WO2019037755A1 - 一类干扰素调节剂及其制备方法和用途 - Google Patents

一类干扰素调节剂及其制备方法和用途 Download PDF

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WO2019037755A1
WO2019037755A1 PCT/CN2018/101899 CN2018101899W WO2019037755A1 WO 2019037755 A1 WO2019037755 A1 WO 2019037755A1 CN 2018101899 W CN2018101899 W CN 2018101899W WO 2019037755 A1 WO2019037755 A1 WO 2019037755A1
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alkyl
aryl
coo
heteroaryl
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French (fr)
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鲍红丽
熊海根
库玛尔• 纳卡拉占 拉姆•
钱波
葛亮
简武军
冯薇薇
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中国科学院福建物质结构研究所
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Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a kind of interferon regulator and a preparation method and use thereof.
  • Interferon is a large class of important immune signaling proteins. When infected by a pathogen, the infected cells release signals to improve the immune defense of surrounding cells. These include type I, type II, and type III, and type I and type II interferons are responsible for activating or regulating immune responses.
  • Interferon- ⁇ IFN ⁇
  • IFN ⁇ Interferon- ⁇
  • the beta interferon recruits immune defense cells such as macrophages to establish an immune defense; for such diseases, elevated beta interferon contributes to the treatment of the disease.
  • the body easily releases a large amount of beta interferon to recruit macrophages to cause accidental injury to normal cells and cause diseases; the treatment of such diseases needs to inhibit the secretion of beta interferon. Therefore, the direct activation and regulation of ⁇ -interferon and upstream regulation are important for the treatment of diseases.
  • a further object of the invention is to provide the use of the above compounds.
  • the compound has an inhibitory or enhanced activity on beta interferon (IFN ⁇ ) in cells.
  • IFN ⁇ beta interferon
  • R 1 is an aryl group, a heteroaryl group, said aryl, heteroaryl groups are optionally substituted with one or more substituents R a
  • R a is the: halo, alkyl, alkenyl, alkynyl, Cycloalkyl, aryl, heteroaryl, heterocyclic, -CN, -NO 2 , oxo, -CO-R 10 , -COO-R 11 , -NH-CO-R 10 , -NH-COO- R 11 , -NR 12 R 13 , -OR 14 , -SO 2 -R 15 , a boronic acid group, a silane group; an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heterocyclic group in the above R a substituent
  • the aryl group, heterocyclic group may be optionally substituted by a halogen, an al
  • R 2 is -(CH 2 ) 0-4 CO-R 7 , -SO 2 -R 8 , -PO-(R 9 ) 2 , -CN, -NO 2 , R 7 , R 8 , R 9 are alkyl groups Alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -NR 12 R 13 , -NH-CO-R 10 , -NH-COO-R 11 , -OR 14
  • the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl can be optionally substituted by a halogen, an alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, CN, -NO 2 , oxo, -CO-R 10 , -COO-R 11 , -NH-CO-R 10 , -NH-COO-
  • R 4 is halogen, alkyl, alkenyl, alkynyl, -alkyl-O-CO-alkyl, -alkyl-O-alkyl, -alkyl-CO-alkyl, alkyl-COO-alkyl , at least one H atom of the above alkyl, alkenyl or alkynyl group is substituted by a halogen;
  • R 3 and R 6 are the same or different and are independently selected from H, halogen, hydroxy, alkyl, aryl.
  • the alkyl or aryl group in the above group may be substituted by one or more substituents: halogen, hydroxy, Alkyl, alkoxy, -CO-alkyl, -O-CO-alkyl, -COO-alkyl;
  • R 5 is N 3 , or R 5 'is halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, -NO 2 , oxo, -CO-R 10 , -COO-R 11 , -NH-CO-R 10 , -NH-COO-R 11 , -NR 12 R 13 , -OR 14 , -SO 2 -R 15 , a boronic acid group, a silyl group; wherein the alkyl group, the alkenyl group An alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group may be optionally substituted by a halogen, an alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, -CN, -NO 2 , Oxo, -CO-R 10
  • R 10 , R 11 , R 12 , R 13 , R 14 and R 15 may be the same or different and are independently selected from H, alkyl, aryl, heteroaryl, heterocyclic; above alkyl, aryl, hetero
  • the aryl group and the heterocyclic group may also be substituted by halogen, alkyl, aryl, heteroaryl, heterocyclic, -CN, -NO 2 , oxo, -CO-R 10 , -COO- R 11 , -NH-CO-R 10 , -NH-COO-R 11 , -NR 12 R 13 , -OR 14 , -SO 2 -R 15 ;
  • the compound is not a specific compound as follows:
  • R 1 is an aryl group such as phenyl, naphthyl or the like; or R 1 is a heteroaryl group such as a thienyl group, a benzothienyl group, a furyl group or a benzofuranyl group.
