阅读说明：本技术 抑制钙/钙调蛋白依赖性蛋白激酶ⅱ的化合物及其应用 (Inhibit calcium/calmodulin dependent protein kinase II compound and its application ) 是由 李文山 林宜玲 陈维家 史曼均 于 2019-03-28 设计创作，主要内容包括：本发明是关于一种抑制钙/钙调蛋白依赖性蛋白激酶II(calcium/calmodulin-dependent protein kinase II,CaMKII)的化合物及其应用。本发明特别是关于一种新颖的苯磺酰胺(benzenesulfonamide)衍生物以及将其用于制备CaMKII抑制剂的用途。本发明提供式(I)所示的化合物,以及含有该式(I)所示的化合物的医药组合物。本发明亦提供利用该式(I)所示的化合物制备治疗与CaMKII活性相关的疾病或状态如黄病毒感染的医药组合物的用途。<Image he="501" wi="669" file="DSA0000181164290000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to a kind of compound of inhibition calcium/calmodulin-dependent protein kinase ii (calcium/calmodulin-dependent protein kinase II, CaMKII) and its applications.The present invention is especially with regard to a kind of novel benzsulfamide (benzenesulfonamide) derivative and is used for preparing the purposes of CaMKII inhibitor.The present invention provides formula (I) compound represented, and contains the medical composition of formula (I) compound represented.The present invention also provides the purposes of the medical composition using formula (I) compound represented preparation treatment disease relevant to CaMKII activity or state such as flaviviridae infections.)

1. a kind of formula (I) compound represented:

Wherein, R₁For hydrogen, the naphthenic base with 3 to 7 ring carbons, there are 2 to 8 ring carbons and at least one to be selected from By nitrogen, the heteroatomic heterocycle of oxygen and the formed group of sulphur or with 2 to 3 rings and each ring has 4 to 6 annular atoms Aryl；Or R₁With connect R₁Phenyl ring formed have 8 to 10 ring carbons condensed carbon it is bicyclic；

R₂For with 4 to 10 ring carbons naphthenic base or for selected from by thiazole, imidazoles, tetrazolium, imidazolidine, imidazoline, Isoxazole and the heterocycle of the formed group of benzimidazole；And

N is 1,2,4 or 6.

2. compound according to claim 1, which is characterized in that the R₁It is 1 for hydrogen and n.

3. compound according to claim 2, which is characterized in that be shown in one of following formula:

And

4. compound according to claim 1, which is characterized in that the R₁For hydrogen；R₂For cycloheptyl alkyl；And n is 2,4 Or 6.

5. compound according to claim 1, which is characterized in that the R₂It is 1 for cycloheptyl alkyl and n.

6. compound according to claim 5, which is characterized in that be shown in one of following formula:

And

7. a kind of medical composition includes compound described in claim 1 and a pharmaceutically acceptable carrier.

8. a kind of calcium/calmodulin-dependent protein kinase ii (CaMKII) active method in inhibition cell, comprising this is thin Born of the same parents contact an a effective amount of compound described in claim 1.

9. a kind of purposes of compound described in claim 1 is to be used to prepare treatment to swash with calcium/calmodulindependent protein The medical composition of the relevant disease of enzyme II (CaMKII) activity or state.

10. purposes according to claim 9, which is characterized in that should be with calcium/calmodulin-dependent protein kinase ii activity Relevant disease or state are a flaviviridae infections.

11. purposes according to claim 10, which is characterized in that the flavivirus is to be selected from by dengue virus, hereby block disease Group composed by poison, japanese encephalitis virus, West Nile Virus, flavivirus and any combination thereof.

12. purposes according to claim 9, which is characterized in that should be with calcium/calmodulin-dependent protein kinase ii activity Relevant disease or state are a cancers.

13. purposes according to claim 12, which is characterized in that the cancer is selected from by lung cancer, breast cancer, prostate Group composed by cancer, colon cancer and any combination thereof.

14. purposes according to claim 9, which is characterized in that should be with calcium/calmodulin-dependent protein kinase ii activity Relevant disease or state are a cardiovascular disease or state.

15. purposes according to claim 14, which is characterized in that the cardiovascular disease or state be selected from by the rhythm of the heart not Group composed by whole, ischemic-reperfusion, heart failure and any combination thereof.

