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CN109422664B - Interferon regulator and its prepn and use - Google Patents

Interferon regulator and its prepn and use Download PDF

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Publication number
CN109422664B
CN109422664B CN201711408870.2A CN201711408870A CN109422664B CN 109422664 B CN109422664 B CN 109422664B CN 201711408870 A CN201711408870 A CN 201711408870A CN 109422664 B CN109422664 B CN 109422664B
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alkyl
compound
aryl
pharmaceutical composition
heteroaryl
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CN109422664A (en
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鲍红丽
熊海根
拉姆·库玛尔·纳卡拉占
钱波
葛亮
简武军
冯薇薇
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Fujian Institute of Research on the Structure of Matter of CAS
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Abstract

The invention relates to a compound of general formula (I), and a racemate, a stereoisomer, a tautomer, a polymorphic substance, a solvate or pharmaceutically acceptable salts thereof. The invention also relates to the preparation of the compounds of the general formula (I)Preparation method and composition containing the same. The compound can be used for treating diseases caused by interferon-beta disorder, such as systemic lupus erythematosus, polyneuritis, juvenile diabetes, autoimmune hemolytic anemia, ulcerative colitis or rheumatoid arthritis.

Description

Interferon regulator and its prepn and use
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to an interferon regulator, and a preparation method and application thereof.
Background
Interferons are a large group of important immune signal proteins of organisms, and have the function that when pathogens infect host cells, infected cells release signals to improve the immune defense of surrounding cells. These include type I, type II and type III interferons, which are responsible for activating or modulating immune responses. Interferon beta (IFN β) is an important type I interferon and is commonly used to study immune response and immune regulation: when host cells are subjected to immune stimulation (virus invasion or cancer development), the immune response of the body secretes a large amount of beta interferon to recruit immune defense cells such as macrophages and the like to establish immune defense; for such diseases, an increase in interferon-beta may be helpful in the treatment of the disease. For some immunodeficiency diseases, a large amount of beta interferon is easily released by an organism to recruit macrophages to cause accidental injury to normal cells, so that the diseases are caused; the treatment of such diseases requires inhibition of interferon beta secretion. Therefore, direct activation and regulation of interferon-beta and upstream regulation are of great significance for the treatment of diseases.
Disclosure of Invention
The invention aims to provide a compound shown in formula (I) and a preparation method thereof.
It is a further object of the present invention to provide the use of the above compounds. The compounds have inhibitory or enhancing activity against interferon-beta (IFN β) in a cell.
The invention is realized by the following technical scheme:
a compound of formula (I), and racemates, stereoisomers, tautomers, polymorphs, solvates, or pharmaceutically acceptable salts thereof, said compound having the structure:
Figure BDA0001520878140000021
wherein R is1Is aryl, heteroaryl, said aryl, heteroaryl being optionally substituted by one or more RaSubstituted by a substituent, said RaComprises the following steps: halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, -NO2Oxo, -CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、 -OR14、-SO2-R15Boronic acid groups, silane groups; r is as defined aboveaThe alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups in the substituents may be optionally substituted with: halogen, alkyl, aryl, heteroaryl, -CN, -NO2Oxo, -CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、 -NR12R13、-OR14、-SO2-R15；
R2Is- (CH)2)0-4CO-R7，-SO2-R8，-PO-(R9)2，-CN，-NO2，R7、R8、R9Is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -NR12R13、-NH-CO-R10、-NH-COO-R11、 -OR14Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl may be optionally substituted with: halogen, alkyl, aryl, heteroaryl, heterocyclyl, -CN, -NO2Oxo, -CO-R10、 -COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15；
