CN115925640A - ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate and preparation method and application thereof - Google Patents
((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical chemicals, and relates to ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate, a preparation method thereof and application thereof in antivirus. The compound ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate) related to the invention can be converted into corresponding 6-fluoro-3-oxo-3,4-dihydropyrazine-2-carboxamide (T705) through hydrolysis or metabolism of esterase or P450 enzyme in vivo to play an antiviral role. Compared with the prototype drug 6-fluoro-3-oxo-3,4-dihydropyrazine-2-formamide (T705), the compound shown in the formula I has the obvious advantages of high bioavailability, long in-vivo acting time and the like.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a compound ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate, a pharmaceutical composition thereof, a preparation method thereof and application thereof in antivirus.
Background
The 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide (T705, the structure is shown as follows) is an inhibitor of RNA polymerase of a virus, and has a good antiviral effect. T705 has been reported to have a good effect against influenza viruses, either alone or in combination with neuraminidase inhibitors (inhibitory Agents and Chemotherapy,2007, vol.51, no.3,845-851, inhibitory Agents and Chemotherapy,2010,126-133, PCT patent: WO 2000010569). In addition, T705 has good curative effect on diseases caused by other RNA viruses. For example, T705 has therapeutic effects on Western equine encephalitis in mouse models (Antiviral Research 82 (2009) 169-171); t705 has therapeutic effects on yellow fever in hamsters (antibacterial Agents and Chemotherapy,2009, 202-209); t705 is useful in vivo and in vitro for the treatment of diseases caused by arenavirus and bunyavirus infections (Antimicrobial Agents and Chemotherapy,2007, 3168-3176). T705 has therapeutic effects on rodents infected with West Nile Virus (Antiviral Research 80 (2008) 377-379); t705 has therapeutic effects on venous viral infections (Antiviral Research 86 (2010) 121-127).
T705 can be converted in vivo to the corresponding nucleoside triphosphate form and exerts its antiviral action by mimicking the competitive inhibition of viral RNA polymerase by Guanosine Triphosphate (GTP) (Antimicrobial Agents and Chemotherapy,2005, vol.49, no.3, p.981-986).
However, T705 has some poor pharmacokinetic properties, which are not favorable for exerting the drug effect. In particular, T705 has a serious first-pass effect, is metabolized by aldehyde oxidase (XO) soon after oral administration, causes the metabolic elimination to be quicker, has the problem of short half-life, causes the administration dosage to be larger, and has the daily oral dosage of 800-2400 mg.
Disclosure of Invention
The present inventors have conducted intensive studies to obtain a novel compound, namely ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate (compound represented by formula I), and have surprisingly found that the compound can be converted into T705 in vivo, shows a good antiviral effect, has a significantly improved bioavailability compared to T705, and has a potential as an antiviral drug. The following invention is thus provided:
one aspect of the present invention is directed to a compound of formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof,
the experiments of examples 4 and 5 demonstrate that the compound of formula I (3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate is capable of being converted to T705 in mice and monkeys. Furthermore, example 4 demonstrates that the oral bioavailability of the compound (3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate (i.e., the compound of formula I) orally administered to mice is significantly higher than T705. Example 5 demonstrates that the bioavailability of the compound (3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate (i.e., the compound of formula I) orally administered to monkeys is significantly higher than T705. In addition, since the various antiviral and disease-treating effects of T705 are known in the art, one skilled in the art would expect the compounds of formula I to also have the same antiviral and disease-treating (e.g., against foot-and-mouth disease) activity.
Furthermore, the skilled person knows that solvates do not change the structure of the compound, only the physical properties of the compound and therefore the same biological activity should be expected.
Another aspect of the present invention relates to a pharmaceutical composition comprising a compound represented by formula i, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, as described herein.
In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
In some embodiments, the pharmaceutical composition is a solid formulation, an injection, an external preparation, a spray, a liquid formulation, or a combination formulation.
Typically, the pharmaceutical composition contains 0.1 to 90% by weight of a compound of formula i and/or a pharmaceutically acceptable salt thereof and/or a hydrate thereof and/or a solvate thereof. The pharmaceutical compositions may be prepared according to methods known in the art. For this purpose, if desired, a compound of formula i or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants and brought into a suitable administration form or dosage form for use as a mammal.
