CN112409379A - Deuterated dihydrodibenzothiazepine compounds and pharmaceutical compositions containing the same - Google Patents
Deuterated dihydrodibenzothiazepine compounds and pharmaceutical compositions containing the same Download PDFInfo
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- CN112409379A CN112409379A CN202011036892.2A CN202011036892A CN112409379A CN 112409379 A CN112409379 A CN 112409379A CN 202011036892 A CN202011036892 A CN 202011036892A CN 112409379 A CN112409379 A CN 112409379A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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- 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
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- 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
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
The invention relates to deuterated dihydrodibenzothiazepine compounds and prodrugs thereof, and pharmaceutical compositions containing the compounds and uses thereof. The deuterated dihydrodibenzothiazepine compound is a compound shown as a formula (I) or a tautomer, a stereoisomer, a prodrug, a crystal pharmaceutically acceptable salt, a hydrate or a solvate thereof. The compound and the composition have good cap-dependent endonuclease activity and better pharmacokinetic property, and can be used for treating and/or preventing symptoms and/or diseases caused by influenza virus infection.
Description
Technical Field
The invention relates to the field of medicine, in particular to a deuterated dihydrodibenzothiazepine compound shown as a formula I, a prodrug thereof, a composition containing the compound and application of the compound in treating influenza.
Background
Deuterium is substantially the same shape and volume as hydrogen in a drug molecule, and deuterated drugs generally retain the original biological activity and selectivity if hydrogen in the drug molecule is selectively replaced with deuterium. Meanwhile, researches prove that the combination of carbon and deuterium bonds is more stable than that of carbon-hydrogen bonds, and the absorption, distribution, metabolism, excretion and other properties of certain medicines can be directly influenced, so that the curative effect, safety and tolerance of the medicines are improved. Therefore, if a certain decomposed carbon-hydrogen bond in the drug molecule is deuterated to be a corresponding carbon-deuterium bond, the decomposition process of the drug molecule can be delayed, so that the deuterated drug can act in the body for a longer time, and the effect is better. Such as: sorafenib and deuterated compounds thereof, wherein the pharmacokinetic characteristics of the deuterated compounds in rats are better than that of the original drug Sorafenib: the half-life period is longer, the area under the curve is larger when the medicine is taken, and the apparent clearance rate is reduced, so that the action time is longer and the effect is more effective; first clinical experiments show that the metabolism speed of venlafaxine and its deuterated compounds is half of that of venlafaxine, so that the venlafaxine has a longer existing time in vivo and a more obvious curative effect. This demonstrates to some extent the superiority of the deuterated products in treating diseases.
Influenza, influenza or flu, is an acute respiratory infectious disease caused by infection with influenza virus, and has become the most lethal viral infectious disease. Influenza viruses are classified into three types, A, B and C (also known as A, B, C), according to the antigenic properties of the protein and the matrix protein. The influenza A virus has the widest host range and strong pathogenicity, can cause wide-range influenza outbreak in the world and has the greatest harm to human; the pathogenic ability of influenza B virus is low, mainly causing local outbreak; influenza C virus only infects people with low immunity, and causes fewer epidemics and relatively fewer harm.
In recent years, the risk of influenza-associated morbidity and mortality has increased in the elderly, pregnant women and high-risk groups with impaired immune function, and a recent study has shown that there are about 65 million dead fish influenza-associated respiratory diseases worldwide per year. Therefore, effective influenza treatment is crucial. At present, a lot of anti-influenza drugs cover different action mechanisms, but with the wide application of anti-influenza drugs, the problem of drug resistance is more serious, a novel influenza virus with higher lethality is possibly generated, and the global pandemic is caused, so that the development of anti-influenza drugs with new mechanisms is expected.
The dihydrodibenzothiazepine compound shown in formula (I) is a novel compound for resisting influenza virus, and can be used for treating acute simple influenza by inhibiting cap-dependent endonuclease PA to block the process of virus gene in the initial stage of transcription. However, it is known that the main reason for limiting the application range of drugs is the superiority and inferiority of the absorption, distribution, metabolism and/or excretion of drugs, and rapid metabolism results in the drugs not forming active metabolites or being metabolically cleared from the body without exerting therapeutic effects, thereby failing to exert better effects of drugs.