R4Is halogen, alkyl, alkenyl, alkynyl, -alkyl-O-CO-alkyl, -alkyl-O-alkyl, -alkyl-CO-alkyl, alkyl-COO-alkyl, at least one H atom in the alkyl, alkenyl, alkynyl is substituted by halogen;
R3、R6the alkyl and the aryl in the groups can be substituted by one or more of the following substituents: halogen, hydroxy, alkyl, alkoxy, -CO-alkyl, -O-CO-alkyl, -COO-alkyl;
R5is N3Or is
Figure BDA0001520878140000022
R5' is halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, -NO2Oxo, -CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、 -NR12R13、-OR14、-SO2-R15Boronic acid groups, silane groups; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl may be optionally substituted with: halogen, alkyl, aryl, heteroaryl, heterocyclyl, -CN, -NO2Oxo, -CO-R10、-COO-R11、-NH-CO-R10、 -NH-COO-R11、-NR12R13、-OR14、-SO2-R15；
R10、R11、R12、R13、R14、R15May be the same or different and is independently selected from H, alkyl, aryl, heteroaryl, heterocyclyl; the above alkyl, aryl, heteroaryl, and heterocyclic groups may be further substituted with: halogen, alkyl, aryl, heteroaryl, heterocyclyl, -CN, -NO2Oxo, -CO-R10、-COO-R11、 -NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15；
The compounds are not specific compounds as follows:
Figure BDA0001520878140000031
according to the invention, R1Aryl, such as phenyl, naphthyl, and the like; or R1Is heteroaryl, such as thienyl, benzothienyl, furyl, benzofuryl. Said aryl, heteroaryl being optionally substituted with 1-5RaSubstituted by a substituent, said RaFor example, the following are: halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, -NO2Oxo, -CO-alkyl, -CO-aryl, -COO-alkyl, -COO-aryl, -NH-CO-alkyl, -NH-CO-aryl, -NH2-NH-alkyl, -N (alkyl)2-OH, -O-alkyl, -O-aryl, -O-heteroaryl, boronic acid group, silyl group; r is as defined aboveaThe alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups in the substituents may be optionally substituted with: halogen, alkyl, aryl, heteroaryl, -CN, -NO2Oxo, -CO-alkyl, -CO-aryl, -COO-alkyl, -COO-aryl, -NH-CO-alkyl, -NH-CO-aryl, -NH2-NH-alkyl, -N (alkyl)2-OH, -O-alkyl, -O-aryl;
according to the invention, R2Is- (CH)2)0-4CO-R7For example, -CO-R7、-CH2-CO-R7、 -CH2-CH2-CO-R7。
According to the invention, R7Is alkyl, aryl, heteroaryl, -O-alkyl, -O-aryl, -O-heteroaryl, wherein said alkyl, aryl, heteroaryl may be optionally substituted with: halogen, alkyl, aryl, heteroaryl, heterocyclyl, -CN, -NO2Oxo, -CO-R10、-COO-R11、-NH-CO-R10、 -NH-COO-R11、-NR12R13、-OR14；
According to the invention, R4Is perfluoroalkyl, -perfluoroalkyl-O-CO-alkyl, -perfluoroalkyl-O-alkyl, -perfluoroalkyl-CO-alkyl, -perfluoroalkyl-COO-alkyl;
according to the invention, R5Is N3Or is
Figure BDA0001520878140000041
The R is5' is halogen, alkyl, aryl, heteroaryl, -CN, -NO2Oxo, -CO-alkyl, -CO-aryl, -COO-alkyl, -COO-aryl, -NH-CO-alkyl, -NH-CO-aryl, -NH2-NH-alkyl, -N (alkyl)2-OH, -O-alkyl, -O-aryl, -O-heteroaryl, boronate, silyl, wherein the alkyl, aryl, heteroaryl groups may be optionally substituted with: halogen, alkyl, aryl, heteroaryl, -CN, -NO2Oxo, -CO-alkyl, -CO-aryl, -COO-alkyl, -COO-aryl, -NH-CO-alkyl, -NH-CO-aryl, -NH2-NH-alkyl, -N (alkyl)2-OH, -O-alkyl, -O-aryl.
According to the invention, the compound of formula (I) is selected from the following specific compounds:
Figure BDA0001520878140000042
Figure BDA0001520878140000051
Figure BDA0001520878140000061
Figure BDA0001520878140000071
the present invention also provides a process for the preparation of a compound of formula (I) as defined above, comprising:
Figure BDA0001520878140000081
wherein X is halogen, R' are the same or different and are optionally alkyl, R1-R4、R5’、R6As defined above;
1) reacting the compound of formula (II) with the compound of formula (III) and the compound of formula (IV) to obtain the compound of general formula (I-1), namely R5Is N3A compound of the general formula (I);
2) optionally, reacting a compound of formula (I-1) with a compound of formula (V) to give a compound of formula (I-2), i.e. R5Is composed of
Figure BDA0001520878140000082
A compound of the general formula (I);
optionally, reacting the compound shown in the formula (I) with a pharmaceutically acceptable organic acid or inorganic acid to obtain a pharmaceutically acceptable salt shown in the formula (I).