The compound of formula I or pharmaceutical compositions containing it may be administered in unit dosage form by enteral or parenteral routes, such as oral, intramuscular, subcutaneous, nasal, oromucosal, dermal, peritoneal or rectal administration. The administration dosage forms include tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized powder for injection, etc. Can be common preparation, sustained release preparation, controlled release preparation and various microparticle drug delivery systems. In order to form the unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearates, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets. For making the administration units into pills, a wide variety of carriers well known in the art can be used. Examples of the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, gelucire, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc. For making the administration unit into a suppository, various carriers well known in the art can be widely used. As the carrier, for example, polyethylene glycol, lecithin, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like are exemplified. To encapsulate the administration units, the active ingredient compound of formula i or a pharmaceutically acceptable salt, hydrate, or solvate thereof is mixed with the various carriers described above and the resulting mixture is placed in hard gelatin or soft gelatin capsules. Or making the effective component of compound of formula I or its pharmaceutically acceptable salt or its hydrate or its solvate into microcapsule, suspending in aqueous medium to form suspension, or making into hard capsule or injection. For the preparation of the administration units into preparations for injection, such as solutions, emulsions, lyophilized powders and suspensions, all diluents commonly used in the art can be used, for example, water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid esters, and the like. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added.
In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparation, if desired.
In a further aspect the invention relates to a process for the preparation of a compound of formula I according to the invention:
x represents Cl, br or I
Nucleophilic substitution reaction is carried out on a compound A (6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide) and a compound B (namely chloromethyl isobutyrate, bromomethyl isobutyrate or iodomethyl isobutyrate) to obtain the compound shown in the formula I.
In some embodiments, the nucleophilic substitution reaction is performed in the presence of an organic or inorganic base.
In some embodiments, the nucleophilic substitution reaction is performed in the presence of an organic base.
In some embodiments, the organic base is selected from triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), diisopropylethylamine, or any combination thereof.
In some embodiments, the reaction solvent for the nucleophilic substitution reaction is an organic solvent.
In some embodiments, the organic solvent is selected from dichloromethane, N-Dimethylformamide (DMF), acetonitrile, dimethyl ether (DME), tetrahydrofuran (THF), or any combination thereof.
In some embodiments, where compound B is chloromethyl-isobutyrate, the nucleophilic substitution reaction is carried out in the presence of a catalyst.
In some embodiments, the catalyst is selected from KI, liBr, or a combination thereof.
In some embodiments, the method comprises:
reacting 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide with halogenated methyl isobutyrate in an aprotic organic solvent in the presence of an organic or inorganic base, separating and purifying to obtain ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate,
wherein X represents Cl, br or I.
Yet another aspect of the present invention relates to a compound represented by formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, as described in the present invention, or a pharmaceutical composition as described in the present invention, or a use of a compound represented by formula I, as prepared by the method described in the present invention, in the preparation of a medicament for preventing and/or treating a disease caused by a viral infection.
In some embodiments, the virus is an RNA virus.
In some embodiments, the Virus is an Influenza Virus (Influenza Virus), an HCV Virus (Hepatitis C Virus), a Bunyavirus (Bunyavirus), a white ream Virus (Phlebovirus), a Foot and Mouth Disease Virus (Foot and mouse Disease Virus), a West Nile Virus (West Nile Virus), an Arenavirus (Arenavirus), a Western Equine Encephalitis Virus (Western Encephalitis Virus), or a Yellow Fever Virus (Yellow Fever Virus).
In some embodiments, the influenza virus is an influenza a 1 (H1N 1) subtype a virus.
In some embodiments, the disease caused by the viral infection is foot-and-mouth disease.
Yet another aspect of the present invention relates to a compound represented by formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, as defined in the present invention, or a pharmaceutical composition thereof, or a compound represented by formula I prepared by the method of the present invention, for preventing and/or treating diseases caused by viral infection.
In some embodiments, the virus is an RNA virus.
