CN108530484A - Liver-targeted anti-HBV drug - Google Patents
Liver-targeted anti-HBV drug Download PDFInfo
- Publication number
- CN108530484A CN108530484A CN201710116211.5A CN201710116211A CN108530484A CN 108530484 A CN108530484 A CN 108530484A CN 201710116211 A CN201710116211 A CN 201710116211A CN 108530484 A CN108530484 A CN 108530484A
- Authority
- CN
- China
- Prior art keywords
- peak
- fumarate
- powder
- formula
- nucleotide analogues
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of liver-targeted anti-HBV drugs, provide the salt of the double O-ethoxyl phenolic esters (TDP) of tenofovir shown in Formula II and the fumaric acid formation of 1/2 equivalent：
Description
Technical field
Shown in Formula II, the fumaric acid shape of tenofovir double O-ethoxyl phenolic esters (TDP) and 1/2 equivalent
At salt, and contain pharmaceutical composition of the salt shown in Formula II as active constituent, and its preparing virus B hepatitis
Purposes in medicine：
Background technology
[[(R) -2- (6- Amino-purin -9- bases) -1- methyl-ethoxies -] methyl] phosphonic acids (PMPA) is with Anti-HBV activity
Active nucleotide analog.But PMPA oral administration biaavailabilities are low, and it is rich to have developed its prodrug tenofovir pyrrole furan ester thus
Horse hydrochlorate (tenofovir disoproxil fumarate, TDF)：
The oral PMPA for entering rear release active form in vivo of TDF, play antivirus action；Clinically TDF can
The HBV DNA levels in hepatitis B patient blood are quickly reduced, effective to lamivudine resistance Strain, itself drug resistance is low.But
It is that TDF prolonged applications can lead to the side effect of osteoporosis.
File CN102485229B discloses the Acyclic nucleotide analogues and its non-toxic pharmacy of crystalline state shown in Formulas I
Upper acceptable salt：
Free alkali (the I of Acyclic nucleotide analogues including crystalline state shown in Formulas I1), hydrochloride (I2), phosphate
(I3), mesylate (I4), citrate (I5), fumarate (I6), L-TARTARIC ACID salt (I7), L MALIC ACID salt (I8) and D-
Malate (I8).Wherein, I2、I4And I6Show preferable crystal character, preferable pharmacokinetic property and higher body
Interior anti-dhbv dna effect.
But results of stability shows I2、I4And I6After placing 12 months, crystal form changes；And place 12
Sample its pharmacokinetic property after a month also significantly changes.
Invention content
Present invention offer is formed by the fumaric acid of the double O-ethoxyl phenolic esters (TDP) of 1 equivalent tenofovir and 1/2 equivalent
Salt, structure is as shown in Formula II：
The present invention also provides the fumarates of the TDP of crystalline state shown in Formula II (code name MBT1316), it is characterised in that makes
It is radiated with Cu-K α, with the powder x-ray diffraction collection of illustrative plates that 2 θ angles indicate, has at least three to be selected from about following position
Absorption peak：8.63±0.10、11.74±0.10、14.02±0.10、18.70±0.10、20.88±0.10、21.72±
0.10、25.10±0.10、28.37±0.10。
The present invention also provides the fumarates of the TDP of crystalline state shown in Formula II (code name MBT1316), it is characterised in that makes
It is radiated with Cu-K α, with the powder x-ray diffraction collection of illustrative plates that 2 θ angles indicate, has at least three to be selected from about following position
Absorption peak：8.63±0.10、11.74±0.10、14.02±0.10、18.70±0.10、20.88±0.10、21.72±
0.10、25.10±0.10、28.37±0.10；Wherein 25.10 ± 0.10 peak is highest peak.
The present invention also provides the fumarates of the TDP of crystalline state shown in Formula II (code name MBT1316), it is characterised in that makes
It is radiated with Cu-K α, with the powder x-ray diffraction collection of illustrative plates that 2 θ angles indicate, has at least three to be selected from about following position
Absorption peak：8.63±0.10、11.74±0.10、12.95±0.10、14.02±0.10、16.98±0.10、18.70±
0.10、20.88±0.10、21.72±0.10、25.10±0.10、25.95±0.10、28.37±0.10；Wherein 25.10 ±
0.10 peak is highest peak.
Another aspect of the present invention provides a kind of pharmaceutical composition, and it includes crystalline states shown in Formula II (code name MBT1316)
TDP fumarate as common pharmaceutical excipient in active constituent and pharmaceutical field.
