[go: up one dir, main page]

CN114426537A - 2-methyl-2H-tetrazole compound and medical application thereof - Google Patents

2-methyl-2H-tetrazole compound and medical application thereof Download PDF

Info

Publication number
CN114426537A
CN114426537A CN202011175539.2A CN202011175539A CN114426537A CN 114426537 A CN114426537 A CN 114426537A CN 202011175539 A CN202011175539 A CN 202011175539A CN 114426537 A CN114426537 A CN 114426537A
Authority
CN
China
Prior art keywords
methyl
phenyl
alkyl
compound
amino
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
Application number
CN202011175539.2A
Other languages
Chinese (zh)
Inventor
裴剑锋
侯石
徐优俊
张伟林
邓小兵
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Yingfeizhi Pharmaceutical Technology Co ltd
Original Assignee
Beijing Yingfeizhi Pharmaceutical Technology Co ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Beijing Yingfeizhi Pharmaceutical Technology Co ltd filed Critical Beijing Yingfeizhi Pharmaceutical Technology Co ltd
Priority to CN202011175539.2A priority Critical patent/CN114426537A/en
Publication of CN114426537A publication Critical patent/CN114426537A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Virology (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Otolaryngology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a compound shown in formula I, a racemate or an optical isomer thereof, a pharmaceutically acceptable salt, a solvate or a hydrate thereof, a novel broad-spectrum anti-influenza virus infection medicine and application thereof in preparing medicines for preventing and/or treating viral diseases caused by various influenza viruses.

