CN105524049A - Deuterated hepatitis C virus NS5A protein inhibitor - Google Patents
Deuterated hepatitis C virus NS5A protein inhibitor Download PDFInfo
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- CN105524049A CN105524049A CN201410510406.4A CN201410510406A CN105524049A CN 105524049 A CN105524049 A CN 105524049A CN 201410510406 A CN201410510406 A CN 201410510406A CN 105524049 A CN105524049 A CN 105524049A
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- compound
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- acceptable salt
- hepatitis
- alkali
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- AGPKZVBTJJNPAG-AKGZTFGVSA-N CCC(C)[C@@H](C(O)=O)N Chemical compound CCC(C)[C@@H](C(O)=O)N AGPKZVBTJJNPAG-AKGZTFGVSA-N 0.000 description 1
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Abstract
The invention relates to the field of pharmaceutical chemistry, and specifically relates to a deuterated hepatitis C virus NS5A protein inhibitor, a preparation method thereof, a pharmaceutical composition containing the inhibitor, and applications of the inhibitor and the pharmaceutical composition thereof in preparing medicines used for treating hepatitis C virus infections. The compound represented by the formula I and pharmaceutically acceptable salt thereof have excellent pharmacokinetic properties, and thus are suitable to be used as compounds for inhibiting hepatitis C virus NS5A protein. Further, the compound and the pharmaceutically acceptable salt thereof are suitable to be used for preparing medicines used for treating hepatitis C virus infections.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to deuterated hepatitis C virus NS 5 A protein on NS inhibitor, its preparation method, pharmaceutical composition, this inhibitor and pharmaceutical composition thereof containing this inhibitor purposes in the medicine of preparation treatment infection with hepatitis C virus.
Background technology
Daclatasvir is a kind of new drug for potential treatment hepatitis C developed by Bristol-Myers Squibb Co., and it plays a role by suppressing hepatitis C virus NS 5 A protein on NS, granted in Europe at present.The several genes type of Daclatasvir to HCV all reaches the inhibit activities of picomole, wherein with optimum to the inhibit activities of 1a, 1b and 4a.In the Daclatasvir clinical I phase for slow virus type hepatitis C patients is studied, for genotype 1 b HCV, single 100mg dosage can reach the viral reduction of 3.3log10 at 24h.
But this area still needs to develop compound hepatitis C virus NS 5 A protein on NS being had to inhibit activities or better pharmacodynamics performance.
Summary of the invention
The invention provides formula I or its pharmacy acceptable salt,
Wherein, R
1and R
2can be identical, also can be different, be selected from C independently of one another
1-4the C that alkyl, wherein part or all of hydrogen are replaced by deuterium (D)
1-4alkyl, prerequisite is R
1or R
2in at least containing deuterium (D) atom, and formula I does not comprise following compound:
In some embodiments, R
1and R
2identical, be selected from wherein the C that partly or entirely hydrogen is replaced by deuterium (D)
1-4alkyl.
In some embodiments, R
1and R
2identical, be selected from wherein the C that all hydrogen is replaced by deuterium (D)
1-4alkyl.Such as R
1and R
2be-CD
2cD
3,-CD
2cD
2cD
3,-CD (CD
3)
2,-CD
2cD
2cD
2cD
3,-CD
2cD (CD
3)
2, C (CD
3)
3.
In some embodiments, R
1and R
2difference, wherein R
1be selected from C
1-4alkyl, R
2be selected from the C that wherein part or all of hydrogen is replaced by deuterium (D)
1-4alkyl.
In some embodiments, R
1and R
2difference, wherein R
1be selected from C
1-4alkyl, R
2be selected from the C that wherein whole hydrogen is replaced by deuterium (D)
1-4alkyl.