16. purposes according to claim 9, which is characterized in that should be with calcium/calmodulin-dependent protein kinase ii activity Relevant disease or state are a neurological diseases.

17. purposes according to claim 16, which is characterized in that the neurological disease is selected from by Alzheimer's disease, pa Group composed by golden Sen Shi disease, epilepsy and any combination thereof.

18. a kind of method for inhibiting flavivirus to enter cell, comprising cell contact one is a effective amount of described in claim 1 Compound.

19. according to the method for claim 18, which is characterized in that the flavivirus is to be selected from by dengue virus, hereby block disease Group composed by poison, japanese encephalitis virus, West Nile Virus, flavivirus and any combination thereof.

Technical field

The present invention relates to a kind of inhibition calcium/calmodulin-dependent protein kinase ii (calcium/ calmodulin- Dependent protein kinase II, CaMKII) compound and its application.The present invention is especially with regard to a kind of novelty Benzsulfamide (benzenesulfonamide) derivative and be used for preparing the purposes of CaMKII inhibitor.

Background technique

Calcium/calmodulin-dependent protein kinase ii (CaMKII) is serine (serine)/threonine (threonine) Specificity protein kinase, activity are adjusted by the compound of calcium and calmodulin.CaMKII common manifestation is in various tissues In, unique effect is played in neuron, cardiac muscle cell, endothelial cell and immunocyte.The rising of CaMKII activity is painstaking effort The key pathogenetic target of pipe and neurological disease.It has been reported that the reason of CaMKII is also cancer progression.In addition, a nearest research Point out japanese encephalitis virus (the Japanese encephalitis of CaMKII mediate fiavivirus section (Flaviviridae) a member Virus, JEV) cell combination and/or cell enter (referring to Simanjuntak et al., Front Microbiol 2017,8:651).Drugmaker is just competitively developing safe and efficient CaMKII inhibitor now.However, CaMKII inhibitor Unknown is still belonged to the possibility effect of flaviviridae infections.

Dengue virus (dengue virus, DENV) and hereby to block viral (Zika virus, ZIKV) be emerging to pass through mosquito Spread-yellow virus, constitutes a threat to global public health.Hereby card virus can cause extensive Clinical symptoms to the infection of crowd, From slight dengue fever (dengue fever) to serious dengue hemorrhagic fever (dengue hemorrhagic fever) and endanger And the dengue shock syndrome (dengue shock syndrome) of life.One research expression recently, dengue virus sense The prevalence rate of dye increases to annual 3.9 hundred million.Although having become the power control death rate, the Epidemic Situation of Dengue Fever right pop that repeated The social economy of sick the country in which it is located causes significant impact.Similarly, although hereby the case mortality of card virus infection is low, This infection is with Ji Lan-Ba Rui syndrome (Guillain-Barr é syndrome) and including microcephalus (microcephaly) Birth defect inside is related.The public affairs that hereby card virus infection already becomes international concern defend emergency.It has been reported that in Brazil There are about suffer from microcephalus when 4300 baby dues during great outburst.

Dengue virus and hereby card virus be the small virus for having mantle, have be about 11kb positive chain RNA genome.It should One polyprotein of genome encoding (polyprotein) is processed into three kinds of structural protein (structural Proteins), i.e. capsid (capsid) albumen, cephacoria (premembrane, prM) albumen and mantle (envelope, E) egg White and seven kinds of non-structural proteins (nonstructural proteins), be referred to as NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5.Virus infection begins at the set memebrane protein of main structure in conjunction with cell surface receptor, and utilizes cell Endocytosis (endocytosis) enters cell.The topographical variations and film of intracellular virus experience acid induction merge to release Put viral genome.The translation of viral RNA is by RNA Dependent RNA polymerization reaction (RNA-dependent RNA Polymerization) required protein is replicated to generate viral RNA.The assembling of viral RNA and virus protein can be generated into Ripe virion is discharged through cell secretory pathway thereafter.