Description

2-methyl-2H-tetrazole compound and medical application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a novel broad-spectrum anti-influenza virus infection medicine and application thereof in preparing a medicine for preventing and/or treating viral diseases caused by various influenza viruses.
Background
Influenza virus is one of the major causes of severe respiratory disease. Influenza is a serious public health problem, with high morbidity among the population, often leading to massive morbidity and mortality. Influenza is a highly contagious disease in which viruses can be transmitted from person to person by direct contact with infected individuals or with substances contaminated by the virus, resulting in acute, systemic and febrile symptoms. Systemic symptoms vary in severity and patients may exhibit mild fatigue, respiratory failure and even death.
According to data of World Health Organization (WHO), there are 10 million cases of epidemic infection per year on average in the World, wherein 300-500 ten thousand cases are serious patients, and the number of deaths is about 30-50 ten thousand. Influenza virus is a negative single-stranded member of the RNA virus family of orthomyxoviridae. Influenza viruses can be classified into A, B, C, D subtypes based on their antigenic differences between nucleoproteins and matrix proteins. Influenza a viruses are both responsible for influenza and, in comparison, influenza a viruses are the more critical factor in seasonal and epidemic epidemics. Influenza C virus primarily infects children, but the symptoms are much milder and do not cause epidemics. However, influenza type D virus has been recently discovered and is under investigation, and its effect on humans has not been revealed.
Influenza viruses are composed mainly of a core, a matrix protein and a viral envelope, and each subtype has a similar genome structure. The genome consists of 8 fragments, and 9-11 proteins are coded according to the difference of subtypes. Influenza a virus is a virus genome consisting of eight negative-strand RNA fragments encoding 11 proteins, including Hemagglutinin (HA), Neuraminidase (NA), Nucleoprotein (NP), polymerase complex (PA, PB1 and PB2), membrane protein (M1 and M2), and other proteins (NS1, NS2, NEP). In addition, among the three common influenza viruses, the variation rate of influenza a is the highest. Influenza B has a slower rate of evolution than influenza a but evolves faster than influenza C. The segmented genome allows for gene exchange between different virus strains, thereby generating new influenza variants.
Anti-influenza drugs can be divided into two types depending on the treatment mode: direct antiviral drugs and drugs for relieving symptoms caused by influenza. Currently, there are few classes of anti-influenza virus drugs available on the market, mainly M2 channel inhibitors and NA inhibitors. M2 channel inhibitors, such as amantadine and rimantadine, are effective against influenza a strains but not against influenza B strains. Since 2004, influenza a viruses that are circulating have rapidly increased resistance to amantadine worldwide. Thus, the currently prevalent influenza a virus strains do not recommend the use of amantadine or rimantadine for antiviral treatment or prevention. Oseltamivir and zanamivir are representative drugs of NA inhibitors, and both are also the most widely used drugs in the clinical prevention and treatment of influenza, but development of viral resistance has been found.
In addition to the two traditional target inhibitors, the development of inhibitors against potential targets of viruses, including HA, NP and RNA polymerase, HAs also advanced greatly, and inhibitors against these targets show good in vitro and in vivo anti-influenza activity and greater resistance to drugs. Given that HA mediates influenza virus entry into the host is the initial step in viral infection, it means that inhibition of HA can effectively block viral infection. Meanwhile, the conservation of the HA target point enables the related inhibitor to be expected to play a broad-spectrum anti-influenza role. Therefore, the present invention aims to synthesize a novel HA inhibitor for the preparation of a broad-spectrum antiviral drug for the prevention and/or treatment of viral diseases caused by influenza virus.
Disclosure of Invention
The first aspect of the invention relates to a compound shown in formula I, a racemate or an optical isomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof,
Figure BSA0000222990230000021
wherein,
x is NH or- (CH)2)n-, where n is 0 to 3;
Y1is-CH-, -NCH2-、-CHCH2-or-CHCH2CH2-；
Y2Is O or S;
z is carbonyl or sulfonyl;
a is a six-membered aromatic ring or a heteroaromatic ring, cyclohexane or heteroazacyclohexane;
ar is a six-membered aromatic or heteroaromatic ring, optionally substituted with one or more halogens;
r is 1, 2 or 3 same or different substituents optionally existing on a benzene ring, and R is independently selected from the following groups: hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, alkoxy, amino mono-or di-substituted by alkyl, carboxyl, acetoxy, amido, phenyl, nitro.