  • Said aryl, heteroaryl is optionally substituted with 1-5 R a, R a, for example, the: halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, Heterocyclyl, -CN, -NO 2 , oxo, -CO-alkyl, -CO-aryl, -COO-alkyl, -COO-aryl, -NH-CO-alkyl, -NH-CO -aryl, -NH 2 , -NH-alkyl, -N(alkyl) 2 , -OH, -O-alkyl, -O-aryl, -O-heteroaryl, boronic acid, silane;
  • the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic group in the above R a substituent may be optionally substituted by a
  • R 2 is -(CH 2 ) 0-4 CO-R 7 , for example -CO-R 7 , -CH 2 -CO-R 7 , -CH 2 -CH 2 -CO-R 7 .
  • R 7 is alkyl, aryl, heteroaryl, -O-alkyl, -O-aryl, -O-heteroaryl, wherein the alkyl, aryl, heteroaryl can be Substituted by the following groups: halogen, alkyl, aryl, heteroaryl, heterocyclic, -CN, -NO 2 , oxo, -CO-R 10 , -COO-R 11 , -NH-CO- R 10 , -NH-COO-R 11 , -NR 12 R 13 , -OR 14 ;
  • R 4 is perfluoroalkyl, -perfluoroalkyl-O-CO-alkyl, -perfluoroalkyl-O-alkyl, -perfluoroalkyl-CO-alkyl, -perfluoro Alkyl-COO-alkyl;
  • R 5 is N 3 , or
  • the R 5 ' is halogen, alkyl, aryl, heteroaryl, -CN, -NO 2 , oxo, -CO-alkyl, -CO-aryl, -COO-alkyl, -COO-aryl , -NH-CO-alkyl, -NH-CO-aryl, -NH 2 , -NH-alkyl, -N(alkyl) 2 , -OH, -O-alkyl, -O-aryl , -O-heteroaryl, boronic acid, silane group, the above alkyl, aryl, heteroaryl group may be optionally substituted by a halogen, an alkyl group, an aryl group, a heteroaryl group, -CN, -NO 2 , oxo, -CO-alkyl, -CO-aryl, -COO-alkyl, -COO
  • the compound of formula (I) is selected from the following specific compounds:
  • the invention also provides a preparation method of the above compound of the general formula (I), comprising:
  • R' is the same or different, optionally an alkyl group, and R 1 -R 4 , R 5 ', R 6 are as defined above;
  • the compound of formula (I) is reacted with a pharmaceutically acceptable organic or inorganic acid to provide a pharmaceutically acceptable salt of formula (I).
  • step 1) in the step 1),
  • the reaction is carried out in the presence of a catalyst and a free radical initiator.
  • the catalyst is selected from at least one of an iron metal catalyst and a triflate anion metal catalyst;
  • the catalyst is selected from the group consisting of ferrous trifluoromethanesulfonate, ferrous chloride, ferrous acetate, iron p-toluenesulfonate, palladium triflate, indium triflate, trifluoro Bismuth methanesulfonate, bismuth triflate, iron triflate, trifluoromethanesulfonic acid, copper triflate, silver triflate, bismuth triflate, trifluoromethane At least one of acid bismuth;
  • the radical initiator is selected from at least one of organic peroxides
  • the radical initiator is selected from the group consisting of an acyl peroxide, a hydroperoxide, a dialkyl peroxide, an ester peroxide, a ketone peroxide, and a dicarbonate peroxide. At least one
  • the radical initiator is selected from the group consisting of benzoyl peroxide, lauroyl peroxide, cumene hydroperoxide, t-butyl hydroperoxide, di-tert-butyl peroxide, and t-butyl peroxyacetate.