Therefore, the development of compounds with better pharmacokinetics and capability of inhibiting cap-dependent endonuclease activity of the PA still needs to be carried out in the field, and the deuterated dihydrodibenzothiazepine compound provided by the invention is the compound.
Disclosure of Invention
The invention aims to provide a novel deuterated compound with anti-influenza virus activity and better pharmacodynamic property, a prodrug thereof and a composition containing the compound.
In a first aspect of the present invention, there is provided a deuterated dihydrodibenzothiazepine compound represented by formula i, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof:
in the formula:
r is deuterium or the following deuterium (D) -substituted group forming a prodrug
a)
b)
c)
d)
e)
R1，R2、R3、R4、R5、R6、R7、R8、R9Each independently is hydrogen or deuterium, or all are deuterium;
R10、R11、R12、R13、R14、R15、R16、R17、R18、R19，R20each independently is hydrogen or deuterium, or all are deuterium;
R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31each independently is hydrogen or deuterium, or all are deuterium;
R32、R33、R34、R35、R36、R37，R38、R39、R40each independently is hydrogen or deuterium, or all are deuterium;
R41、R42、R43、R44、R45each independently is hydrogen or deuterium, or all are deuterium;
with the additional condition that: the above compounds contain at least one deuterium atom.
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the first aspect of the present invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
Definition of
Herein, "deuterated", unless otherwise specified, means that one or more hydrogens of the compound or group are replaced with deuteration; deuterium can be mono-, di-, poly-, or fully substituted. The terms "deuterated one or more" and "deuterated one or more" are used interchangeably.
Herein, unless otherwise specified, "non-deuterated compound" refers to a compound in which the deuterium atomic ratio is not higher than the natural deuterium isotope content (0.015%).
As used herein, the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.
As used herein, the term "crystalline form" refers to a different arrangement of chemical drug molecules, typically in the form of drug material in a solid state.
Compared with the prior art, the deuterated dihydrodibenzothiazepine compound has a series of advantages compared with the original compound:
(1) the compound has excellent inhibition on cap-dependent accounting PA endonuclease polymerization;
(2) the metabolism in organisms is changed by the deuteration technology, so that the metabolism of the drug is difficult, the half-life period of the drug can be prolonged, and a long-acting preparation is formed;
(3) after deuteration, the medicine concentration of the compound in an animal body can be improved due to the isotope effect, so that the medicine curative effect is improved.
Detailed Description
The inventor of the invention unexpectedly discovers that the deuterated dihydrodibenzothiazepine and the prodrug and the pharmaceutically acceptable salt thereof have obviously better pharmacokinetic and pharmacodynamic properties compared with non-deuterated compounds, so that the deuterated dihydrodibenzothiazepine and the prodrug are more suitable for resisting influenza viruses and are further more suitable for preparing medicaments for treating influenza and related diseases.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When the compound of the present invention or the pharmaceutical composition is used, the dosage form is not particularly limited. Solid dosage forms for oral administration include, but are not limited to, tablets, pills, dry suspensions, granules, powders, and capsules, and liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1: preparation of deuterated dihydrodibenzothiazepine
According to formula (i), when R is the per-deuterated formula a forming a prodrug, compounds of formula (ii) are obtained, which can be prepared by reaction scheme 1:
reaction scheme 1
In which the fragment a compound can be prepared by reaction scheme 2 below:
reaction scheme 2
In which the fragment B compound can be prepared by the following scheme 3:
reaction scheme 3
When R is the per-deuterated formula b forming a prodrug, according to formula (i), compounds of formula (iii) are obtained, which can be prepared by reaction scheme 4:
scheme 4:
in the formula, the compound of the fragment A can be prepared by the above reaction scheme 2, and the compound of the fragment B can be prepared by the above reaction scheme 3.
When R is the per-deuterated formula c, which forms a prodrug, according to formula (i), a compound of formula (iv) is obtained, which can be prepared by reaction scheme 5:
scheme 5:
in the formula, the compound of the fragment A can be prepared by the above reaction scheme 2, and the compound of the fragment B can be prepared by the above reaction scheme 3.
When R is the per-deuterated formula d, which forms a prodrug, according to formula (i), a compound of formula (v) is obtained, which can be prepared by reaction scheme 6:
scheme 6:
in the formula, the compound of the fragment A can be prepared by the above reaction scheme 2, and the compound of the fragment B can be prepared by the above reaction scheme 3.