The present invention also provides the fumarates of the TDP of crystalline state shown in Formula II to prepare virus B hepatitis medicine
Purposes in object.
Pharmaceutical composition according to the present invention can be dosage form below：Tablet is such as, but not limited to fast-release tablet, slowly
Piece, controlled release tablet, Film coated tablets, sugar coated tablet, buccal tablet, sublingual tablet, biological adhesive tablet etc.；Capsule is such as, but not limited to hard capsule
Agent, soft capsule etc.；Injection is such as, but not limited to sterile or bacteriostatic agent water type injection, oleo-injection, freezing
Dry powder-injection, microsphere for injection etc.；Spray is such as, but not limited to mouthspray use, nasal spray is used, local skin spraying
With equal spray；Aerosol is such as, but not limited to lung inhalation aerosol, local skin aerosol etc.；Nasal drop for example but
It is not limited to collunarium solution, drop nasal gel etc.；Powder spray is such as, but not limited to oral cavity powder spray, nasal cavity powder spray, office
Portion's skin powder spray etc..The preparation process of these preparations is that people in the art has knowledge or reference related religion section according to it
Book or reference book and can prepare.
Specific implementation mode
It is further illustrated the present invention below by specific embodiment, it should be understood, however, that, these embodiments are only
It is used for specifically describing in more detail, and is not to be construed as limiting the present invention in any form.
Reference implementation example 1 [[(R) -2- (6- Amino-purin -9- bases) -1- methyl-ethoxies -] methyl] (2- of phosphonic acids-two
Ethyoxyl-phenol) -ester hydrochloride (I2) preparation
By 144g (0.50mol) [[(R) -2- (6- Amino-purin -9- bases) -1- methyl-ethoxies -] methyl] phosphonic acids,
276g (2.00mmol) o-ethoxyphenols and 390g 1-Methyl-2-Pyrrolidones are heated to 85 DEG C, and tri- second of 63g is then added
309g (1.50mmol) DCC was added in amine, in 100 DEG C of heating stirrings 16 hours.It is cooling, filter off solid；Filtrate decompression is concentrated,
Required component is collected with dichloromethane: methanol (20: 1) mixed solvent elutes with silica gel (200-300 mesh) post separation, decompression is steamed
It is dry, obtain [[(R) -2- (6- Amino-purin -9- bases) -1- methyl-ethoxies -] methyl] phosphonic acids-two (2- ethyoxyls-phenol) -ester
(the double O-ethoxyl phenolic esters of tenofovir, TDP) 62g.
13g (25.3mmol) TDP is dissolved in 50ml acetone (water content ＜ 0.2%), the diethyl ether solution of hydrogen chloride is added dropwise, is controlled
Rate of addition processed finishes for about 5 minutes, until pH is 2-3, the fixing fabric structure of ether and acetone is in (1: 5~1: 30), and flow back 10min,
Solid is precipitated in Temperature fall.Filtering, is washed, natural drying at room temperature 6 hours with cold recrystallisation solvent, then 60 DEG C of vacuum drying 8
Hour, obtain I213.1g, 185-186 DEG C of fusing point.
Reference implementation example 2 [[(R) -2- (6- Amino-purin -9- bases) -1- methyl-ethoxies -] methyl] (2- of phosphonic acids-two
Ethyoxyl-phenol) -ester mesylate (I4) preparation
13g (25.3mmol) TDP is dissolved in 50ml acetone (water content 2%~5%), 4ml methanesulfonic acids are added, stands nature
It is cooled to room temperature, there is crystallization to be slowly precipitated, be subsequently placed in 0-4 DEG C of refrigerator overnight.Filtering, is washed, room with cold recrystallisation solvent
Temperature spontaneously dries 6 hours, is then dried in vacuo 8 hours for 60 DEG C, obtains I411.4g, 140-142 DEG C of fusing point.