In some embodiments, the Virus is an Influenza Virus (Influenza Virus), an HCV Virus (Hepatitis C Virus), a Bunyavirus (Bunyavirus), a leucovirus (phyllovirus), a Foot and Mouth Disease Virus (Foot and Mouth Disease Virus), a West Nile Virus (West Nile Virus), an Arenavirus (Arenavirus), a Western Equine Encephalitis Virus (Western Encephalitis Virus), or a Yellow Fever Virus (Yellow Fever Virus).
In some embodiments, the influenza virus is an influenza a 1 (H1N 1) subtype a virus.
In some embodiments, the disease caused by the viral infection is foot and mouth disease.
Yet another aspect of the present invention relates to a method for preventing and/or treating a disease caused by a viral infection, which comprises administering to a subject in need thereof an effective amount of a compound represented by formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof according to the present invention, or a pharmaceutical composition according to the present invention, or a compound represented by formula I prepared by the method of the present invention.
In some embodiments, the virus is an RNA virus.
In some embodiments, the Virus is an Influenza Virus (Influenza Virus), an HCV Virus (Hepatitis C Virus), a Bunyavirus (Bunyavirus), a leucovirus (phyllovirus), a Foot and Mouth Disease Virus (Foot and Mouth Disease Virus), a West Nile Virus (West Nile Virus), an Arenavirus (Arenavirus), a Western Equine Encephalitis Virus (Western Encephalitis Virus), or a Yellow Fever Virus (Yellow Fever Virus).
In some embodiments, the influenza virus is an influenza a 1 (H1N 1) subtype a virus.
In some embodiments, the disease caused by the viral infection is foot and mouth disease.
Yet another aspect of the present invention relates to a method for treating and/or preventing foot-and-mouth disease in a mammal, comprising the step of administering to a subject (such as a mammal) in need thereof an effective amount of a compound represented by formula i or a pharmaceutically acceptable salt thereof or a hydrate thereof or a solvate thereof as described herein, or an effective amount of a pharmaceutical composition comprising a compound represented by formula i or a pharmaceutically acceptable salt thereof or a hydrate thereof or a solvate thereof. The compound represented by formula i or a pharmaceutically acceptable salt thereof or a hydrate thereof or a solvate thereof, or an effective amount of a pharmaceutical composition comprising the compound represented by formula i or a pharmaceutically acceptable salt thereof or a hydrate thereof or a solvate thereof, may be used alone.
In another aspect, the present invention relates to a compound represented by formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, or a pharmaceutical composition thereof, or a use of a compound represented by formula I prepared by the method of the present invention in preparing a virus inhibitor or in preparing a medicament for inhibiting replication or propagation of a virus in a cell.
In some embodiments, the virus is an RNA virus.
In some embodiments, the Virus is an Influenza Virus (Influenza Virus), an HCV Virus (Hepatitis C Virus), a Bunyavirus (Bunyavirus), a leucovirus (phyllovirus), a Foot and Mouth Disease Virus (Foot and Mouth Disease Virus), a West Nile Virus (West Nile Virus), an Arenavirus (Arenavirus), a Western Equine Encephalitis Virus (Western Encephalitis Virus), or a Yellow Fever Virus (Yellow Fever Virus).
In some embodiments, the influenza virus is an influenza a 1 (H1N 1) subtype a virus.
In some embodiments, the cell is a mammalian cell.
In some embodiments, the mammal comprises a bovine, equine, ovine, porcine, canine, feline, rodent, primate, e.g., a human, cat, dog, or pig.
Yet another aspect of the present invention relates to a compound of formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, as defined herein, or a pharmaceutical composition thereof, or a compound of formula I prepared by the method of the present invention, for use in inhibiting replication or propagation of a virus in a cell.
In some embodiments, the virus is an RNA virus.
In some embodiments, the Virus is an Influenza Virus (Influenza Virus), an HCV Virus (Hepatitis C Virus), a Bunyavirus (Bunyavirus), a leucovirus (phyllovirus), a Foot and Mouth Disease Virus (Foot and Mouth Disease Virus), a West Nile Virus (West Nile Virus), an Arenavirus (Arenavirus), a Western Equine Encephalitis Virus (Western Encephalitis Virus), or a Yellow Fever Virus (Yellow Fever Virus).