When R is the per-deuterated formula e, which forms a prodrug, according to formula (i), a compound of formula (vi) is obtained, which can be prepared by reaction scheme 7:
scheme 7:
in the formula, the compound of the fragment A can be prepared by the above reaction scheme 2, and the compound of the fragment B can be prepared by the above reaction scheme 3.
Abbreviations in the above schemes are defined:
DMSO, DMSO: dimethyl sulfoxide (Dimethyl sulfoxide)
TsOH: p-toluenesulfonic acid
THF: tetrahydrofuran (Tetrahydrofuran)
DBU: is a sterically hindered amidine of basic nature
EA: ethyl acetate (ethyl acetate)
DMA: dimethylacetamide (DMAC or DMA), collectively known as N, N-Dimethylacetamide.
Example 2: dry suspension
Premixing the compound of the invention, mannitol, maltose, sodium chloride and hydroxypropyl methylcellulose by adopting a wet granulator, preparing povidone adhesive by using purified water, and adding the povidone adhesive into the premix for granulation; drying with a fluidized bed to obtain dry particles with proper particle size; adding colloidal silicon dioxide, talcum powder, sucralose, essence and dry particles, and totally mixing by a two-dimensional mixer to obtain the dry suspension.
Example 3: tablet formulation
The compound of the present invention, lactose hydrate, croscarmellose sodium, polyvinylpyrrolidone, crystalline cellulose, sodium stearyl fumarate, hydroxypropyl glucose and titanium oxide were mixed. The mixture was granulated and dried to obtain granules of suitable size. Talc was then added to the granules and mixed and the mixture compressed into tablets.
Example 4: granules
The compound of the invention (10 mg) and lactose were passed through a 60 mesh screen. The corn starch was passed through a 120 mesh screen. They were mixed with a V-blender. To this mixture was added an aqueous solution of HPC-L (low viscosity hydroxypropyl cellulose), and then the mixture was kneaded, granulated (extrusion granulation pore size 0.5-1 mm), and dried. The obtained dried granules were passed through a vibrating screen (12/60 mesh) to obtain granules.
Example 5: capsule preparation
The compound of the invention (15 mg) and lactose were passed through a 60 mesh screen. The corn starch was passed through a 120 mesh screen. They were mixed with a V-blender. Aqueous HPC-L (low viscosity hydroxypropyl cellulose) was added thereto, and then the mixture was kneaded, granulated (extrusion granulation pore size 0.5-1 mm), and dried. The obtained dry granules were granulated and filled in a size 4 hard gelatin capsule in a 150mg loading.
Example 6: pharmacokinetic evaluation in mice
Deuterated dihydrodibenzothiazepines and non-deuterated dihydrodibenzothiazepines of the formula (II) are used as examples.
8 mature mice, 7-8 weeks old, weighing about 30g, divided into 2 groups of 4 mice each, given a single oral dose of 1mg/kg of (a) control group: dihydrodibenzothiazepine compounds or (b) test group: deuterated dihydrodibenzothiazepine compounds were compared for their pharmacokinetic differences.
Each animal was anesthetized with isoflurane each time and then about 0.10ml of blood, EDTAK, was drawn through the orbit2Anticoagulation, the collection time points were: 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24 h. After completion of blood collection at the last time point, rats were sacrificed after ether anesthesia.
Plasma was separated by centrifugation within 1 hour after blood collection (centrifugation conditions: 5000 rpm, 5min, 4 ℃), 100 microliters of supernatant was pipetted into a clean plastic centrifuge tube, the name and time point of the compound was indicated, and stored at-80 ℃ for future use. After the collection of all time points is completed, analyzing and detecting samples by adopting LC-MS (liquid chromatography-mass spectrometry), obtaining concentration-time data, and analyzing and calculating by using DAS3.0 pharmacokinetic software to obtain a main absorption kinetic parameter T after a compound is administered to a mouse1/2(h)、AUC(0-t)(ng eq•h/mL)、AUC(0-∞)(ng eq.h/mL), and the like.
The results are as follows:
| compound (I) | Dihydrodibenzothiazepine | Deuterated dihydrodibenzothiazepine |
| T1/2(h) | 6.31±3.22 | 9.04±4.12 |
| AUC(0-t)(ng eq•h/mL) | 132±13 | 189±21 |
| AUC(0-∞) (ng eq•h/mL) | 141±34 | 196±41 |
Note: mean ± standard deviation.