Antiviral drugs and vaccine are two kinds of main means for controlling viral disease.It there is no at present for dengue virus And hereby the antiviral drugs of card virus infection or vaccine are approved.It is faced with challenge for the vaccine development of these flavivirus, because It has been demonstrated to enhance in immune body with dengue virus or hereby to block viral E protein or the protein bound existing antibody of prM Monocyte infected by subsequent viral.In terms of antiviral drugs development, virus needed for virus replication and cell protein are all It is potential target.As described above, whether CaMKII is that suitable antiviral target still needs to be differentiated.

Summary of the invention

The present invention is to have been surprisingly found that that is, newly-designed benzenesulfonamide derivatives can be used as CaMKII inhibitor based on one, And it can be used for treating and the active relevant disease of CaMKII, such as dengue virus and hereby card virus infection.

Edge this, a purpose of the invention is providing a kind of formula (I) compound represented:

Wherein, R₁For hydrogen, the naphthenic base with 3 to 7 ring carbons, there are 2 to 8 ring carbons and at least 1 A heteroatomic heterocycle selected from by nitrogen, oxygen and the formed group of sulphur or with 2 to 3 rings and each ring is with 4 to 6 The aryl of annular atom；Or R₁With connect R₁Phenyl ring formed have 8 to 10 ring carbons condensed carbon it is bicyclic；R₂For with The naphthenic base of 4 to 10 ring carbons or for selected from by thiazole (thiazole), imidazoles (imidazole), tetrazolium (tetrazole), imidazolidine (imidazolidine), imidazoline (imidazoline), isoxazole (isoxazole) and benzene And the heterocycle of imidazoles (benzimidazole) formed group；And n is 1,2,4 or 6.

In one embodiment of this invention, R₁It is 1 for hydrogen and n.In a preferred embodiment, the compound such as following formula One of shown in:

And

In another embodiment of the invention, R₁For hydrogen；R₂For cycloheptyl alkyl；And n is 2,4 or 6.

In another embodiment of the invention, R₂It is 1 for cycloheptyl alkyl and n.In a preferred embodiment, the chemical combination Object is as shown in one of following formula:

And

Another object of the present invention is providing a kind of medical composition, includes at least one compound as defined above, and One pharmaceutically acceptable carrier.

A further object of the present invention a kind of active method of CaMKII in inhibition cell is provided, comprising connecing the cell A effective amount of formula (I) compound is touched, or contact one contains the medical composition of effective quantity formula (I) compound.

A further object of the present invention is providing a kind of purposes of formula (I) compound, is to be used to prepare treatment to live with CaMKII The medical composition of the relevant disease of property or state..

The non-diseased individuals compared with the relevant disease of CaMKII activity or state refer to are somebody's turn to do, need to treat individual with one CaMKII activity increase in specific cells or tissue has cause and effect to close the disease or state for being.This disease or state also include The symptom for being caused and/or being aggravated by CaMKII activity.In one embodiment, the disease or state are a flaviviridae infections, In the flavivirus be selected from by dengue virus, hereby block virus, japanese encephalitis virus, West Nile Virus (West Nile Virus), group composed by flavivirus (yellow fever virus) and any combination thereof.In another embodiment In, the disease or state are a cancer, such as lung cancer, breast cancer, prostate cancer and colon cancer.In another embodiment, institute It states disease or state is for a cardiovascular disease or state, such as cardiac arrhythmia (arrhythmia), ischemic-reperfusion (ischemia-reperfusion injury) and heart failure (heart failure).In another embodiment, described Disease or state are a neurological disease, such as Alzheimer's disease (Alzheimer ' s disease), Parkinson's disease (Parkinson ' s disease) and epilepsy (epilepsy).

A further object of the present invention is providing a kind of method for inhibiting flavivirus to enter cell, comprising contacting the cell One a effective amount of formula (I) compound.

In one embodiment of this invention, the flavivirus be selected from by dengue virus, hereby block virus, japanese encephalitis virus, Group composed by West Nile Virus, flavivirus and any combination thereof.

The invention discloses formula (I) compounds, and the protein phosphorylation that CaMKII facilitates can be effectively suppressed, and improves Dengue Virus or the hereby survival condition of card virus-infected animal.Therefore, the present invention provides treatment diseases relevant to CaMKII activity Or the new strategy of state.

