CN112409379B

CN112409379B - Deuterated dihydrodibenzothiazepine compound and pharmaceutical composition containing same

Info

Publication number: CN112409379B
Application number: CN202011036892.2A
Authority: CN
Inventors: 张海龙; 张小娇; 徐军
Original assignee: Changsha Jingyi Pharmaceutical Technology Co ltd
Current assignee: Changsha Jingyi Pharmaceutical Technology Co ltd
Priority date: 2020-09-28
Filing date: 2020-09-28
Publication date: 2023-07-28
Anticipated expiration: 2040-09-28
Also published as: CN112409379A; WO2022063016A1

Abstract

The present invention relates to deuterated dihydrodibenzothiazepine compounds and to prodrugs thereof, to pharmaceutical compositions comprising said compounds and to the use thereof. The deuterated dihydrodibenzothiazepine compound is shown in a formula (I) or a tautomer, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate or a solvate thereof. The compounds and compositions of the present invention have good cap-dependent endonuclease activity and superior pharmacokinetic properties and are useful for the treatment and/or prevention of symptoms and/or diseases caused by influenza virus infection.

Description

Deuterated dihydrodibenzothiazepine compound and pharmaceutical composition containing same

Technical Field

The invention relates to the field of medicine, in particular to a deuterated dihydrodibenzothiazepine compound shown in 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 in a drug molecule as hydrogen, and deuterated drugs generally retain their original bioactivity and selectivity if hydrogen in the drug molecule is selectively replaced with deuterium. Meanwhile, research proves that the combination of carbon-deuterium bonds is more stable than carbon-hydrogen bonds, and can directly influence the absorption, distribution, metabolism, excretion and other attributes of certain medicaments, thereby improving the curative effect, safety and tolerance of the medicaments. Therefore, if a specific hydrocarbon bond decomposed in the drug molecule is deuterated into a corresponding carbon-deuterium bond, the decomposition process of the specific hydrocarbon bond can be delayed, so that the deuterated drug acts in the body for a longer time and has better effect. Such as: sorafenib and its deuterated compounds, the pharmacokinetic profile of the deuterated compounds in rats is better than the original drug sorafenib: the half life 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 medicine is more effective; clinical experiments on venlafaxine and deuterated compounds thereof show that the metabolism speed of the venlafaxine is half that of the venlafaxine, so that the venlafaxine exists in vivo for a longer time and has more obvious curative effect. This demonstrates to some extent the superiority of deuterated products in the treatment of disease.

Influenza abbreviated influenza (influenza or flu) is an acute respiratory infectious disease caused by infection of influenza viruses, and has become a viral infectious disease with highest mortality rate. Influenza viruses are classified into three types, namely a, b and c (also A, B, C) according to the antigenic properties of the proteins and the matrix proteins. The influenza A virus has the widest host range and strong pathogenicity, can cause global large-scale influenza outbreaks and has the greatest harm to human beings; influenza B viruses have low pathogenicity, mainly causing local outbreaks; influenza C virus only infects people with low immunity, causes fewer epidemics and is relatively less harmful.

In recent years, the risk of influenza-related morbidity and mortality has increased in the elderly, pregnant women, and in high risk groups with impaired immune function, and recent studies have shown that about 65 tens of thousands of deaths each year are associated with influenza-related respiratory diseases in fish worldwide. Therefore, effective influenza treatment is of paramount importance. At present, many anti-influenza drugs are available and cover different action mechanisms, but with the wide application of anti-influenza drugs, the problem of drug resistance is more and more serious, and new influenza viruses with higher lethality are possibly generated and cause global pandemics, so that development of anti-influenza drugs with new mechanisms is expected.

The dihydrodibenzothiazepine compound shown in the formula (I) is a novel anti-influenza virus compound, and can treat acute simple influenza by inhibiting cap-dependent endonuclease from blocking the process of viral genes in the transcription initiation stage. However, it is known that the main reasons for limiting the scope of application of drugs are the advantages and disadvantages of 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 therapeutic action, thus failing to exert better effects.

Thus, there remains a need in the art to develop compounds having improved pharmacokinetic properties that inhibit cap-dependent endo-nuclease activity, as do deuterated dihydrodibenzothiazepine compounds provided herein.

Disclosure of Invention

The object of the present invention is to provide a novel class of deuterated compounds having anti-influenza virus activity and better pharmacodynamic properties, prodrugs thereof and compositions comprising the same.