Reference implementation example 3 [[(R) -2- (6- Amino-purin -9- bases) -1- methyl-ethoxies -] methyl] (2- of phosphonic acids-two
Ethyoxyl-phenol) -ester fumarate (I6) preparation
26g (50.6mmol) TDP is dissolved in 160ml acetone, 6g (51.6mmol) fumaric acid and the (control of suitable water is added
The ratio of acetone and water is 16: 1~100: 1), being back to clarification, natural cooling cooling is precipitated white solid, filters, and filter cake is used
Then the cold ethyl alcohol washings of 50ml, natural drying at room temperature 6 hours are dried in vacuo 8 hours for 60 DEG C, obtain I626.8g, fusing point 154-157
℃。
Embodiment 1 [[(R) -2- (6- Amino-purin -9- bases) -1- methyl-ethoxies -] methyl] (2- ethoxies of phosphonic acids-two
Base-phenol) -ester 1/2 fumarate (II, code name MBT1316) preparation
In 150ml absolute methanols, 9g TDP, 0.5g fumaric acid is added, heating makes to be completely dissolved, and keeps the temperature 15 minutes.Subtract
Solvent is evaporated off in pressure, obtains white solid；150ml ethyl alcohol is added in obtained solid, dissolves by heating；It is slowly cooled to room temperature, is precipitated
Crystallization；Then it stands overnight, filters in 5 DEG C of refrigerators, solid is washed with a small amount of ice-cold ethyl alcohol, is then dried in vacuo 12 in 90 DEG C
Hour, obtain II (code name MBT1316) 7.4g.
2 stability of crystal form of embodiment is investigated
By compound I2、I4、I6And MBT1316 simulation listing packagings (vial tin plate cover) are in 25 DEG C of RT, RH 60%
(KNO3Saturated solution) under the conditions of place, sampled after December, obtain study on the stability sample I2(12)、I4(12)、I6(12) and
MBT1316 (12) measures powder X-ray diffracting spectrum and investigates its stability of crystal form with 0 day trace analysis.
The characterization of 3 crystal type of embodiment
Using powder x-ray diffraction method and differential scanning calorimetry (DSC) to target compound I of the invention2、I4、I6
With 12 months sample I of MBT1316 and study on the stability2(12)、I4(12)、I6(12) and the crystal type of MBT1316 (12) carries out
Characterization.
Powder x-ray diffraction test condition and method：Instrument model：DMAX-2500；Experimental method：Sample to be tested is ground
It is carefully 200-300 mesh, scanning angle range 3.0-60.0 degree, sweep speed is the counting of 0.15 degrees second.
Test result：
Fig. 1 is I2Powder X-ray diffracting spectrum；Abscissa is 2 angles θ, and ordinate is the intensity of absorption peak.
Fig. 2 is I4Powder X-ray diffracting spectrum；Abscissa is 2 angles θ, and ordinate is the intensity of absorption peak.
Fig. 3 is I6Powder X-ray diffracting spectrum；Abscissa is 2 angles θ, and ordinate is the intensity of absorption peak.
Fig. 4 is the powder X-ray diffracting spectrum of MBT1316；Abscissa is 2 angles θ, and ordinate is the intensity of absorption peak.
Fig. 5 is I2(12) powder X-ray diffracting spectrum；Abscissa is 2 angles θ, and ordinate is the intensity of absorption peak.
Fig. 6 is I4(12) powder X-ray diffracting spectrum；Abscissa is 2 angles θ, and ordinate is the intensity of absorption peak.
Fig. 7 is I6(12) powder X-ray diffracting spectrum；Abscissa is 2 angles θ, and ordinate is the intensity of absorption peak.
Fig. 8 is the powder X-ray diffracting spectrum of MBT1316 (12)；Abscissa is 2 angles θ, and ordinate is the intensity of absorption peak.
The Pharmacokinetic Evaluation of 4 Oral Administration in Rats of embodiment administration
4.1HPLC experiment condition
By conditions such as more different mobile phase composition ratio, flow velocity and pH, determines and measure activity with following chromatographic condition
The concentration of molecule PMPA.
Analytical column：Discovery ODS, 250 × 4.6mm I.D., 5 μm of grain sizes, Supelco companies
Pre-column：C18Guard column, Phenomenex companies of the U.S. 4.0 × 3.0mm I.D.
Column temperature：24℃；Mobile phase：Methanol-water-formic acid (20: 80: 0.5, v/v/v)
Flow velocity：0.5mL/min；Sample size：20μL
Internal standard：PMEA (4 μ g/mL aqueous solutions)
The concentration of PMPA is measured with following Mass Spectrometry Conditions：Ion source is the source electro-spray ionization (Turbo Ionspray)；
Positive ion mode detects；Injection electric is 4000V；Source temperature is 350 DEG C；Atomization gas (NEB) is 8；Roller shutter gas (CUR) is 11；
Collision gas (CAD) is 5；Scan mode is multiple-reaction monitoring (MRM), and the ionic reaction for quantitative analysis is respectively m/z 274
→ m/z 162 (PMPA, collision voltage CE are 40V) and 288 → m/z of m/z 176 (internal standard PMEA, CE 35V)；Sweep time
For 200msec.