According to the present invention, in the step 1),
preferably, the reaction is carried out in the presence of a catalyst and a free radical initiator.
Preferably, the catalyst is selected from at least one of an iron metal catalyst and a triflate anion metal catalyst;
further preferably, the catalyst is selected from at least one of ferrous triflate, ferrous chloride, ferrous acetate, ferric p-toluenesulfonate, palladium triflate, indium triflate, neodymium triflate, yttrium triflate, ferric triflate, trifluoromethanesulfonate, copper triflate, silver triflate, lanthanum triflate, cerium triflate;
preferably, the radical initiator is selected from at least one of organic peroxides;
further preferably, the radical initiator is selected from at least one of acyl peroxides, hydroperoxides, dialkyl peroxides, ester peroxides, ketone peroxides, and dicarbonate peroxides;
still more preferably, the radical initiator is selected from at least one of benzoyl peroxide, lauroyl peroxide, cumene hydroperoxide, t-butyl hydroperoxide, di-t-butyl peroxide, t-butyl peroxyacetate, dicumyl peroxide, t-butyl peroxybenzoate, t-butyl peroxypivalate, methyl ethyl ketone peroxide, cyclohexanone peroxide, diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate;
preferably, the free radical initiator is tert-butyl peroxybenzoate;
preferably, the molar ratio of the compound (II), the compound (III), the compound (IV), the radical initiator and the catalyst is as follows: 1: 1-2: 2-3: 2-3: 0.03 to 0.07;
preferably, the reaction temperature of the reaction is-20 ℃ to 80 ℃, and the reaction time is 0.5h to 12 h;
preferably, the temperature of the reaction is 0 ℃ to 50 ℃ and the reaction time is 0.5h to 3 h.
According to the invention, in step 2), preferably, the reaction is carried out in the presence of a catalyst, such as Cu (OAc)2Or 2-aminophenol, in a solvent, which may be, for example, dichloromethane, or water, etc.
The compounds of the present invention are modulators of interferon-beta (IFN β), which may increase or inhibit the secretion of interferon-beta. Can be used for regulating immune system.
The invention also provides a pharmaceutical composition, which comprises the compound shown in the general formula (I) and racemate, stereoisomer, tautomer, polymorph, solvate and pharmaceutically acceptable salt thereof.
According to the present invention, the pharmaceutical composition may optionally further comprise at least one pharmaceutically acceptable adjuvant, such as a carrier, an excipient, etc. As an example, the adjuvant may be one or more selected from the group consisting of: disintegrants, glidants, lubricants, diluents, fillers, binders, colorants, effervescent agents, flavoring agents, preservatives, coating materials, and the like.
According to the present invention, the pharmaceutical composition may be in a form including, but not limited to, oral dosage forms, parenteral dosage forms, external dosage forms, and rectal dosage forms.
In some embodiments, the pharmaceutical compositions may be tablets, capsules, pills, powders, sustained release formulations, solutions and suspensions for oral administration, sterile solutions, suspensions or emulsions for parenteral injection, or suppositories for rectal administration.
In other embodiments, the pharmaceutical composition is in unit dosage form suitable for single administration of a precise dose.
In other embodiments, the amount of the compound ranges from about 0.001mg/kg body weight/day to about 1000mg/kg body weight/day.
In other embodiments, the amount of the compound ranges from about 0.1mg/kg body weight/day to about 50mg/kg body weight/day.
In other embodiments, the amount of the compound ranges from about 0.1mg/kg body weight/day to about 10 mg/kg body weight/day.
In some embodiments, the compound is administered in a single dose, once per day.
In other embodiments, the compound is administered in multiple doses more than once per day.
In some embodiments, the compound is administered twice daily.
In other embodiments, the compound is administered three or more times per day.
In some embodiments, the subject to which the pharmaceutical composition is administered is a mammal.
In other embodiments, the mammal is a human.
In other embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent (i.e., formulated as a dosage form).
In some embodiments, the pharmaceutical composition and the at least one therapeutic agent are each combined in separate dosage forms into a combination product, such as a kit of parts.
In some embodiments, the pharmaceutical composition contains a compound of the invention and one or more interferon modulator drugs.
In some embodiments, the pharmaceutical combination set comprises two or more separately packaged pharmaceutical compositions, wherein one of the separately packaged pharmaceutical compositions comprises the novel compound of formula (la) and the remaining separately packaged pharmaceutical compositions each comprise one or more interferon modulator drugs.