In some embodiments, the influenza virus is an influenza a 1 (H1N 1) subtype a virus.
In some embodiments, the cell is a mammalian cell.
In some embodiments, the mammal comprises a bovine, equine, ovine, porcine, canine, feline, rodent, primate, e.g., a human, cat, dog, or pig.
Yet another aspect of the present invention relates to a method of inhibiting replication or propagation of a virus in a cell, comprising administering to the cell an effective amount of a compound of formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, as described herein, or a pharmaceutical composition as described herein, or a compound of formula I prepared by a process as described herein.
In some embodiments, the virus is an RNA virus.
In some embodiments, the Virus is an Influenza Virus (Influenza Virus), an HCV Virus (Hepatitis C Virus), a Bunyavirus (Bunyavirus), a leucovirus (phyllovirus), a Foot and Mouth Disease Virus (Foot and Mouth Disease Virus), a West Nile Virus (West Nile Virus), an Arenavirus (Arenavirus), a Western Equine Encephalitis Virus (Western Encephalitis Virus), or a Yellow Fever Virus (Yellow Fever Virus).
In some embodiments, the influenza virus is an influenza a 1 (H1N 1) subtype a virus.
In some embodiments, the cell is a mammalian cell.
In some embodiments, the mammal comprises a bovine, equine, ovine, porcine, canine, feline, rodent, primate, e.g., a human, cat, dog, or pig.
In another aspect, the invention relates to a compound shown in formula I, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, or a pharmaceutical composition thereof, and the application of the compound, the pharmaceutically acceptable salt, the hydrate or the solvate thereof, or the pharmaceutical composition thereof in preparing antiviral drugs.
In particular, the virus is an RNA virus; specifically, influenza Virus (Influenza Virus), HCV Virus (Hepatitis C Virus), bunyavirus (Bunyavirus), leucovirus (pherbovirus), foot and Mouth Disease Virus (Foot and mouse Disease Virus), west Nile Virus (West Nile Virus), arenavirus (Arenavirus), western Equine Encephalitis Virus (Western Equine enchaitis Virus), or Yellow Fever Virus (Yellow Fever river Virus); specifically, the influenza virus is influenza A1 (H1N 1) methylene.
Yet another aspect of the present invention relates to a method for combating viruses, in vivo or in vitro, comprising the step of administering to a subject an effective amount of a compound of formula i, or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof, or an effective amount of a pharmaceutical composition comprising a compound of formula i, or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof.
In the present invention, "subject" refers to a vertebrate. In certain embodiments, the vertebrate is a mammal. The mammal includes bovine, equine, ovine, porcine, canine, feline, rodent, primate, such as a human, cat, dog, or pig. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.
In the present invention, the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof to be administered depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight and individual response of the patient or animal, the specific compound used, the route of administration and the number of administrations, and the like. The above-mentioned dosage may be administered in a single dosage form or divided into several, e.g. two, three or four dosage forms.
The actual dosage level of the active ingredient in the pharmaceutical composition can be varied so that the resulting amount of active compound is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. Dosage levels will be selected with regard to the activity of the compound of formula I, the route of administration, the severity of the condition being treated and the condition and prior history of the patient being treated. However, it is common practice in the art to start doses of the compounds at levels below those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
When used in the above-mentioned therapeutic and/or prophylactic or adjuvant treatment, a therapeutically and/or prophylactically effective amount of one of the compounds of the present invention may be employed in pure form or, where present, in the form of a pharmaceutically acceptable ester or prodrug. Alternatively, the compounds may be administered in a pharmaceutical composition comprising the compound of interest together with one or more pharmaceutically acceptable excipients. The phrase "prophylactically and/or therapeutically effective amount" of a compound of the present invention refers to a sufficient amount of the compound to treat a disorder at a reasonable benefit/risk ratio applicable to any medical prophylaxis and/or treatment. It will be appreciated, however, that the total daily amount of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors well known in the medical arts. For example, it is common in the art to start doses of the compound at levels below those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. In general, the dosage of a compound of formula I of the invention for use in mammals, especially humans, may be between 0.001 and 1000mg/kg body weight/day, for example between 0.01 and 100mg/kg body weight/day, for example between 0.01 and 10mg/kg body weight/day.