In a preferred embodiment of the present invention, the compound of formula I, or its racemate or optical isomer, pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R is 1 or 2 same or different substituents optionally present on the benzene ring, and R is independently selected from the following groups: hydrogen, halogen, hydroxy, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, amino, or C1-6Alkyl mono-or disubstituted amino, carboxy, R '(C ═ O) NH-, phenyl, nitro, wherein R' is C1-6An alkyl group;
preferably, R is 1 or 2 identical or different substituents optionally present on the phenyl ring, R being independently selected from the following groups: hydrogen, halogen, hydroxy, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, amino, or C1-4Alkyl mono-or disubstituted amino, carboxy, R '(C ═ O) NH-, phenyl, nitro, wherein R' is C1-4An alkyl group;
further preferably, R is 1 or 2 identical or different substituents optionally present on the phenyl ring, R is independently selected from the following groups: hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, carboxyl, CH3(C＝O)NH-、C2H5(C ═ O) NH-, phenyl, nitro;
still further preferably, R is 1 or 2 identical or different substituents optionally present on the phenyl ring, R is independently selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxy, amino, diethylamino, propylamino, carboxyl, CH3(C ═ O) NH-, phenyl, nitro.
In a preferred embodiment of the invention, the compounds of formula I, or their racemates or optical isomers, pharmaceutically acceptable salts, solvates, hydrates thereof, are selected from the following compounds:
n- (2- (2- ((3S) -3- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) amino) pyrrolidine-1-carbonyl) pyridin-4-yl) benzo [ d ] oxazol-5-yl) acetamide (Compound 1),
n- (2- (2- ((3R) -3- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) amino) pyrrolidine-1-carbonyl) pyridin-4-yl) benzo [ d ] oxazol-5-yl) acetamide (Compound 2),
2- ((3R) -1- ((4- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) piperazin-1-yl) sulfonylpiperidin-3-yl) -5-nitrobenzo [ d ] oxazole (Compound 3),
2- ((3R) -1- ((4- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) piperazin-1-yl) sulfonylpiperidin-3-yl) benzo [ d ] oxazol-5-amine (Compound 4),
n- (2- ((3R) -1- ((4- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) piperazin-1-yl) sulfonylpiperidin-3-yl) benzo [ d ] oxazol-5-yl) acetamide (Compound 5).
The second aspect of the invention relates to a process for the preparation of compounds of formula I,
in the present invention, the compounds of formula I, racemates or optical isomers, pharmaceutically acceptable salts, solvates, hydrates thereof can be prepared exemplarily by the following reaction scheme:
Figure BSA0000222990230000041
for example, compounds of formula I are coupled in acetonitrile containing potassium carbonate or cesium carbonate at room temperature or under heating using compounds of formula Ia as starting materials with compounds of formula Ib, wherein the group involved in coupling is an amino group or a hydrogen on a nitrogen in an azacycle, and R is as defined in the first aspect of the invention.
The third aspect of the present invention relates to the use of a compound of formula I, a racemate, or an optical isomer, a pharmaceutically acceptable salt, solvate or hydrate thereof, as defined in any one of the first aspect of the present invention, in the preparation of a medicament for the treatment and/or prevention of a disease or condition associated with influenza virus infection. Wherein said influenza virus infection includes but is not limited to: influenza A virus, influenza B virus, influenza C virus, and the like. Wherein the disease or condition associated with viral infection is selected from respiratory diseases (including but not limited to common cold, pharyngitis, tonsillitis and epiglottitis), digestive diseases, hemorrhagic fever diseases, meningitis/encephalitis, immunodeficiency diseases, hepatitis, etc.
Features of any aspect of the invention or any sub-aspect of any aspect are equally applicable to any other aspect or any sub-aspect of any other aspect. In the present invention, for example, reference to "any sub-aspect" of the first aspect of the invention is a reference to any sub-aspect of the first aspect of the invention, which is referred to in a similar manner in other aspects, and which has the same meaning.
Various aspects and features of the disclosure are described further below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
As used herein, the term "pharmaceutically acceptable" when describing a "pharmaceutically acceptable salt," means that the salt is not only physiologically acceptable to the subject, but may also refer to a synthetic substance of pharmaceutical value.
When the name of the compound used herein is not consistent with the chemical structural formula, the chemical structural formula is taken as the standard.
As used herein, the term "effective amount" refers to a dose that achieves treatment and/or prevention of a disease or disorder described herein in a subject.
As used herein, the term "pharmaceutical composition" may also refer to a "composition" that may be used to effect treatment and/or prevention of a disease or disorder described herein in a subject, particularly a mammal.