In a first aspect of the invention there is provided a deuterated dihydrodibenzothiazepine compound of formula i, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

，

wherein:

r is deuterium or the following deuterium (D) substituent groups forming prodrugs

a)

b)

c)

d)

e)

R ¹ ，R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ Each independently is hydrogen or deuterium, or all are deuterium;

R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ 、R ¹⁵ 、R1 ⁶ 、R ¹⁷ 、R ¹⁸ 、R ¹⁹ ，R ²⁰ each independently is hydrogen or deuterium, or all are deuterium;

R ²¹ 、R ²² 、R ²³ 、R ²⁴ 、R ²⁵ 、R ²⁶ 、R ²⁷ 、R ²⁸ 、R ²⁹ 、R ³⁰ 、R ³¹ each independently is hydrogen or deuterium, or all are deuterium;

R ³² 、R ³³ 、R ³⁴ 、R ³⁵ 、R ³⁶ 、R ³⁷ ，R ³⁸ 、R ³⁹ 、R ⁴⁰ each independently is hydrogen or deuterium, or all are deuterium;

R ⁴¹ 、R ⁴² 、R ⁴³ 、R ⁴⁴ 、R ⁴⁵ each independently is hydrogen or deuterium, or all are deuterium;

the additional conditions are: the above compound contains at least one deuterium atom.

In a second aspect of the invention there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as described in the first aspect of the invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof.

Definition of the definition

Herein, "deuterated" refers to a compound or group in which one or more hydrogens are replaced with deuteration, unless otherwise indicated; deuteration may be mono-, di-, poly-or full-substituted. The term "one or more deuterated" is used interchangeably with "one or more deuterated".

Herein, unless otherwise specified, "non-deuterated compound" refers to a compound having a deuterium atom ratio not higher than the natural deuterium isotope content (0.015%).

As used herein, the term "pharmaceutically acceptable salts" refers to those salts that are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are 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 expressed as the presence of a drug substance in a solid state.

Compared with the prior art, the deuterated dihydrodibenzothiazepine compound has a series of advantages:

(1) The compound has excellent inhibition on cap-dependent accounting PA endoenzyme polymerization;

(2) Changing metabolism in organisms by deuteration makes metabolism of the drug difficult, which can prolong half-life of the drug, forming a long-acting preparation;

(3) After deuteration, the drug concentration of the compound in the animal body can be improved due to the isotope effect so as to improve the drug curative effect.

Detailed Description

The inventors have studied and unexpectedly found that deuterated dihydrodibenzothiazepine and prodrugs and pharmaceutically acceptable salts thereof of the invention have significantly more excellent pharmacokinetic and pharmacodynamic properties than non-deuterated compounds, and thus are more suitable for anti-influenza virus and thus for the preparation of medicaments for treating influenza and related diseases.

The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds. The dosage form is not particularly limited when the compound of the present invention or the pharmaceutical composition is used. 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 above-described aspects of the present invention will be described in further detail below by way of specific embodiments of the present invention. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.

Example 1: preparation of deuterated dihydrodibenzothiazepine

According to formula (I), when R is the perdeuterated formula a forming the prodrug, a compound of formula (II) is obtained, which can be prepared by scheme 1:

scheme 1

Wherein the fragment a compound can be prepared by the following scheme 2:

scheme 2

Wherein the fragment B compound can be prepared by the following scheme 3:

scheme 3

According to formula (i), when R is the perdeuterated formula b forming the prodrug, a compound of formula (iii) may be obtained, which may be prepared by scheme 4:

scheme 4:

wherein, the fragment A compound can be prepared by the above scheme 2, and the fragment B compound can be prepared by the above scheme 3.

According to formula (I), when R is the perdeuterated formula c forming the prodrug, a compound of formula (IV) is obtained, which can be prepared by scheme 5:

scheme 5:

According to formula (i), when R is the perdeuterated formula d forming the prodrug, a compound of formula (v) may be obtained, which may be prepared by scheme 6:

scheme 6:

According to formula (I), when R is perdeuterated formula e, which forms a prodrug, a compound of formula (VI) can be obtained, which can be prepared by scheme 7:

scheme 7:

Abbreviations in the above schemes are defined:

DMSO: dimethyl sulfoxide (Dimethyl sulfoxide)

TsOH: para-toluene sulfonic acid

THF: tetrahydrofuran (Tetrahydrofuran)

DBU: is a sterically hindered amidine with alkalinity

EA: ethyl acetate (ethyl acetate)

DMA: dimethylacetamide (DMAC or DMA), all known as N, N-Dimethylacetamide.

