salt, including but not limited to sulfate, pyrosulfate, disulfate, sulphite, phosphate,
Dibasic alkaliine, metaphosphate, hydrochloride, hydrobromate, hydriodate, acetate, propionate, acrylates, formates, third
Hydrochlorate, oxalates, malonate, succinate, fumarate, maleate, citrate, tartrate, mesylate, benzene
Formates, phenyl acetate salt, mandelate.
In a preferred embodiment, pharmaceutically acceptable salt is dihydrochloride.
Another aspect of the present invention provides the preparation method of compound a, including：In the presence of alkali and catalyst, compound 7
Compound a is made through coupling reaction with compound 8,
Wherein above-mentioned reaction can carry out under the protection of the inert gases such as nitrogen, argon gas.
The wherein described alkali is selected from sodium bicarbonate, sodium carbonate, potassium carbonate or potassium acetate.
The wherein described catalyst is selected from palladium catalyst, such as tetrakis triphenylphosphine palladium, palladium etc..
Wherein reaction dissolvent is one or more in six alkane of dioxy, tetrahydrofuran, dimethyl ether or water.
Wherein compound 8 can be prepared according to method disclosed in existing literature, for example, according to WO2010132601 or
It is prepared by method disclosed in WO2010148006.
In another aspect, the present invention provides compound 7,
Further aspect of the present invention provides the purposes that compound 7 is used to prepare compound a.
Further aspect of the present invention provides the preparation method of compound 7, including：In the presence of alkali and condensing agent, compound 5
It is reacted with compound 6 and generates compound 7, the alkali is selected from sodium carbonate, potassium carbonate, potassium acetate, triethylamine or N, N- diisopropyls
Ethamine (DIPEA), the condensing agent are selected from 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters
(HATU), benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphate (HBTU) or N, N'- dicyclohexylcarbodiimide
(DCC), reaction dissolvent is selected from dichloromethane, acetonitrile, DMF or tetrahydrofuran.
Wherein compound 6 can be prepared according to method disclosed in existing literature, for example, according to WO2010138791 or
It is prepared by method disclosed in WO2010132538.
The wherein preparation method of compound 5, including：In the presence of a base, compound 3 and compound 4 (i.e. Valine) are anti-
Should generate compound 5, the alkali in sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium acetate or triethylamine one
Kind is a variety of.
The preparation method of wherein compound 3 includes：In the presence of a base, compound 1 carries out substitution reaction with compound 2, raw
At compound 3, the alkali is selected from sodium carbonate, potassium carbonate, potassium acetate, triethylamine or n,N-diisopropylethylamine.
Wherein compound 1 and compound 2 can be obtained by commercially available purchase.
Specifically, the present invention provides the preparation method of compound a, include the following steps：
(1) in the presence of alkali and condensing agent, compound 5 and the reaction of compound 6 generate compound 7；
(2) in the presence of alkali and catalyst, compound a is made through coupling reaction in compound 7 and compound 8.
Wherein, alkali described in step (1) is selected from sodium carbonate, potassium carbonate, potassium acetate, triethylamine or n,N-diisopropylethylamine
(DIPEA), the condensing agent is selected from 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters
(HATU), benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphate (HBTU) or N, N'- dicyclohexylcarbodiimide
(DCC), reaction dissolvent is selected from dichloromethane, acetonitrile, DMF or tetrahydrofuran.
Wherein, step (2) can carry out under the protection of the inert gases such as nitrogen, argon gas；The alkali is selected from sodium bicarbonate, carbon
Sour sodium, potassium carbonate or potassium acetate；The catalyst is selected from palladium catalyst, such as tetrakis triphenylphosphine palladium, palladium etc.；React molten
Agent is one or more in six alkane of dioxy, tetrahydrofuran, dimethyl ether or water.
The present invention also provides a kind of pharmaceutical compositions, contain compound of formula I or its pharmaceutically acceptable salt and medicine
Acceptable carrier on.In one embodiment of the invention, wherein the compound of formula I is selected from compound a, changes
Close object b or compound c.Carrier is that " acceptable " is meant, compatible with the other compositions of preparation, and can pharmaceutically be connect
In the case of the carrier received, the amount used in drug is harmless to its recipient.
The pharmaceutically acceptable carrier that can be used in pharmaceutical composition of the present invention includes but not limited to any glidant, increasing
Edulcorant, preservative, dyestuff/colorant, flavoring reinforcing agent, surfactant, wetting agent, dispersant, disintegrant, helps diluent
Suspension, stabilizer, isotonic agent, solvent or emulsifier.