As used herein, the term "subject" can refer to a patient or other animal, particularly a mammal, e.g., a human, dog, larynx, cow, horse, etc., that receives a compound of formula I of the present invention or a pharmaceutical composition thereof to treat and/or prevent a disease or condition described herein.
As used herein, "%" refers to weight/weight percentages, particularly where solid matter is described, as well as where not specifically indicated. Of course, in describing liquid materials, the "%" may refer to weight/volume percentages (for the case of solids dissolved in liquids) or may refer to volume/volume percentages (for the case of liquids dissolved in liquids).
In the present invention, the influenza virus infection includes but is not limited to: influenza A virus, influenza B virus, influenza C virus, and the like.
In the present invention, the disease or condition associated with viral infection is selected from respiratory diseases including but not limited to: common cold (e.g., summer cold), pharyngitis, tonsillitis and Yimengyuan laryngitis, digestive system diseases, hemorrhagic fever diseases, meningitis/encephalitis, immunodeficiency diseases, hepatitis, etc. In one embodiment, the present invention relates to a medicament for preventing and/or treating diseases associated with viral infections including influenza a virus, influenza B virus, influenza C virus, and the like, comprising administering a prophylactically and/or therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, to a patient in need of prevention and/or treatment of diseases associated with viral infections including influenza a virus, influenza B virus, influenza C virus, and the like.
According to the present invention, a pharmaceutical composition of a compound of the present invention may be administered in any of the following ways: oral, aerosol inhalation, rectal, nasal, buccal, vaginal, topical, parenteral such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or via an external reservoir. Among them, oral, intraperitoneal or intravenous administration is preferable. In addition, for the compounds of the present invention to be effective in the treatment of disorders of the cns system, intraventricular administration may be preferred to overcome the potentially low blood-brain barrier permeability of the compounds.
When administered orally, the compounds of the present invention may be formulated in any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions or suspensions. Among them, the carriers generally used for tablets include lactose and corn starch, and additionally, a lubricant such as magnesium stearate may be added. Typical diluents used in capsule formulations include lactose and dried corn starch. Aqueous suspension formulations are generally prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, sweetening, flavoring or coloring agents may be added to the above oral dosage forms.
When administered rectally, the compounds of the present invention are generally prepared in the form of suppositories by mixing the drug with a suitable non-irritating excipient. The excipient is in a solid state at room temperature and melts to release the drug at rectal temperature. Such excipients include cocoa butter, beeswax and polyethylene glycols.
When the compound is used for local administration, particularly for treating affected surfaces or organs which are easy to reach by local external application, such as eyes, skin or lower intestinal tract neurogenic diseases, the compound can be prepared into different forms of local administration preparations according to different affected surfaces or organs, and the specific description is as follows:
when administered topically to the eye, the compounds of the present invention may be formulated as a micronized suspension or solution in sterile saline at a pH that is isotonic, with or without the addition of preservatives such as benzylalkenoxides. In addition, for ophthalmic use, the compounds may also be formulated in the form of ointments such as vaseline.
When applied topically to the skin, the compounds of the present invention may be formulated in a suitable ointment, lotion, or cream formulation in which the active ingredient is suspended or dissolved in one or more carriers. The carrier that may be used in the ointment herein includes, but is not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
When administered topically to the lower intestinal tract, the compounds of the present invention may be formulated in the form of rectal suppositories or suitable enemas as described above, or alternatively, topical transdermal patches may be used.
The compounds of the present invention may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oleaginous suspensions, or sterile injectable solutions. Among the carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be employed as a solvent or suspending medium, such as a monoglyceride or diglyceride.
It is further noted that the specific dosage and method of administration of the compounds of the present invention for each individual patient will depend upon a variety of factors including the age, body weight, sex, physical condition, nutritional status, the activity level of the compound, the time of administration, the metabolic rate, the severity of the condition, and the subjective judgment of the treating physician. The preferred dosage is between 0.01 and 100mg/kg body weight/day.