4.2 experimental program
Male SD rat, fasting 16h is random to be grouped, 5/group, and gavage gives the I of Tween 80 suspension respectively4With
12 months sample I of MBT1316 and study on the stability4(12) and MBT1316 (12).Dosage is 50mg/kg.In administration before and
0.25,0.5,0.75,1.0,1.5,2.0,3.0,6.0,12.0,24.0 hour after administration, take a blood sample in rat eyeground vein clump
0.5mL centrifuges 10min in 3500r.p.m., isolates blood plasma, to be measured in -20 DEG C of freezen protectives.Measure to obtain its different time
The content of PMPA in blood plasma.
4.3 pharmacokinetic parameters calculate
Blood concentration-time data are inputted into computer, pharmacokinetic parameter is calculated using non-room modelling.TmaxWith
CmaxUsing measured value, AUC is calculated with trapezoidal method0-tValue and AUC0-∞Value, with semilog graphing method, by the concentration of elimination phase end
Point calculates T1/2, and find out main pharmacokinetic parameter.It the results are shown in Table 1.
The dominant dynamic parameters of 1 rat oral gavage of table administration
| Parameter | Unit | I4 | I4(12) | MBT1316 | MBT1316(12) |
| AUC(0-t) | ug/L*h | 14821.08±3079.65 | 8409.89±3191.76 | 13719.18±3356.68 | 13041.27±3367.88 |
| AUC(0-∞) | ug/L*h | 15711.65±3618.29 | 8807.99±3324.77 | 14662.17±3673.37 | 13392.96±3506.8 |
| t1/2 | h | 5.80±1.3 | 5.51±0.98 | 5.84±1.34 | 4.41±0.33 |
| Tmax | h | 2.33±0.82 | 2.10±1.25 | 1.67±1.33 | 2.00±0.00 |
| Cmax | ug/L | 1200.58±308.33 | 884.20±243.18 | 1363.19±313.32 | 1483.12±326.56 |
The evaluation of 5 hepatic targeting of embodiment
4.1HPLC experiment condition
With embodiment 4.
4.2 experimental program
Male SD rat, fasting 16h is random to be grouped, 15/group, and gavage is given the fumaric acid that Tween 80 is suspended and replaced respectively
Nuo Fuwei pyrrole furan esters (TNF) and target compound MBT1316.Dosage is 10mg/kg.Every group 0.5 after administration, 1,2,
4,8 and 12 3 animals are respectively taken, taken a blood sample in rat eyeground vein clump, 3500r.p.m. centrifuges 10min, blood plasma is isolated, in -20
DEG C freezen protective measures PMPA contents；Animal is put to death simultaneously, liver is taken, weighs, prepares homogenate, measures PMPA contents in liver,
Evaluate hepatic targeting.It the results are shown in Table 2：
The hepatic targeting measurement result of 2 rat oral gavage of table administration
Claims (6)
1. the fumarate of Acyclic nucleotide analogues shown in Formula II：
2. the fumarate of Acyclic nucleotide analogues shown in Formula II described in claim 1：
It is characterized in that being radiated using Cu-K α, its powder x-ray diffraction collection of illustrative plates indicated with 2 θ angles, including 2 θ angle value are
8.63±0.10、11.74±0.10、14.02±0.10、18.70±0.10、20.88±0.10、21.72±0.10、25.10
± 0.10 and 28.37 ± 0.10 peak.
3. the fumarate of Acyclic nucleotide analogues shown in Formula II described in claim 1：
It is characterized in that being radiated using Cu-K α, its powder x-ray diffraction collection of illustrative plates indicated with 2 θ angles, including 2 θ angle value are
8.63±0.10、11.74±0.10、14.02±0.10、18.70±0.10、20.88±0.10、21.72±0.10、25.10
± 0.10 and 28.37 ± 0.10 peak；Wherein 25.10 ± 0.10 peak is highest peak.