Embodiments of the present invention are further illustrated below in conjunction with schema.Following cited embodiments are to explain Bright invention feature and application of the invention, rather than to limit the scope of the invention.It is any to be familiar with this those skilled in the art, it is not departing from In the spirit and scope of the present invention, when a little change and retouch can be done.Therefore, protection scope of the present invention is when the appended Shen of view It please be subject to the scope of the patents institute defender.

Detailed description of the invention

Figure 1A is to assume to will affect four minor structures of antiviral activity and cytotoxicity, including one in lead compound 1 A connection between phenyl moiety, a benzenesulfonamide Part, an end-rings and the benzenesulfonamide Part and the end-rings is single Member；

Figure 1B is the flow chart that lead compound 1 with sulfonamide and fluorobenzene unit and the like 2 is made；

Fig. 1 C is to introduce proton (H) and methyl (CH by the N- substituting group position in 4- methoxybenzenesulphoismide₃) group Original phenyl ring is replaced, generates the flow chart of different substituted sulfonamide 3 and 4；

Fig. 1 D is to synthesize benzsulfamide similar to the flow chart of object 5-16；

Fig. 2A is cytotoxic effect figure of the compound 9 to BE (2) C cell of various dose；The cell is to specify agent The compound 9 of amount is handled, and LDH cell toxicity test, XTT cell proliferation test and trypan blue (Trypan are carried out to it Blue) cell count；* it indicates to be comparably P < 0.05 based on student T calibrating, with solvent control；

Fig. 2 B is that BE (2) C cell infects the 2nd type dengue virus with or without prescribed dose compound 9 (DENV-2), the immunofluorescence striograph after and to it carrying out the immunostaining of DENV-2 NS3 albumen and nucleus；

Fig. 2 C is with the DENV-2 NS3 albumen and beta-actin (β-of cell in Western blot analysis chart 2B actin；As sample inject compare) protein content figure；NS3 albumen is with solvent pair relative to the ratio of actin According to being standardized；

Fig. 2 D is the virus titer figure of the culture supernatants of cell in Fig. 2 B；* it respectively indicates with * * and is examined based on student T Fixed and solvent control is comparably P < 0.05 and P < 0.01；

Fig. 2 E is that BE (2) C cell infects hereby card virus (ZIKV) 48 with or without prescribed dose compound 9 Hour, and the immunofluorescence striograph after the immunostaining of ZIKV E protein and nucleus is carried out to it；

Fig. 2 F is that the ZIKV E protein of cell in Fig. 2 E and the protein of beta-actin (inject and compare as sample) contain Spirogram；E protein relative to the ratio of actin is standardized with solvent control；

Fig. 2 G is the virus titer figure of the culture supernatants of cell in Fig. 2 E；* it respectively indicates with * * and is examined based on student T Fixed and solvent control is comparably P < 0.05 and P < 0.01；

Fig. 3 A is that BE (2) C cell (0 to 3 hour after infection, is denoted as 0-3hpi) during viruses adsorption or virus is inhaled Attached (3 to 24 hours after infection, being denoted as 3-24hpi) with or without prescribed dose compound 9 in the case where infect DENV-2, And the DENV-2 NS3 albumen of the cell and the albumen of beta-actin (inject and compare as sample) are analyzed using Western blot Matter contains spirogram；NS3 albumen relative to the ratio of actin is standardized with solvent control；

Fig. 3 B is with or without prescribed dose compound 9, and ZIKV combines and enter the quantity of BE (2) C cell Figure；* and * * is respectively indicated and is comparably P < 0.05 and P < 0.01 based on student T calibrating, with solvent control；

Fig. 3 C is the number of DENV-2 or ZIKV combination BE (2) C cell with or without prescribed dose compound 9 Spirogram；

Fig. 3 D is with or without prescribed dose compound 9, and ZIKV enters the quantity figure of BE (2) C cell；It is empty Line indicates detecting limit (DL)；

Fig. 4 A is Stat1 of the real-time treatment to infection DENV-2 of compound 9 (being denoted as C9)^-/-The survival condition of mouse Protective effect figure；Day is treated with arrow mark；

Fig. 4 B is Stat1 of the real-time treatment to infection ZIKV of compound 9 (C9)^-/-The protection of the survival condition of mouse is made With figure；Day is treated with arrow mark；