  • the free radical initiator is tert-butyl peroxybenzoate
  • the molar ratio of the compound (II), the compound (III), the compound (IV), the radical initiator, and the catalyst is from 1:1 to 2:2 to 3:2 to 3:0.03 to 0.07;
  • the reaction temperature of the reaction is -20 ° C to 80 ° C, the reaction time is 0.5 h to 12 h;
  • the temperature of the reaction is from 0 ° C to 50 ° C and the reaction time is from 0.5 h to 3 h.
  • the reaction is carried out under a catalyst such as Cu(OAc) 2 or 2-aminophenol, and the reaction is carried out in a solvent, which may be, for example, dichloro Methane, or water, etc.
  • a catalyst such as Cu(OAc) 2 or 2-aminophenol
  • a solvent which may be, for example, dichloro Methane, or water, etc.
  • the compounds of the invention are modulators of interferon beta (IFN beta) which increase or inhibit the secretion of beta interferon. Used to regulate the immune system.
  • IFN beta interferon beta
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the formula (I) of the present invention, and its racemate, stereoisomer, tautomer, polymorph, solvate, and pharmacy thereof. Acceptable salt.
  • the pharmaceutical composition may also optionally comprise at least one pharmaceutically acceptable excipient, such as a carrier, excipient, and the like.
  • the excipient may be one or more selected from the group consisting of a disintegrant, a glidant, a lubricant, a diluent, a filler, a binder, a colorant, an effervescent, and a flavoring agent. , preservatives, coating materials, etc.
  • the pharmaceutical composition may be in the form of, but not limited to, an oral dosage form, a parenteral administration dosage form, an external dosage form, and a rectal administration dosage form.
  • the pharmaceutical composition may be an oral tablet, capsule, pill, powder, sustained release formulation, solution and suspension, sterile solution, suspension or emulsion for parenteral injection, or A suppository for rectal administration.
  • the pharmaceutical composition is in a unit dosage form suitable for single administration of precise dosages.
  • the amount of the compound ranges from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day.
  • the amount of the compound ranges from about 0.1 mg/kg body weight/day to about 50 mg/kg body weight/day.
  • the amount of the compound ranges from about 0.1 mg/kg body weight/day to about 10 mg/kg body weight/day.
  • the compound is administered in a single dose once daily.
  • the compound is administered in multiple doses more than once a day.
  • the compound is administered twice daily.
  • the compound is administered three or more times per day.
  • the individual to which the pharmaceutical composition is administered is a mammal.
  • the mammal is a human.
  • the pharmaceutical composition further comprises at least one additional therapeutic agent (ie, made into a dosage form).
  • the pharmaceutical composition and the at least one therapeutic agent are each combined in a separate dosage form into a combined product, such as a kit of parts.
  • the pharmaceutical composition comprises a compound of the invention and another or more interferon modulator drugs.
  • the pharmaceutical combination kit contains two or more individually packaged pharmaceutical compositions, wherein one individually packaged pharmaceutical composition contains a novel compound of the formula, and the remaining individually packaged pharmaceutical compositions contain One or more interferon modulator drugs.
  • the present invention also provides a compound of the above formula (I), and racemates, stereoisomers, tautomers, polymorphs, solvates thereof, and pharmaceutically acceptable salts thereof, or the above pharmaceutical compositions, Use in the preparation of a medicament for the treatment of a disease caused by a disorder of beta interferon.
  • the disease is systemic lupus erythematosus, polyneuritis, juvenile diabetes, autoimmune hemolytic anemia, ulcerative colitis or rheumatoid arthritis.
  • the invention also provides a method of treating a disorder of beta interferon comprising contacting an interferon with an effective amount of a compound described above, or a pharmaceutically acceptable salt thereof.
  • the method can be used in vivo as well as in vitro.
  • the specific dose to be administered is selected and adjusted according to the state of the tumor cells in the patient and the overall physical state.
  • alkyl refers to a straight or branched alkyl group having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl.
  • Base isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl.
  • alkenyl refers to a straight or branched alkenyl group having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, such as ethenyl, propenyl, isopropenyl.
  • alkynyl refers to a straight or branched alkynyl group having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl.
  • alkoxy refers to a straight or branched alkoxy group having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, Butoxy, isobutoxy, tert-butoxy, sec-butoxy.
  • halogen is fluoro, chloro, bromo, iodo, preferably fluoro, chloro, bromo.
  • aryl is understood to mean preferably a monovalent, aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6-14 aryl".
  • C 6-14 aryl is understood to mean preferably a monovalent, bicyclic or monovalent aromatic or partially aromatic having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms.
  • C 6-14 aryl a tricyclic hydrocarbon ring
  • C 6 aryl a ring having 6 carbon atoms
  • C 9 aryl such as indanyl or fluorenyl
  • C 10 aryl a ring having 10 carbon atoms
  • C13 aryl such as a fluorenyl group
  • C14 aryl a ring having 14 carbon atoms
  • heteroaryl is understood to be a monocyclic ring containing 5-20 ring atoms, 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms. , bicyclic and tricyclic systems wherein at least one ring system is aromatic and at least one ring system comprises one or more heteroatoms (eg, N, O, S, Se, etc.), wherein each ring system comprises 5-7 A ring of atoms, with one or more attachment points attached to the rest of the molecule.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • a heteroaryl group of 5-10 atoms comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S, Se and N.
  • a heteroaryl group of 5-6 atoms comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S, Se and N.
  • Examples of monocyclic groups of heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, dioxins Azolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazole Group, benzimidazolyl, benzotriazolyl, oxazolyl, fluorenyl, isodecyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their a benzo derivative such as a quinolyl group, a quinazolinyl group, an
  • heterocyclyl means a monocyclic, bicyclic or tricyclic ring system wherein one or more atoms on the ring are independently, optionally, substituted by a hetero atom, and the ring may be fully saturated or contain one or more unsaturations. , but not aromatic, with one or more attachment points connected to other molecules. Hydrogen atoms on one or more of the rings may be independently unsubstituted or substituted by one or more substituents described herein.
  • the "heterocyclyl” is a monocyclic ring of 3-7 atoms, or a bicyclic ring of 7-10 atoms, which comprises 1-5, preferably 1-3, selected from N, O. , S and Se heteroatoms.
  • the heterocyclic group may include, but is not limited to, a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl Or a trithiaalkyl group; or a 7-membered ring such as a diazepanyl group.
  • a 4-membered ring such as azetidinyl, oxetanyl
  • a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidin
  • the heterocyclic group can be benzofused.
  • the heterocyclic group may be bicyclic, such as but not limited to a 5,5 membered ring such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6 membered bicyclic ring such as hexahydropyrrole.
  • [1,2-a]pyrazine-2(1H)-yl ring [1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing a nitrogen atom may be partially unsaturated, that is, it may contain one or more double bonds such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiene.
  • heterocyclyl, heteroaryl includes all possible isomeric forms thereof, such as positional isomers thereof.
  • pyridyl or pyridinyl includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl And pyridin-4-yl;
  • thienyl or thienylene includes thiophen-2-yl, thiophen-2-yl, thiophen-3-yl and thiophen-3-yl.
  • the compounds of the invention may be chiral and thus may exist in various enantiomeric forms. Thus these compounds may exist in racemic or optically active form.
  • the compound of the present invention or an intermediate thereof can be isolated as an enantiomeric compound by chemical or physical methods known to those skilled in the art, or used in the form of synthesis. In the case of racemic, the diastereomers are prepared from the mixture by reaction with an optically active resolving agent.
  • suitable resolving agents are optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N- in the R and S forms). Benzoyl valine or N-benzenesulfonyl valine) or various optically active camphorsulfonic acids.
  • optically active resolving agents for example dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers
  • Chromatographic enantiomer resolution is advantageously carried out.
  • Suitable eluents for this purpose are aqueous or alcohol-containing solvent mixtures, for example, hexane/isopropanol/acetonitrile.
  • tautomer refers to a functional group isomer that is produced by the rapid movement of an atom in a molecule at two positions.
  • the compounds of the invention may exhibit tautomerism.
  • Tautomeric compounds may exist in two or more interconvertible species.
  • Proton-shifting tautomers are derived from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer typically result in a mixture having physicochemical properties consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates
  • phenol in phenol, the enol form predominates.
  • the invention encompasses all tautomeric forms of the compounds.
  • solvate refers 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.
  • water, ethanol, propanol, acetone, and the like can be used.
  • subject refers to an individual, including a mammal, and a non-mammal, having a disease, disorder, condition, or the like.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domesticated Animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs.
  • non-human mammals include, but are not limited to, birds and fish.
  • the mammal is a human.
  • treatment includes alleviating, alleviating or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing a potential metabolic cause of the symptoms, inhibiting the disease or condition, such as preventing the progression of the disease or condition, Ameliorating a disease or condition, ameliorating the disease or condition, alleviating the symptoms caused by the disease or condition, or terminating the symptoms of the disease or condition, and further, the term includes the purpose of prevention.
  • the term also includes obtaining a therapeutic effect and/or a preventive effect.
  • the therapeutic effect refers to curing or ameliorating the underlying disease to be treated.
  • the healing or amelioration of one or more physiological symptoms associated with a underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, an improvement in the patient's condition is observed.
  • the composition can be administered to a patient at risk of developing a particular disease, or even if a diagnosis of the disease has not been made, the composition is administered to a patient who develops one or more physiological symptoms of the disease.
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Techniques of administration that are useful in the compounds and methods described herein are well known to those skilled in the art. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.
  • composition refers to a biologically active compound, optionally in admixture with at least one pharmaceutically acceptable chemical component, including but not limited to carriers, stabilizers, diluents. , dispersing agents, suspending agents, thickening agents and/or excipients.
  • carrier refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of a compound into a cell or tissue.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acid and free base of the specified compound, and which has no adverse effects biologically or otherwise.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, basic or organic salts of acidic residues such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from, for example, non-toxic inorganic or organic acids.
  • these conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; 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, p-aminobenzenesulfonic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.
  • 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, to
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, 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 both.
  • TMS is trimethylsilyl
  • TBPB is tert-butyl peroxybenzoate
  • Tf is triflate
  • DCM is dichloromethane
  • Fe(OTf) 2 (0.025 mmol) was added to a 25 mL reaction tube, vacuumed, and replaced with nitrogen three times, ethylene glycol dimethyl ether (2 ml), 1-(3,4-dichlorobenzene Methyl acrylate (0.5 mmol), nonafluoro iodine butane (1.5 mmol), TMSN 3 (1.7 mmol), TBPB (1.75 mmol) was added to the reaction tube, and reacted at room temperature for 2 hours.
  • a preferred compound of formula (I), preferred compounds and NMR data thereof are prepared in a manner similar to that described in Example 1 above.
  • RNA is extracted from the stimulated cells and reverse transcribed into cDNA.

Abstract

本发明涉及一种通式(I)化合物，及其消旋体、立体异构体、互变异构体、多晶型物、溶剂化物、或它们药学上可接受的盐。本发明还涉及上述通式(I)化合物的制备方法及含有它的物组合物。本发明所述化合物可以用于治疗β干扰素失调引起的疾病，例如系统性红斑狼疮、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等。(I)

Description

一类干扰素调节剂及其制备方法和用途 技术领域
本发明属于药物化学领域，涉及一类干扰素调节剂及其制备方法与用途。
背景技术
干扰素是一大类重要的机体免疫信号蛋白，作用是在病原侵染宿主细胞时被侵染细胞会释放信号提高周围细胞的免疫防御。其中包括I型、II型和III型三类，I型和II型干扰素负责激活或调控免疫响应。β干扰素(IFNβ)是I型干扰素中重要的一种，常用于研究免疫应答反应及免疫调控：当宿主细胞受到免疫刺激(病毒侵入或癌症发生发展)时，机体的免疫应答会分泌大量的β干扰素来招募巨噬细胞等免疫防御细胞来建立免疫防御；对于这类疾病，β干扰素的升高有助于疾病的治疗。对于某些免疫缺陷疾病，机体容易释放大量的β干扰素招募巨噬细胞造成对正常细胞的误伤进而导致疾病；这类疾病的治疗需要抑制β干扰素的分泌。因此，β干扰素的直接激活和调控及上游调控对于疾病的治疗具有重要意义。
发明内容
本发明的目的是提供一类式(I)化合物及其制备方法。
本发明又一目的是提供上述化合物的用途。所述化合物对于细胞中β干扰素(IFNβ)具有抑制或增强的活性。
本发明通过如下技术方案实现：
一种通式(I)化合物，及其消旋体、立体异构体、互变异构体、多晶型物、 溶剂化物、或它们药学上可接受的盐，所述化合物的结构如下：
Figure PCTCN2018101899-appb-000001
其中，R 1为芳基，杂芳基，所述芳基、杂芳基任选被一个或多个R a取代基取代，所述R a为：卤素、烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15、硼酸基、硅烷基；上述R a取代基中的烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基可以任选被如下基团取代：卤素、烷基、芳基、杂芳基、-CN，-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15；
R 2为-(CH 2) 0-4CO-R 7，-SO 2-R 8，-PO-(R 9) 2，-CN，-NO 2，R 7、R 8、R 9为烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基、-NR 12R 13、-NH-CO-R 10、-NH-COO-R 11、-OR 14，其中所述烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基可以任选被如下基团取代：卤素、烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15；
R 4为卤素、烷基、烯基、炔基、-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、烯基、炔基中至少有一个H原子被卤素取代；
R 3、R 6相同或不同，独立的选自H、卤素、羟基、烷基、芳基，上述基团中的烷基、芳基可以被如下一个或多个取代基取代：卤素、羟基、烷基、烷氧基、-CO-烷基、-O-CO-烷基、-COO-烷基；
R 5为N 3、或
Figure PCTCN2018101899-appb-000002
R 5’为卤素、烷基、烯基、炔基、环烷基、芳基、杂 芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15、硼酸基、硅烷基；其中所述的烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基可以任选被如下基团取代：卤素、烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15；
R 10、R 11、R 12、R 13、R 14、R 15可相同或不同，独立地选自H、烷基、芳基、杂芳基、杂环基；上述烷基、芳基、杂芳基、杂环基还可以被如下基团所取代：卤素、烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15；
所述化合物不为如下具体化合物：
Figure PCTCN2018101899-appb-000003