The invention also provides the application of the compound of the general formula (I) and racemate, stereoisomer, tautomer, polymorphic substance, solvate and pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing medicaments for treating diseases caused by the dysregulation of the beta interferon. According to the invention, the disease is systemic lupus erythematosus, polyneuritis, juvenile diabetes, autoimmune hemolytic anemia, ulcerative colitis, rheumatoid arthritis, or the like.
The present invention also provides a method of treating interferon-beta disorders comprising contacting interferon with an effective amount of a compound as described above or a pharmaceutically acceptable salt thereof.
Preferably, the method is used in vivo, as well as in vitro.
The specific dosage is selected and adjusted according to the tumor cell state and the whole body state in the body of the patient.
Definition and introduction of termsMing dynasty
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definition in this section controls.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter of the application. In this application, the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not limiting.
The term "alkyl" refers to a straight or branched alkyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl.
The term "alkenyl" refers to straight or branched chain alkenyl groups having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, such as ethenyl, propenyl, isopropenyl.
The term "alkynyl" refers to straight or branched chain alkynyl groups having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl.
The term "alkoxy" denotes a straight or branched chain alkoxy group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy.
The term "halogen" is fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine, bromine.
The term "aryl" is understood to mean preferably a mono-, bi-or tricyclic hydrocarbon ring having a monovalent aromatic or partially aromatic character of 6 to 20 carbon atoms, preferably "C6-14Aryl ". The term "C6-14Aryl "is understood as preferably meaning having 6, 7, 8, 9, 10, 11, 12Monocyclic, bicyclic or tricyclic hydrocarbon ring of monovalent or partially aromatic character of 13 or 14 carbon atoms ("C6-14Aryl group "), in particular a ring having 6 carbon atoms (" C6Aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C9Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C10Aryl radicals), such as tetralinyl, dihydronaphthyl or naphthyl, or rings having 13 carbon atoms ("C13Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C)14Aryl), such as anthracenyl.
The term "heteroaryl" is understood to mean monocyclic, bicyclic and tricyclic ring systems containing 5 to 20 ring atoms, 5 to 14 ring atoms, or 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, at least one of which is aromatic, and at least one of which contains one or more heteroatoms (e.g., N, O, S, Se, etc.), wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, a heteroaryl group of 5-10 atoms contains 1,2,3, or 4 heteroatoms independently selected from O, S, Se and N. In other embodiments, a 5-6 atom heteroaryl group contains 1,2,3, or 4 heteroatoms independently selected from O, S, Se and N.
Examples of monocyclic rings of heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
The term "heterocyclyl" means a monocyclic, bicyclic or tricyclic ring system in which one or more atoms in the ring are independently optionally substituted with a heteroatom, the ring may be fully saturated or contain one or more unsaturations, but is not aromatic, having one or more points of attachment to other molecules. One or more ring hydrogen atoms may be independently unsubstituted or substituted with one or more substituents described herein. Some of these embodiments are "heterocyclyl" groups which are monocyclic of 3 to 7 atoms, or bicyclic of 7 to 10 atoms, containing 1 to 5, preferably 1 to 3 heteroatoms selected from N, O, S and Se. In particular, the heterocyclic group may include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclyl group may be bicyclic, for example but not limited to a 5,5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring. The nitrogen atom containing ring may be partially unsaturated, i.e. it may contain one or more double bonds, such as but not limited to 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydrooxazolyl or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolyl, 1, 3-benzoxazolyl, 1, 3-benzodioxolyl.
Unless otherwise indicated, heterocyclyl, heteroaryl include all possible isomeric forms thereof, e.g. positional isomers thereof. Thus, for some illustrative, non-limiting examples, pyridyl or pyridinylene includes pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, pyridinylene-3-yl, pyridin-4-yl, and pyridinylene-4-yl; thienyl or thienylene includes thien-2-yl, thien-3-yl and thien-3-yl.
Depending on the molecular structure, the compounds of the invention may be chiral and may therefore exist in various enantiomeric forms. These compounds may thus be present in racemic or optically active form. The compounds of the invention or intermediates thereof may be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemization, diastereoisomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulphonic acids. The chromatographic enantiomeric resolution can also advantageously be carried out with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers, which are immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile.
The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; whereas in phenol the enol type predominates. The present invention encompasses all tautomeric forms of the compounds.
The terms "solvate", "polymorph" and "polymorphs" refer to any possible solvate and polymorph. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.