In some embodiments, R
1and R
2difference, wherein R
1be selected from methyl, R
2be selected from the C that wherein whole hydrogen is replaced by deuterium (D)
1-4alkyl.Such as R
2be selected from-CD
3,-CD
2cD
3,-CD
2cD
2cD
3,-CD (CD
3)
2,-CD
2cD
2cD
2cD
3,-CD
2cD (CD
3)
2, C (CD
3)
3.
In some embodiments, R
1and R
2difference, wherein R
1be selected from C
1-4alkyl, R
2be selected from the C that wherein whole hydrogen is replaced by deuterium (D)
1-4alkyl, and R
1and R
2containing identical carbon atom number.
In some embodiments, R
1and R
2difference, wherein R
1be selected from C
1-4alkyl, R
2be selected from the C that wherein whole hydrogen is replaced by deuterium (D)
1-4alkyl, and R
1and R
2there is identical carbon atom number and carbochain structure.Such as R
1for-CH (CH
3)
2, R
2for-CD (CD
3)
2; R
1for-CH
2cH (CH
3)
2, R
2for-CD
2cD (CD
3)
2.
In a preferred embodiment of the invention, formula I is selected from following compounds:
Described " pharmacy acceptable salt " refers to the biological efficacy of the free bronsted lowry acids and bases bronsted lowry remaining specific compound and does not have the salt of biology undesirable action.The example of pharmacy acceptable salt of the present invention comprises those salt prepared by formula I and organic acid or inorganic acid reaction, includes but not limited to vitriol, pyrosulphate, hydrosulfate, sulphite, phosphoric acid salt, monohydric phosphate, metaphosphate, hydrochloride, hydrobromate, hydriodate, acetate, propionic salt, acrylate, formate, propionic salt, oxalate, malonate, succinate, fumarate, maleate, Citrate trianion, tartrate, mesylate, benzoate, phenyl acetate salt, mandelate.
In a preferred embodiment, pharmacy acceptable salt is dihydrochloride.
The present invention provides on the other hand the preparation method of compound a, comprising: under the existence of alkali and catalyzer, compound 7 and compound 8 obtain compound a through linked reaction,
Wherein above-mentioned reaction can be carried out under the protection of the rare gas element such as nitrogen, argon gas.
Wherein said alkali is selected from sodium bicarbonate, sodium carbonate, salt of wormwood or Potassium ethanoate.
Wherein said catalyzer is selected from palladium catalyst, such as tetrakis triphenylphosphine palladium, palladium etc.
Wherein reaction solvent is selected from one or more in dioxy six alkane, tetrahydrofuran (THF), dme or water.
Wherein compound 8 can prepare according to method disclosed in existing document, such as, be prepared according to method disclosed in WO2010132601 or WO2010148006.
Again on the one hand, the invention provides compound 7,
Further aspect of the present invention provides compound 7 for the preparation of the purposes of compound a.
Further aspect of the present invention provides the preparation method of compound 7, comprise: under the existence of alkali and condensing agent, compound 5 and compound 6 reacting generating compound 7, described alkali is selected from sodium carbonate, salt of wormwood, Potassium ethanoate, triethylamine or N, N-diisopropylethylamine (DIPEA), described condensing agent is selected from 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate (HBTU) or N, N'-dicyclohexylcarbodiimide (DCC), reaction solvent is selected from methylene dichloride, acetonitrile, DMF or tetrahydrofuran (THF).
Wherein compound 6 can prepare according to method disclosed in existing document, such as, be prepared according to method disclosed in WO2010138791 or WO2010132538.
The wherein preparation method of compound 5, comprise: in the presence of a base, compound 3 and compound 4 (i.e. Valine) reacting generating compound 5, described alkali be selected from sodium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, Potassium ethanoate or triethylamine one or more.
Wherein the preparation method of compound 3 comprises: in the presence of a base, and compound 1 and compound 2 carry out substitution reaction, and generate compound 3, described alkali is selected from sodium carbonate, salt of wormwood, Potassium ethanoate, triethylamine or DIPEA.