Fig. 4 C be acquired by the mouse in Fig. 4 A-4B Jing Guo different disposal blood serum sample virus titer figure；And * * * It respectively indicates and is comparably P < 0.05 and P < 0.01 based on student T calibrating, with solvent control；

Fig. 4 D is Stat1 of the delay treatments in 8 hours to infection DENV-2 of compound 9 (C9)^-/-The survival condition of mouse Protective effect figure；Day is treated with arrow mark；

Fig. 4 E is Stat1 of the delay treatments in 8 hours to infection ZIKV of compound 9 (C9)^-/-The survival condition of mouse Protective effect figure；Day is treated with arrow mark；

Fig. 5 A is chimeric configuration figure of the compound 9 in CaMKII；

Fig. 5 B is the hydrogen bond (dotted line) and hydrophobic reciprocation (reality between compound 9 and the specified amino acid residue of CaMKII Line) figure；

The compound 9 and KN-62 of Fig. 6 A is to the active inhibiting effect figure of CaMKII；* it respectively indicates with * * based on student T Calibrating is comparably P < 0.05 and P < 0.01 with solvent control；

Fig. 6 B is 7,8 and 16 pairs of active inhibiting effect figures of CaMKII of compound；* it respectively indicates with * * based on student T Calibrating is comparably P < 0.05 and P < 0.01 with solvent control.

Specific embodiment

Unless otherwise defined, belonging to all technologies used herein and scientific term and the meaning and the present invention of abbreviation The general understanding that field is familiar with those skilled in the art is identical.

Definition

Numerical value given herein is approximation, and experimental data can change in the range of 20%, preferably 10% In the range of change, most preferably change in the range of 5%.Therefore, " about " and the terms such as " approximation " refer in a given numerical value Or in 20% range of range, preferably in the range of 10%, most preferably in the range of 5%.

Unless otherwise defined, term " naphthenic base (cycloalkyl) " refers to that one has the non-of 3 to 10 ring carbons Aromatic carbon ring, and so-called ring carbons are bonded each other to form the carbon atom of ring.The ring can be saturation (saturated) or with one or more carbon-to-carbon double bonds.The example of naphthenic base includes but is not limited to cyclopropyl alkyl, cyclobutane Base, pentamethylene base, cyclopentenyl, cyclohexyl, cyclohexenyl group and cycloheptyl alkyl and bridging (bridged) and cage type (caged) saturation cyclic group, such as norborneol alkyl (norbornyl) and adamantyl (adamantyl).

Term " carbocyclic ring (carbocycle) " refers to a saturated carbon ring containing 3 to 14 ring carbons, fractional saturation Carbocyclic ring or aromatic rings system.Carbocyclic ring usually contains 3 to 10 ring carbons, such as cyclopropyl alkyl, cyclobutane base, pentamethylene Base, cyclopentenyl, cyclopentadienyl group, cyclohexyl, cyclohexenyl group, cyclohexadienyl and phenyl.Alternatively, carbocyclic ring can be it is thick Close two or three carbocyclic rings, such as naphthalene (naphthalenyl), tetralyl (tetrahydronaphthalenyl), Indenyl (indenyl), different indenyl (isoindenyl), bicyclodecanyl (bicyclodecanyl), anthryl (anthracenyl), phenanthrene (phenanthrenyl), benzo naphthalene (benzonaphthenyl, Yi Cheng Fu base (phenalenyl)), fluorenyl (fluorenyl) and decahydro naphthalene (decalinyl).