As used herein, reference to the term "subject", "patient" or "individual" refers to an individual suffering from a disease, disorder or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment related to the methods and compositions provided herein, the mammal is a human.
As used herein, the term "treating" and other similar synonyms include alleviating, or ameliorating a symptom of a disease or disorder, preventing other symptoms, ameliorating, or preventing an underlying metabolic cause of a symptom, inhibiting a disease or disorder, e.g., arresting the development of a disease or disorder, alleviating a disease or disorder, ameliorating a disease or disorder, alleviating a symptom of a disease or disorder, or discontinuing a symptom of a disease or disorder, and further, the term encompasses prophylactic purposes. The term also includes obtaining a therapeutic effect and/or a prophylactic effect. The therapeutic effect refers to curing or ameliorating the underlying disease being treated. In addition, a cure or amelioration of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, e.g., an improvement in the condition of the patient is observed, although the patient may still be affected by the underlying disease. For prophylactic effect, the composition can be administered to a patient at risk of developing a particular disease, or to a patient presenting with one or more physiological symptoms of the disease, even if a diagnosis of the disease has not yet been made.
The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.
The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that there is no long-term deleterious effect on the general health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.
The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical ingredient including, but not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and/or excipients.
The term "carrier" as used herein refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of the compound into a cell or tissue.
The term "pharmaceutically acceptable salt" as used herein refers to salts that retain the biological potency of the free acid and free base of the specified compound, and that are biologically or otherwise non-adverse. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines), basic or organic salts of acidic residues (e.g., carboxylic acids), and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, methanesulfonic acid, toluenesulfonic acid, salicylic acid, sulfanilic acid, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are not intended to limit the scope of the present invention, and any modifications made on the basis of the present invention do not depart from the spirit of the present invention.
Wherein, the synthesis processes of the intermediate and the target compound are shown as representatives in the examples, and the synthesis processes of the rest intermediate and the target compound are the same as the representative compounds.
TMS is trimethylsilyl, TBPB is tert-butyl peroxybenzoate, Tf is trifluoromethanesulfonate, and DCM is dichloromethane.
Example 1
Figure BDA0001520878140000161
Under the protection of nitrogen, Fe (OTf)2(0.025mmol) was placed in a 25mL reaction tube, vacuum was applied, nitrogen was replaced three times, and ethylene glycol dimethyl ether (2mL), 1-phenyl-methyl acrylate (0.5mmol), trifluoroiodomethane (1.5mmol), TMSN3(1.7mmol) and TBPB (1.75mmol) are added into a reaction tube and react for 2 hours at room temperature, after the reaction is finished, ethyl acetate is diluted, silica gel is rapidly filtered, a rotary evaporator is decompressed to remove the solvent, and then column chromatography separation is carried out to obtain the product (CS-1). The physicochemical data are presented in table 1.
Example 2
Figure BDA0001520878140000171
Under the protection of nitrogen, Fe (OTf)2(0.025mmol) was placed in a 25mL reaction tube, vacuum was applied, nitrogen was replaced three times, and ethylene glycol dimethyl ether (2mL), methyl 1- (3, 4-dichlorophenyl) -acrylate (0.5mmol), nonafluoroiodobutane (1.5mmol), TMSN3(1.7mmol) and TBPB (1.75mmol) are added into a reaction tube and react for 2 hours at room temperature, after the reaction is finished, ethyl acetate is diluted, silica gel is rapidly filtered, a rotary evaporator is decompressed to remove the solvent, and then column chromatography separation is carried out to obtain a product sample which is recorded as CS-9. The physicochemical data are presented in table 1.
Example 3
Figure BDA0001520878140000172
Under the protection of nitrogen, Fe (OTf)2(0.025mmol) was placed in a 25mL reaction tube, vacuum was applied, nitrogen was replaced three times, and ethylene glycol dimethyl ether (2mL), phenyl ketene (0.5mmol), pentafluoroethyl iodide (1.5mmol), TMSN were added3(1.7mmol) and TBPB (1.75mmol) are added into a reaction tube and react for 2 hours at room temperature, after the reaction is finished, ethyl acetate is diluted, silica gel is rapidly filtered, a rotary evaporator is decompressed to remove the solvent, and then column chromatography separation is carried out to obtain the product CS-48. The physicochemical parameters are shown in Table 1 below.