The results show that the half-life T of the deuterated dihydrodibenzothiazepine compound is longer than that of the dihydrodibenzothiazepine compound1/2The AUC under the drug time curve is prolonged by 2.7 hours(0-∞)(ng eq.h/mL) increased by 43%. The deuterated dihydrodibenzothiazepine compound has good pharmacokinetic properties.
Claims (10)
1. A deuterated dihydrodibenzothiazepine compound represented by formula (I), or a tautomer, a stereoisomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof:
in the formula:
r is deuterium or the following deuterium (D) -substituted group forming a prodrug
a)
b)
c)
d)
e)
R1，R2、R3、R4、R5、R6、R7、R8、R9Each independently is hydrogen or deuterium;
R10、R11、R12、R13、R14、R15、R16、R17、R18、R19，R20each independently is hydrogen or deuterium;
R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31each independently is hydrogen or deuterium;
R32、R33、R34、R35、R36、R37，R38、R39、R40each independently is hydrogen or deuterium;
R41、R42、R43、R44、R45each independently is hydrogen or deuterium;
with the additional condition that: the above compounds contain at least one deuterium atom.
2. The compound of claim 1, wherein R is deuterium or the following per-deuterium (D) -substituted group forming a prodrug
3. The compound of claim 1, wherein R is deuterium or the following per-deuterium (D) -substituted group forming a prodrug
4. The compound of claim 1, wherein R is deuterium or the following per-deuterium (D) -substituted group forming a prodrug
5. The compound of claim 1, wherein R is deuterium or the following per-deuterium (D) -substituted group forming a prodrug
6. The compound of claim 1, wherein R is deuterium or the following per-deuterium (D) -substituted group forming a prodrug
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-6, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
8. Use of a compound according to any one of claims 1-6, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of claim 7, for the preparation of a medicament for the treatment or prevention of a disease caused by a virus having a cap-dependent endonuclease.
9. The use according to claim 8, wherein the disease caused by a virus having a cap-dependent endonuclease is selected from influenza a, influenza b or influenza c.
10. The process for the preparation of deuterated dihydrodibenzothiazepine compounds of formula (I) according to claim 1, which can be prepared by reacting a compound of the fragment A with a compound of the fragment B to give a compound of the formula (II) when R of formula (I) is a perheuterodeuterated compound of formula a) forming a prodrug,
1) the fragment a compound is prepared by the following route,
2) the fragment B compound is prepared by the following route,
the method is characterized in that: the reaction route of the method is as follows,
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| CN202011036892.2A CN112409379B (en) | 2020-09-28 | 2020-09-28 | Deuterated dihydrodibenzothiazepine compound and pharmaceutical composition containing same |
| PCT/CN2021/118711 WO2022063016A1 (en) | 2020-09-28 | 2021-09-16 | Deuterated dihydrodibenzothiepine compound, and pharmaceutical composition containing same |
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| CN113717199A (en) * | 2021-08-13 | 2021-11-30 | 北京北朋科技有限公司 | Deuterated derivative of baroxavir and application of deuterated derivative in anti-influenza virus |
| WO2022063016A1 (en) * | 2020-09-28 | 2022-03-31 | 长沙晶易医药科技有限公司 | Deuterated dihydrodibenzothiepine compound, and pharmaceutical composition containing same |
| CN115677656A (en) * | 2022-11-30 | 2023-02-03 | 南通常佑药业科技有限公司 | Preparation method of baroxavir key intermediate |
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| CN113717199A (en) * | 2021-08-13 | 2021-11-30 | 北京北朋科技有限公司 | Deuterated derivative of baroxavir and application of deuterated derivative in anti-influenza virus |
| CN113717199B (en) * | 2021-08-13 | 2022-04-01 | 北京北朋科技有限公司 | Deuterated derivative of baroxavir and application of deuterated derivative in anti-influenza virus |
| CN115677656A (en) * | 2022-11-30 | 2023-02-03 | 南通常佑药业科技有限公司 | Preparation method of baroxavir key intermediate |
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| WO2022063016A1 (en) | 2022-03-31 |
| CN112409379B (en) | 2023-07-28 |
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