4. the fumarate of Acyclic nucleotide analogues shown in Formula II described in claim 1：
It is characterized in that being radiated using Cu-K α, its powder x-ray diffraction collection of illustrative plates indicated with 2 θ angles, including 2 θ angle value are
8.63±0.10、11.74±0.10、12.95±0.10、14.02±0.10、16.98±0.10、18.70±0.10、20.88
± 0.10,21.72 ± 0.10,25.10 ± 0.10,25.95 ± 0.10 and 28.37 ± 0.10 peak；Wherein 25.10 ± 0.10
Peak is highest peak.
5. a kind of pharmaceutical composition, it includes the fumarates of the Acyclic nucleotide analogues described in claim 1-4 as work
Common pharmaceutical excipient in property ingredient and pharmaceutical field.
6. the fumarate of the Acyclic nucleotide analogues described in claim 1-4, and include the nothing described in claim 1-4
Cyclic nucleotide is preparing virus B hepatitis medicine similar to pharmaceutical composition of the fumarate as active constituent of object
In purposes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710116211.5A CN108530484A (en) | 2017-03-01 | 2017-03-01 | Liver-targeted anti-HBV drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710116211.5A CN108530484A (en) | 2017-03-01 | 2017-03-01 | Liver-targeted anti-HBV drug |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108530484A true CN108530484A (en) | 2018-09-14 |
Family
ID=63488371
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710116211.5A Pending CN108530484A (en) | 2017-03-01 | 2017-03-01 | Liver-targeted anti-HBV drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108530484A (en) |
-
2017
- 2017-03-01 CN CN201710116211.5A patent/CN108530484A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105229007B (en) | 2 ((base of 4 amino 3 (hydroxy phenyl of 3 fluorine 5) 1H pyrazolos [3,4 D] pyrimidine 1) methyl) 3 (2 (trifluoromethyl) benzyl) (3H) ketone derivatives of quinazoline 4 and its purposes as the kinase inhibitor of phosphoinositide 3 | |
| JP5539224B2 (en) | Therapeutic formulations based on asiatic acid and selected salts thereof | |
| TWI617561B (en) | Novel compound in crystalline form, pharmaceutical composition comprising the same, process for the preparation of said compound, and inhalation device comprising the pharmaceutical composition | |
| EP2742048B1 (en) | Inhibiting transient receptor potential ion channel trpa1 | |
| KR20100056488A (en) | Novel forms of cddo methyl ester | |
| CN109311832A (en) | The pa of Vortioxetine not hydrochlorate and its crystal form | |
| WO2009152160A1 (en) | Inhaled carbaprostacyclin and prostacyclin prodrugs for the treatment of pulmonary arterial hypertension | |
| CN103351367A (en) | Hydrochloride salt of 5-r3-f3-tivdroxyphenoxy)azetidip-1-vp-5-methyl-2.2- diphenylhexanamide | |
| CN105859814A (en) | Obeticholic acid compound and pharmaceutical composition thereof | |
| CN101314579B (en) | Waterless Peramivir crystal and medicament composition thereof | |
| CN104447904A (en) | Stable gastrodin crystal with high bioavailability for oral administration as well as preparation method, preparation and application thereof | |
| CN106138012B (en) | A kind of preparation method of Isosorbide Mononitrate spansule | |
| CN102099334A (en) | Novel compounds active as muscarinic receptor antagonists | |
| MX2012010952A (en) | Aildenafil citrate crystal form o, preparation method and use thereof. | |
| CN108530484A (en) | Liver-targeted anti-HBV drug | |
| US20140158116A1 (en) | Inhibiting trpa1 for the treatment of asthma | |
| CN115461052B (en) | Pharmaceutical use of complexes of ARB metabolites with NEP inhibitors for the prevention and/or treatment of kidney disease | |
| CN106536532A (en) | New polycrystalline form of tenofovir prodrug, and preparation method and application therefor | |
| KR20190126291A (en) | Pharmaceutical compositions comprising oxazine derivatives and their use in the treatment or prevention of Alzheimer's disease | |
| CN102485229B (en) | antiviral drugs | |
| CN109988104A (en) | Kaempferol and Pyrazinamide eutectic object and preparation method and its pharmaceutical composition and purposes | |
| CN103923124A (en) | Crystalline-state anti-hepatitis B virus drug | |
| Jia et al. | The bioavailability enhancement and insight into the action mechanism of poorly soluble natural compounds from co-crystals preparation: Oridonin as an example | |
| ES2598162T3 (en) | Zinc salt of rosuvastatin form I crystalline | |
| CN101323613B (en) | Berberine additive product, medicament containing the same and preparation thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180914 |