Following a similar procedure to that described in example 1 above, a preferred compound of formula (I) was prepared, with the preferred compound and its NMR data shown in the following table:
TABLE 1-preferred Compound Structure, numbering and physicochemical data
Figure BDA0001520878140000173
Figure BDA0001520878140000181
Figure BDA0001520878140000191
Figure BDA0001520878140000201
Figure BDA0001520878140000211
Figure BDA0001520878140000221
Figure BDA0001520878140000231
Figure BDA0001520878140000241
Figure BDA0001520878140000251
Figure BDA0001520878140000261
Figure BDA0001520878140000271
Figure BDA0001520878140000281
Example 4
Figure BDA0001520878140000291
Under the protection of nitrogen, adding Cu (OAc)2·H2O (0.01mmol) and 2-aminophenol (0.005mmol) were added to a 10mL reaction flask, vacuum was applied, nitrogen was replaced three times, DCM (0.2mL), H2O (0.2ml), a compound (CS-34) (0.1mmol) and phenylacetylene (0.1mmol) are added into a reaction bottle and reacted for 12 hours at room temperature, after the reaction is finished, the ethyl acetate is used for extraction, the magnesium sulfate is used for drying and filtering, a rotary evaporator is used for decompressing to remove the solvent, and the column chromatography separation is carried out to obtain the product CS-58. See table 2 for data.
Following a similar procedure to that described in example 4 above, preferred compounds of formula (I) were prepared, and the preferred compounds and their physicochemical data are shown in table 2 below:
table 2-preferred compound structures, numbers and physicochemical data thereof
Figure BDA0001520878140000292
Figure BDA0001520878140000301
Example 5 biological Activity assay
The biological activities of the compounds prepared in examples 1 to 4 above were measured on a high-throughput real-time fluorescent quantitative PCR instrument (QuantStudio 6Flex, ABI) using ravplus cells to detect changes in interferon-beta (IFN β) activity. The method comprises the following specific steps:
(1) pre-plated cells (containing 1mL of culture) were pretreated with 1mM of compound 1ul as described above (DMSO as solvent) for 60 min.
(2) After changing the medium, the cells were stimulated with HT-DNA or Poly (I: C), respectively, for 6 hours.
(3) RNA was extracted from the stimulated cells and reverse transcribed into cDNA.
(4) QRT-PCR was used to detect the relative expression of IFN- β and CXCL10 at the mRNA level in cells.
See table 3 below for results.
TABLE 3 stress inflammation levels of Compounds
Figure BDA0001520878140000311
Figure BDA0001520878140000321
。

Claims (22)

1.一种通式(I)化合物，及其药学上可接受的盐，所述化合物的结构如下：1. a compound of general formula (I), and a pharmaceutically acceptable salt thereof, the structure of the compound is as follows:
Figure FDA0003362020690000011
Figure FDA0003362020690000011
 其中，R1为芳基、杂芳基，所述芳基、杂芳基未被取代或被一个或多个Ra取代基取代，所述Ra为：卤素、烷基、芳基、-CO-R10、-COO-R11、-OR14；上述Ra取代基中的烷基、芳基未被取代或被如下基团取代：卤素、烷基；Wherein, R 1 is an aryl group, a heteroaryl group, the aryl group and the heteroaryl group are unsubstituted or substituted by one or more R a substituents, and the R a is: halogen, alkyl, aryl, - CO-R 10 , -COO-R 11 , -OR 14 ; the alkyl and aryl groups in the above-mentioned R a substituent are unsubstituted or substituted by the following groups: halogen, alkyl; R2为-(CH2)0-4CO-R7，R7为烷基、芳基、杂芳基、-OR14，其中所述烷基、芳基、杂芳基未被取代或被如下基团取代：卤素、烷基；R 2 is -(CH 2 ) 0-4 CO-R 7 , and R 7 is alkyl, aryl, heteroaryl, -OR 14 , wherein said alkyl, aryl, heteroaryl is unsubstituted or substituted by The following groups are substituted: halogen, alkyl; R4为烷基、-烷基-O-CO-烷基、-烷基-O-烷基、-烷基-CO-烷基、-烷基-COO-烷基，上述烷基中至少有一个H原子被卤素取代；R 4 is alkyl, -alkyl-O-CO-alkyl, -alkyl-O-alkyl, -alkyl-CO-alkyl, -alkyl-COO-alkyl, and at least one of the above alkyl groups has One H atom is replaced by a halogen; R3、R6为H；R 3 and R 6 are H; R5为N3、或