Detailed Description
The present invention will be further described by the following examples and test examples. However, the scope of the present invention is not limited to the following examples or experimental examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible.
For all of the following examples, standard procedures and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structure of the compounds was determined by Nuclear Magnetic Resonance (NMR) or mass spectrometry (HRMS/MS). The melting point m.p. of the compound is determined by a model RY-1 melting point apparatus, the thermometer is uncorrected and m.p. is given in ° C.1H NMR and13c NMR was measured by an Ascend 600 NMR spectrometer from Bruker, Switzerland. Mass spectra were determined by a Waters corporation Xevo G2 TOF mass spectrometer, USA. All solvents for the reaction are not indicated to have been subjected to a standardized pretreatment.
In the following examples,% means mass% unless otherwise specified.
EXAMPLE 1 Synthesis of N- (2- (2- ((3S) -3- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) amino) pyrrolidine-1-carbonyl) pyridin-4-yl) benzo [ d ] oxazol-5-yl) acetamide (Compound 1)
Taking a 50mL reaction bottle, adding (S) -N- (2- (2- (3-aminopyrrolidine-1-carbonyl) pyridine-4-yl) benzo [ d]Oxazol-5-yl) acetamide (intermediate 1, 18.01mg, 0.05mmol), 5- (bromo (phenyl) methyl) -2-methyl-2H-tetrazole (intermediate 2, 9.85mg, 0.05mmol), anhydrous potassium carbonate (20.02mg, 0.10mmol), acetonitrile 2mL, nitrogen substitution, oil bath reaction at 60 ℃ for 12H, extraction with ethyl acetate, washing of the organic layer with saturated brine, drying over anhydrous sodium sulfate, concentration under reduced pressure, column layerPurification by chromatography (MeOH: DCM ═ 1: 20) gave compound 1 as a pale yellow solid weighing 7.98mg, 30.8% yield.1H NMR(600MHz，DMSO)δ10.22(s，1H)，8.77(d，1H)，8.37-7.96(m，3H)，7.73(d，1H)，7.54(d，1H)，7.47(d，1H)，7.38(d，1H)，7.30-7.13(m，3H)，5.22(s，1H)，4.24(d，3H)，3.77-3.63(m，1H)，3.64-3.51(m，2H)，3.50-3.36(m，2H)，3.17-2.97(m，2H)，2.03(s，3H).HRMS(ESI)m/z[M+H]+calculated for C28H27N9O3：537.2237 found 537.2235。
Example 2 Synthesis of N- (2- (2- ((3R) -3- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) amino) pyrrolidine-1-carbonyl) pyridin-4-yl) benzo [ d ] oxazol-5-yl) acetamide (Compound 2)
The starting material intermediate 1 was replaced with (R) -N- (2- (2- (3-aminopyrrolidine-1-carbonyl) pyridin-4-yl) benzo [ d ] according to the procedure described in example 1 above]Oxazol-5-yl) acetamide, in proportions to give 4.21mg of brown solid, in a total yield of 26.9%.1H NMR(600MHz，DMSO)δ10.22(s，1H)，8.77(d，1H)，8.37-7.96(m，3H)，7.73(d，1H)，7.54(d，1H)，7.47(d，1H)，7.38(d，1H)，7.30-7.13(m，3H)，5.22(s，1H)，4.24(d，3H)，3.77-3.63(m，1H)，3.64-3.51(m，2H)，3.50-3.36(m，2H)，3.17-2.97(m，2H)，2.03(s，3H).HRMS(ESI)m/z[M+H]+calculated for C28H27N9O3：537.2237 found 537.2233。
Example Synthesis of 32- ((3R) -1- ((4- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) piperazin-1-yl) sulfonylpiperidin-3-yl) -5-nitrobenzo [ d ] oxazole (Compound 3)
Taking (R) -5-nitro-2- (1- (piperazine-1-yl sulfonyl) piperidine-3-yl) benzo [ d]Oxazole (352.02mg, 0.10mmol), 2-methyl-5-bromomethylphenyl tetrazole (255.04mg, 1.01mmol), acetonitrile 20mL, cesium carbonate (442.03mg, 1.30mmol) in a 100mL reaction flask, reacting at room temperature for 30min, detecting the reaction progress by thin layer chromatography, filtering, washing filter residues with acetonitrile, combining organic layers, concentrating, and separating by column chromatography (MeOH: DCM ═ 1: 50) to obtain 293.03mg of a yellow-white solid with a yield of 52.1%.1H NMR(400MHz，CDCl3)δ8.57(t，J＝2.6Hz，1H)，8.35-8.28(m，1H)，7.62(dd，J＝8.9，2.7Hz，1H)，7.50(d，J＝3.6Hz，2H)，7.35(dd，J＝13.8，7.4Hz，3H)，4.90(d，J＝37.9Hz，1H)，4.37-4.32(m，3H)，4.02(d，J＝9.2Hz，1H)，3.65(d，J＝9.5Hz，1H)，3.31(dd，J＝10.5，6.9Hz，6H)，2.99(t，J＝10.7Hz，1H)，2.51(d，J＝56.1Hz，4H)，2.30(d，J＝10.4Hz，1H)，1.90(ddd，J＝18.4，11.3，7.5Hz，2H)，1.83-1.70(m，1H).MS(ESI)m/z[M+H]+calculated for C25H29N9O5S：568.20 found 568.30。
Example Synthesis of 42- ((3R) -1- ((4- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) piperazin-1-yl) sulfonylpiperidin-3-yl) benzo [ d ] oxazol-5-amine (Compound 4)
Providing 2- ((3R) -1- ((4- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) piperazin-1-yl) sulfonylpiperidin-3-yl) -5-nitrobenzo [ d]Oxazole (320.01mg, 0.56mmol), dichloromethane 10mL, methanol 10mL, 10% palladium on carbon 50.05mg in 100mL eggplant type bottle, hydrogen gas replaced air, room temperature reaction for 12h, TLC showed reaction completion, pad filtration with celite, concentration to obtain 280.03mg of solid, yield 92.3%.1H NMR(400MHz，DMSO)δ7.46(d，J＝7.5Hz，2H)，7.35(t，J＝7.4Hz，2H)，7.32-7.25(m，2H)，6.77(d，J＝2.1Hz，1H)，6.59(dd，J＝8.7，2.2Hz，1H)，5.04(d，J＝7.1Hz，3H)，4.37-4.30(m，3H)，3.79(d，J＝11.7Hz，1H)，3.43(s，1H)，3.28-3.20(m，1H)，3.13(d，J＝4.1Hz，4H)，2.98(s，1H)，2.48-2.40(m，2H)，2.31(dd，J＝11.1，5.5Hz，2H)，2.13(s，1H)，1.76(s，2H)，1.59(s，1H).MS(ESI)m/z[M+H]+calculated for C25H31N9O3S：538.20 found 538.30。
Example 5 Synthesis of N- (2- ((3R) -1- ((4- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) piperazin-1-yl) sulfonylpiperidin-3-yl) benzo [ d ] oxazol-5-yl) acetamide (Compound 5)