Example 2: dry suspension

Premixing the compound of the invention with mannitol, maltose, sodium chloride and hydroxypropyl methylcellulose by adopting a wet granulator, preparing a povidone adhesive by using purified water, and adding the povidone adhesive into the premix for granulating; drying by using a fluidized bed to obtain dry particles with proper particle size; adding colloidal silicon dioxide, talcum powder, sucralose, essence and dry particles, and adopting a two-dimensional mixer to carry out total mixing 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 are mixed. The mixture is granulated and dried to obtain granules of suitable size. Talc is then added to the granules and mixed, and the mixture is compressed into tablets.

Example 4: granule preparation

The compound of the present invention (10 mg) and lactose were passed through a 60 mesh screen. Corn starch was passed through a 120 mesh screen. They were mixed with a V-blender. To this mixture was added an aqueous HPC-L solution (low viscosity hydroxypropylcellulose), and the mixture was kneaded, granulated (extrusion granulation pore size 0.5-1 mm), and dried. The obtained dried pellets were passed through a vibrating screen (12/60 mesh) to obtain pellets.

Example 5: capsule preparation

The compound of the present invention (15 mg) and lactose were passed through a 60 mesh sieve. Corn starch was passed through a 120 mesh screen. They were mixed with a V-blender. To this, aqueous HPC-L (low viscosity hydroxypropylcellulose) was added, and the mixture was kneaded, granulated (extrusion granulation pore size 0.5-1 mm), and dried. The obtained dry granules were granulated and filled into size 4 hard gelatin capsules at a loading level of 150 mg.

Example 6: pharmacokinetic assessment in mice

Taking deuterated dihydrodibenzothiazepine and non-deuterated dihydrodibenzothiazepine as examples shown in formula (II).

8 mature mice, 7-8 weeks old, weighing about 30g, divided into 2 groups of 4, each orally administered a single dose of 1mg/kg of (a) control group: a dihydrodibenzothiazepine compound or (b) test group: deuterated dihydrodibenzothiazepine compounds are compared for their pharmacokinetic differences.

About 0.10ml of blood was obtained from each animal through the orbit after each isoflurane anesthesia, EDTAK ₂ Anticoagulation, acquisition time points are: 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h. After completion of blood sample collection at the last time point, rats were sacrificed after ether anesthesia。

Blood samples were collected and plasma was centrifuged (centrifugation conditions: 5000 rpm, 5min,4 ℃) and 100 μl of supernatant was aspirated by a pipette into a clean plastic centrifuge tube, the name and time point of the compound were indicated and stored at-80 ℃. After all time points are collected, LC-MS analysis is adopted to analyze and detect samples, the obtained concentration-time data is analyzed and calculated by DAS3.0 pharmacokinetic software to obtain the principal absorption kinetic parameter T after the compound is given to the mice _1/2 (h)、AUC _(0-t) (ng eq•h/mL)、AUC _(0-∞) (ng eq.h/mL) and the like.

The results were as follows:

compounds of formula (I)	Dihydrodibenzothiazepine	Deuterated dihydrodibenzothiazepine
			T _1/2 (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 that: mean ± standard deviation.

The results show that the half-life T of deuterated dihydrodibenzothiazepine compound compared with dihydrodibenzothiazepine compound _1/2 Prolonged 2.7 hours, AUC under drug time curve _(0-∞) (ng eq.h/mL) was increased by 43%. The deuterated dihydrodibenzothiazepine compound disclosed by the invention has good pharmacokinetic properties.

Claims

1. A deuterated dihydrodibenzothiazepine compound of formula (II):

2. a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 2, for the manufacture of a medicament for the treatment or prevention of a disease caused by a virus having a cap-dependent endonuclease.

4. The use according to claim 3, wherein the disease caused by a virus having a cap-dependent endonuclease is selected from influenza a, influenza b or influenza c.

5. The process for preparing deuterated dihydrodibenzothiazepine compound represented by formula (II) according to claim 1 by preparing a fragment A compound and a fragment B compound to obtain a compound of formula (II),

the fragment a compounds are prepared by the following route,

the fragment B compounds are prepared by the following route,

the reaction scheme for preparing the compound of formula (II) by fragment A and fragment B compounds is as follows,