Figure FDA0003362020690000012
R5 ’为卤素、烷基、芳基、杂芳基；其中所述的烷基、芳基、杂芳基未被取代或被如下基团取代：卤素、烷基、NH2；R 5 is N 3 , or
Figure FDA0003362020690000012
R 5 ' is halogen, alkyl, aryl, heteroaryl; wherein said alkyl, aryl, heteroaryl are unsubstituted or substituted by the following groups: halogen, alkyl, NH 2 ; R10、R11、R14可相同或不同，独立地选自H、烷基、芳基；R 10 , R 11 , and R 14 may be the same or different, and are independently selected from H, alkyl, and aryl; 其中，in, 烷基为具有1-10个碳原子的直链或支链烷基；Alkyl is a straight or branched chain alkyl group having 1-10 carbon atoms; 芳基为苯基、萘基、蒽基；Aryl is phenyl, naphthyl, anthracenyl; 杂芳基为噻吩基、苯并噻吩基、呋喃基、或苯并呋喃基、吡咯基、吲哚基、吡啶基、喹啉基；Heteroaryl is thienyl, benzothienyl, furyl, or benzofuranyl, pyrrolyl, indolyl, pyridyl, quinolyl; 所述化合物不为如下具体化合物：The compound is not the following specific compound:
Figure FDA0003362020690000021
Figure FDA0003362020690000021
 2.根据权利要求1所述的化合物，其中，R1为苯基、或萘基。2 . The compound according to claim 1 , wherein R 1 is phenyl or naphthyl. 3 . 3.根据权利要求1所述的化合物，其中，R2为-CO-R7。3. The compound of claim 1 , wherein R2 is -CO- R7 . 4.根据权利要求1所述的化合物，其中R2为-CH2-CO-R7、-CH2-CH2-CO-R7。4. The compound of claim 1, wherein R2 is -CH2 - CO- R7 , -CH2 - CH2 -CO- R7 . 5.根据权利要求1所述的化合物，其中，R7为烷基、芳基、杂芳基、-O-烷基、-O-芳基。5. The compound of claim 1, wherein R7 is alkyl, aryl, heteroaryl, -O-alkyl, -O-aryl. 6.根据权利要求1所述的化合物，其中，R4为全氟烷基、-全氟烷基-O-CO-烷基、-全氟烷基-O-烷基、-全氟烷基-CO-烷基、-全氟烷基-COO-烷基。6. The compound of claim 1 , wherein R4 is perfluoroalkyl, -perfluoroalkyl-O-CO-alkyl, -perfluoroalkyl-O-alkyl, -perfluoroalkyl -CO-alkyl, -perfluoroalkyl-COO-alkyl. 7.根据权利要求1所述的化合物，其中，R5为N3、或
Figure FDA0003362020690000022
所述R5 ’为卤素、取代的烷基、取代的芳基、取代的杂芳基，所述取代基为卤素、烷基、NH2-。7. The compound of claim 1, wherein R 5 is N 3 , or
Figure FDA0003362020690000022
The R 5 ' is halogen, substituted alkyl, substituted aryl, substituted heteroaryl, and the substituent is halogen, alkyl, NH 2 -. 8.化合物，其中，所述化合物选自如下具体化合物：8. A compound, wherein the compound is selected from the following specific compounds:
Figure FDA0003362020690000023
Figure FDA0003362020690000023
Figure FDA0003362020690000031
Figure FDA0003362020690000031
Figure FDA0003362020690000041
Figure FDA0003362020690000041
Figure FDA0003362020690000051
Figure FDA0003362020690000051
 9.一种权利要求1-8任一项所述化合物的制备方法，包括：9. a preparation method of the compound described in any one of claim 1-8, comprising:
Figure FDA0003362020690000052
Figure FDA0003362020690000052
Figure FDA0003362020690000061
Figure FDA0003362020690000061
 其中，X为卤素，R’相同或不同，选自烷基，R1-R4、R6如权利要求1-8任一项所定义；Wherein, X is halogen, R' is the same or different, selected from alkyl, R 1 -R 4 , R 6 are as defined in any one of claims 1-8; 1)将式(II)化合物与式(III)化合物、式(IV)化合物进行反应，得到通式(I-1)化合物，即R5为N3的通式(I)化合物；1) reacting the compound of formula (II) with the compound of formula (III) and the compound of formula (IV) to obtain the compound of general formula (I-1), that is, the compound of general formula (I) in which R 5 is N 3 ; 2)任选的，将通式(I-1)化合物与式(V)化合物反应，得到通式(I-2)化合物，即R5为