Pharmaceutical composition of the present invention can be configured to solid-state, semisolid, liquid or gaseous state preparation, such as tablet, pill, capsule
Agent, pulvis, granule, paste, emulsion, suspending agent, solution, suppository, injection, inhalant, gelling agent, microballoon and aerosol
Deng.
The classical pathway for giving pharmaceutical composition of the present invention includes but not limited to oral, rectum, saturating mucous membrane, through enteral administration,
Or part, percutaneous, sucking, parenteral, sublingual, intravaginal, intranasal, intraocular, in peritonaeum, intramuscular, subcutaneous, intravenous administration.
It is preferred that oral medication or drug administration by injection.
The pharmaceutical composition of the present invention may be used method manufacture well known in the art, such as conventional mixing method, dissolution method,
Granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc..
In some embodiments, pharmaceutical composition of the invention includes other at least one reactive compounds, other work
Property compound includes but not limited to：Immunomodulator such as interferons, other antiviral agents such as Ribavirin, adamantane
Other targets (such as unwindase, protease, polymerase, metalloprotein in amine, other inhibitor of NS5A, HCV life cycles
Enzyme or internal ribosome entry site) inhibitor.
Further aspect of the present invention provides compound of formula I or its pharmaceutically acceptable salt, contains compound of formula I or its pharmacy
Purposes of the pharmaceutical composition of upper acceptable salt in preparing the drug that treatment Hepatitis C Virus (HCV) infects.In this hair
In a bright specific embodiment, wherein the compound of formula I is selected from compound a, compound b or compound c.
The HCV includes its Multi-genotype and several genes hypotype, for example, 1a, 1b, 2a, 2b, 3a, 3b, 4a,
5a、6a。
Inventors have surprisingly discovered that compound of formula I (including compound a) and its pharmaceutically acceptable salt have
Superior pharmacokinetic property, therefore be suitable as inhibiting the compound of hepatitis C virus NS 5 A protein on NS, and then be suitble to
Prepare the drug for the treatment of infection with hepatitis C virus.
Specific implementation mode
The present invention can be described in more detail in the following examples, but the invention is not limited in any way.
The synthesis of 1 compound a of embodiment
Step (1)
At 0 DEG C, bis- (trichloromethyl) carbonic esters (4.97g, 16.75mmol) are added with stirring in chloroform (30ml)
CD3The mixed solution of triethylamine (50mmol) and chloroform (10ml) is slowly added dropwise in OD (2ml, 46.96mmol) later, during which protects
Temperature is held in 0 DEG C.Drop finish, continue stir 1h, after be warmed to room temperature stirring 2h, TLC monitoring reaction complete.Reaction solution is washed through ice water
It washs, anhydrous magnesium sulfate drying, filtering removes solvent under reduced pressure, obtains compound 3, is colorless oil.
Step (2)
Sodium carbonate (1.83g, 17.2mmol) is added to the sodium hydroxide (1.32g) of Valine (3.9g, 33.29mmol)
In aqueous solution (33ml, 1mol/L).Ice bath is slowly added to compound 3 (40mmol) after being cooled to 0 DEG C, after be slowly increased to room temperature,
Continue to stir 4h, TLC monitoring reactions are completed.Reaction solution is washed through dichloromethane, and ice-water bath is used in combination to cool down, concentrated hydrochloric acid tune pH to 1-
2, after extracted with dichloromethane, merge organic phase, anhydrous magnesium sulfate drying, filtering, remove solvent under reduced pressure and obtain compound 5, be white
Color solid.
APCI-MS m/z:201.1(M+Na)+。
1H-NMR(DMSO-d6,500MHz)δ:12.49 (s, H, ValCOOH), 7.29 (s, H, ValNH), 3.86~3.81
(m, H, ValCH), 2.08~1.97 (m, H, ValCH (CH3)3), 0.87 (d, J=3.4Hz, 6H, CH (CH3)2)。
Step (3)
Compound 6 (1.49g, 5.11mmol) dissolves in appropriate anhydrous THF, addition compound 5 (1.1g,
6.16mmol), adjust pH value of solution to 8~9 with n,N-diisopropylethylamine (DIPEA), be added condensing agent HATU (3.91g,
10.26mmol).It stirs at room temperature, reaction solution becomes claret from dark brown.TLC monitoring reactions are completed.Solvent is removed under reduced pressure,
It is dissolved afterwards with q. s. methylene chloride, after washing organic phase successively with saturated sodium bicarbonate aqueous solution and saline solution, silica gel column chromatography
Purify to obtain yellow solid compound 7.Eluant, eluent is ethyl acetate：Petroleum ether=1:2.
APCI-MS m/z:452.1(M+1)+。
1H-NMR(DMSO-d6,500MHz)δ:11.88 (s, H, imidazoleNH), 7.59~7.40 (m, 4H, ArH),
7.23~7.05 (m, 2H, NHCO+imidazoleCH), 5.24~5.08 (m, H, ProCH), 3.85~3.75 (m, 3H,
ProNCH2CH2CH2+ ValCH), 2.24~1.98 (m, 5H, ProNCH2CH2CH2+ValCH(CH3)3), 0.89 (d, J=3.4Hz,
6H,CH(CH3)2)。
Step (4)
Compound 7 (0.25g, 0.56mmol), compound 8 (0.28g, 0.56mmol), sodium carbonate (0.152g,
1.44mmol), catalyst tetrakis triphenylphosphine palladium is in tetrahydrofuran/water=10:In 1 (30mL).Nitrogen protection is reacted at 80 DEG C
Hour for 24 hours, TLC monitoring reactions terminate.Q. s. methylene chloride dissolving is added after solvent is removed under reduced pressure.It is molten with saturated sodium bicarbonate water
After liquid and saline solution wash organic phase successively, silica gel column chromatography purification obtains white foam solid compound a.Eluant, eluent is second
Acetoacetic ester:Petroleum ether=1:1.
APCI-MS m/z:764.51(M+Na)+。
1H NMR(DMSO-d6,500MHz)δ:11.56 (s, 2H, imidazoleNH), 7.69~7.48 (m, 8H, ArH),
7.26~7.03 (m, 4H, NHCO+imidazoleCH), 5.24~5.05 (m, 2H, ProCH), 4.09~4.04 (m, 2H,
), ValCH 3.85~3.75 (m, 4H, ProNHCH2CH2CH2),3.58(s,3H,OCH3), 2.24~1.98 (m, 10H,
ProNHCH2CH2CH2+CH(CH3)2), 0.87 (d, J=3.6Hz, 12H, CH (CH3)2)。
In nuclear magnetic data, Val indicates that valine structure division, imidazole indicate that imidazoles loop section, Ar indicate phenyl portion
Point, Pro indicates pyrrolidine ring part." H " indicates the hydrogen corresponding to specific peak.
Pharmacokinetic Evaluation in 2 rat of embodiment
Experiment purpose：After research rat gives daclatasvir, compound a, investigates relative bioavailability and medicine generation is dynamic
Mechanical behavior.
Experimental animal：
Type and strain：SPF grades of SD rats
Gender and quantity：Male, 6
Weight range：200~210g
Source：Shanghai western Poole-Bi Kai experimental animals Co., Ltd
Experiment and animal quality certification number：SCXK (Shanghai) 2013-0016
Experimentation：
Rat, male, 200~210g of weight is randomly divided into 2 groups, is fasted in experiment noon before that day overnight but can
Free water.Before blood specimen collection, the 2M Fluorinse (esterase inhibitions of 20 μ L are added in EDTA-K2 anticoagulant tubes in advance
Agent), after 80 degree of drying in oven, it is placed in 4 degree of refrigerator storages.
Fasting 12h (can't help water) before animal subject administration, A groups i.g. give daclatasvir 5mg/kg, and B groups i.g. gives
Give compound a 5.04mg/kg, before administration (0h) and administration after 15min, 30min, 1h, 2h, 3h, 5h, 8h, 10h and
For 24 hours, blood 0.1-0.2mL is taken in eye socket, after anti-freezing, after test tube is gently overturned mixing 5-6 times as early as possible, 4000rpm immediately,
Centrifugal separation plasma under the conditions of 10min.It is to be measured in -20 DEG C of preservations after the whole blood plasma of collection.It is surveyed after all time point sample collections
Determine the blood concentration in the blood plasma of each time point.
According to mean blood plasma concentration-time data after the administration of above-mentioned gained, main medicine is calculated using Winnonin softwares
For kinetic parameter.Refer to table 1.