Weighing 2- ((3R) -1- ((4- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) piperazin-1-yl) sulfonylpiperidin-3-yl) benzo [ d]Oxazol-5-amine (120.02mg, 0.22mmol), anhydrous dichloromethane 10mL,n, N-diisopropylethylamine 2 drops and acetyl chloride 0.2mL were placed in a 100mL eggplant type bottle and reacted at room temperature for 2h, TLC showed complete reaction, saturated sodium bicarbonate adjusted to pH 8-9, dichloromethane was extracted, the organic layer was washed successively with brine, dried over anhydrous sodium sulfate, and the solid was separated by column chromatography (MeOH: DCM ═ 1: 150) to give 50.03mg of an off-white solid with a yield of 38.5%.1H NMR(400MHz，CDCl3)δ7.85(dd，J＝8.2，1.7Hz，1H)，7.63-7.46(m，4H)，7.42(dd，J＝8.7，3.3Hz，1H)，7.33(dd，J＝16.0，10.2Hz，3H)，4.89(dd，J＝20.4，12.2Hz，1H)，4.34(t，J＝4.1Hz，3H)，3.92(t，J＝10.4Hz，1H)，3.58(t，J＝12.2Hz，1H)，3.42-3.12(m，6H)，3.01(dd，J＝20.1，10.0Hz，1H)，2.41(dd，J＝74.8，35.2Hz，4H)，2.28-2.21(m，1H)，2.19(d，J＝5.8Hz，3H)，1.89(dd，J＝25.1，14.0Hz，2H)，1.79-1.69(m，1H).13C NMR(151MHz，CDCl3)δ167.57，166.18，146.35，140.26，133.88，127.68，127.29，117.06，110.61，110.57，109.33，65.29，49.47，48.21，46.01，45.99，45.19，38.60，35.00，34.95，30.56，26.76，26.61，23.44，23.11，23.04，13.11.MS(ESI)m/z[M+H]+calculated for C27H33N9O4S：580.23 found 580.30。
The chemical names and structural formulas of the compounds 1 to 5 prepared in examples 1 to 5 and the positive control arbidol hydrochloride are shown in the following table.
Figure BSA0000222990230000101
Example 6 Activity of Compounds of the invention against influenza Virus in an in vitro model
6.1 test items: testing of binding of Compounds to protein HA (SPR)
1. The test principle is as follows:
HA protein is coupled on the surface of CM5 chip by amino coupling method, when compound solution flows through the surface, it is combined with the protein coupled on the chip, a certain response signal is generated, and the response signal is combined with the protein coupled on the sensing coreThe amount of the analytes on the chip is in direct proportion, and K can be obtained by analyzing the response value curves of different concentrations of the compounds by using Biacore T200 analysis software EvaluationDThe value is obtained. Determination of binding affinity K of compound targeting HA by SPR techniqueDThe value is obtained.
2. Testing materials:
reagent: 10mM compound stock, 1mg/mL H1N1 HA (A/Michigan/45/2015), H3N2 HA (A/Aichi/2/1968), Yamagata HA (B/Yamagata/16/1988), Victoria HA (B/Victoria/02/1987), coupling buffer (HBS), running buffer (PBS), amino coupling kit (GE healthcare, BR-1000-50). Consumable material: CM5 chip (GE healthcare, BR-1005-30), a few rubber stoppers, a few 1.5mL polypropylene EP tubes (GE healthcare, BR-1002-87), etc.
3. The test method comprises the following steps:
3.1 coupling protein: HA protein was coupled to CM5 chip using amino coupling, the coupling conditions and coupling amounts are shown in Table 1.
TABLE 1 protein HA conjugation conditions and conjugation amounts
Figure BSA0000222990230000111
3.2 binding affinity assay: solutions of compounds (0. mu.M, 1.56. mu.M, 3.16. mu.M, 6.25. mu.M, 12.50. mu.M, 25.00. mu.M, 50.00. mu.M, 100.00. mu.M) at different concentrations were flowed over the chip surface, the binding time was set to 180s, the flow rate was set to 30. mu.L/min, the dissociation time was set to 300s, and the response curves were analyzed by Biacore T200 analysis software Evaluation to obtain K for analytes and proteinsDThe value is obtained.
4. And (3) testing results:
TABLE 2 results of target Compound binding affinity assay
Figure BSA0000222990230000121
6.2 test items: anti-influenza virus activity of compounds
1. The test principle is as follows:
Figure BSA0000222990230000122
the luminescence Cell Viability Assay kit (Luminescent Cell Viability Assay) is a homogeneous Assay method for detecting the number of viable cells in a culture by quantitative determination of Adenosine Triphosphate (ATP).
Figure BSA0000222990230000123
The test kit is designed for multi-well plates and is an ideal choice for automated High Throughput Screening (HTS), cell proliferation and toxicity analysis. ATP is involved in a plurality of enzymatic reactions in organisms, is an index of living cell metabolism, and the content of ATP directly reflects the number and the state of cells: adding equal volume to the cell culture medium during the experiment
Figure BSA0000222990230000124
The reagent measures the luminous value, in the optical signal and system, the luminous value is in direct proportion to the ATP amount, and ATP is positively correlated with the number of living cells, so that the cell activity can be obtained by detecting the ATP content.
2. The test method comprises the following steps:
MDCK cells were seeded in 96-well plates and infected overnight with influenza virus (A/WSN/33). Cells were suspended in DMEM containing 1% FBS and 0.1% TPCK treated trypsin, and each concentration of the formulated compound or final concentration of 1% dimethyl sulfoxide (DMSO) was added to each well. After 40h incubation, CellTiter-Glo reagent was added and data was read using a plate reader (Tecan InfinitedM2000 PRO).
3. And (3) testing results:
TABLE 3 measurement results of inhibitory Activity of target Compounds against influenza Virus
Figure BSA0000222990230000131

