阅读说明：本技术 替洛酮类似物在抗病毒感染中的应用 (Application of ketorolac analogue in resisting virus infection ) 是由 王飞 仲志峰 柴换娜 王登文 于 2020-02-17 设计创作，主要内容包括：本发明提供了替洛酮类似物在抗病毒感染中的应用。具体地,本发明涉及替洛酮类似物在制备用于预防和/或治疗冠状病毒、流行性感冒病毒、副流感病毒、巨细胞病毒、腺病毒、鼻病毒、单纯疱疹、水痘-带状疱疹、风疹病毒、麻疹病毒、登革热病毒、黄热病病毒、西尼罗病毒、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、肠道病毒、呼吸道合胞病毒、埃博拉病毒感染的药物中的用途,以及用于预防和/或治疗上述病毒感染的药物组合物。优选地,所述冠状病毒为2019新型冠状病毒(2019-nCoV)。(The invention provides application of a ketorolac analogue in resisting virus infection. In particular, the invention relates to the use of a tiolone analogue in the preparation of a medicament for the prevention and/or treatment of coronavirus, influenza virus, parainfluenza virus, cytomegalovirus, adenovirus, rhinovirus, herpes simplex, varicella-zoster, rubella virus, measles virus, dengue virus, yellow fever virus, west nile virus, hepatitis a virus, hepatitis b virus, hepatitis c virus, enterovirus, respiratory syncytial virus, ebola virus infections, and pharmaceutical compositions for the prevention and/or treatment of the above viral infections. Preferably, the coronavirus is a 2019 novel coronavirus (2019-nCoV).)

1. Use of a compound of the structure:

wherein X is: a nitrogen atom, a carbon atom, a carbonyl group, an oximo group, an oxygen atom or a carbinol group; r is: diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl.

2. The use of claim 1, wherein:

a) in the formula, X is a nitrogen atom; r is diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl;

b) in the formula, X is a carbon atom; r is diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl;

c) in the formula, X is carbonyl; r is diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl;

d) in the structural formula, X is an oximino group; r is diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl;

e) in the formula, X is an oxygen atom; r is diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl;

f) in the structural formula, X is a carbinol group; r is diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl.

3. The use of claim 1, wherein:

a) the compound is BKP-01-010: 2, 7-bis [2- (diethylamino) -methoxy ] -carbazole dihydrochloride, BKP-01-011: 2, 7-bis [2- (diethylamino) -ethoxy ] -carbazole dihydrochloride, BKP-01-012: 2, 7-bis [2- (dipropylamino) -ethoxy ] -carbazole dihydrochloride, BKP-01-013: 2, 7-bis- (pyrrolidine-ethoxy) -carbazole dihydrochloride, BKP-01-014: 2, 7-bis- (morphine-ethoxy) -carbazole dihydrochloride, BKP-01-015: 2, 7-bis- (piperazine-ethoxy) -carbazole dihydrochloride, BKP-01-016: 2, 7-bis- (4-methylpiperazine-ethoxy) -carbazole dihydrochloride, BKP-01-017: 2, 7-bis- (piperidine-ethoxy) -carbazole dihydrochloride or BKP-01-018: 2, 7-bis [2- (dimethylamino) -propylcarbonyl ] -carbazole dihydrochloride; or

b) The compound is: BKP-01-020: 2, 7-bis [2- (diethylamino) -methoxy ] -fluorene dihydrochloride, BKP-01-021: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorene dihydrochloride, BKP-01-022: 2, 7-bis [2- (dipropylamino) -ethoxy ] -fluorene dihydrochloride, BKP-01-023: 2, 7-bis- (pyrrolidine-ethoxy) -fluorene dihydrochloride, BKP-01-024: 2, 7-bis- (morpholine-ethoxy) -fluorene dihydrochloride, BKP-01-025: 2, 7-bis- (piperazine-ethoxy) -fluorene dihydrochloride, BKP-01-026: 2, 7-bis- (4-methylpiperazine-ethoxy) -fluorene dihydrochloride, BKP-01-027: 2, 7-bis- (piperidine-ethoxy) -fluorene dihydrochloride or BKP-01-028: 2, 7-bis [2- (dimethylamino) -propylcarbonyl ] -fluorene dihydrochloride; or

c) The compound is: BKP-01-030: 2, 7-bis [2- (diethylamino) -methoxy ] -fluorenone-9 dihydrochloride, BKP-01-031: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenone-9-dihydrochloride, BKP-01-032: 2, 7-bis [2- (dipropylamino) -ethoxy ] -fluorenone-9-dihydrochloride, BKP-01-033: 2, 7-bis- (pyrrolidine-ethoxy) -fluorenone-9-dihydrochloride, BKP-01-034: 2, 7-bis- (morphine-ethoxy) -fluorenone-9. dihydrochloride, BKP-01-035: 2, 7-bis- (piperazine-ethoxy) -fluorenone-9-dihydrochloride, BKP-01-036: 2, 7-bis- (4-methylpiperazine-ethoxy) -fluorenone-9 dihydrochloride, BKP-01-037: 2, 7-bis- (piperidine-ethoxy) -fluorenone-9-dihydrochloride or BKP-01-038: 2, 7-bis [2- (dimethylamino) -propylcarbonyl ] -fluorenone-9-dihydrochloride; or

d) The compound is: BKP-01-040: 2, 7-bis [2- (diethylamino) -methoxy ] -fluorenoxime-9-dihydrochloride, BKP-01-041: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenoxime-9 dihydrochloride, BKP-01-042: 2, 7-bis [2- (dipropylamino) -ethoxy ] -fluorenoxime-9-dihydrochloride, BKP-01-043: 2, 7-bis- (pyrrolidine-ethoxy) -fluorenoxime-9 dihydrochloride, BKP-01-044: 2, 7-bis- (morphine-ethoxy) -fluorenoxime-9. dihydrochloride, BKP-01-045: 2, 7-bis- (piperazine-ethoxy) -fluorenoxime-9 dihydrochloride, BKP-01-046: 2, 7-bis- (4-methylpiperazine-ethoxy) -fluorenoxime-9 dihydrochloride, BKP-01-047: 2, 7-bis- (piperidine-ethoxy) -fluorenoxime-9-dihydrochloride or BKP-01-048: 2, 7-bis [2- (dimethylamino) -propylcarbonyl ] -fluorenoxime-9-dihydrochloride; or

e) The compound is: BKP-01-050: 2, 7-bis [2- (diethylamino) -methoxy ] -dibenzofuran dihydrochloride, BKP-01-051: 2, 7-bis [2- (diethylamino) -ethoxy ] -dibenzofuran dihydrochloride, BKP-01-052: 2, 7-bis [2- (dipropylamino) -ethoxy ] -dibenzofuran dihydrochloride, BKP-01-053: 2, 7-bis- (pyrrolidine-ethoxy) -dibenzofuran dihydrochloride, BKP-01-054: 2, 7-bis- (morphine-ethoxy) -dibenzofuran dihydrochloride, BKP-01-055: 2, 7-bis- (piperazine-ethoxy) -dibenzofuran dihydrochloride, BKP-01-056: 2, 7-bis- (4-methylpiperazine-ethoxy) -dibenzofuran dihydrochloride, BKP-01-057: 2, 7-bis- (piperidine-ethoxy) -dibenzofuran dihydrochloride or BKP-01-058: 2, 7-bis [2- (diethylamino) -propylcarbonyl ] -dibenzofuran dihydrochloride; or

f) The compound is: BKP-01-060: 2, 7-bis [2- (dimethylamino) -methoxy ] -fluorenol-9-dihydrochloride, BKP-01-061: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenol-9 dihydrochloride, BKP-01-062: 2, 7-bis [2- (dipropylamino) -ethoxy ] -fluorenol-9-dihydrochloride, BKP-01-063: 2, 7-bis- (pyrrolidine-ethoxy) -fluorenol-9 dihydrochloride, BKP-01-064: 2, 7-bis- (morphine-ethoxy) -fluorenol-9 dihydrochloride, BKP-01-065: 2, 7-bis- (piperazine-ethoxy) -fluorenol-9 dihydrochloride, BKP-01-066: 2, 7-bis- (4-methylpiperazine-ethoxy) -fluorenol-9 dihydrochloride, BKP-01-067: 2, 7-bis- (piperidine-ethoxy) -fluorenol-9-dihydrochloride or BKP-01-068: 2, 7-bis [2- (dimethylamino) -propylcarbonyl ] -fluorenol-9-dihydrochloride.

4. The use of claim 3, wherein the compound is BKP-01-021: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorene dihydrochloride, BKP-01-030: 2, 7-bis [2- (diethylamino) -methoxy ] -fluorenone-9 dihydrochloride, BKP-01-031: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenone-9-dihydrochloride, BKP-01-041: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenoxime-9 dihydrochloride, BKP-01-58: 2, 7-bis [2- (diethylamino) -propylcarbonyl ] -dibenzofuran dihydrochloride or BKP-01-61: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenol-9 dihydrochloride.

5. The use of claim 4, wherein the compound is a BKP-01-041: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenoxime-9 dihydrochloride.

6. The use of claim 1, wherein the virus is selected from the group consisting of coronavirus, influenza virus, parainfluenza virus, cytomegalovirus, adenovirus, rhinovirus, herpes simplex, varicella-zoster, rubella virus, measles virus, dengue virus, yellow fever virus, west nile virus, hepatitis a virus, hepatitis b virus, hepatitis c virus, enterovirus, respiratory syncytial virus, and ebola virus.

7. The use of claim 6, wherein the coronavirus is selected from the group consisting of human coronavirus OC43(HCoV-OC43), human coronavirus 229E (HCoV-229E), human coronavirus NL63(HCoV-NL63), human coronavirus HKU1(HCoV-HKU1), severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV), and 2019 novel coronavirus (2019-nCoV).

8. The use of claim 7, wherein the coronavirus is selected from the group consisting of 2019 novel coronavirus (2019-nCoV).

9. The use of claim 1, wherein the medicament further optionally comprises at least one additional therapeutic agent.

10. The use of claim 9, wherein the therapeutic agent is selected from corticosteroids, anti-inflammatory signal transduction modulators, β 2-adrenoceptor agonist bronchodilators, anticholinergics, mucolytics, hypertonic saline, and other drugs used to treat viral infections, particularly infections with viruses of the family coronaviridae; or mixtures thereof.

11. The use of any one of claims 1-10, wherein the medicament is in any pharmaceutically acceptable dosage form.

12. The use of claim 11, wherein the dosage form is a tablet, capsule, granule, spray, oral liquid, injection, suspension, suppository, patch, dry powder inhaler.

13. The use according to claim 11, wherein the tablet is a slow release tablet or a regular tablet.

14. The use of any one of claims 1-13, wherein the viral infection is a coronavirus infectious pneumonia, preferably a neocoronary pneumonia.

15. A pharmaceutical composition for the prevention and/or treatment of a viral infection comprising a compound of any one of claims 1-5 and pharmaceutically acceptable salts thereof, and optionally at least one other therapeutic agent, and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15, wherein the virus is selected from the group consisting of coronavirus, influenza virus, parainfluenza virus, cytomegalovirus, adenovirus, rhinovirus, herpes simplex, varicella-zoster, rubella virus, measles virus, dengue virus, yellow fever virus, west nile virus, hepatitis a virus, hepatitis b virus, hepatitis c virus, enterovirus, respiratory syncytial virus, and ebola virus.

17. The pharmaceutical composition of any one of claims 15-16, wherein the additional therapeutic agent is selected from corticosteroids, anti-inflammatory signal transduction modulators, β 2-adrenoreceptor agonists bronchodilators, anticholinergics, mucolytics, hypertonic saline, and other drugs used to treat viral infections, particularly infections with viruses of the family coronaviridae; or mixtures thereof.

18. The pharmaceutical composition of claim 16, wherein the coronavirus is selected from the group consisting of a 2019 novel coronavirus (2019-nCoV).

19. The pharmaceutical composition of claim 16, wherein the coronavirus infection is a coronavirus infectious pneumonia, preferably a neocoronavirus infectious pneumonia.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an application of a ketorolac analogue in resisting virus infection, particularly coronavirus infection.

Background

The virological classification of coronaviruses (CoV) belongs to the order reticulovirales (Nidovirales) Coronaviridae (Coronaviridae) genus coronaviruses (Coronavirinae). Coronaviruses are further classified into α -coronavirus, β -coronavirus and γ -coronavirus according to their evolution (Gorbalenya AE, Enjuanes L, Ziebuhr J, etc., Nidovirales: evolving the largest RNA virus genome. Virus Res.2006,117: 17-37).

Coronaviruses are spherical enveloped viruses with the diameter of 50-200nm, the genome of the coronaviruses is single-stranded positive-strand RNA, and the coronaviruses code for 4 structural proteins: spike protein (S), membrane protein (M), envelope protein (E) and nucleocapsid protein (N). Where the S protein is the only protein responsible for mediating viral entry into the host cell. S is a transmembrane protein with a molecular weight of 128-160kDa, and the S protein is embedded in the virus coat in a trimeric form. Each S protein is in turn composed of S1 and S2 subunits, where Sl is highly variable and functions primarily to bind to host cell surface receptors; s2 is a conserved region responsible for the fusion process of the virus (Masters, PS.; Perlman, S.Coronavir, In: Knipe, DM.; Howley, eds. PM., Fields virology, Philadelphia: Lippincott Williams & Wilkins.2013, 825-858). After the coronavirus enters the host cell in a pH-dependent manner, the genetic material is released into the cytosol, allowing its RNA to bind to the ribosome and initiate the translation process, synthesizing polyproteins, due to the structural characteristics of its genomic 5 '-methylation and 3' -poly A sequences (Sethna PB, Hung SL, BrianDA. Coronavir. subgenomic minus strand RNAs and the potential for mRNAreplicons. Proc Natl Acad Sci. l989,86: 5626-. The genome of a coronavirus also encodes a polymerase, and new RNA can be generated using the coronavirus genomic RNA as a template by the polymerase using a host element. When both polyprotein and RNA genomes are synthesized, progeny new viral packaging begins, polyprotein is hydrolyzed by coronavirus proteases to become functional structural proteins, and the newly produced coronavirus buds out, is released outside the cell and begins a new round of the infection process (Hogue BG, Machaler CE. Coronavir structural proteins and viral infection. in: Perlman S, Gallagher T, Snijder EJ eds., Nidovirus. Washington, DC: ASMPres. 2008, 179-200).

Coronaviruses infect the upper respiratory or digestive tract in mammals and humans. There are seven types of coronavirus known to infect humans: human coronavirus OC43(HCoV-OC43), human coronavirus 229E (HCoV-229E), human coronavirus NL63(HCoV-NL63), human coronavirus HKU1(HCoV-HKU1), severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV), and the most prevalent 2019 novel coronavirus (2019-nCoV). After a person is infected with coronavirus, respiratory system diseases are generally caused, the first four coronavirus strains generally cause common cold of the person, and the clinical manifestations of the three coronavirus strains after the person is infected with the coronavirus are highly pathogenic respiratory distress syndrome.

Prior to 2003, it was generally recognized that human coronaviruses caused a low mortality rate of upper respiratory tract infections in patients with such viral infections. HCoV-229E and HCoV-OC43 are strains isolated from the upper respiratory tract of patients in the sixties of the last century. Coronavirus is reported to be prevalent worldwide, with 10-15% of the common cold being caused by coronavirus infection. Infection of humans with HCoV-OC43, HCoV-229E, HCoV-NL63, or HCoV-HKUl causes the common cold, and there are currently no vaccines or specific drugs against these four viruses.

The initial symptoms of SARS-CoV infection of patients with severe acute respiratory syndrome coronavirus (SARS-CoV) include fever, muscular soreness, and sore throat. As the condition progresses, the breath is short and rapid, then the symptoms of viral pneumonia or pneumonia caused by bacterial secondary infection. Patients are treated mainly with interferon and symptomatic or supportive therapy.

The middle east respiratory syndrome coronavirus (MERS-CoV) is another coronavirus that can infect humans. MERS-CoV was first isolated in 2012 at saudi arabia, originally named "new coronavirus 2012". Epidemiological studies have shown that bat is the original host for the virus, which is transmitted by bat to camel and then by camel to humans, approximately in the mid-nineties of the last century. There is no evidence that the virus can spread interpersonal. The clinical manifestations of respiratory syndrome in the middle east are fever, fever with chills, cough, shortness of breath, muscular soreness, diarrhea, nausea, vomiting, abdominal pain, etc.

2019 the novel coronavirus (2019-nCoV) is a new strain of coronavirus that has not been previously found in humans. After a person is infected with the 2019 novel coronavirus, common signs comprise respiratory symptoms, fever, cough, shortness of breath, dyspnea and the like. In more severe cases, the infection can lead to pneumonia, severe acute respiratory syndrome, renal failure, and even death. There is currently a lack of specific treatments for the disease caused by this novel coronavirus. In the diagnosis and treatment scheme for pneumonia infected by novel coronavirus (trial fourth edition), interferon atomization inhalation and lopinavir/ritonavir are considered to be used for antiviral treatment in the state, but the treatment method also lacks specificity, and the clinical treatment effect needs to be improved.

Due to the lack of clinical medication for treating coronavirus infection, there is great significance in drug development of such viruses.

In the last 70 th century, it was found that tiolone hydrochloride (2, 7-bis [2- (diethylamino) ethoxy ] fluoren-9-one dihydrochloride) orally administered before infection in mice was active against at least 9 RNA and DNA viruses, and the mode of action was probably to induce interferon production in mice (science.1970 Sep 18; 169(3951): 1213-4; science.1970 Sep 18; 169(3951): 1213-5). Later, there were also domestic scholars who used the tiolone analogs in the study of silicosis efficacy (Chengyehai et al, Stylon's analog in the study of experimental silicosis efficacy in Chengyihai et al, J.A. Zhonghua labour and health occupational diseases, 1989,7(5): 288-. The applicant's prior application of chinese patent CN103896802A, which uses a tiolone analogue for the prevention and treatment of pulmonary fibrosis, also produces beneficial therapeutic effects. However, to date, there has been no report of using ketorolone analogs for the prevention and treatment of coronavirus infections including 2019 novel coronaviruses.

Disclosure of Invention

In order to solve the technical problems, the invention provides the application of the ketorolone analogue in resisting virus infection. In particular, the invention relates to the application of a tiolone analogue in preparing a medicament for preventing and/or treating virus infection and a pharmaceutical composition for preventing and/or treating virus infection. Preferably, the virus is a coronavirus, more preferably a 2019 novel coronavirus (2019-nCoV).

In one aspect, the present invention provides the use of a compound of the structure and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prevention and/or treatment of viral infections.

Wherein X is: a group such as a nitrogen atom, a carbon atom, a carbonyl group, an oxime group, an oxygen atom or a carbinol group; r is: diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl.

In a preferred embodiment, the compound satisfies the following condition:

a) in the formula, X is a nitrogen atom; r is diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl;

b) in the formula, X is a carbon atom; r is diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl;

c) in the formula, X is carbonyl; r is diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl;

d) in the structural formula, X is an oximino group; r is diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl;

e) in the formula, X is an oxygen atom; r is diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl;

f) in the structural formula, X is a carbinol group; r is diethylaminomethoxy, diethylaminoethoxy, dipropylaminoethoxy, pyrrolidinylethoxy, N-morphinylethoxy, 4-methylpiperazinylethoxy, N-piperidinylethoxy or dimethylaminopropylcarbonyl.

Pharmaceutically acceptable salts of the compounds of the present invention include: (a) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; (b) salts with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts formed from elemental anions, such as chlorine, bromine, and iodine.

In a preferred embodiment, the hydrochloride salt of the pharmaceutically acceptable salt, more preferably the dihydrochloride salt.

In a preferred embodiment, the compound satisfies the following condition:

a) the compound is BKP-01-010: 2, 7-bis [2- (diethylamino) -methoxy ] -carbazolyl dihydrochloride, BKP-01-011: 2, 7-bis [2- (diethylamino) -ethoxy ] -carbazole dihydrochloride, BKP-01-012: 2, 7-bis [2- (dipropylamino) -ethoxy ] -carbazole dihydrochloride, BKP-01-013: 2, 7-bis- (pyrrolidine-ethoxy) -carbazole dihydrochloride, BKP-01-014: 2, 7-bis- (morphine-ethoxy) -carbazole dihydrochloride, BKP-01-015: 2, 7-bis- (piperazine-ethoxy) -carbazole dihydrochloride, BKP-01-016: 2, 7-bis- (4-methylpiperazine-ethoxy) -carbazole dihydrochloride, BKP-01-017: 2, 7-bis- (piperidine-ethoxy) -carbazole dihydrochloride or BKP-01-018: 2, 7-bis [2- (dimethylamino) -propylcarbonyl ] -carbazole dihydrochloride; or

b) The compound is: BKP-01-020: 2, 7-bis [2- (diethylamino) -methoxy ] -fluorene dihydrochloride, BKP-01-021: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorene dihydrochloride, BKP-01-022: 2, 7-bis [2- (dipropylamino) -ethoxy ] -fluorene dihydrochloride, BKP-01-023: 2, 7-bis- (pyrrolidine-ethoxy) -fluorene dihydrochloride, BKP-01-024: 2, 7-bis- (morpholine-ethoxy) -fluorene dihydrochloride, BKP-01-025: 2, 7-bis- (piperazine-ethoxy) -fluorene dihydrochloride, BKP-01-026: 2, 7-bis- (4-methylpiperazine-ethoxy) -fluorene dihydrochloride, BKP-01-027: 2, 7-bis- (piperidine-ethoxy) -fluorene dihydrochloride or BKP-01-028: 2, 7-bis [2- (dimethylamino) -propylcarbonyl ] -fluorene dihydrochloride; or

c) The compound is: BKP-01-030: 2, 7-bis [2- (diethylamino) -methoxy ] -fluorenone-9 dihydrochloride, BKP-01-031: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenone-9-dihydrochloride, BKP-01-032: 2, 7-bis [2- (dipropylamino) -ethoxy ] -fluorenone-9-dihydrochloride, BKP-01-033: 2, 7-bis- (pyrrolidine-ethoxy) -fluorenone-9-dihydrochloride, BKP-01-034: 2, 7-bis- (morphine-ethoxy) -fluorenone-9. dihydrochloride, BKP-01-035: 2, 7-bis- (piperazine-ethoxy) -fluorenone-9-dihydrochloride, BKP-01-036: 2, 7-bis- (4-methylpiperazine-ethoxy) -fluorenone-9 dihydrochloride, BKP-01-037: 2, 7-bis- (piperidine-ethoxy) -fluorenone-9-dihydrochloride or BKP-01-038: 2, 7-bis [2- (dimethylamino) -propylcarbonyl ] -fluorenone-9-dihydrochloride; or

d) The compound is: BKP-01-040: 2, 7-bis [2- (diethylamino) -methoxy ] -fluorenoxime-9-dihydrochloride, BKP-01-041: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenoxime-9 dihydrochloride, BKP-01-042: 2, 7-bis [2- (dipropylamino) -ethoxy ] -fluorenoxime-9-dihydrochloride, BKP-01-043: 2, 7-bis- (pyrrolidine-ethoxy) -fluorenoxime-9 dihydrochloride, BKP-01-044: 2, 7-bis- (morphine-ethoxy) -fluorenoxime-9. dihydrochloride, BKP-01-045: 2, 7-bis- (piperazine-ethoxy) -fluorenoxime-9 dihydrochloride, BKP-01-046: 2, 7-bis- (4-methylpiperazine-ethoxy) -fluorenoxime-9 dihydrochloride, BKP-01-047: 2, 7-bis- (piperidine-ethoxy) -fluorenoxime-9-dihydrochloride or BKP-01-048: 2, 7-bis [2- (dimethylamino) -propylcarbonyl ] -fluorenoxime-9-dihydrochloride; or

e) The compound is: BKP-01-050: 2, 7-bis [2- (diethylamino) -methoxy ] -dibenzofuran dihydrochloride, BKP-01-051: 2, 7-bis [2- (diethylamino) -ethoxy ] -dibenzofuran dihydrochloride, BKP-01-052: 2, 7-bis [2- (dipropylamino) -ethoxy ] -dibenzofuran dihydrochloride, BKP-01-053: 2, 7-bis- (pyrrolidine-ethoxy) -dibenzofuran dihydrochloride, BKP-01-054: 2, 7-bis- (morphine-ethoxy) -dibenzofuran dihydrochloride, BKP-01-055: 2, 7-bis- (piperazine-ethoxy) -dibenzofuran dihydrochloride, BKP-01-056: 2, 7-bis- (4-methylpiperazine-ethoxy) -dibenzofuran dihydrochloride, BKP-01-057: 2, 7-bis- (piperidine-ethoxy) -dibenzofuran dihydrochloride or BKP-01-058: 2, 7-bis [2- (dimethylamino) -propylcarbonyl ] -dibenzofuran dihydrochloride; or

f) The compound is: BKP-01-060: 2, 7-bis [2- (diethylamino) -methoxy ] -fluorenol-9-dihydrochloride, BKP-01-061: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenol-9 dihydrochloride, BKP-01-062: 2, 7-bis [2- (dipropylamino) -ethoxy ] -fluorenol-9-dihydrochloride, BKP-01-063: 2, 7-bis- (pyrrolidine-ethoxy) -fluorenol-9 dihydrochloride, BKP-01-064: 2, 7-bis- (morphine-ethoxy) -fluorenol-9 dihydrochloride, BKP-01-065: 2, 7-bis- (piperazine-ethoxy) -fluorenol-9 dihydrochloride, BKP-01-066: 2, 7-bis- (4-methylpiperazine-ethoxy) -fluorenol-9 dihydrochloride, BKP-01-067: 2, 7-bis- (piperidine-ethoxy) -fluorenol-9-dihydrochloride or BKP-01-068: 2, 7-bis [2- (dimethylamino) -propylcarbonyl ] -fluorenol-9-dihydrochloride.

In a preferred embodiment, the compound is BKP-01-021: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorene dihydrochloride, BKP-01-030: 2, 7-bis [2- (diethylamino) -methoxy ] -fluorenone-9 dihydrochloride, BKP-01-031: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenone-9-dihydrochloride, BKP-01-041: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenoxime-9 dihydrochloride, BKP-01-58: 2, 7-bis [2- (diethylamino) -propylcarbonyl ] -dibenzofuran dihydrochloride or BKP-01-61: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenol-9 dihydrochloride.

In a further preferred embodiment, the compound is BKP-01-041: 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenoxime-9 dihydrochloride.

The preparation method of the BKP-01-041 comprises the following steps:

a) dissolving raw material fluorene in dichloromethane, dripping a dichloromethane solution of halogen at 0 ℃, then heating to room temperature, and continuing to react to generate a compound 2, 7-dihalogenated fluorene;

b) dissolving 2, 7-dihalogenated fluorene in glacial acetic acid, adding an oxidant, and carrying out reflux reaction to generate 2, 7-dihalogenated fluorenone;

c) dissolving 2, 7-dihalofluorenone and ethylenediamine ethanol in toluene, performing condensation reaction, and adding isopropanol hydrogen chloride solution to form salt to generate 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenone dihydrochloride;

d) dissolving 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenone dihydrochloride in isopropanol, and adding hydroxylamine hydrochloride while stirring to generate a target compound BKP-01-041(2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenoxime-9 dihydrochloride).

Preferably, the specific steps of step a) include: dissolving fluorene in dichloromethane, cooling to 0 deg.c, dropping bromodichloromethane solution into the reaction system, maintaining at 0 deg.c for 0.5 hr, raising the temperature to 25 deg.c and stirring for 2 hr.

Preferably, the specific steps of step b) include: dissolving the 2, 7-dibromofluorene obtained in the step a) in glacial acetic acid, adding chromium trioxide glacial acetic acid solution, and heating and refluxing for 5 hours to obtain 2, 7-dibromofluorenone.

Preferably, the specific steps of step c) include: dissolving the 2, 7-dibromo fluorenone obtained in the step b) in toluene, adding a potassium hydroxide solution, adding ethylenediamine ethanol hydrochloride in batches, finally adding tetrabutylammonium bromide, and refluxing for 30 hours. After layering, evaporating the organic phase to remove the solvent, adding a hydrogen chloride isopropanol solution to form salt, and filtering to obtain 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenone dihydrochloride.

Preferably, the specific steps of step d) include: dissolving 2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenone dihydrochloride in isopropanol, adding hydroxylamine hydrochloride while stirring, and stirring for 3 hours to obtain the target compound BKP-01-041(2, 7-bis [2- (diethylamino) -ethoxy ] -fluorenoxime-9-dihydrochloride).

In a preferred embodiment, the virus is selected from the group consisting of coronavirus, influenza virus, parainfluenza virus, cytomegalovirus, adenovirus, rhinovirus, herpes simplex, varicella-zoster, rubella virus, measles virus, dengue virus, yellow fever virus, west nile virus, hepatitis a virus, hepatitis b virus, hepatitis c virus, enterovirus, respiratory syncytial virus and ebola virus. Further preferably, the virus is selected from the group consisting of coronaviruses.

In a preferred embodiment, the coronavirus is selected from the group consisting of human coronavirus OC43(HCoV-OC43), human coronavirus 229E (HCoV-229E), human coronavirus NL63(HCoV-NL63), human coronavirus HKU1(HCoV-HKU1), severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV), and 2019 novel coronavirus (2019-nCoV).

In a further preferred embodiment, the coronavirus is selected from the 2019 novel coronavirus (2019-nCoV).

In a preferred embodiment, the coronavirus infection is coronavirus infectious pneumonia, preferably neocoronary pneumonia.

In a preferred embodiment, the medicament further optionally comprises at least one other therapeutic agent. Preferably, the at least one further therapeutic agent is active against the virus, preferably a coronavirus. In a further preferred embodiment, the therapeutic agent is selected from corticosteroids, anti-inflammatory signal transduction modulators, β 2-adrenoceptor agonist bronchodilators, anticholinergics, mucolytics, hypertonic saline, and other drugs used to treat viral infections, especially infections with viruses of the family coronaviridae; or mixtures thereof.

The tiolone analogs of the invention can be administered to a patient simultaneously or sequentially with at least one other therapeutic agent in a unit dosage combination. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be given in two or more administrations.

Coadministration of a tilolone analog of the invention with at least one other active therapeutic agent generally refers to administering the tilolone analog of the invention and at least one other active therapeutic agent simultaneously or sequentially such that a therapeutically effective amount of both the tilolone analog of the invention and the at least one other active therapeutic agent are present in the patient.

Co-administration includes administering a unit dose of a tiolone analog of the invention before or after administering a unit dose of one or more other active therapeutic agents, e.g., within seconds, minutes, or hours of administering one or more other active therapeutic agents. For example, a unit dose of an analog of the invention, a ketotifen analog, can be administered first, followed by a unit dose of one or more additional active therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed by a unit dose of a tiolone analog of the invention within seconds or minutes.

In a preferred embodiment, the medicament may be in any pharmaceutically acceptable dosage form, including those suitable for different routes of administration. The dosage forms may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are commonly found in Remington's pharmaceutical sciences (Mack publishing co., Easton, PA). These methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, dosage forms are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

In a further preferred embodiment, the dosage form is a tablet, capsule, granule, spray, oral liquid, injection, suspension, suppository, patch, dry powder inhaler. In one embodiment, the tablet may be a sustained release tablet or a regular tablet.

Further preferred dosage forms are sustained release tablets. The sustained-release tablet can reduce the frequency of administration, prolong the action time of the medicine and maintain stable effective treatment concentration. Compared with the common tablet specification, the daily administration dosage of the sustained-release preparation is not changed, but the sustained-release preparation is convenient for patients to take, has better compliance, can reduce toxic and side effects, reduces adverse symptoms caused by rapid rise of blood concentration, and achieves better treatment effect.

For tableting the drug of the present invention, a wide variety of pharmaceutically acceptable carriers known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.; the adhesive can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate, citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.

Suitable routes of administration for the compounds, compositions or medicaments of the present invention include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It will be appreciated that the preferred route may vary depending on, for example, the condition of the recipient.

An effective dose of a compound, composition or drug of the invention will depend at least on the nature, toxicity of the condition being treated, whether the compound is being used prophylactically (lower dose) or against a live viral infection, the method of delivery and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It is contemplated that about 0.0001 to about 100mg per kilogram body weight per day. For example, a candidate daily dose for an adult human of about 70kg body weight will range from 0.1mg to 1000mg, and may take the form of a single or multiple doses. In a preferred embodiment, the single pharmaceutically effective amount ranges from 0.1mg to 1000mg, preferably from 1mg to 500 mg.

In a second aspect, the present invention provides a pharmaceutical composition for the prevention and/or treatment of a viral infection comprising a compound as described in any of the above embodiments of the present invention and pharmaceutically acceptable salts thereof, and optionally at least one further therapeutic agent, and a pharmaceutically acceptable carrier.

In a preferred embodiment, the virus is selected from the group consisting of coronavirus, influenza virus, parainfluenza virus, cytomegalovirus, adenovirus, rhinovirus, herpes simplex, varicella-zoster, rubella virus, measles virus, dengue virus, yellow fever virus, west nile virus, hepatitis a virus, hepatitis b virus, hepatitis c virus, enterovirus, respiratory syncytial virus and ebola virus. Further preferably, the virus is selected from the group consisting of coronaviruses.

In a preferred embodiment, the additional therapeutic agent is selected from corticosteroids, anti-inflammatory signal transduction modulators, β 2-adrenoceptor agonist bronchodilators, anticholinergics, mucolytics, hypertonic saline, and other drugs used to treat viral infections, particularly infections with viruses of the family coronaviridae; or mixtures thereof.

In a preferred embodiment, the coronavirus is preferably selected from the 2019 novel coronavirus (2019-nCoV).

In a preferred embodiment, the coronavirus infection is coronavirus infectious pneumonia, preferably neocoronary pneumonia.

Drawings

FIG. 1 is a UV spectrum of a BKP-01-041 compound.

FIG. 2 is a chart of HPLC assay for BKP-01-041 compound.

FIG. 3 is an infrared spectrum of a BKP-01-041 compound.

Examples