根据本发明，R 1为芳基，例如苯基、萘基等；或者R 1为杂芳基，例如噻吩基、苯并噻吩基、呋喃基、苯并呋喃基。所述芳基、杂芳基任选被1-5个R a取代基取代，所述R a例如为：卤素、烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-烷基、-CO-芳基、-COO-烷基、-COO-芳基、-NH-CO-烷基、-NH-CO-芳基、-NH 2、-NH-烷基、-N(烷基) 2、-OH、-O-烷基、-O-芳基、-O-杂芳基、硼酸基、硅烷基；上述R a取代基中的烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基可以任选被如下基团取代：卤素、烷基、芳基、杂芳基、-CN，-NO 2、氧代、-CO-烷基、-CO-芳基、-COO-烷基、-COO-芳基、-NH-CO-烷基、-NH-CO-芳基、-NH 2、-NH-烷基、-N(烷基) 2、-OH、-O-烷基、-O- 芳基；
根据本发明，R 2为-(CH 2) 0-4CO-R 7，例如为-CO-R 7、-CH 2-CO-R 7、-CH 2-CH 2-CO-R 7。
根据本发明，R 7为烷基、芳基、杂芳基、-O-烷基、-O-芳基、-O-杂芳基，其中所述烷基、芳基、杂芳基可以任选被如下基团取代：卤素、烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14；
根据本发明，R 4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；
根据本发明，R 5为N 3、或
Figure PCTCN2018101899-appb-000004
所述R 5’为卤素、烷基、芳基、杂芳基、-CN、-NO 2、氧代、-CO-烷基、-CO-芳基、-COO-烷基、-COO-芳基、-NH-CO-烷基、-NH-CO-芳基、-NH 2、-NH-烷基、-N(烷基) 2、-OH、-O-烷基、-O-芳基、-O-杂芳基、硼酸基、硅烷基，上述中的烷基、芳基、杂芳基可以任选被如下基团取代：卤素、烷基、芳基、杂芳基、-CN，-NO 2、氧代、-CO-烷基、-CO-芳基、-COO-烷基、-COO-芳基、-NH-CO-烷基、-NH-CO-芳基、-NH 2、-NH-烷基、-N(烷基) 2、-OH、-O-烷基、-O-芳基。
根据本发明，所述式(I)化合物选自如下具体化合物：
Figure PCTCN2018101899-appb-000005
Figure PCTCN2018101899-appb-000006
Figure PCTCN2018101899-appb-000007
Figure PCTCN2018101899-appb-000008
Figure PCTCN2018101899-appb-000009
本发明还提供一种上述通式(I)化合物的制备方法，包括：
Figure PCTCN2018101899-appb-000010
其中，X为卤素，R’相同或不同，任选的为烷基，R 1-R 4、R 5’、R 6如上述所定义；
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R 5为N 3的通式(I)化合物；
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R 5为
Figure PCTCN2018101899-appb-000011
的通式(I)化合物；
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。
根据本发明，所述步骤1)中，
优选的，所述反应在催化剂和自由基引发剂的存在下进行。
优选地，所述催化剂选自铁金属催化剂和三氟甲磺酸根阴离子金属催化剂 中的至少一种；
进一步优选地，所述催化剂选自三氟甲磺酸亚铁、氯化亚铁、醋酸亚铁、对甲基苯磺酸铁、三氟甲磺酸钯、三氟甲磺酸铟、三氟甲磺酸钕、三氟甲磺酸钇、三氟甲磺酸铁、三氟甲磺酸、三氟甲磺酸铜、三氟甲磺酸银、三氟甲磺酸镧、三氟甲磺酸铈中的至少一种；
优选地，所述自由基引发剂选自有机过氧化物中的至少一种；
进一步优选地，所述自由基引发剂选自酰类过氧化物、氢过氧化物、二烷基过氧化物、酯类过氧化物、酮类过氧化物、二碳酸酯过氧化物中的至少一种；
更进一步优选地，所述自由基引发剂选自过氧化苯甲酰、过氧化月桂酰、异丙苯过氧化氢、叔丁基过氧化氢、过氧化二叔丁基、过氧化乙酸叔丁酯、过氧化二异丙苯、过氧化苯甲酸叔丁酯、过氧化叔戊酸叔丁基酯、过氧化甲乙酮、过氧化环己酮、过氧化二碳酸二异丙酯、过氧化二碳酸二环己酯中的至少一种；
优选地，所述自由基引发剂为过氧化苯甲酸叔丁酯；
优选地，化合物(II)、化合物(III)、化合物(IV)、自由基引发剂、催化剂的摩尔比例为：1：1～2：2～3：2～3：0.03～0.07；
优选地，所述反应的反应温度为-20℃至80℃，反应时间为0.5h至12h；
优选地，所述反应的温度为0℃至50℃，反应时间为0.5h至3h。
根据本发明，所述步骤2)中，优选的，所述反应在催化剂下进行，例如Cu(OAc) 2或2-氨基苯酚，所述反应在溶剂中进行，所述溶剂例如可为二氯甲烷、或水等。
本发明化合物是β干扰素(IFNβ)的调节剂，其可以增加或抑制β干扰素的分泌。用于调节免疫系统。
本发明还提供一种药物组合物，包含本发明通式(I)所示的化合物、及其消旋体、立体异构体、互变异构体、多晶型物、溶剂化物、其药学可接受的盐。
根据本发明，所述药物组合物还可任选包含至少一种药学上可接受的辅料，例如载体、赋形剂等。作为实例，所述辅料可以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、包衣材料等。
根据本发明，所述药物组合物可以为包括但不限于口服剂型、胃肠外给药剂型、外用剂型和直肠给药剂型的形式。
在一些实施方案中，所述药物组合物可以是口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液和悬浮液，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。
在其它实施方案中，所述药物组合物为适合单次施予精确剂量的单位剂型。
在其它实施方案中，所述化合物的量在约0.001mg/kg体重/天-约1000mg/kg体重/天的范围内。
在其它实施方案中，所述化合物的量的范围为约0.1mg/kg体重/天-约50mg/kg体重/天。
在其它实施方案中，所述化合物的量的范围为约0.1mg/kg体重/天-约10mg/kg体重/天。
在一些实施方案中，以单剂量施用所述化合物，每天一次。
在其它实施方案中，以多剂量施用所述化合物，每天不止一次。
在一些实施方案中，每天施用两次所述化合物。
在其它实施方案中，每天施用三次或三次以上所述化合物。
在一些实施方案中，所述药物组合物施用于的个体为哺乳动物。
在其它实施方案中，所述哺乳动物是人。