Term " heterocycle (heterocycle) " refers to a saturated cyclic containing 3 to 14 ring member nitrogen atoms, fractional saturation Cyclic annular or aromatic rings system, wherein at least one ring member nitrogen atoms are hetero atoms, i.e. oxygen, nitrogen or sulphur.Heterocycle can be monocycle, Bicyclic or three-loop system may include fused rings.The example of heterocycle includes but is not limited to nitrogen Boom (azepine), pyrroles (pyrroles), thiophene (thiophene), imidazoles (imidazole), furans (furan), thiazole (thiazole), isothiazole (isothiazole), isoxazole (isoxazole), indoles (indole), pyridine (pyridine), pyridazine (pyridazine), pyrazine (pyrazine), piperidines (piperidine), piperazine (piperazine), tetrahydrofuran (tetrahydrofuran), tetrahydro piperazine mutter (tetrahydropyran), Isosorbide-5-Nitrae-dioxanes (Isosorbide-5-Nitrae-dioxane), triazole (triazoles), tetrazolium (tetrazole), benzimidazole (benzimidazole), benzothiazole (benzothiazole), Benzo pyrimidine (benzopyrimidine), thiadiazoles (thiadiazole), purine (purine) and quinolinone (quinolone)。

Unless otherwise defined, term " aryl (aryl) " refers to one containing one or two to three separation or fused rings Substituent group, wherein at least one ring are five yuan or hexa-atomic of carbon aromatic rings, such as benzene.Aryl substituent can have 6 to 18 carbon Atom.The example of aryl substituent includes phenyl, naphthalene and anthryl.The example of aryl substituent further includes a C₄-C₆Carbocyclic ring or One condensed with phenyl, naphthalene or anthryl four to hexa-member heterocycle, such as tetralyl, indenyl, different indenyl, dihydro indenyl (indanyl), phenanthryl, benzo naphthalene and fluorenyl.Aryl substituent can be substituted (substituted) or unsubstituted (unsubstituted)." substituted " refers to that one or more hydrogen atoms in a group are identical or different each independently Substituent group replaced.Typical substituent group includes but is not limited to-X ,-R^1a、-O^-,=O ,-OR^1a、-SR^1a、-S^-,=S ,- NR^1aR^1b,=NR^1a、-CX₃、-CF₃、-CN、-OCN、-SCN、-NO、-NO₂,=N₂、-N₃、-S(O)₂O^-、-S(O)₂OH、-S(O)₂R^1a、-OS(O₂)O^-、-OS(O)₂R^1a、-P(O)(O^-)₂、 -P(O)(OR^1a)(O^-)、-OP(O)(OR^1a)(OR^1b)、-C(O)R^1a、- C(S)R^1a、-C(O)OR^1a、 -C(O)NR^1aR^1b、-C(O)O^-、-C(S)OR^1a、-NR^2aC(O)NR^1aR^1b、-NR^2aC(S)NR^1aR^1b、 -NR^2aC(NR^1a)NR^1aR^1b、-C(NR^1a)NR^1aR^1b、-S(O)₂NR^1aR^1b、-NR^2aS(O)₂R^1a、 -NR^2aC(O)R^1aAnd-S (O) R^1a, wherein each X independently is halogen；Each R^1aAnd R^1bIndependently be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, Aryl alkyl (arylalkyl), the aryl alkyl replaced, naphthenic base, substituted naphthenic base, Heterocyclylalkyl (cycloheteroalkyl), Heterocyclylalkyl, the heteroaryl, substituted heteroaryl, heteroaryl alkyl, substituted heteroaryl replaced Base alkyl ,-NR^2aR^2b、-C(O)R^2aOr-S (O)₂R^2a；Optionally, R^1aAnd R^1bOne is formed together with the atom for connecting the two A or multiple Heterocyclylalkyls, substituted Heterocyclylalkyl, heteroaryl or the heteroaryl ring replaced；R^2aAnd R^2bIndependently be hydrogen, Alkyl, substituted alkyl, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, naphthenic base, substituted naphthenic base, Heterocyclylalkyl, substituted Heterocyclylalkyl, heteroaryl, substituted heteroaryl, heteroaryl alkyl or the heteroaryl alkyl replaced；Or Optionally, R^2aAnd R^2bWith the nitrogen-atoms for connecting the two be formed together one or more Heterocyclylalkyls, substituted Heterocyclylalkyl, Heteroaryl or the heteroaryl ring replaced.In certain embodiments, a tertiary amine or aromatic series nitrogen can be by one or more oxygen Atom replaces to form corresponding nitrogen oxides.

The compound disclosed herein can give individual in need, preferable administration mode via any suitable approach It is the medical composition for adapting to this classpath.For example, administration mode can be it is oral, through mucous membrane or enteral administration, or In the parenteral administration of person, including intramuscular, subcutaneous, intrathecal, intra-ventricle, intravenous, peritonaeum, intranasal and intraocular injection.