The compounds of the present invention are effective in the prevention and/or treatment of various diseases or disorders described herein.
In the present invention, the term "effective amount" refers to a dose that achieves treatment, prevention, alleviation and/or alleviation of the disease or disorder described herein in a subject.
Advantageous effects of the invention
The compound of the invention can be converted into a form of T705 in vivo to play an antiviral role, and simultaneously, the bioavailability of the compound can be obviously improved, and the action time of the compound T705 in vivo can be prolonged. Alternatively, the compound ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate) of the present invention can be converted into the corresponding 6-fluoro-3-oxo-3,4-dihydropyrazine-2-carboxamide (T705) by hydrolysis or metabolism by esterase or P450 enzyme in vivo to exert antiviral action. Compared with the prototype drug 6-fluoro-3-oxo-3,4-dihydropyrazine-2-formamide (T705), the compound shown in the formula I has the obvious advantages of high bioavailability, long in-vivo acting time and the like.
Drawings
Fig. 1 shows drug concentration-time curves of T705 in blood after oral administration of compound 1 and T705 in mice according to an example of the present invention.
Fig. 2 shows the drug concentration-time curves of T705 in blood after oral administration of compound 1 and T705 to cynomolgus monkeys in an example of the present invention.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1: preparation of ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate (1)
Under the protection of nitrogen, 1.57g (10 mmol) of T705 is dissolved in 10mL of anhydrous acetonitrile, stirred for 15min at room temperature, 3.03g (30 mmol) of triethylamine is added dropwise, the temperature is reduced to 0 ℃, then 3.41g (25 mmol) of chloromethyl acetate is added dropwise, KI or LiBr with or without catalytic amount is added, and the reaction is carried out for 24 hours at the temperature of 0 DEG CAfter that time, the reaction was warmed to room temperature. The reaction solution was washed in 100mL cold water, extracted three times with dichloromethane, the organic phases were combined, washed twice with 1N hydrochloric acid, washed with saturated sodium bicarbonate solution, washed with sodium chloride solution, dried over sodium sulfate, concentrated to dryness, and separated by Flash column chromatography (dichloromethane/methanol elution) after silica gel mixing to give ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate. 1 HNMR(DMSO)δ1.066(6H,d,J＝6.96Hz),2.56(1H,m),6.06(2H，s),7.83(1H,bs),7.96(1H,brs),8.45(1H,d,J＝8.14Hz)；ESIMS(m/e)258(MH + )。
Example 2: preparation of ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate (2)
Under the protection of nitrogen, 1.57g (10 mmol) of T705 is dissolved in 10mL of anhydrous acetonitrile, stirred for 15min at room temperature, 3.03g (30 mmol) of triethylamine is added dropwise, the temperature is reduced to-20 ℃, then 3.41g (25 mmol) of bromomethyl acetate is added dropwise, after reaction is completed at-20 ℃ for 24 h, the reaction liquid is flushed into 100mL of cold water, extracted with dichloromethane for three times, organic phases are combined, washed twice with 1N hydrochloric acid, washed with saturated sodium bicarbonate solution, washed with sodium chloride solution, dried with sodium sulfate and concentrated to be dry, and after silica gel is mixed, flash column chromatography separation (dichloromethane/methanol elution) is carried out to obtain ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate.
Example 3: preparation of ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate (3)
Under the protection of nitrogen, 1.57g (10 mmol) of T705 is dissolved in 10mL of anhydrous acetonitrile, stirred for 15min at room temperature, 3.03g (30 mmol) of triethylamine is added dropwise, the temperature is reduced to-40 ℃, then 2.12g (20 mmol) of acetonitrile solution of iodomethyl acetate is added dropwise, after reaction is completed at-40 ℃ for 48 h, the temperature is gradually increased to 0 ℃, the reaction liquid is flushed into 100mL of cold water, extracted with dichloromethane for three times, organic phases are combined, washed with 1N hydrochloric acid twice, washed with saturated sodium bicarbonate solution, washed with sodium chloride solution, dried with sodium sulfate and concentrated to dryness, and after silica gel is stirred, flash column chromatography separation (dichloromethane/methanol elution) is carried out to obtain ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate.