Wherein compound 1 and compound 2 obtain by commercially available purchase.
Concrete, the invention provides the preparation method of compound a, comprise the steps:
(1) under the existence of alkali and condensing agent, compound 5 and compound 6 reacting generating compound 7;
(2) under the existence of alkali and catalyzer, compound 7 and compound 8 obtain compound a through linked reaction.
Wherein, described in step (1), alkali is selected from sodium carbonate, salt of wormwood, Potassium ethanoate, triethylamine or N, N-diisopropylethylamine (DIPEA), described condensing agent is selected from 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate (HBTU) or N, N'-dicyclohexylcarbodiimide (DCC), reaction solvent is selected from methylene dichloride, acetonitrile, DMF or tetrahydrofuran (THF).
Wherein, step (2) can be carried out under the protection of the rare gas element such as nitrogen, argon gas; Described alkali is selected from sodium bicarbonate, sodium carbonate, salt of wormwood or Potassium ethanoate; Described catalyzer is selected from palladium catalyst, such as tetrakis triphenylphosphine palladium, palladium etc.; Reaction solvent be selected from dioxy six alkane, tetrahydrofuran (THF), dme or water one or more.
The present invention also provides a kind of pharmaceutical composition, and it contains formula I or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.In a specific embodiments of the present invention, wherein said formula I is selected from compound a, compound b or compound c.Carrier is that " acceptable " is meant to, and other compositions of itself and preparation are compatible, and pharmaceutically in acceptable carrier situation, the amount used in medicine 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, sweetener, thinner, sanitas, dyestuff/tinting material, flavoring toughener, tensio-active agent, wetting agent, dispersion agent, disintegrating agent, suspending agent, stablizer, isotonic agent, solvent or emulsifying agent.
Pharmaceutical composition of the present invention can be mixed with solid-state, semi-solid state, liquid state or gaseous state preparation, as tablet, pill, capsule, pulvis, granule, paste, emulsion, suspension agent, solution, suppository, injection, inhalation, gelifying agent, microballoon and aerosol etc.
The classical pathway giving pharmaceutical composition of the present invention includes but not limited to oral, rectum, thoroughly mucous membrane, through enteral administration, or local, in skin, suction, parenteral, sublingual, intravaginal, nose, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.Preferred oral administration or drug administration by injection.
The method manufacture that pharmaceutical composition of the present invention can adopt this area known, as the hybrid system, dissolution method, granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc. of routine.
In some embodiments, pharmaceutical composition of the present invention comprises other active compounds of at least one, other active compounds include but not limited to: immunomodulator is interferons such as, the inhibitor of other target (such as helicase, proteolytic enzyme, polysaccharase, metalloprotease or internal ribosome entry site) in other inhibitor of other antiviral drugs such as ribavirin, amantadine, NS5A, HCV life cycle.
Purposes in the medicine that further aspect of the present invention provides formula I or its pharmacy acceptable salt, pharmaceutical composition containing formula I or its pharmacy acceptable salt to infect in preparation treatment hepatitis C virus (HCV).In a specific embodiments of the present invention, wherein said formula I is selected from compound a, compound b or compound c.
Described HCV comprises its Multi-genotype and several genes hypotype, such as 1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a, 6a.
The present inventor unexpectedly discoverable type I (comprising compound a) and pharmacy acceptable salt thereof has more excellent pharmacokinetic property, therefore be suitable as the compound suppressing hepatitis C virus NS 5 A protein on NS, and then be applicable to the medicine of preparation treatment infection with hepatitis C virus.