Figure FDA0003362020690000062
的通式(I)化合物；2) Optionally, react the compound of general formula (I-1) with the compound of formula (V) to obtain the compound of general formula (I-2), that is, R 5 is
Figure FDA0003362020690000062
The compound of general formula (I); 任选地，将所述式(I)化合物与药学上可接受的有机酸或无机酸反应得到式(I)所示的药学上可接受的盐。Optionally, the compound of formula (I) is reacted with a pharmaceutically acceptable organic or inorganic acid to obtain a pharmaceutically acceptable salt of formula (I). 10.一种药物组合物，包含权利要求1-8任一项所述的化合物或其药学上可接受的盐。10. A pharmaceutical composition comprising the compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof. 11.如权利要求10所述的药物组合物，其中，所述药物组合物还包含至少一种药学上可接受的辅料。11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant. 12.如权利要求11所述的药物组合物，其中，所述辅料为载体、赋形剂。12. The pharmaceutical composition of claim 11, wherein the adjuvant is a carrier or an excipient. 13.如权利要求11所述的药物组合物，其中，所述辅料为选自下列中的一种或多种：崩解剂、助流剂、润滑剂、稀释剂、填充剂、粘合剂、着色剂、泡腾剂、矫味剂、防腐剂、包衣材料。13. pharmaceutical composition as claimed in claim 11, wherein, described adjuvant is one or more selected from following: disintegrant, glidant, lubricant, diluent, filler, adhesive , coloring agents, effervescent agents, flavoring agents, preservatives, coating materials. 14.如权利要求10所述药物组合物，其中，所述药物组合物为口服剂型、胃肠外给药剂型或直肠给药剂型的形式。14. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is in the form of an oral dosage form, a parenteral dosage form, or a rectal dosage form. 15.如权利要求10所述药物组合物，其中所述药物组合物是口服的片剂、胶囊、丸剂、粉剂、溶液或悬浮液。15. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is an oral tablet, capsule, pill, powder, solution or suspension. 16.如权利要求10所述药物组合物，其中所述药物组合物是用于胃肠外注射的无菌溶液、悬浮液或乳液，或者用于直肠给药的栓剂。16. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is a sterile solution, suspension or emulsion for parenteral injection, or a suppository for rectal administration. 17.如权利要求10所述药物组合物，其中，所述化合物的量在0.001mg/kg体重/天-1000mg/kg体重/天的范围内。17. The pharmaceutical composition of claim 10, wherein the amount of the compound is in the range of 0.001 mg/kg body weight/day to 1000 mg/kg body weight/day. 18.如权利要求17所述药物组合物，其中，所述化合物的量的范围为0.1mg/kg体重/天-50mg/kg体重/天。18. The pharmaceutical composition of claim 17, wherein the amount of the compound ranges from 0.1 mg/kg body weight/day to 50 mg/kg body weight/day. 19.权利要求1-8中任一项所述的化合物及其药学可接受的盐、或权利要求10-18中任一项所述的药物组合物在制备治疗β干扰素失调引起的疾病的药物中的用途。19. The compound according to any one of claims 1-8 and a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 10-18, is used in the preparation and treatment of diseases caused by interferon beta disorders. Use in medicine. 20.根据权利要求19的用途，所述疾病为系统性红斑狼疮、多发性神经炎、青少年糖尿病、自身免疫性溶血性贫血、溃疡性结肠炎或类风湿性关节炎。20. The use according to claim 19, wherein the disease is systemic lupus erythematosus, polyneuritis, juvenile diabetes, autoimmune hemolytic anemia, ulcerative colitis or rheumatoid arthritis. 21.下述化合物在制备治疗β干扰素失调引起的疾病的药物中的用途，21. Use of the following compounds in the preparation of a medicine for the treatment of diseases caused by interferon beta disorders,
Figure FDA0003362020690000071
Figure FDA0003362020690000071
 22.根据权利要求21的用途，所述疾病为系统性红斑狼疮、多发性神经炎、青少年糖尿病、自身免疫性溶血性贫血、溃疡性结肠炎或类风湿性关节炎。22. Use according to claim 21, wherein the disease is systemic lupus erythematosus, polyneuritis, juvenile diabetes, autoimmune hemolytic anemia, ulcerative colitis or rheumatoid arthritis.
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