Example 4: metabolism test in mice
Experimental drugs: compound 1[ ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate ], T705.
Subject: KM mice (male, 27. + -.2 g) were randomly divided into 15 groups of 3 mice each based on body weight.
The experimental method comprises the following steps: t705 and Compound 1 were administered orally by gavage at a dose of 0.0637mmol/10ml/kg (equivalent to 10mg/10ml/kg for T705), respectively. At different time points of administration, 20 mu L of orbital blood is collected, 20 mu L of cation internal standard acetonitrile solution, 20 mu L of anion internal standard acetonitrile solution and 40 mu L of acetonitrile are added, oscillation is carried out, 18000g is centrifuged for 10min, and the supernatant is taken for LC/MS/MS sample injection to determine the corresponding concentration of the tested compound and T705.
The experimental results are as follows: the drug concentration-time curves of T705 in blood after oral administration of compound 1 and T705 in mice are shown in fig. 1; values for bioavailability [ AUC (umol/L x h) ] and blood concentration Cmax of T705 and compound 1 orally administered to mice are shown in table 1.
The experimental conclusion is that: the experiment proves that the compound (3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate can be converted into T705 in a mouse body, and the oral bioavailability of the compound (3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate orally administered to the mouse is obviously higher than that of T705.
Example 5: in vivo metabolism assay in monkeys
Experimental drugs: the compounds [ ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate ] and T705.
Subject: 3 macaques are used.
3 macaques are orally administrated with one test drug by intragastric gavage according to 0.0637mmol/1ml/kg (the administration dose is one tenth of the administration dose of mice). At different time points of administration, 50. Mu.L of monkey plasma was intravenously sampled, 50. Mu.L of T705 acetonitrile standard solutions with different concentrations were added, 50. Mu.L of anion internal standard acetonitrile solution and 100. Mu.L of acetonitrile were added, and the samples to be analyzed were made to correspond to plasma concentrations of 100, 500, 1000, 5000 and 10000ng/ml. Shaking, centrifuging at 18000g for 10min, sampling supernatant by LC/MS/MS, and determining the concentration of T705. After a wash period of not less than 3 days, another test drug was administered in exactly the same manner and the T705 concentration was measured under exactly the same conditions.
The experimental results are as follows: the drug concentration-time curves of T705 in blood after oral administration of compound 1 and T705 to cynomolgus monkeys are shown in fig. 2; values for bioavailability [ AUC (μmol/L × h) ] and blood concentration Cmax after oral administration of T705 and compound 1 in macaques are shown in table 1.
And (4) experimental conclusion: the experiment proves that the compound (3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate can be converted into T705 in a monkey body, and the bioavailability of the compound (3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate orally administered to the monkey body is obviously higher than that of the T705.
Table 1: bioavailability of T705 and Compound 1[ ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate ] metabolised in mice and monkeys [ AUC (μmol/L ×) and plasma Cmax parameter values
To summarize: the above research results show that compound 1[ ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate ] is effective in improving the pharmacokinetic properties of T705 under the condition of oral administration to mice, can increase the blood concentration (Cmax) calculated as T705 in mice, has a ratio of Cmax (compound 1)/Cmax (T705) of 1.05, and can significantly increase the oral bioavailability [ AUC (μmol/L h) ] calculated as T705 in mice, and has a value of AUC (compound 1)/AUC (T705) of 1.57. The results also show that compound 1[ ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate ] is effective in improving the pharmacokinetic properties of T705 under conditions of oral monkey administration, significantly increasing plasma concentrations in monkeys as calculated by T705 (Cmax), with a ratio of Cmax (compound 1)/Cmax (T705) of 2.74, and significantly increasing oral bioavailability in monkeys as calculated by T705 [ AUC (μmol/L h) ], with a value of AUC (compound 1)/AUC (T705) of 3.49.
