CN111358787B - Application of heterocyclic compound in preparation of medicine for treating pneumonia - Google Patents
Application of heterocyclic compound in preparation of medicine for treating pneumonia Download PDFInfo
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- CN111358787B CN111358787B CN202010222115.0A CN202010222115A CN111358787B CN 111358787 B CN111358787 B CN 111358787B CN 202010222115 A CN202010222115 A CN 202010222115A CN 111358787 B CN111358787 B CN 111358787B
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- 206010035664 Pneumonia Diseases 0.000 title claims abstract description 71
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- 230000000694 effects Effects 0.000 claims abstract description 40
- 208000001572 Mycoplasma Pneumonia Diseases 0.000 claims abstract description 8
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Abstract
The invention discloses an application of a heterocyclic compound in preparing a medicine for treating pneumonia, and relates to the technical field of biological medicines. The heterocyclic compound has anti-pneumonia activity, and the pneumonia comprises but not limited to viral pneumonia, bacterial pneumonia, mycoplasma pneumonia and chlamydia pneumonia. According to the invention, the anti-pneumonia pharmacological activity of the heterocyclic compound after structural modification and reconstruction is detected, the pharmacological activity of the compound is tested in various pneumonia models, and data of anti-different pneumonia activities are provided, so that the heterocyclic compound is proved to have excellent anti-pneumonia activity. The invention can provide a novel framework for screening a new compound for preparing a medicament for treating pneumonia by screening out the heterocyclic compound with anti-pneumonia activity, and lays a theoretical foundation for developing a novel lead compound.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of a heterocyclic compound in preparation of a medicine for treating pneumonia.
Background
Pneumonia is a disease of the respiratory system, but if this inflammation is poorly controlled, it causes various complications. First, pneumonia can cause damage to the lungs, damaging the alveolar respiratory mucosa. If inflammation is poorly controlled, respiratory failure and septic shock may also occur. Sepsis can also be caused when viruses or bacteria spread into the blood circulation. Myocarditis is also caused when inflammatory factors enter the heart through blood circulation, and even sudden death from heart failure.
Viral pneumonia is caused by virus to cause upper respiratory tract infection, and spread to lung to cause inflammation, accompanied by symptoms such as fever, ache, headache, dry cough, etc., and the symptoms are more serious with the development of disease. The degree and severity of viral pneumonia is related to the immunity and age of the patient, but both require timely treatment and control. At present, antiviral drugs such as oseltamivir are mainly used for treatment, but obvious drug resistance can occur after long-term use.
Bacterial pneumonia is mainly caused by bacterial infection of the upper respiratory tract, accompanied by purulent or bloody sputum, cough, chest pain and other symptoms. The pathogenic bacteria mainly comprise streptococcus pneumoniae, klebsiella pneumoniae, staphylococcus aureus, pseudomonas aeruginosa, haemophilus influenzae and other bacteria.
Mycoplasma pneumonia is mainly pulmonary inflammation caused by mycoplasma, and is mostly seen in children acquired pneumonia; meanwhile, mycoplasma pneumoniae can cause other diseases such as encephalitis and myocarditis, and with the annual increase of the incidence rate of mycoplasma pneumoniae infection, the timely diagnosis and treatment of the diseases are very important. In recent years, the classical drug azithromycin clinically used for treating mycoplasma pneumoniae has a drug resistance phenomenon, which causes recurrence after pneumonia treatment, and patients with refractory mycoplasma pneumonia increase year by year.
Therefore, the development of new drugs for treating pneumonia is urgent and necessary.
Disclosure of Invention
One of the purposes of the invention is to provide an application of a heterocyclic compound in preparing a medicament for treating pneumonia, and provide a framework for developing a novel medicament for treating pneumonia. The various technical effects that can be produced by the preferred technical solution of the present invention are described in detail below.
In order to achieve the purpose, the invention provides the following technical scheme:
the invention discloses an application of a heterocyclic compound in preparing a medicament for treating pneumonia, wherein the heterocyclic compound has anti-pneumonia activity and one of the following structures:
preferably, the pneumonia comprises viral pneumonia, bacterial pneumonia, mycoplasma pneumonia and chlamydia pneumonia. The pneumonia can be fungal pneumonia, immune pneumonia and other pathogen pneumonia, such as Klebsiella pneumoniae, Acinetobacter baumannii pneumonia, Streptococcus pneumoniae pneumonia, vancoreococcus pneumonia and drug-resistant Staphylococcus aureus pneumonia.
According to a preferred embodiment, the pneumonia treatment medicine comprises a medicine with the effect of treating pneumonia infection and complications thereof.
According to a preferred embodiment, the pneumonia is streptococcus pneumoniae.
According to a preferred embodiment, the pneumonia is influenza a virus pneumonia.
According to a preferred embodiment, said influenza a virus comprises H1N1 and H3N 2. The influenza a virus is not limited thereto, and may be other influenza a viruses.
According to a preferred embodiment, the pneumonia is influenza b virus pneumonia.
According to a preferred embodiment, said influenza B virus comprises H7N9, H5N1, H9N2 and B/Lee/40. The influenza B virus is not limited thereto, and may be other influenza B viruses.
According to a preferred embodiment, the pneumonia is a coronavirus pneumonia.
According to a preferred embodiment, the coronaviruses include COVID-19, HCoVOC43, HCoVNL63, MERS-CoV, PEDV, TGEV and PRCV.
According to a preferred embodiment, the pneumonia is mycoplasma pneumonia.
The application of the heterocyclic compound in preparing the medicine for treating pneumonia at least has the following beneficial technical effects:
according to the invention, the anti-pneumonia pharmacological activity of the heterocyclic compound after structural modification and reconstruction is detected, the pharmacological activity of the compound is tested in various pneumonia models, and data of anti-different pneumonia activities are provided, so that the heterocyclic compound is proved to have excellent anti-pneumonia activity. The invention can provide a novel framework for screening a new compound for preparing a medicament for treating pneumonia by screening out the heterocyclic compound with anti-pneumonia activity, and lays a theoretical foundation for developing a novel lead compound.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. Based on the examples of the present invention, all other embodiments obtained by those skilled in the art without any creative effort, including the extended research on the activity of the heterocyclic compound of the present invention in treating pneumonia, are within the protection scope of the present invention.
Through chemical and medicinal chemical research on natural products, many plant endogenous compounds and derivatives have been developed. The structure of the natural product is modified and modified to obtain more derivatives with excellent pharmacological activity. The invention carries out anti-pneumonia activity detection on a series of heterocyclic compounds, and proves that the compounds have obvious anti-pneumonia activity, the effect is obviously superior to that of antiviral positive drugs commonly used in clinic, and the effect is also superior to that of caffeine and caffeine analogue A, B, C.
The following describes in detail the use of the heterocyclic compounds provided by the present invention in the preparation of a medicament for treating pneumonia, with reference to examples 1 to 7.
Example 1
This example describes the preparation of compounds 1 to 24 in detail.
According to a preferred embodiment, compounds 1 to 24 are prepared by one or more of cyclization, acidification, ethylation, addition, substitution, catalytic nitrosation, reduction, formylation, and methylation.
This example provides a method for the preparation of 24 heterocyclic compounds, all of which are structurally characterized by infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry.
Preparation of Compound 1
Compound 1 has the following structure:
the preparation of compound 1 was as follows, starting from 1mmol of the main starting material for each reaction step below.
(1mmol of CNCH)2COCH3(CH2CH3)CONH2Cyclization of the derivative in DMF (150mL) with NaOH (0.5mmol) as catalyst (reaction 3 h); ② then 1mmol of cyclized product through H2SO4(120mL, reaction 9h) acidification; ③ acidifying the product with sodium nitrite (3mmol) in H2SO4Nitrosation (reaction for 6h) is carried out under the catalytic condition (100 mL); fourthly, passing through H2SO4Reducing the nitrosation product (reaction for 6h) by using (100mL) and iron (3 mmol); fifthly, formylating 1mmol of reduction product with formic acid (3mmol) (reaction time 6 h); is in (CH)3)2SO4(3mmol) and NaOH (0.5mmol) to methylate the formylated product (reaction 2 h); seventhly, cyclizing the methylation product under the catalysis of NaOH (0.5mmol) (reacting for 12 h); is in (CH)3)2SO4Methylating the cyclized product of the previous step in the presence of (3mmol) and NaOH (0.5mmol) (reaction time 2 h); the compound was then purified by chromatography to give compound 1.
The nmr data for compound 1 was: 1H NMR (500MHz, Chloroform-d) δ 7.92(s,1H),4.21(t, J ═ 6.6Hz,1H),4.06(s,3H),3.52(s,3H), 1.92-1.81 (m,1H), 1.82-1.63 (m,1H),0.92(t, J ═ 7.3Hz,3H).
Preparation of Compound 2
Compound 2 has the following structure:
the preparation of compound 2 was as follows, starting from 1mmol of the main starting material for each reaction step below.
Is prepared by NH2COCH2C(NH)CH(CH3) COOH (1mmol) as the starting material in (CH)3CO)O2(1mmol) catalyzed for 3h to yield the cyclized product of the following structure:
② the cyclization product is subjected to ethylation reaction under the condition of iodoethane (3mmol) and NaH (1mmol) (reaction time is 3 h); (iii) passing the ethylation product over sodium nitrite (3mmol) in H2SO4Nitrosation (reaction for 6h) is carried out under the catalytic condition (100 mL); fourthly, passing through H2SO4Reduction of the compound (150mL) with iron (3mmol) (reaction 3 h); the reduction product is formylated by formic acid (3mmol) (reaction time is 6 h); is in (CH)3)2SO4(3mmol) and NaOH (0.5mmol) to methylate the formylated product (reaction time 3 h); seventhly, cyclizing the methylation product under the catalysis of NaOH (1mmol) (reacting for 3 h); is in (CH)3)2SO4Methylating the cyclized product of the previous step in the presence of (3mmol) and NaOH (1mmol) (reaction time 3 h); the compound was then purified by chromatography to give compound 2.
The nmr data for compound 2 was: 1H NMR (500MHz, Chloroform-d) δ 8.17(s,1H),4.13(q, J ═ 7.0Hz,1H),4.05(s,3H), 4.01-3.90 (m,1H),3.82(dq, J ═ 11.9,7.2Hz,1H),1.54(d, J ═ 6.8Hz,3H),1.16(t, J ═ 7.2Hz,3H).
Preparation of Compound 3
Compound 3 has the following structure:
the preparation of compound 3 was as follows, starting from 1mmol of the main starting material for each reaction step below.
Is prepared by NH2CON(CH2CH3) COCH ═ CHC ≡ CH (1mmol) as raw material and Br2(2mmol) Synthesis to NH2CON(CH2CH3) COCH ═ C (br) C ≡ CH (reaction 3 h); ② the cyclization is carried out under the conditions of DMF (150mL) and NaH (2mmol) (reaction time is 3h) to generate the cyclization product with the following structure:
③ carrying out methylation reaction on the cyclized product under the conditions of DMF (150mL), methyl iodide (3mmol) and NaH (1mmol) (reaction time is 3 h); fourthly, adding sodium nitrite (5mmol) in H2SO4Nitrosation (reaction for 5h) of the methylated product under catalytic conditions (200 mL); fifthly, passing through H2SO4Reducing the nitrosation product (reaction 12h) by using (150mL) and iron (5 mmol); sixthly, the reduction product is subjected to addition reaction under the condition of HBr (1mmol) to replace alkynyl (reaction for 6 h); seventhly, carrying out ring-closing reaction on the addition product under the condition of NaH (2mmol) (reaction time is 12 h); the closed-loop product of the previous step is subjected to methylation reaction (reaction for 3h) in a DMF solvent (150mL), methyl iodide (2mmol) and NaH (1mmol) to obtain a compound 3.
The nmr data for compound 3 was: 1H NMR (500MHz, Chloroform-d) δ 7.34(d, J ═ 4.2Hz,1H),6.13(d, J ═ 4.4Hz,1H), 3.93-3.81 (m,4H),3.31(s,2H),1.21(t, J ═ 7.2Hz,3H).
Preparation of Compound 4
Compound 4 has the following structure:
the preparation of compound 4 was as follows, starting from 1mmol of the main starting material in each of the following steps.
①NH2CONHCOC(CH2CHO) CN (1mmol) was ethylated under DMF (150mL), iodoethane (2mmol) and NaH (1mol) (reaction 3 h); ② cyclizing the ethylation product by taking NaOH (1mmol) as a catalyst (reacting for 3 h); thirdly, then passes through H2SO4(150mL) the cyclised product was acidified (reaction 6 h); tetra to (CH)3)2SO4Methylation of the acidified product in the presence of (3mmol) and NaOH (1mmol) (reaction time 3 h); fifthly, carrying out ring-closing reaction on the methylation product under the catalysis of NaOH (1mmol) (reaction time 6h) to obtain a compound 4.
The nmr data for compound 4 was: 1H NMR (500MHz, Chloroform-d) δ 7.44(d, J ═ 6.6Hz,1H),4.03(dq, J ═ 11.9,7.2Hz,1H), 3.92-3.80 (m,1H),3.52(s,2H), 1.23-1.12 (m,6H).
Preparation of Compound 5
Compound 5 has the following structure:
the preparation of compound 5 was as follows, starting from 1mmol of the main starting material for each reaction step below.
OHCOCH ═ C (OH) -C.ident.C (1mmol) as a raw material, DMF (150mL) as a solvent, and Br2(3mmol) under the condition of halogenation to generate OHCO (Br) ═ C (OH) -C ≡ CH (reaction 6 h); ② the post-halogenated product uses DMF (200mL) as solvent and CH2Reaction of ═ CHBr (1mmol) to OHCOC (CHBrCH)3) C (oh) -C ≡ CH (reaction 6 h); ③ carrying out ring-closing reaction on the reaction product of the last step in DMF (150mL) by taking NaOH (2mmol) as a catalyst (reaction for 6 h); fourthly, NH is added into DMF (100mL)2CONH2(3mmol) in (CH)3CO)O2(2mmol) and cyclizing the ring-closed product (reaction for 12 h); fifthly, ethylating (reacting) the cyclization product with iodoethane (2mmol) and NaH (1mmol) in DMF (150 mL); sixthly, methylating the ethylation product under the condition of methyl iodide (3mmol) and NaH (2mmol) (reacting for 6h) to obtain a compound 5.
The nmr data for compound 5 was: 1H NMR (500MHz, Chloroform-d) δ 6.79(dd, J ═ 9.2,6.6Hz,1H),6.52(d, J ═ 9.1Hz,1H),4.03(dq, J ═ 11.9,7.2Hz,1H),3.92(dq, J ═ 11.9,7.2Hz,1H), 3.41-3.35 (m,3H), 1.29-1.13 (m,6H).
Preparation of Compound 6
Compound 6 has the following structure:
the preparation of compound 6 was as follows, starting from 1mmol of the main starting material for each reaction step below.
(ii) adding HOCOC (CHBrCH) into DMF (200mL)3)＝C(C≡CH)CH(CH3) Cyclizing COOH (1mmol) serving as a raw material under the catalysis of NaOH (1mmol) (reacting for 6 h); ② use SOCl in DMF (150mL)2(1mmol) halogenating the hydroxyl group of the cyclization product (reaction for 6 h); ③ using ethylamine agent (1mmol) to carry out ring-closure reaction on the halogenated product in DMF (200mL) to obtain a compound 6 (reaction for 12 h).
The nmr data for compound 6 was: 1H NMR (500MHz, Chloroform-d) δ 6.67(d, J ═ 9.2Hz,1H),6.42(dd, J ═ 9.2,6.6Hz,1H),3.92(dq, J ═ 11.9,7.2Hz,1H),3.85(dq, J ═ 11.9,7.2Hz,1H),3.71(q, J ═ 7.5Hz,1H),3.43(p, J ═ 6.9Hz,1H),1.21(dd, J ═ 16.2,7.2Hz,6H),1.17(t, J ═ 7.2Hz,3H).
Preparation of Compound 7
Compound 7 has the following structure:
the preparation of compound 7 was as follows, starting from 1mmol of the main starting material in each of the following steps.
In DMF (150mL), with CH3CHBrCOCH(CH2CH3) COC ≡ CH (1mmol) is taken as a raw material to be cyclized under the condition of NaH (1mmol) (reaction time is 3 h); ② then Cl2(25mmol) chlorination of the cyclization product under illumination (reaction time 5 h); ③ then the chlorinated product is reacted with CH ═ CHC ≡ CH (1mmo ≡ CH) in DMF (100mL)l) cyclization (reaction for 6h) to give compound 7.
The nmr data for compound 7 was: 1H NMR (500MHz, Chloroform-d) δ 6.69(d, J ═ 9.1Hz,1H),6.53(dd, J ═ 9.3,6.6Hz,1H), 3.75-3.61 (m,2H),3.40(p, J ═ 6.9Hz,1H), 1.99-1.82 (m,1H), 1.79-1.63 (m,1H),1.26(dd, J ═ 15.9,7.3Hz,6H),0.94(t, J ═ 7.3Hz,3H).
Preparation of Compounds 8-10
The compounds 8-10 were prepared as follows, starting from 1mmol of the main starting material in each reaction step.
Taking theobromine (1mmol) and CH2ClCH2OH (1mmol) reacts under the catalytic condition of NaH (1mmol) to generate hydroxyethyl-substituted theobromine (reaction time 6 h); secondly, acetic anhydride (2mmol, so as to obtain a compound 8), propionic anhydride (2mmol, so as to obtain a compound 9) or isopropyl anhydride (2mmol, so as to obtain a compound 10) are used for reaction in DMF (150mL) to obtain a corresponding compound (reaction for 2 h).
The nmr data for compound 8 was: 1H NMR (400MHz, DMSO) δ 8.06(s,1H),4.24(t, J ═ 5.5Hz,2H),4.14(t, J ═ 5.6Hz,2H),3.89(s,3H),3.44(s,3H),1.92(s,3H).13C NMR (101MHz, DMSO) δ 170.74(s),154.86(s),151.39(s),148.82(s),143.52(s),107.01(s),61.34(s),33.63(s),29.83(s), 21.09(s).
The nmr data for compound 9 was: 1H NMR (500MHz, Chloroform-d) δ 7.53(s,1H),4.32(t, J ═ 6.3Hz,1H),3.73(s,1H),3.52(t, J ═ 6.32Hz,1H),3.51(s,1H),2.31(q, J ═ 7.4Hz,1H),1.48(t, J ═ 7.9Hz, 1H).
The nmr data for compound 10 was: 1H NMR (500MHz, Chloroform-d) δ 7.64(s,0H),4.41(t, J ═ 6.2Hz,1H),3.41(s,1H),3.44(t, J ═ 6.5Hz,1H),3.48(s,1H),2.54(hept, J ═ 7.2Hz,0H),1.22(d, J ═ 7.4Hz, 3H).
Preparation of Compounds 11-14
Compounds 11-14 were prepared as follows, starting with 1mmol of the starting material for each reaction step below.
Taking theobromine (1mmol) and CH2ClCH2Cl (1mmol) reacted to form chlorinated theobromine (reaction 3 h); ② using methylamine (1mmol, getting compound 11), ethylamine (1mmol, getting compound 12) and isopropylAmine (1mmol, to give compound 13) or propylamine (1mmol, to give compound 14) were reacted under NaH conditions to give the corresponding compound.
The nmr data for compound 11 was: 1H NMR (500MHz, Chloroform-d) δ 7.52(s,1H),4.31(t, J ═ 5.1Hz,2H),3.72(s,2H),3.37(s,2H),2.83(td, J ═ 5.4,3.5Hz,2H),2.53(d, J ═ 4.8Hz,3H),2.32(qt, J ═ 4.3,3.5Hz, 1H).
The nmr data for compound 12 were: 1H NMR (500MHz, Chloroform-d) δ 7.52(s,1H), 4.04-3.71 (m,4H),3.43(s,2H),2.82(td, J ═ 5.2,4.0Hz,2H),2.73(p, J ═ 4.3Hz,1H),2.61(qd, J ═ 7.2,4.2Hz,2H),1.31(t, J ═ 7.3Hz,3H).
The nmr data for compound 13 was: 1H NMR (500MHz, Chloroform-d) δ 7.55(s,1H),4.23(t, J ═ 5.3Hz,2H),3.90(s,2H),3.43(s,2H),3.04(td, J ═ 5.5,3.5Hz,2H),2.83(dp, J ═ 7.4,6.4Hz,1H),2.38(dt, J ═ 7.3,3.7Hz,1H),1.16(d, J ═ 6.1Hz, 6H).
The nmr data for compound 14 was: 1H NMR (500MHz, Chloroform-d) δ 7.67(s,1H),4.06(t, J ═ 5.4Hz,2H),3.95(s,2H),3.42(s,2H),2.85(td, J ═ 5.4,4.2Hz,2H),2.72(p, J ═ 4.3Hz,1H),2.81(td, J ═ 6.2,4.2Hz,2H),1.56(qt, J ═ 7.4,6.1Hz,2H),0.91(t, J ═ 7.4Hz, 3H).
Preparation of Compounds 15-18
Compounds 15-18 were prepared as follows, starting with 1mmol of the starting material for each reaction step below.
Taking theobromine (1mmol) and CH2ClCH2NH2(1mmol) in DMF (200mL) to produce ethylamino theobromine (reaction for 3 h); secondly, acetic anhydride (1mmol) is used in acetonitrile (200mL) to obtain a compound 15, propionic anhydride (1mmol) to obtain a compound 16, isopropyl anhydride (1mmol) to obtain a compound 17 or butyric anhydride (1mmol) to obtain a compound 18, and the reaction is carried out under the condition of NaH (0.5mmol) for 6h to obtain a corresponding compound.
The nmr data for compound 15 were: 1H NMR (500MHz, Chloroform-d) δ 7.56-7.63 (m,1H),4.16(t, J ═ 5.4Hz,1H),3.63(s,1H),3.62(td, J ═ 5.4,4.4Hz,1H),3.49(s,1H),1.82(s, 1H).
The nmr data for compound 16 was: 1H NMR (500MHz, Chloroform-d) δ 7.52(t, J ═ 4.1Hz,1H),7.61(s,1H),4.23(t, J ═ 5.3Hz,2H),3.73(s,2H),3.62(td, J ═ 5.4,4.4Hz,2H),3.53(s,2H),2.29(q, J ═ 7.9Hz,2H),1.22(t, J ═ 7.9Hz, 3H).
The nmr data for compound 17 were: 1H NMR (500MHz, Chloroform-d) δ 7.46(s,1H),7.68(t, J ═ 4.4Hz,1H),4.48(t, J ═ 5.3Hz,2H),3.69(s,2H),3.69(td, J ═ 5.5,4.1Hz,2H),3.43(s,2H),2.38(hept, J ═ 7.2Hz,1H),1.35(d, J ═ 7.3Hz, 5H).
The nmr data for compound 18 was: 1H NMR (500MHz, Chloroform-d) δ 7.75-7.61 (m,1H),4.16(t, J ═ 5.5Hz,1H),3.72(s,1H),3.42(td, J ═ 5.4,4.2Hz,1H),3.46(s,1H), 2.42-2.16 (m,1H),1.55(H, J ═ 7.4Hz,1H),0.93(t, J ═ 7.4Hz, 1H).
Preparation of Compound 19
Compound 19 was prepared as follows, starting with 1mmol of the starting material for each reaction step below.
5-Fluorouracil (1mmol) was taken and reacted with iodoisopropyl (2mmol) and NaH (0.5mmol) to give compound 19 (reaction 6h).
The nmr data for compound 19 was: 1H NMR (400MHz, DMSO) δ 11.76(s,1H),8.14(d, J ═ 7.3Hz,1H),4.66(dt, J ═ 13.6,6.8Hz,1H),1.26(d, J ═ 6.8Hz, 6H).
Preparation of Compound 20
Compound 20 was prepared as follows, starting with 1mmol of the starting material for each reaction step below.
Taking hypoxanthine (1mmol), isopropylating with iodo-isopropyl (1mmol) under the catalysis of NaH (0.5mmol) (reaction for 6h) to obtain a compound 20.
The nmr data for compound 20 was: 1H NMR (500MHz, Chloroform-d) δ 8.26(d, J ═ 7.3Hz,1H),7.95(s,1H),4.76(p, J ═ 6.4Hz,1H),1.54(d, J ═ 6.4Hz, 6H).
Preparation of Compound 21
The preparation of compound 21 was as follows, starting from 1mmol of the main starting material in each of the following steps.
Alkylation of theobromine (1mmol) in DMF (150mL) with iodoethane (3mmol) under NaH (0.5mmol) catalysis provided compound 21. After 4 hours of reactionAdding water to quench the reaction, drying under reduced pressure, separating with silica gel column (mobile phase: petroleum ether: CH)3CH2OCOCH33: 1) to obtain the product compound 21.
The nmr data for compound 21 was: 1H NMR (400MHz, DMSO) δ 8.04(s,1H), 3.91-3.86 (M,5H),3.42(s,3H),1.14(t, J ═ 7.0Hz,3H), 13C NMR (101MHz, DMSO) δ 154.03(s),150.55(s),148.09(s),142.76(s),106.58(s),35.46(s),33.08(s),29.21(s),13.06(s), HRMS (TOF MS ES +) C9H12N4O2Na + (M + Na +) calcd 231.0858, found 231.0856.
Preparation of Compound 22
Compound 22 was prepared as follows, starting with 1mmol of the starting material for each reaction step below.
Compound 21(1mmol) was thiolated using Lawson's reagent (3mmol) to give compound 22 (reaction time 6h).
The nmr data for compound 22 was: 1H NMR (500MHz, Chloroform-d) δ 7.75(s,1H),4.54(q, J ═ 7.2Hz,3H),4.06(s,3H),3.85(s,3H),1.26(t, J ═ 7.2Hz, 4H).
Preparation of Compound 23
The preparation of compound 23 was as follows, starting from 1mmol of the main starting material for each reaction step below.
Compound 21(1mmol) was aminated using aqueous ammonia (10mmol) under ethanol (50mL) and glacial acetic acid (50mL) to give compound 23 (reaction 12 h).
The nmr data for compound 23 was: 1H NMR (500MHz, Chloroform-d) δ 7.69(s,1H),7.19(s,1H),7.09(s,1H),4.34(q, J ═ 7.2Hz,3H),3.95(s,3H),3.68(s,3H),1.18(t, J ═ 7.2Hz, 4H).
Preparation of Compound 24
Compound 24 was prepared as follows, starting with 1mmol of the starting material for each reaction step below.
(ii) use of CNCH in DMF (100mL)2C(＝C)N(CH2CH3)C(＝C)CH2C(＝C)NH2(1mmol) in the presence of sodium hydroxide (1mmol) catalytic cyclization (reaction for 6 h); adding sulfuric acid (150mL) to acidify the cyclization product (reacting for 6 h); ③ reaction of sodium nitrite (4mmol) in H2SO4Nitrosation (reaction for 5h) of the acidified product under catalytic conditions (150 mL); fourthly, passing through H2SO4Reducing the nitrosation product (reaction 12h) by using (100mL) and iron (5 mmol); formylating the reduction product by formic acid (150mL) (reaction time 6 h); is in (CH)3)2SO4(3mmol) and NaOH (1mmol) to methylate the formylated product (reaction time 5 h); seventhly, cyclizing the methylated product in DMF (150mL) under the catalysis of NaOH (1mmol) (reacting for 6 h); is in (CH)3)2SO4Methylating the cyclized product of the previous step in the presence of (3mmol) and NaOH (1mmol) (reaction time 3 h); the compound is then purified by chromatography to afford compound 24.
The nmr data for compound 24 was: 1H NMR (500MHz, Chloroform-d) δ 7.68(s,1H),7.15(s,1H),7.09(s,1H),4.38(q, J ═ 7.2Hz,3H),3.93(s,3H),3.63(s,3H),1.17(t, J ═ 7.2Hz, 4H).
Example 2
In this example, the activity of the compounds 1 to 24 prepared in example 1 against pneumonia caused by Streptococcus pneumoniae was examined.
The experimental method comprises the following steps: model of pneumonia caused by streptococcus pneumoniae in vivo: SPF-grade SD male rats (weighing about 200g) were randomly and evenly divided into several groups, including a blank control group, a model group, a cefuroxime axetil positive control group, an analog caffeine group, a caffeine analog group (the caffeine analog group uses 1-propyl 3, 7-dimethyl xanthine (caffeine analog A), 1-isopropyl 3, 7-dimethyl xanthine (caffeine analog B), 3-ethyl 3, 7-dimethyl xanthine (caffeine analog C)) and compounds 1-24, and 8 rats were bred in a standard environment for 7 days. Before the experiment, the rats were lightly anesthetized by ether inhalation, and then the rats of the model group, the cefuroxime axetil tablet positive control group, the analog caffeine, the caffeine analog A, B, C group and the compound 1-24 group were administered 0.5mL/kg of bacterial solution (concentration 1.0X 109CFU/mL) respectively by nasal inhalation method except that the rats of the blank control group were instilled with normal saline in the nasal cavity, and the bacterial solution was slowly instilled into the nasal cavity of the rats with the syringe needle at the instillation rate of about 0.05 mL/min. After molding, mice in the blank control group and the model group were administered with the same dose of physiological saline for intragastric administration at 12h and 24h, the cefuroxime axetil tablet (50mg/kg) was administered to the positive control group, caffeine (50mg/kg) was administered to the caffeine analogue group, caffeine analogue A, B, C was administered to caffeine analogue A, B, C (50mg/kg) and compounds 1 to 24 were administered to compounds 1 to 24(50mg/kg) prepared in example 1, respectively. 2h after the last administration, the rats were anesthetized with a 0.4% sodium pentobarbital solution (10mL/kg), blood was taken from the abdominal aorta and the blood routine changes were examined, the results of which are shown in Table 1 below.
TABLE 1
As can be seen from table 1, all of compounds 1 to 24 prepared in example 1 significantly reduced the level of leukocytes, neutrophils and lymphocytes in blood, indicating that compounds 1 to 24 have significant activity against pneumonia induced by streptococcus pneumoniae, and the effect is superior to that of cefuroxime axetil tablets, and the effect is also superior to that of caffeine and caffeine analog A, B, C.
Example 3
In this example, the anti-influenza A virus pneumonia activity of the compounds 1 to 24 prepared in example 1 was examined.
C57 mice (22-25g) were randomly divided into several groups, namely blank control group (Normal), Model group (Model), oseltamivir positive control group, analog caffeine group, caffeine analog group (the caffeine analog group uses 1-propyl 3, 7-dimethyl xanthine (caffeine analog A), 1-isopropyl 3, 7-dimethyl xanthine (caffeine analog B), 3-ethyl 3, 7-dimethyl xanthine (caffeine analog C)), and compound 1-24 groups. Influenza A virus was inoculated on day 1, and mice in each group were infected with influenza A H1N1 strain FM1 (30. mu.L) by nasal drip, except for the placebo group of mice, which were inoculated with normal saline by nasal drip. After 24h, the gavage was continued for 4 days for intervention as follows: the mice of the blank control group and the model group are administrated by the same dose of normal saline for intragastric administration, the mice of the analog caffeine group are administrated by intragastric administration with 100mg/kg/d of caffeine with the same volume, the mice of the caffeine analog group are administrated by intragastric administration with A, B, C100 mg/kg/d of caffeine analog with the same volume, the mice of the positive control group are administrated by intragastric administration with 100mg/kg/d of oseltamivir with the same volume, different compound groups are administrated by intragastric administration with different compounds 1-24 respectively, and the doses are all 100 mg/kg/d. Mice were dosed for 4 consecutive days, and body weight and mortality were recorded daily. On the last day, blood was taken from the eyeball and the expression levels of NF-. kappa. B, TNF-. alpha.IL-1 and IL-6 in the serum were immediately examined, the results are shown in Table 2 below.
TABLE 2
As can be seen from Table 2, the compounds 1 to 24 prepared in example 1 all significantly reduce and significantly reduce the levels of NF-kappa B, TNF-alpha, IL-1 beta and IL-6 in serum, which indicates that the compounds 1 to 24 have significant activity against influenza A virus pneumonia, and the effect is superior to oseltamivir, and the effect is also superior to the analog caffeine and caffeine analog A, B, C.
Example 4
In this example, the activity of compounds 1 to 24 prepared in example 1 against influenza B virus pneumonia was examined.
C57 mice (22-25g) were randomly divided into several groups, namely blank group (Normal), Model group (Model), oseltamivir positive control group, analog caffeine group, caffeine analog group (the caffeine analog group uses 1-propyl 3, 7-dimethyl xanthine (caffeine analog A), 1-isopropyl 3, 7-dimethyl xanthine (caffeine analog B), 3-ethyl 3, 7-dimethyl xanthine (caffeine analog C)), and compound 1-24 groups. Influenza B virus was inoculated on day 1, and mice in each group were infected with influenza B H7N9 virus strain (30. mu.L) by nasal drip, except for the mice in the control group. After 24h, the gavage was continued for 4 days for intervention as follows: the normal group and the model group are administrated to the mice by the same dose of normal saline for intragastric administration, the mice of the analog caffeine group are administrated 100mg/kg/d by intragastric administration, the mice of the caffeine analog group are administrated A, B, C100 mg/kg/d by intragastric administration, the mice of the positive control group are administrated 100mg/kg/d by intragastric administration, the mice of the different compound groups are administrated 1-24 by intragastric administration, and the doses are all 100 mg/kg/d. Mice were dosed for 4 consecutive days, and body weight and mortality were recorded daily. On the last day, blood was taken from the eyeball and the serum expression levels of NF-. kappa. B, TNF-. alpha.IL-1 and IL-6 were immediately examined, the results of which are shown in Table 3 below.
TABLE 3
As can be seen from Table 3, the compounds 1 to 24 prepared in example 1 all significantly reduce and significantly reduce the levels of NF-kappa B, TNF-alpha, IL-1 beta and IL-6 in serum, which indicates that the compounds 1 to 24 have significant activity against influenza B virus pneumonia, and the effect is superior to oseltamivir, and the effect is also superior to the analog caffeine and caffeine analog A, B, C.
Example 5
In this example, the anti-coronavirus pneumonia activity of the compounds 1 to 24 prepared in example 1 was examined.
C57 mice (22-25g) were randomly divided into several groups, namely blank group (Normal), Model group (Model), oseltamivir positive control group, analog caffeine group, caffeine analog group (the caffeine analog group uses 1-propyl 3, 7-dimethyl xanthine (caffeine analog A), 1-isopropyl 3, 7-dimethyl xanthine (caffeine analog B), 3-ethyl 3, 7-dimethyl xanthine (caffeine analog C)), and compound 1-24 groups. Coronaviruses (HcoV-OC43) were inoculated on day 1, and mice in each group were infected with HcoV-OC43 coronaviruses (30. mu.L) by nasal instillation, except for the placebo group, in which normal saline was instilled into the nasal cavity. After 24h, the gavage was continued for 4 days for intervention as follows: the normal group and the model group are administrated to the mice by the same dose of normal saline for intragastric administration, the mice of the analog caffeine group are administrated 100mg/kg/d by intragastric administration, the mice of the caffeine analog group are administrated A, B, C100 mg/kg/d by intragastric administration, the mice of the positive control group are administrated 100mg/kg/d by intragastric administration, the mice of the different compound groups are administrated 1-24 by intragastric administration, and the doses are all 100 mg/kg/d. Mice were dosed for 4 consecutive days, and body weight and mortality were recorded daily. On the last day, blood was taken from the eyeball and the serum expression levels of NF-. kappa. B, TNF-. alpha.IL-1 and IL-6 were immediately examined, the results of which are shown in Table 4 below.
TABLE 4
As can be seen from Table 4, the compounds 1 to 24 prepared in example 1 all significantly reduce and significantly reduce the levels of NF-kappa B, TNF-alpha, IL-1 beta and IL-6 in serum, which indicates that the compounds 1 to 24 have significant activity against coronavirus pneumonia, and the effects are superior to that of oseltamivir and are also superior to that of caffeine analogue A, B, C.
Example 6
In this example, the compounds 1 to 24 prepared in example 1 were examined for their activity against novel coronavirus pneumonitis.
C57 mice (22-25g) were randomly divided into several groups, each of which was a blank group (Normal), a Model group (Model), a chloroquine phosphate positive control group, an analog caffeine group, a caffeine analog group (the caffeine analog group used substances were 1-propyl 3, 7-dimethylxanthine (caffeine analog A), 1-isopropyl 3, 7-dimethylxanthine (caffeine analog B), 3-ethyl 3, 7-dimethylxanthine (caffeine analog C)), and a compound group 1-24. The day 1, the mice were inoculated with the novel coronavirus (COVID-19), and the mice in each group were infected with the COVID-19 coronavirus strain (30. mu.L) by nasal instillation, except for the mice in the placebo group, which were administered with normal saline by nasal instillation. After 24h, the gavage was continued for 4 days for intervention as follows: the normal group and the model group are administrated to the mice by the same dose of normal saline for intragastric administration, the mice of the analog caffeine group are administrated 100mg/kg/d by intragastric administration, the mice of the caffeine analog group are administrated A, B, C100 mg/kg/d by intragastric administration, the mice of the positive control group are administrated 1-24 by intragastric administration, and the doses are all 100 mg/kg/d. Mice were dosed for 4 consecutive days, and body weight and mortality were recorded daily. On the last day, blood was taken from the eyeball and the serum expression levels of NF-. kappa. B, TNF-. alpha.IL-1 and IL-6 were immediately examined, the results of which are shown in Table 5 below.
TABLE 5
As can be seen from Table 5, the compounds 1 to 24 prepared in example 1 all significantly reduce and all significantly reduce the levels of NF-kappa B, TNF-alpha, IL-1 beta and IL-6 in serum, which indicates that the compounds 1 to 24 have significant activity against pneumonia caused by novel coronavirus (COVID-19), and the effects are superior to chloroquine phosphate and the effects are also superior to caffeine analogue A, B, C.
Example 7
In this example, the anti-mycoplasma pneumonia activity of the compounds 1 to 24 prepared in example 1 was examined.
BALB/C mice were randomly and evenly divided into blank control group, model group, azithromycin positive control group, analog caffeine group, caffeine analog group (the caffeine analog group uses 1-propyl 3, 7-dimethyl xanthine (caffeine analog A), 1-isopropyl 3, 7-dimethyl xanthine (caffeine analog B), 3-ethyl 3, 7-dimethyl xanthine (caffeine analog C)), and compound 1-24 groups. Before molding, mice were anesthetized with ether, the nasal cavity was instilled with 100. mu.L of physiological saline in the normal group, and the same volume of MPFH strain solution (containing 1X 10) was added to each of the other groups7mL-1)The nasal cavity is slowly instilled, so that the nasal cavity is inhaled into the bronchus and continuously instilled for 3 days. Starting administration treatment after the infection day 2, and performing intragastric administration on the blank control group and the model group by using normal saline with the same dose; the mice of the caffeine analogue group are gavaged to give 100mg/kg of caffeine with the same volume, the mice of the caffeine analogue group are gavaged to give A, B, C100 mg/kg of caffeine analogue with the same volume, and the mice of the positive control group are gavaged to give 100mg/kg of azithromycin liquid; the compounds 1-24 were administered by gavage at a dose of 100mg/kg 1 time daily for 3 consecutive days in different groups. After the treatment is finished, the mice are sacrificed, blood is taken from the eyeballs, and the conventional indexes of the blood to be detected are stored at the temperature of minus 80 ℃. Meanwhile, the lung was lavaged with physiological saline, and the lavages were separated and collected, and white blood cell count and classification were examined, and the results are shown in Table 6.
TABLE 6
As is clear from Table 6, each of the compounds 1 to 24 prepared in example 1 was able to reduce the level of leukocytes, neutrophils and lymphocytes in blood, indicating that the compounds 1 to 24 had an activity against pneumonia caused by Mycoplasma pneumoniae, and had an effect superior to that of azithromycin and an effect superior to that of caffeine analogue A, B, C and caffeine analogue.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (2)
1. Use of a heterocyclic compound for the manufacture of a medicament for the treatment of pneumonia, wherein the heterocyclic compound has anti-pneumonia activity and has one of the following structures:
the pneumonia is one or more of streptococcus pneumoniae pneumonia, influenza A virus pneumonia, influenza B virus pneumonia, coronavirus pneumonia and mycoplasma pneumonia; and is
The influenza A virus is H1N1, the influenza B virus is H7N9, and the coronavirus is COVID-19 and HCoVOC 43.
2. The use of the heterocyclic compound of claim 1 for the preparation of a medicament for the treatment of pneumonia, wherein the medicament for the treatment of pneumonia comprises a medicament having efficacy in the treatment of pneumonia infection and its complications.
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