Claims (6)

1. A compound shown as a formula I, a racemate or an optical isomer thereof, a pharmaceutically acceptable salt, a solvate or a hydrate thereof,
Figure FSA0000222990220000011
wherein,
x is NH or- (CH)2)n-, where n is 0 to 3;
Y1is-CH-, -NCH2-、-CHCH2-or-CHCH2CH2-；
Y2Is O or S;
z is carbonyl or sulfonyl;
a is a six-membered aromatic ring or a heteroaromatic ring, cyclohexane or heteroazacyclohexane;
ar is a six-membered aromatic or heteroaromatic ring, optionally substituted with one or more halogens;
r is 1, 2 or 3 same or different substituents optionally existing on a benzene ring, and R is independently selected from the following groups: hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, alkoxy, amino mono-or di-substituted by alkyl, carboxyl, acetoxy, amido, phenyl, nitro.
2. The compound according to claim 1, wherein R is 1 or 2 same or different substituents optionally present on the benzene ring, R is independently selected from the group consisting of: hydrogen, halogen, hydroxy, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, amino, or C1-6Alkyl mono-or disubstituted amino, carboxy, R '(C ═ O) NH-, phenyl, nitro, wherein R' is C1-6An alkyl group;
preferably, R is 1 or 2 identical or different substituents optionally present on the phenyl ring, R being independently selected from the following groups: hydrogen, halogen, hydroxy, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, amino, or C1-4Alkyl mono-or disubstituted amino, carboxyl, R' (C ═ O) NH-, benzeneA nitro group, wherein R' is C1-4An alkyl group;
further preferably, R is 1 or 2 identical or different substituents optionally present on the phenyl ring, R is independently selected from the following groups: hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, carboxyl, CH3(C＝O)NH-、C2H5(C ═ O) NH-, phenyl, nitro;
still further preferably, R is 1 or 2 identical or different substituents optionally present on the phenyl ring, R is independently selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxy, amino, diethylamino, propylamino, carboxyl, CH3(C ═ O) NH-, phenyl, nitro.
3. A compound according to any one of claims 1, 2, racemates or optical isomers thereof, pharmaceutically acceptable salts, solvates, hydrates thereof, selected from the group consisting of:
n- (2- (2- ((3S) -3- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) amino) pyrrolidine-1-carbonyl) pyridin-4-yl) benzo [ d ] oxazol-5-yl) acetamide (Compound 1),
n- (2- (2- ((3R) -3- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) amino) pyrrolidine-1-carbonyl) pyridin-4-yl) benzo [ d ] oxazol-5-yl) acetamide (Compound 2),
2- ((3R) -1- ((4- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) piperazin-1-yl) sulfonylpiperidin-3-yl) -5-nitrobenzo [ d ] oxazole (Compound 3),
2- ((3R) -1- ((4- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) piperazin-1-yl) sulfonylpiperidin-3-yl) benzo [ d ] oxazol-5-amine (Compound 4),
n- (2- ((3R) -1- ((4- ((2-methyl-2H-tetrazol-5-yl) (phenyl) methyl) piperazin-1-yl) sulfonylpiperidin-3-yl) benzo [ d ] oxazol-5-yl) acetamide (Compound 5).
4. Use of a compound according to any one of claims 1 and 2, a racemate or an optical isomer thereof, a pharmaceutically acceptable salt, solvate or hydrate thereof for the manufacture of a medicament for the treatment and/or prevention of diseases or conditions associated with influenza virus infection.
5. The use of claim 4, wherein said viral infection includes but is not limited to: influenza A virus, influenza B virus, influenza C virus, and the like.
6. The use of claim 4, wherein the disease or condition associated with viral infection is selected from the group consisting of respiratory diseases (including but not limited to the common cold, pharyngitis, tonsillitis, and pharyngitis), digestive diseases, hemorrhagic fever, meningitis/encephalitis, immunodeficiency diseases, hepatitis, and the like.
CN202011175539.2A 2020-10-29 2020-10-29 2-methyl-2H-tetrazole compound and medical application thereof Pending CN114426537A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011175539.2A CN114426537A (en) 2020-10-29 2020-10-29 2-methyl-2H-tetrazole compound and medical application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011175539.2A CN114426537A (en) 2020-10-29 2020-10-29 2-methyl-2H-tetrazole compound and medical application thereof