Claims (10)
1. A compound represented by the formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof,
2. a pharmaceutical composition comprising a compound represented by formula i, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, as claimed in claim 1.
3. The pharmaceutical composition of claim 2, further comprising a pharmaceutically acceptable carrier or adjuvant; specifically, the pharmaceutical composition is a solid preparation, an injection, an external preparation, a spray, a liquid preparation or a compound preparation.
4. A process for preparing a compound of formula i as claimed in claim 1, which comprises:
x represents Cl, br or I
Nucleophilic substitution reaction is carried out on a compound A (6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide) and a compound B (namely chloromethyl isobutyrate, bromomethyl isobutyrate or iodomethyl isobutyrate) to obtain the compound shown in the formula I.
5. The method of claim 4, wherein the nucleophilic substitution reaction is carried out in the presence of an organic or inorganic base;
preferably, the nucleophilic substitution reaction is carried out in the presence of an organic base;
preferably, the organic base is selected from triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), diisopropylethylamine, or any combination thereof;
or the reaction solvent of the nucleophilic substitution reaction is an organic solvent;
preferably, the organic solvent is selected from dichloromethane, N-Dimethylformamide (DMF), acetonitrile, dimethyl ether (DME), tetrahydrofuran (THF), or any combination thereof.
6. The process according to any one of claims 4 to 5, wherein, when the compound B is chloromethyl isobutyrate, the nucleophilic substitution reaction is carried out in the presence of a catalyst;
preferably, the catalyst is selected from KI, liBr or a combination thereof.
7. Use of the compound of claim 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, or the pharmaceutical composition of any one of claims 2 to 3, or the compound prepared by the process of any one of claims 4 to 6, for the preparation of a medicament for the prophylaxis and/or treatment of diseases caused by viral infections.
8. The use of claim 7, wherein the virus is an RNA virus;
preferably, the Virus is an Influenza Virus (Influenza Virus), an HCV Virus (Hepatitis C Virus), a Bunyavirus (Bunyavirus), a leucovirus (philibovirus), a Foot and Mouth Disease Virus (Foot and Mouth Disease Virus), a West Nile Virus (West Nile Virus), an Arenavirus (Arenavirus), a Western Equine Encephalitis Virus (Western Equine Encephalitis Virus), or a Yellow Fever Virus (Yellow Fever river Virus);
preferably, the influenza virus is an influenza a 1 (H1N 1) subtype a virus;
preferably, the disease caused by viral infection is foot-and-mouth disease.
9. Use of a compound of claim 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, or a pharmaceutical composition of any one of claims 2-3, or a compound prepared by the process of any one of claims 4-6, in the manufacture of a viral inhibitor or in the manufacture of a medicament for inhibiting replication or propagation of a virus in a cell.
10. The use of claim 9, wherein the virus is an RNA virus;
preferably, the Virus is an Influenza Virus (Influenza Virus), an HCV Virus (Hepatitis C Virus), a Bunyavirus (Bunyavirus), a leucovirus (philibovirus), a Foot and Mouth Disease Virus (Foot and Mouth Disease Virus), a West Nile Virus (West Nile Virus), an Arenavirus (Arenavirus), a Western Equine Encephalitis Virus (Western Equine Encephalitis Virus), or a Yellow Fever Virus (Yellow Fever river Virus);
preferably, the influenza virus is an influenza a 1 (H1N 1) subtype a virus;
alternatively, the cell is a mammalian cell;
preferably, the mammal comprises a bovine, equine, ovine, porcine, canine, feline, rodent, primate, e.g., human, cat, dog or pig.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116687932A (en) * | 2022-02-25 | 2023-09-05 | 中国人民解放军军事科学院军事医学研究院 | Medical application of ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116687932A (en) * | 2022-02-25 | 2023-09-05 | 中国人民解放军军事科学院军事医学研究院 | Medical application of ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate |
| CN116687932B (en) * | 2022-02-25 | 2024-03-29 | 中国人民解放军军事科学院军事医学研究院 | Medical application of ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate |
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