Term " effective quantity " used herein, which refers to, assigns active constituent needed for individual treatment effect is treated in receiving Amount.If this field is familiar with known to those skilled in the art, effective dose will be according to administration route, may control using excipient and with other The property treated disposition is used in conjunction with and changes.

Term " pharmaceutically acceptable carrier " used herein refer to it is compatible with the active constituent of composition (preferably, Being capable of stabilizing active ingredient) and any carrier harmless to individual to be treated.Pharmaceutically acceptable carrier or figuration Agent may include buffer, such as phosphate, citrate and other organic acids；Antioxidant, including ascorbic acid and first thiamines Sour (methionine)；Preservative, such as stearyl dimethyl benzyl ammonium chloride (octadecyldimethylbenzyl Ammonium chloride), pregnancy ammonium chloride (hexamethonium chloride), benzalkonium chloride (benzalkonium chloride), benzethonium chloride (benzethonium chloride), phenol, benzyl alcohol, such as to hydroxyl Alkyl paraben (alkyl parabens), catechol, resorcinol, the cyclohexanol, 3- penta of methyl benzoate Alcohol and metacresol；The polypeptide of low molecular weight (less than about 10 residues)；Amino acid, such as glycine (glycine), bran amide Sour (glutamine), asparagine sour (asparagine), histidine (histidine), spermine acid (arginine) or from Amino acid (lysine)；Hydrophilic polymer, such as polyvinylpyrrolidone (polyvinylpyrrolidone)；It is monosaccharide, double Sugar and other carbohydrate, including glucose, mannose (mannose), glucan (dextran), sucrose, mannitol (mannitol), trehalose (trehalose) and sorbierite (sorbitol)；Chelating agent such as ethylenediamine tetra-acetic acid (ethylenediaminetetraacetic acid, EDTA)；At salt relative ion, such as sodium；Metal composite (such as Zinc-protein complex)；And non-ionic surfactant, such as TWEEN^TM(polysorbate), PLURONICS^TM(pool Luo Shamu (poloxamer)) or polyethylene glycol (polyethylene glycol, PEG).

Term " individual ", which refers to, to need to treat and the active relevant disease of CaMKII or state (such as flaviviridae infections) Mammal.The individual is the mankind or non-human, such as primate, mouse, dog, cat, ox, horse, rabbit, pig etc..

Method and material

Chemicals identification

Unless otherwise indicated, all reagents and solvent are obtained from commercial source and are used by form when purchase.Tetrahydro furan Mutter (tetrahydrofuran, THF) be newly to be distilled out from sodium/benzophenone carbonyl under inert nitrogen.¹H nuclear magnetic resonance (nuclear magnetic resonance, NMR) and¹³C NMR spectra is with Bruker AVIII-400, AV-400 or AV- 500 records.Chemical shift of proton is relative to deuterated chloroform for unit with parts per million (ppm) (deuteriochloroform) remaining CHCl in₃In the unimodal of 7.24ppm.Carbon chemical shifts as unit of parts per million, It is relative to CDCl₃(77.0ppm) and acetone-d₆The inside of (29.1 ppm)¹³C signal.High resolution mass spec (high Resolution mass spectra, HRMS) be using Waters LCT Premier XE (Waters company, Manchester, Britain) and Bruker New ultrafleXtreme (Bruker, Bremen, Germany) and obtain.Analytic type Thin-layer chromatography (thin layer chromatography, TLC) is in silica gel 60F₂₅₄(Merck) it is carried out on.Col-umn chromatography (column chromatography) is carried out on silica gel 60 (230-400 mesh) (Merck).By normal phase high performance liquid phase layer Analysis (high-performance liquid chromatography, HPLC) determines that the purity of compound is higher than 95%, HPLC It is to cooperate 2489 pairs of λ extinction detectors of Waters and Purospher STAR Si using 1525 binary system of Waters (5 μm) (Merck) and Venusil XBP Silica (Agela Technologies) tubing string.Purge with liquid be ethyl acetate and Hexane.The detecting of all compounds is in 254nm.

Cell strain