Medicine is for parameter after 1. rat of table gives daclatasvir and compound a
Claims (12)
1. compound a or its pharmaceutically acceptable salt, wherein D are deuteriums,
2. the compound a of claim 1 or its pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is two hydrochloric acid
Salt.
3. compound 7,
4. a kind of preparation method of compound a, including：In the presence of alkali and catalyst, compound 7 and compound 8 are through coupling
Compound a is made in reaction,
5. the preparation method of claim 4, wherein the alkali is selected from sodium bicarbonate, sodium carbonate, potassium carbonate or potassium acetate.
6. the preparation method of claim 4, wherein the catalyst is selected from palladium catalyst.
7. the preparation method of claim 4, wherein reaction dissolvent in six alkane of dioxy, tetrahydrofuran, dimethyl ether or water one
Kind is a variety of.
8. a kind of preparation method of compound a, includes the following steps：
(1) in the presence of alkali and condensing agent, compound 5 and the reaction of compound 6 generate compound 7；
(2) in the presence of alkali and catalyst, compound a is made through coupling reaction in compound 7 and compound 8.
9. the preparation method of claim 8, wherein alkali described in step (1) is selected from sodium carbonate, potassium carbonate, potassium acetate, triethylamine
Or N, N- diisopropylethylamine；The condensing agent is selected from 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluoros
Phosphate, benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphate or N, N'- dicyclohexylcarbodiimide；React molten
Agent is selected from dichloromethane, acetonitrile, DMF or tetrahydrofuran.
10. the preparation method of claim 8, wherein alkali described in step (2) is selected from sodium bicarbonate, sodium carbonate, potassium carbonate or vinegar
Sour potassium；The catalyst is selected from palladium catalyst；The one kind of reaction dissolvent in six alkane of dioxy, tetrahydrofuran, dimethyl ether or water
Or it is a variety of.
11. a kind of pharmaceutical composition contains the compound a of claims 1 or 2 or its pharmaceutically acceptable salt and medicine
Acceptable carrier on.
12. prepared by the pharmaceutical composition of the compound a of claims 1 or 2 or its pharmaceutically acceptable salt, claim 11
Treat the purposes in the drug of infection with hepatitis C virus.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410510406.4A CN105524049B (en) | 2014-09-28 | 2014-09-28 | Deuterated hepatitis C virus NS 5 A protein on NS inhibitor |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410510406.4A CN105524049B (en) | 2014-09-28 | 2014-09-28 | Deuterated hepatitis C virus NS 5 A protein on NS inhibitor |
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| Publication Number | Publication Date |
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| CN105524049B true CN105524049B (en) | 2018-11-06 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101558059A (en) * | 2006-08-11 | 2009-10-14 | 百时美施贵宝公司 | Hepatitis C virus inhibitors |
| CN101778841A (en) * | 2007-08-08 | 2010-07-14 | 百时美施贵宝公司 | Be used for the synthetic method that is used for the treatment of the compound of hepatitis C |
| CN102596936A (en) * | 2009-05-13 | 2012-07-18 | 吉里德科学公司 | Antiviral compounds |
-
2014
- 2014-09-28 CN CN201410510406.4A patent/CN105524049B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101558059A (en) * | 2006-08-11 | 2009-10-14 | 百时美施贵宝公司 | Hepatitis C virus inhibitors |
| CN101778841A (en) * | 2007-08-08 | 2010-07-14 | 百时美施贵宝公司 | Be used for the synthetic method that is used for the treatment of the compound of hepatitis C |
| CN102596936A (en) * | 2009-05-13 | 2012-07-18 | 吉里德科学公司 | Antiviral compounds |
Non-Patent Citations (2)
| Title |
|---|
| Synthesis and biological evaluation of new potent and selective HCV NS5A inhibitors;Junxing Shi等;《Bioorganic & Medicinal Chemistry Letters》;20120329;第22卷(第10期);第3488页Figure 1 * |
| 氘代作用在药物研究中的应用;江文峰，李文保;《齐鲁药事》;20101115;第29卷(第11期);第682页右栏 * |
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Effective date of registration: 20191021 Address after: 222062 No. 369 Yuzhou South Road, Lianyungang City, Jiangsu Province Patentee after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Address before: 222006 No. 8 Julong North Road, Sinpo District, Jiangsu, Lianyungang Co-patentee before: Suzhou Southeast Pharmaceuticals Co., Ltd. Patentee before: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. |