Publications (1)

Publication Number Publication Date
CN114426537A true CN114426537A (en) 2022-05-03

Family

ID=81310348

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011175539.2A Pending CN114426537A (en) 2020-10-29 2020-10-29 2-methyl-2H-tetrazole compound and medical application thereof

Country Status (1)

Country Link
CN (1) CN114426537A (en)

Similar Documents

Publication Publication Date Title
US10155747B2 (en) Glutarimide derivatives, use thereof, pharmaceutical composition based thereon and methods for producing glutarimide derivatives
US8440720B2 (en) Methods of use of antiviral compounds
JP2024003097A (en) Use of favipiravir in treatment of coronavirus infection
JP7001601B2 (en) Functionalized pentanic acid for use in influenza virus infection
CN111743899B (en) Application of nitazoxanide and its active form tizoxanide in preparing medicine for treating SARS-CoV-2 infection
US20110065762A1 (en) Methods of use of antiviral compounds
CN111686095A (en) Use of cannabidiol in preparation of medicament for treating coronavirus infection
US20230233573A1 (en) Treating influenza using substituted polycyclic pyridone derivatives and prodrugs thereof
WO2020241759A1 (en) Prophylactic and/or therapeutic agent for influenza virus infection or corona virus infection
Xu et al. Discovery of novel substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent human adenovirus inhibitors
Wang et al. Optimization and SAR research at the piperazine and phenyl rings of JNJ4796 as new anti-influenza A virus agents, part 1
US20240391876A1 (en) Quinacrine and derivatives thereof for treatment of viral infections
WO2023085432A1 (en) Anti-sars-cov-2 drug
CN114426537A (en) 2-methyl-2H-tetrazole compound and medical application thereof
CN113368121A (en) Anti-coronavirus phillyrin and phillygenin composition
CN107793369A (en) The quianzolinones of 2 [2 (2 methoxyphenoxy) ethylamino-] 3 aryl 4 and its application
CN113754599B (en) Pyrazine amide compound and preparation method thereof
CN109134419A (en) A kind of 2,2- dimethyl -1,3- dioxolanes analog derivative, preparation method and use
US20210121462A1 (en) Pyrrolo[2,3-b]pyridin derivatives as inhibitors of influenza virus replication
Wu et al. Pterostilbene inhibits influenza virus infection through interaction with NS1 protein
WO2018181892A1 (en) Quinolinone compound and anti-rna virus drug
CN117586233A (en) Preparation and application of N-[(1H-indol-4-yl)alkyl]benzamide compounds
WO2024226581A1 (en) Antiviral 1,3-di-oxo-indene compounds
RU2570906C2 (en) 1-[ω-ARYLOXYALKYL(BENZYL)]-SUBSTITUTED 2-AMINOBENZIMIDAZOLES, HAVING ACTIVITY ON INFLUENZA VIRUS
HK40033228B (en) Application of nitazoxanide and its active form tizoxanide in manufacture of a medicament for treating sars-cov-2 infection

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
DD01 Delivery of document by public notice

Addressee: Yang Hua

Document name: Notice of approval for fee reduction

DD01 Delivery of document by public notice
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination