CN113842386A - Medicine with broad-spectrum antiviral activity - Google Patents

Medicine with broad-spectrum antiviral activity Download PDF

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CN113842386A
CN113842386A CN202010600737.2A CN202010600737A CN113842386A CN 113842386 A CN113842386 A CN 113842386A CN 202010600737 A CN202010600737 A CN 202010600737A CN 113842386 A CN113842386 A CN 113842386A
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侯法建
王长万
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Center for Excellence in Molecular Cell Science of CAS
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Abstract

The invention provides a medicament having broad-spectrum antiviral activity. Specifically, the invention provides an application of a compound shown as a formula I or a pharmaceutically acceptable salt thereof in preparing a medicine for treating or preventing I type Interferon (IFN) related diseases. The compounds of the invention are capable of inducing interferon production (e.g., INF β) at the cellular level and are also capable of significantly inhibiting viral infection.

Description

Medicine with broad-spectrum antiviral activity
Technical Field
The invention belongs to the field of medicines, and particularly relates to a medicine with broad-spectrum antiviral activity.
Background
The innate immunity of the host is the first line of defense of the immune system against pathogenic microorganisms. The virus is a pathogen in nature and can cause various diseases, and the inherent immune response against virus can induce host cells to produce interferon to inhibit the propagation and amplification of the virus. Therefore, a new idea is provided for antiviral treatment by inducing interferon production.
At present, the interferon expressed by escherichia coli is widely applied to treatment of viral infection, inflammation, immune dysfunction and the like, but is protein polypeptide, has unstable structure, can not be taken orally and has high requirement on storage condition. Can only be administrated by injection, and the administration mode is single. In addition, its short half-life and high concentration can cause severe toxic side effects. Another disadvantage of recombinant expressed interferon in E.coli is lack of glycosylation modification and limited activity. The purified interferon containing glycosylation expressed by a eukaryotic system has high cost and expensive finished medicine price.
In view of the above, there is an urgent need in the art to develop new drugs having the ability to induce interferon production.
Disclosure of Invention
The invention aims to provide a novel drug capable of inducing interferon production.
In a first aspect of the invention, there is provided a use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of (a) a type I Interferon (IFN) -associated disease and/or (b) a disease associated with viral infection;
Figure BDA0002558527940000011
wherein,
ring a is selected from the group consisting of: c6-10An aromatic ring (preferably, a benzene ring), and a 5-to 10-membered heteroaromatic ring (preferably, a 6-membered heteroaromatic ring, more preferably, a 6-membered heteroaromatic ring containing 1 nitrogen heteroatom);
ring B is selected from the group consisting of: c6-10Aromatic ring (preferably, benzene)A ring), and a5 to 10 membered heteroaromatic ring (preferably, a 6 membered heteroaromatic ring, more preferably, a 6 membered heteroaromatic ring containing 1 nitrogen heteroatom);
R1selected from the group consisting of: c (R)11)、N；
R11Selected from the group consisting of: H. and C1-6An alkyl group;
R2is-W- (R)L)m-N(R21)2or-W- (R)L)m-C(R22)3；
Wherein,
w is selected from the group consisting of: no, -N (R)23) -, and-C (R)24)2-；
RLEach independently is-C (R)25)2-；
m is 2, 3, 4, 5, 6, 7 or 8 (preferably, m is 3, 4 or 5);
R21each independently selected from the group consisting of: H. and C1-6An alkyl group; or two R21And the N atoms to which they are attached together form a5 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl;
R22each independently selected from the group consisting of: H. and C1-6An alkyl group; or two R22And together with the C atom to which they are attached form C4-10Cycloalkyl radical, C6-10Aryl, 5 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl;
R23、R24and R25Each independently selected from the group consisting of: H. and C1-4Alkyl (preferably, methyl or ethyl);
R3represents one or more (preferably, 1, 2 or 3; more preferably, 1) groups selected from the group consisting of: H. -OH, -O-C1-6Alkyl, -S-C1-6Alkyl, and-OC (O) -C1-6An alkyl group;
R4represents one or more (preferably, 1, 2 or 3; more preferably, 1) groups selected from the group consisting of: H. halogen, and C1-6An alkyl group;
unless otherwise specified, the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can also optionally be substitutedOne or more (preferably, 1, 2 or 3) R substitutions; wherein each R is independently selected from the group consisting of; halogen (preferably, F, Cl, Br, I), C1-6Alkyl (preferably, methyl, ethyl), C1-6Haloalkyl, and C3-6Cycloalkyl (preferably, cyclopropyl).
In another preferred embodiment, the 5-to 10-membered heteroaryl group in ring a and ring B contains 1 or 2 heteroatoms selected from O, N and S.
In another preferred embodiment, ring A is C6-10An aryl group; preferably, it is phenyl.
In another preferred embodiment, ring B is C6-10An aryl group; preferably, it is phenyl.
In another preferred embodiment, R1Is N.
In another preferred embodiment, R2is-W- (R)L)m-N(R21)2。
In another preferred embodiment, R2is-W- (R)L)m-N(R21)2(ii) a Wherein W is-N (R)23) -, the remaining radicals being as defined above.
In another preferred embodiment, R2is-W- (R)L)m-N(R21)2；
Wherein,
w is-NH-;
RLeach independently selected from the group consisting of: -CH2-、-CH(CH3)-、-CH(CH3)2-、-CH(CH2CH3)-；
m is 3, 4, or 5; and
R21each independently is C1-6Alkyl (preferably, methyl, ethyl, propyl); or two R21And the N atom to which it is attached, together form a5, 6 or 7 membered heterocycloalkyl (preferably, the heterocycloalkyl contains no other heteroatoms than N).
In another preferred embodiment, R2is-W- (R)L)m-N(R21)2；
Wherein,
w is-NH-;
RLeach independently selected from the group consisting of: -CH2-、-CH(CH3)-、-CH(CH3)2-、-CH(CH2CH3)-；
m is 3, 4, or 5; and
R21each independently is C1-6Alkyl (preferably, R)21Is C1-4An alkyl group; more preferably, R21Each independently selected from the group consisting of: methyl, ethyl, and propyl).
In another preferred embodiment, R21Are the same or different groups.
In another preferred embodiment, R2is-NH-CH (CH)3)-(CH2)3-N(CH2CH3)2。
In another preferred embodiment, R3Selected from the group consisting of: -OH, -O-C1-6An alkyl group; preferably, R3Selected from the group consisting of: -OH, -O-C1-4An alkyl group; more preferably, R3is-OCH3。
In another preferred embodiment, R4Selected from the group consisting of: H. f, Cl, Br, methyl, and ethyl.
In another preferred embodiment, R4Is halogen; preferably, R4Selected from the group consisting of: F. cl and Br.
In another preferred embodiment, each R is independently selected from the group consisting of; F. cl, Br, methyl, ethyl, and cyclopropyl.
In another preferred embodiment, the pharmaceutically acceptable salt of the compound of formula I is the hydrochloride salt of the compound of formula I.
In another preferred embodiment, the compound of formula I is represented by formula II,
Figure BDA0002558527940000041
wherein R is1、R2、R3And R4Is as defined in formula I.
In another preferred embodiment, the compound of formula I is represented by formula III;
Figure BDA0002558527940000042
wherein R is1、R2、R3And R4Is as defined in formula I.
In a further preferred embodiment of the method,
in the formula (III), the reaction solution is prepared,
R1selected from the group consisting of: CH. And N;
R2is-W- (R)L)m-N(R21)2；
Wherein,
w is-NH-;
RLeach independently selected from the group consisting of: -CH2-、-CH(CH3)-、-CH(CH3)2-、-CH(CH2CH3)-；
m is 3, 4 or 5;
R21each independently selected from the group consisting of: H. and C1-6An alkyl group; or two R21And the N atom or two R groups attached thereto21And the N atom to which they are attached together form a 5-, 6-or 7-membered heterocycloalkyl group, which contains no further heteroatoms than the N atom;
R3selected from the group consisting of: -OH, and-O-C1-4An alkyl group;
R4selected from the group consisting of: H. f, Cl, Br, methyl, and ethyl;
unless otherwise specified, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups can also be optionally substituted with one or more R; wherein each R is independently selected from the group consisting of; F. cl, Br, methyl, ethyl, and cyclopropyl.
In another preferred embodiment, the compound of formula I is a compound shown as formula IV;
Figure BDA0002558527940000051
in another preferred embodiment, the pharmaceutically acceptable salt of the compound of formula I is a compound shown as formula IV-a;
Figure BDA0002558527940000052
in another preferred embodiment, the type I interferon related disease is a disease that is ameliorated, treated or prevented by an increase in the level of type I interferon in vivo. In another preferred embodiment, the type I Interferon (IFN) related diseases include: viral infections, and multiple sclerosis and/or chronic myeloid leukemia.
In another preferred embodiment, the virus includes a DNA virus and an RNA virus.
In another preferred embodiment, the DNA virus comprises: HSV (herpes simplex virus), HBV (hepatitis B virus), HAV (hepatitis A virus), HPV (human papilloma virus) and/or EBV (Epstein-Barr virus).
In another preferred embodiment, the RNA virus comprises: ss (+) RNA viruses, ss (-) RNA viruses (e.g., VSV (vesicular stomatitis virus) and/or influenza A viruses), and/or double stranded RNA viruses (e.g., rotavirus).
In another preferred embodiment, the RNA virus comprises: VSV (vesicular stomatitis virus), HCV (hepatitis c virus), EMCV (encephalomyocarditis virus), Ebola (Ebola virus), HIV (aids virus), avian influenza virus, influenza virus (e.g., influenza a, b, and/or c virus), parainfluenza virus, coronavirus, rotavirus, respiratory syncytial virus, and/or Zika virus.
In a second aspect of the invention, there is provided a method of inducing production of type I interferon in a cell, said method comprising the steps of: contacting a cell with a compound of formula I, thereby inducing the cell to produce a type I interferon; wherein the compound of formula I is as defined in the first aspect.
In another preferred embodiment, the cell is a mammalian cell, preferably a human cell.
In another preferred embodiment, the cell is an ex vivo cell.
In another preferred embodiment, the cell comprises: vero cells, THP-1 cells, HEK293T cells, and/or A549 cells.
In another preferred embodiment, the method is non-therapeutic in vitro.
In another preferred embodiment, the method comprises the steps of: incubating the cell in a system comprising a compound of formula I, thereby inducing the cell to produce interferon.
In another preferred embodiment, in the system containing the compound of the formula I, the concentration of the compound of the formula I is more than or equal to 1 mu M; preferably, not less than 3. mu.M.
In another preferred embodiment, the incubation time is 10 min-48 h.
In another preferred embodiment, the type I interferon comprises IFN beta.
In a third aspect of the present invention, there is provided a method of inhibiting viral infection comprising the steps of:
contacting a cell with a compound of formula I, thereby inhibiting infection of the cell by a virus; wherein said compound of formula I is as defined in the first aspect.
In another preferred embodiment, the cell is a mammalian cell, preferably a human cell.
In another preferred embodiment, the cell is an ex vivo cell.
In another preferred embodiment, the cell comprises: vero cells, THP-1 cells, HEK293T cells, and/or A549 cells.
In another preferred embodiment, the virus includes a DNA virus and an RNA virus.
In another preferred embodiment, the RNA virus comprises: ss (+) RNA viruses, ss (-) RNA viruses (e.g., VSV (vesicular stomatitis virus) and/or influenza A viruses), and/or double stranded RNA viruses (e.g., rotavirus).
In another preferred embodiment, the DNA virus comprises: HSV (herpes simplex virus), HBV (hepatitis B virus), HAV (hepatitis A virus), HPV (human papilloma virus) and/or EBV (Epstein-Barr virus).
In another preferred embodiment, the RNA virus comprises: VSV (vesicular stomatitis virus), HCV (hepatitis c virus), EMCV (encephalomyocarditis virus), Ebola (Ebola virus), HIV (aids virus), avian influenza virus, influenza virus (e.g., influenza a, b, and/or c virus), parainfluenza virus, coronavirus, rotavirus, respiratory syncytial virus, and/or Zika virus (Zika virus).
In another preferred embodiment, the method is non-therapeutic in vitro.
In another preferred embodiment, the method comprises the steps of: incubating the cell in a system comprising a compound of formula I, thereby inducing the cell to produce interferon.
In a fourth aspect of the present invention, there is provided a pharmaceutical composition for treating or preventing a type I interferon-related disease, the pharmaceutical composition comprising:
(i) a compound of formula I, or a pharmaceutically acceptable salt thereof, as active ingredient; and (ii) a pharmaceutically acceptable carrier;
the compound of formula I is as defined in the first aspect.
In another preferred embodiment, the pharmaceutical composition further comprises a second active ingredient; the second active ingredient comprises: a type I interferon modulator, an antiviral agent, or a combination thereof.
In a fifth aspect of the invention, there is provided a method of increasing the level of type I interferon in vivo, said method comprising the steps of:
administering to a cell in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof; wherein the compound of formula I is as defined in the first aspect.
In another preferred embodiment, the cell is a mammal; preferably, it is selected from the group consisting of: human, mouse, and rat.
In a sixth aspect of the present invention, there is provided a method of treating or preventing a type I Interferon (IFN) related disease and/or a disease associated with viral infection and/or combating viruses (e.g. inhibiting viral replication), said method comprising the steps of:
administering to a cell in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I;
wherein the compound of formula I is as defined in the first aspect.
In another preferred embodiment, the cell is a mammal; preferably, it is selected from the group consisting of: human, mouse, and rat.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
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FIG. 1 shows mRNA transcription of IFN-. beta.TNF-. alpha.and IL-6 in HEK293 cells after 12 hours of treatment with varying concentrations of mepacrilin.
FIG. 2 shows mRNA transcription of IFN-. beta.TNF-. alpha.and IL-6 in HEK293T cells after 12 hours of treatment with varying concentrations of mepacrilin.
FIG. 3 shows the mRNA transcription of IFN-. beta.TNF-. alpha.and IL-6 in THP-1 cells after 12 hours of treatment with varying concentrations of mepacrilin.
FIG. 4 shows the mRNA transcription of IFN- β, TNF- α and IL-6 in A549 cells after 12 hours of treatment with varying concentrations of mepacrilin.
FIG. 5 shows that IFN- β, TNF- α and IL-6 protein levels were detected in the culture supernatants of A549 cells after 12 hours of treatment with varying concentrations of mepacrilin.
Fig. 6 shows GFP expression (scale bar 500 μm) by VSV virus after treatment of Vero cells at different concentrations of mepacrine and VSV-GFP (MOI 0.5) for 16 hours. The results of observation by phase contrast microscope (DIC), viral infection (GFP) and staining of cell nucleus (Hoechst) are shown, respectively.
FIG. 7 shows the inhibition curves of RNA virus VSV by mepacrilin
Figure 8 shows GFP expression (scale bar 500 μm) of HSV viruses after treatment of Vero cells at different concentrations of mepacrine and HSV-GFP (MOI 0.5) for 16 hours. The results of observation by phase contrast microscope (DIC), viral infection (GFP) and staining of cell nucleus (Hoechst) are shown, respectively.
FIG. 9 shows the inhibition curves of the DNA virus HSV by mepacrilin.
Detailed Description
The inventors have conducted extensive and intensive studies. It has been unexpectedly found that compounds of formula I (in the case of mepacrilin) are capable of inducing expression or production of type I interferons (e.g., IFN β) in different cells. In addition, mepacriline has been shown experimentally to have a broad spectrum of inhibitory effects (dose-related) against RNA virus (e.g., VSV) and DNA virus (e.g., HSV) infection. Thus, a novel drug which induces IFN beta production by cells and has a potential broad-spectrum antiviral effect in clinical treatment is provided. Based on this, the inventors have completed the present invention.
Innate immunity
The innate immunity of the host is the first line of defense of the immune system against pathogenic microorganisms. The virus is a pathogen in nature and can cause various diseases, and the inherent immune response against virus can induce host cells to produce interferon to inhibit the propagation and amplification of the virus. The antiviral innate immune response is mediated by signal transduction pathways, and earlier related studies have revealed how the innate immune system recognizes viral invasion and rapidly triggers immune defense functions, thereby effectively eliminating viral infections. The method is an important research in the fields of life science and medicine, and the research on the molecular level of the subjects provides a theoretical basis for the design of related medicines, and brings a new hope for preventing and treating virus infection. After the host cell recognizes the pathogenic microorganism, the host cell generates interferon, proinflammatory factors and cell chemotactic factors through the transduction of an innate immunity signal pathway, and the effector factors can inhibit the replication of the pathogen on one hand, thereby playing a role in quickly controlling the proliferation of the pathogen; on the other hand, these cytokines can mobilize other immune cells of the host, including antigen presenting cells and T, B lymphocytes in the adaptive immune system, and activate adaptive immunity. In addition, the induction and activation of innate immune response has an anti-tumor effect, which can potentiate the effects of radiotherapy and chemotherapy.
The innate immune signaling pathway begins with the recognition of the relevant molecular pattern of a pathogenic microorganism by the pattern recognition receptors of the host cell. The innate immune signaling pathways that have been discovered to date in association with viral infection include mainly the RLRs-MAVS signaling pathway in the cytoplasm that recognizes RNA viruses and the cGAS-STING signaling pathway that recognizes DNA viruses, as well as the TLRs signaling pathway. After being activated, the two signal paths of the RLRs and the cGAS are recruited and activated by downstream transducin TBK1, and the activated TBK1 ensures that transcription factor IRF3 is phosphorylated into nucleus to induce the generation of type I interferon, thereby finally achieving the effect of inhibiting viruses. During long-term evolution, some viruses also acquire some mechanism to escape the innate immune response.
Because the innate immunity plays an important role in all links of the life activities of the human body, the innate immunity has important guiding significance for the development of vaccines and medicines.
Term(s) for
As used herein, "C" is1-6Alkyl ", by itself or as part of another group (e.g. -O-C)1-6C in alkyl1-6Alkyl) refers to a straight or branched chain alkyl group comprising 1 to 6 carbon atoms, such as methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), or the like. It is to be understood that, unless otherwise specified, alkyl groups are intended to include all isomeric forms thereof which may be present, such as "propyl" including n-propyl and isopropyl. Similarly, "C1-4Alkyl "refers to a straight or branched chain alkyl group comprising 1 to 4 carbon atoms.
As used herein, the term "cycloalkyl" refers to a ring having the indicated number of ring atoms (e.g., C)3-10Cycloalkyl) and a hydrocarbon ring that is fully saturated or has no more than one double bond between ring vertices. "cycloalkyl" also refers to bicyclic and polycyclic hydrocarbon rings. The term "heterocycloalkyl" refers to a cycloalkyl group having the indicated number of ring atoms (e.g., a5 to 10 membered heterocycloalkyl ring) and containing from 1 to 5 (e.g., 1, 2 or 3, preferably 1 or 2) heteroatoms selected from N, O and S as ring atoms, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heterocycloalkyl group may be monocyclic,Bicyclic or polycyclic ring systems. The heterocycloalkyl group can be attached to the rest of the molecule via a ring carbon or a heteroatom. Preferably, the cycloalkyl or heterocycloalkyl group is saturated.
Unless otherwise stated, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. Further, terms such as "haloalkyl" are meant to include monohaloalkyl or polyhaloalkyl. For example, the term "C1-4Haloalkyl "is meant to include trifluoromethyl, 2,2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
Unless otherwise indicated, the term "aryl" or "aromatic ring" refers to a polyunsaturated (usually aromatic) hydrocarbon group or ring, which may be a single ring or multiple rings (up to two rings) fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing 1 to 5 (preferably 1, 2 or 3) heteroatoms selected from N, O and S as ring atoms, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroaryl group may be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, while non-limiting examples of heteroaryl groups include pyridyl and the like.
For the compounds provided herein, a bond from a substituent (typically an R group) to the center of a ring (e.g., a cyclobenzene, phenyl, etc.) will be understood to refer to a bond that provides attachment at any available vertex on the ring.
Herein, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on a group are substituted with a substituent selected from the group consisting of: halogen, unsubstituted or halogenated C1-6An alkyl group.
As used herein, the terms "comprising," "including," or "including" mean that the various ingredients may be used together in a mixture or composition of the invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "comprising.
As used herein, the term "selection index" may be used to judge the safety margin of the effect of a drug, with selection indices above 1.00 being effective and the safety margin being greater for larger indices.
Active ingredient
As used herein, the term "compounds of the invention" refers to compounds of formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, isomers, hydrates, solvates, or prodrugs of the compounds of formula I.
Wherein the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or a base, which is suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and the like; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, etc. Another preferred class of salts are those of the compounds of the invention with bases, for example alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), for example methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, triethanolamine salts, and amine salts formed from morpholine, piperazine, lysine, respectively.
As used herein, the term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specific ratio. "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.
As used herein, the term "prodrug" includes prodrugs which may themselves be biologically active or inactive and which, when administered by an appropriate method, undergo a metabolic or chemical reaction in the human body to convert to a compound of formula I, or a salt or solution of a compound of formula I. The prodrugs include, but are not limited to, carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amide, carbamate, azo, phosphoramide, glucoside, ether, acetal forms of the compounds.
In one embodiment, the compound of the invention is mepacrilin (Mepacrine).
In the present text, Mepacrine (Mepacrine), also known as quinacrine or aclacine, is a drug which is widely applied to malaria control and has the application curative effect on stripe disease, amebic dysentery, pyriform (vermiform stool) disease, trichomoniasis vaginalis, lupus erythematosus and rheumatoid arthritis, and the structure of the drug is shown as formula IV-a (in the form of hydrochloride):
Figure BDA0002558527940000111
pharmaceutical compositions and methods of administration
Because the compound of the present invention has an excellent ability to induce the production of type I interferon and/or to resist viruses (inhibit viral infection), the compound of the present invention and various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient are useful for the treatment, prevention and alleviation of diseases associated with type I interferon (especially those diseases that can be ameliorated, treated or prevented by modulating interferon levels in vivo, such as increasing interferon levels) and/or diseases associated with viral infection. According to the prior art, the compounds of the invention are useful for the treatment of the following diseases: viral infection, multiple sclerosis, systemic lupus erythematosus and chronic granulocytic leukemia. Typically, these viruses may be RNA viruses and/or DNA viruses; exemplary DNA viruses include (but are not limited to): HSV (herpes simplex virus), HBV (hepatitis B virus), HAV (hepatitis A virus), HPV (human papilloma virus) and/or EBV (Epstein-Barr virus); herein, the RNA virus may be: ss (+) RNA viruses, ss (-) RNA viruses (e.g., VSV, influenza A virus, etc.), RNA viruses (e.g., rotavirus), and the like, exemplary RNA viruses include (but are not limited to): VSV (vesicular stomatitis virus), HCV (hepatitis c virus), EMCV (encephalomyocarditis virus), Ebola (Ebola virus), HIV (aids virus), avian influenza virus, influenza virus (e.g., influenza a, b, and/or c virus), parainfluenza virus, coronavirus, rotavirus, respiratory syncytial virus, and/or Zika virus.
As used herein, the terms "inducing production of interferon", "inducing production of type I interferon", or "inducing production of interferon" are used interchangeably and are intended to include: improving the expression, transcription or protein content level of type I interferon or type I interferon related protein, cell factor, etc.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-500mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0002558527940000131
) Wetting agents (e.g., sodium lauryl sulfate), colorants, flavors,Stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
Herpes simplex virus
Herpes Simplex Virus (HSV) is a typical representative of herpes viruses, and is known for the development of vesicular dermatitis, herpes simplex, during the acute phase of infection. Can cause various diseases in human, such as gingivitis, keratoconjunctivitis, encephalitis, reproductive system infection and neonatal infection.
Vesicular stomatitis virus
VSV is a member of Rhabdoviridae (Rhabdoviridae) and vesiculoviruses (Vesiculoviruses), and has a bullet-shaped or cylindrical virus particle shape, a length of about 3 times the diameter, and a size of 150 to 180nm × 50 to 70 nm. The virus has a cyst membrane, and fiber protrusions with the length of about 10nm are uniformly and densely distributed on the cyst membrane. Inside the virus is a tightly coiled, spirally symmetric nucleocapsid.
Coronavirus (coronavirus)
Coronaviruses (CoV) belong to the family of Nidovirales (Nidovirales) Coronaviridae (Coronaviridae), a positive-strand RNA virus with an envelope.
Influenza virus
Influenza viruses are called influenza viruses for short, and common influenza viruses are classified into types a (a), B (B), C (C) and D (D). The influenza virus can cause infection and morbidity of various animals such as human, poultry, pigs, horses, bats and the like, and is a pathogen of epidemic diseases of human and animals such as human influenza, avian influenza, swine influenza, horse influenza and the like.
Clinical symptoms caused by influenza virus include acute hyperthermia, general pain, marked debilitation and respiratory symptoms. Human influenza is mainly caused by influenza a and influenza b viruses.
The main advantages of the invention include:
(a) the compounds of the invention, such as mepacrilin (Mepacrine), exhibit excellent ability to induce the expression of interferons, such as IFN β.
(b) The compound (such as mepacrilin) has excellent capacity of inhibiting virus infection and antiviral activity.
(c) The compounds of the invention (e.g. mepacrilin) have very low cytotoxicity.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
1. Materials and reagents
DMEM and RPMI 1640 medium were purchased from Hyclone, Fetal Bovine Serum (FBS) from ExCell, qPCR kit from Tiangen, and Cell-Titer-Glo kit from Promega. Maparelin was applied from the chemical platform of the central scientific innovation of molecular cell science of the academy of sciences of china.
2. Cell culture
HEK293 was purchased from ATCC. The HEK293T cell line, the THP-1 cell line, the A549 cell line and the Vero cell line used were purchased from the Shanghai Hospital's cell Bank. The cell monolayers were cultured at 37 ℃ in a 5% CO2 incubator and the cells were grown in DMEM medium containing 10% FBS with 100U/ml penicillin and 100. mu.g/ml streptomycin. THP-1 cells were grown in 1640 medium containing 10% FBS with 100U/ml penicillin and 100. mu.g/ml streptomycin.
EXAMPLE 1 Compounds of the invention induce IFN production in cells
1.1) introducing HEK293, HEK293T, THP-1 and A549 cells in logarithmic growth phase into 12-well cell culture plate with cell amount of 5 × 105After the cells are attached to the wall for 6 hours, the cell culture supernatants are respectively replaced by culture media containing mepacrilin with final concentrations of 1 muM, 3 muM and 10 muM, the culture is continued for 12 hours, and finally, the cells are collected and the total RNA of the cells is extracted.
Then, qPCR was used to detect the expression of IFN β mRNA induced by various cells such as HEK293, HEK293T, THP-1 and A549 under drug treatment, and the results are shown in FIG. 1, FIG. 2, FIG. 3 and FIG. 4.
It can be seen that mepacriline can induce the IFN beta transcription level of cells to be increased. While the transcriptional levels of IL-6 and TNF α were not significantly increased in HEK293 and HEK293T cells.
1.2) introducing HEK293, HEK293T, THP-1 and A549 cells in logarithmic growth phase into 12-well cell culture plate respectivelyThe amount of cells per well was 5X 105After 6 hours of cell attachment, the cell culture supernatants were replaced with media containing mepacrilin at final concentrations of 1 μ M, 3 μ M and 10 μ M, respectively, and culture was continued for 12 hours, and finally the cell culture supernatants were collected.
The content of IFN beta, TNF alpha and IL-6 in the cell culture supernatant is detected by ELISA, the result is shown in figure 5, and the result shows that the MAPAKELIN can induce A549 cells to secrete the IFN beta.
EXAMPLE 2 Effect of Compounds of the invention on RNA Virus VSV infection
(2.1) vesicular stomatitis virus VSV was selected as a representative RNA virus in this example; the VSV-GFP strain (gifted to the southwestern medical center of the united states) is used in particular, i.e. VSV is itself capable of expressing the green fluorescent protein GFP, in favour of indicating the proliferation and load of the virus.
Vero cells in logarithmic growth phase were individually transferred into 12-well cell culture plates with a cell count of 5X 10 per well5After 6 hours of cell attachment, the cell culture supernatants were replaced with media containing varying final concentrations of mepacrilin (or DMSO) and 0.5 titer VSV-GFP, respectively, and incubation was continued for an additional 16 hours. At this time, the cell culture supernatant was discarded, and after fixing the cells, the cell nuclei were stained with Hoechst (a fluorescent dye staining the cell nuclei), and the expression of green fluorescent protein and staining of the cell nuclei were observed under a fluorescent microscope. The results are shown in FIG. 6.
As can be seen in FIG. 6, it was found that the signal of GFP expressed by VSV virus was significantly decreased in the drug-treated group compared to the control group, i.e., the DMSO-treated group, indicating that VSV-GFP infection was suppressed. Also, this inhibition is enhanced with increasing drug concentration.
(2.2) after treatment with varying concentrations of mepacriline under conditions of VSV-GFP infection of Vero cells, the inhibitory effect of mepacriline on VSV-GFP infection was calculated to have an EC50 (half the effective concentration) of 1.504 μ M and an SI (selection index) of 100.8 (FIG. 7), depending on the extent of viral inhibition. It can be seen that mepacrilin has excellent antiviral activity and safety.
EXAMPLE 3 Effect of Compounds of the invention on DNA Virus HSV infection
(2.1) similar to example 2, this example uses herpes simplex virus HSV as the representative DNA virus; the HSV-1-GFP virus strain (presented to Shanghai Pasteur institute of Chinese academy of sciences) is specifically used, namely HSV can express green fluorescent protein GFP by itself and can indicate the proliferation and the loading capacity of the virus.
Vero cells in logarithmic growth phase were individually transferred into 12-well cell culture plates with a cell count of 5X 10 per well5After the cells were attached for 6 hours, the cell culture supernatants were replaced with culture media containing varying final concentrations of mepacrilin (or DMSO) and HSV-GFP at a titer of 0.5, respectively, and culture was continued for 16 hours. At this time, the cell culture supernatant was discarded, and after fixing the cells, the cell nuclei were stained with Hoechst, and the green fluorescent protein expression and the staining of the cell nuclei were observed under a fluorescent microscope. The results are shown in FIG. 8.
As can be seen in FIG. 8, mepacrilin has a significant inhibitory effect on HSV viral infection.
(2.2) under the condition that the Vero cells are infected by HSV-GFP and after treatment with different concentrations of mepacriline, the inhibitory effect of mepacriline on HSV-GFP infection, namely EC50 (half effective concentration) is 1.629 mu M and SI (selection index) is 93.1 according to the degree of virus inhibition is calculated (shown in figure 9). It can be seen that mepacrilin has excellent antiviral activity and safety.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of (a) a type I Interferon (IFN) -related disease and/or (b) a viral infection-related disease;
Figure FDA0002558527930000011
wherein,
ring a is selected from the group consisting of: c6-10An aromatic ring, and a5 to 10 membered heteroaromatic ring;
ring B is selected from the group consisting of: c6-10An aromatic ring, and a5 to 10 membered heteroaromatic ring;
R1selected from the group consisting of: c (R)11) And N;
R11selected from the group consisting of: H. and C1-6An alkyl group;
R2is-W- (R)L)m-N(R21)2or-W- (R)L)m-C(R22)3；
Wherein,
w is selected from the group consisting of: no, -N (R)23) -, and-C (R)24)2-；
RLEach independently is-C (R)25)2-；
m is 2, 3, 4, 5, 6, 7 or 8;
R21each independently selected from the group consisting of: H. and C1-6An alkyl group; or two R21And the N atoms to which they are attached together form a5 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl;
R22each independently selected from the group consisting of: H. and C1-6An alkyl group; or two R22And together with the C atom to which they are attached form C4-10Cycloalkyl radical, C6-10Aryl, 5 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl;
R23、R24and R25Each independently selected from the group consisting of: H. and C1-4An alkyl group;
R3represents one or more groups selected from the group consisting of: H. -OH, -O-C1-6Alkyl, -S-C1-6Alkyl, and-OC (O) -C1-6An alkyl group;
R4represents one or more groups selected from the group consisting of: H. halogen, and C1-6An alkyl group;
unless otherwise specified, all references toSaid alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl can also be optionally substituted with one or more R; wherein each R is independently selected from the group consisting of; halogen, C1-6Alkyl radical, C1-6Haloalkyl, and C3-6A cycloalkyl group.
2. The use according to claim 1, wherein the compound of formula I is according to formula III;
Figure FDA0002558527930000021
wherein,
R1selected from the group consisting of: CH. And N;
R2is-W- (R)L)m-N(R21)2；
Wherein,
w is-NH-;
RLeach independently selected from the group consisting of: -CH2-、-CH(CH3)-、-CH(CH3)2-、-CH(CH2CH3)-；
m is 3, 4 or 5;
R21each independently selected from the group consisting of: H. and C1-6An alkyl group; or two R21And the N atom or two R groups attached thereto21And the N atoms to which they are attached together form a5, 6 or 7 membered heterocycloalkyl; and the heterocycloalkyl group contains no other heteroatoms than the N atom;
R3selected from the group consisting of: -OH, and-O-C1-4An alkyl group;
R4selected from the group consisting of: H. f, Cl, Br, methyl, and ethyl;
unless otherwise specified, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups can also be optionally substituted with one or more R; wherein each R is independently selected from the group consisting of; F. cl, Br, methyl, ethyl, and cyclopropyl.
3. The use according to claim 1, wherein the compound of formula I is a compound of formula IV;
Figure FDA0002558527930000022
4. the use of claim 1, wherein the type I Interferon (IFN) -associated disease comprises: viral infection, multiple sclerosis and/or chronic myeloid leukemia.
5. The use of claim 1, wherein the virus comprises a DNA virus and an RNA virus.
6. The use of claim 5, wherein the DNA virus comprises: HSV (herpes simplex virus), HBV (hepatitis B virus), HAV (hepatitis A virus), HPV (human papilloma virus) and/or EBV (Epstein-Barr virus).
7. The use of claim 5, wherein said RNA virus comprises: VSV (vesicular stomatitis virus), HCV (hepatitis C virus), EMCV (encephalomyocarditis virus), Ebola (Ebola virus), HIV (AIDS virus) and/or Zika virus (Zika virus).
8. A method of inducing production of type I interferon in a cell, said method comprising the steps of: contacting a cell with a compound of formula I, thereby inducing the cell to produce a type I interferon; wherein the compound of formula I is as defined in claim 1.
9. A method of inhibiting viral infection comprising the steps of: contacting a cell with a compound of formula I, thereby inhibiting infection of the cell by a virus; wherein the compound of formula I is as defined in claim 1.
10. A pharmaceutical composition for treating or preventing a type I interferon-related disease, comprising:
(i) a compound of formula I, or a pharmaceutically acceptable salt thereof, as active ingredient; and (ii) a pharmaceutically acceptable carrier; wherein the compound of formula I is as defined in claim 1.
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