Embodiment
The following examples can illustrate in greater detail the present invention, but do not limit the present invention in any form.
the synthesis of embodiment 1 compound a
Step (1)
At 0 DEG C, two (trichloromethyl) carbonic ether (4.97g, 16.75mmol), in chloroform (30ml), adds CD under stirring
3oD (2ml, 46.96mmol), slowly drips the mixing solutions of triethylamine (50mmol) and chloroform (10ml) afterwards, and period keeps temperature in 0 DEG C.Drip finish, continue stir 1h, after rise to stirring at room temperature 2h, TLC monitor reaction complete.Reaction solution washs through frozen water, anhydrous magnesium sulfate drying, and filter, removing solvent under reduced pressure, obtain compound 3, is colorless oil.
Step (2)
Sodium carbonate (1.83g, 17.2mmol) is added in the sodium hydroxide (1.32g) aqueous solution (33ml, 1mol/L) of Valine (3.9g, 33.29mmol).Ice bath slowly adds compound 3 (40mmol) after being cooled to 0 DEG C, slowly rise to room temperature afterwards, continues to stir 4h, TLC and monitors reaction and complete.Reaction solution through washed with dichloromethane, and cools with ice-water bath, and concentrated hydrochloric acid adjusts pH to 1-2, rear dichloromethane extraction, merges organic phase, anhydrous magnesium sulfate drying, and filter, removing solvent under reduced pressure and obtain compound 5, is white solid.
APCI-MSm/z:201.1(M+Na)
+。
1H-NMR(DMSO-d
6,500MHz)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(CH
3)
3),0.87(d,J＝3.4Hz,6H,CH(CH
3)
2)。
Step (3)
Compound 6 (1.49g, 5.11mmol) dissolve in appropriate anhydrous THF, add compound 5 (1.1g, 6.16mmol), with N, N-diisopropylethylamine (DIPEA) regulator solution pH to 8 ~ 9, add condensing agent HATU (3.91g, 10.26mmol).Stirred at ambient temperature, reaction solution becomes burgundy from Vandyke brown.TLC monitors reaction and completes.Removal of solvent under reduced pressure, rear q. s. methylene chloride dissolves, and after washing organic phase successively with saturated sodium bicarbonate aqueous solution and salt solution, silica gel column chromatography is purified to obtain yellow solid compound 7.Eluent is ethyl acetate: sherwood oil=1:2.
APCI-MSm/z:452.1(M+1)
+。
1H-NMR(DMSO-d
6,500MHz)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,ProNCH
2CH
2CH
2+ValCH),2.24～1.98(m,5H,ProNCH
2CH
2CH
2+ValCH(CH
3)
3),0.89(d,J＝3.4Hz,6H,CH(CH
3)
2)。
Step (4)
Compound 7 (0.25g, 0.56mmol), compound 8 (0.28g, 0.56mmol), sodium carbonate (0.152g, 1.44mmol), catalyzer tetrakis triphenylphosphine palladium are in tetrahydrofuran (THF)/water=10:1 (30mL).Nitrogen protection, reacts 24h hour at 80 DEG C, and TLC monitoring reaction terminates.Add q. s. methylene chloride after removal of solvent under reduced pressure to dissolve.After washing organic phase successively with saturated sodium bicarbonate aqueous solution and salt solution, silica gel column chromatography is purified, and obtains white foam solid compound a.Eluent is ethyl acetate: sherwood oil=1:1.
APCI-MSm/z:764.51(M+Na)
+。
1HNMR(DMSO-d
6,500MHz)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,ProNHCH
2CH
2CH
2),3.58(s,3H,OCH
3),2.24～1.98(m,10H,ProNHCH
2CH
2CH
2+CH(CH3)
2),0.87(d,J＝3.6Hz,12H,CH(CH
3)
2)。
In nuclear magnetic data, Val represents α-amino-isovaleric acid structure division, and imidazole represents imidazole ring part, and Ar represents phenyl moiety, and Pro represents pyrrolidine ring part." H " represents the hydrogen corresponding to specific peak.
pharmacokinetic Evaluation in embodiment 2 rat
Experiment purpose: after research rat gives daclatasvir, compound a, investigate relative bioavailability and pharmacokinetics behavior.
Laboratory animal:
Kind and strain: SPF level SD rat
Sex and quantity: male, 6
Weight range: 200 ~ 210g
Source: Shanghai western pul-Bi Kai laboratory animal company limited
Experiment and animal conformity certification number: SCXK (Shanghai) 2013-0016
Experimentation:
Rat, male, body weight 200 ~ 210g, is divided into 2 groups at random, starts overnight fasting in testing but can freely drink water noon before that day.Before blood specimen collection, in EDTA-K2 anticoagulant tube, add the 2M Fluorinse (esterase inhibitor) of 20 μ L in advance, after 80 degree of drying in oven, be placed in 4 degree of refrigerators and deposit.
Fasting 12h (can't help water) before animal subject administration, A group i.g. give daclatasvir5mg/kg, B group i.g. gives compound a 5.04mg/kg, respectively at 15min, 30min, 1h, 2h, 3h, 5h, 8h, 10h and 24h after (0h) before administration and administration, get blood 0.1-0.2mL in eye socket, after anti-freezing, as early as possible test tube is put upside down gently after mixing 5-6 time, centrifugal separation plasma under 4000rpm, 10min condition immediately.To be measured in-20 DEG C of preservations after collecting whole blood plasma.The Plasma Concentration in the blood plasma of each time point is measured after all time point sample collectings.
According to mean blood plasma concentration-time data after the administration of above-mentioned gained, adopt Winnonin computed in software main pharmacokinetic parameter.Refer to table 1.
After table 1. rat gives daclatasvir and compound a, medicine is for parameter
Claims (10)
1. compound a or its pharmacy acceptable salt, wherein D is deuterium,
2. the compound a of claim 1 or its pharmacy acceptable salt, wherein said pharmacy acceptable salt is dihydrochloride.
3. compound 7,
4. a preparation method for compound a, comprising: under the existence of alkali and catalyzer, compound 7 and compound 8 obtain compound a through linked reaction,
5. the preparation method of claim 4, wherein said alkali is selected from sodium bicarbonate, sodium carbonate, salt of wormwood or Potassium ethanoate.
6. the preparation method of claim 4, wherein said catalyzer is selected from palladium catalyst.
7. the preparation method of claim 4, wherein reaction solvent is selected from one or more in dioxy six alkane, tetrahydrofuran (THF), dme or water.
8. a preparation method for compound a, comprises the following steps:
(1) under the existence of alkali and condensing agent, compound 5 and compound 6 reacting generating compound 7;
(2) under the existence of alkali and catalyzer, compound 7 and compound 8 obtain compound a through linked reaction.
9. a pharmaceutical composition, it contains formula compound a or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.
10. the purposes of pharmaceutical composition in the medicine of preparation treatment infection with hepatitis C virus of the compound a of claim 1 or 2 or its pharmacy acceptable salt, claim 9.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410510406.4A CN105524049B (en) | 2014-09-28 | 2014-09-28 | Deuterated hepatitis C virus NS 5 A protein on NS inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410510406.4A CN105524049B (en) | 2014-09-28 | 2014-09-28 | Deuterated hepatitis C virus NS 5 A protein on NS inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105524049A true CN105524049A (en) | 2016-04-27 |
| CN105524049B CN105524049B (en) | 2018-11-06 |
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ID=55766619
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410510406.4A Active CN105524049B (en) | 2014-09-28 | 2014-09-28 | Deuterated hepatitis C virus NS 5 A protein on NS inhibitor |
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101558059B (en) * | 2006-08-11 | 2014-12-03 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
| US7728027B2 (en) * | 2007-08-08 | 2010-06-01 | Bristol-Myers Squibb Company | Process for synthesizing compounds useful for treating hepatitis C |
| RS55249B8 (en) * | 2009-05-13 | 2021-06-30 | Gilead Pharmasset Llc | Antiviral compounds |
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2014
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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. |
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