在其它实施方案中，所述药物组合物还包含至少另一种治疗剂(即制成一种剂型)。
在一些实施方案中，所述药物组合物和至少一种治疗剂分别以独立的剂型组合成组合产品，如套装药品(kit of part)。
在一些实施方案中，所述药物组合物含有本发明的化合物和另一种或多种干扰素调节剂药物。
在一些实施方案中，所述药物组合套装含有两种或多种独立包装的药物组合物，其中一种独立包装的药物组合物含有新的通式化合物，其余的独立包装的药物组合物分别含有一种或多种干扰素调剂剂药物。
本发明还提供如上通式(I)化合物及其消旋体、立体异构体、互变异构体、多晶型物、溶剂化物、及其药学可接受的盐、或上述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。根据本发明，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等。
本发明还提供了一种治疗β干扰素失调的方法，其中包括将干扰素与有效量的上述化合物或其药学可接受的盐接触。
优选地，该方法可以用于体内，也可以用于体外。
具体给药剂量，根据患者体内肿瘤细胞状态和整体身体状态，进行选择和调整。
术语定义和说明
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本申请主题作任何限制。在本申请中，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
术语“烷基”指具有1-10个碳原子，优选1-6个碳原子的直链或支链烷基，所述烷基例如为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、新戊基。
术语“烯基”指具有2-10个碳原子，优选2-6个碳原子的直链或支链烯基， 所述烯基例如为乙烯基、丙烯基、异丙烯基。
术语“炔基”指具有2-10个碳原子，优选2-6个碳原子的直链或支链炔基，所述炔基例如为乙炔基、丙炔基、丁炔基。
术语“烷氧基”指具有1-10个碳原子，优选1-6个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、仲丁氧基。
术语“卤素”为氟、氯、溴、碘，优选为氟、氯、溴。
术语“芳基”应理解为优选表示具有6～20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，优选“C 6-14芳基”。术语“C 6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C 6-14芳基”)，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C 13芳基”)，例如芴基，或者是具有14个碳原子的环(“C 14芳基”)，例如蒽基。
术语“杂芳基”应理解为含有5-20个环原子、5-14个环原子，或5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子(例如N、O、S、Se等)，其中每一个环体系包含5-7个原子组成的环，且有一个或多个连接点与分子其余部分相连。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，5-10个原子组成的杂芳基包含1,2,3或4个独立选自O、S、Se和N的杂原子。在另一些实施方案中，5-6个原子组成的杂芳基包含1,2,3或4个独立选自O、S、Se和N的杂原子。
杂芳基基团的单环实例包括，但并不限于，噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩 基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
术语“杂环基”意指单环，双环或三环体系，其中环上一个或多个原子独立任选地被杂原子所取代，环可以是完全饱和的或包含一个或多个不饱和度，但不是芳香族类，有一个或多个连接点连接到其他分子上去。一个或多个环上的氢原子可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。其中一些实施例是，“杂环基”是3-7个原子组成的单环、或7-10个原子组成的的双环，其包含1-5个，优选1-3个选自N、O、S和Se的杂原子。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基、1,3-苯并噁唑基、1,3-苯并二氧杂环戊烯基。
除非另有说明，杂环基、杂芳基包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。
根据分子结构，本发明的化合物可以是手性的，因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的 化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物，或者以此形式用于合成。在外消旋的情况中，通过与光学活性的拆分试剂反应，从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸，例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物)，也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物，例如，己烷/异丙醇/乙腈。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
术语“溶剂化物”、“多晶型”指任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定，只要该溶剂是药理学上可以接受的。例如，水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。
本文所用的有关术语“受试者”、“患者”或“个体”是指患有疾病、病症或病况等的个体，包括哺乳动物和非哺乳动物。哺乳动物的实施例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实施例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方式中，所述哺乳动物为人。
本文所用的术语“治疗”和其它类似的同义词包括缓解、减轻或改善疾病或病症症状，预防其它症状，改善或预防导致症状的潜在代谢原因，抑制疾病或病症，例如阻止疾病或病症的发展，缓解疾病或病症，使疾病或病症好转，缓解由疾病或病症导致的症状，或者中止疾病或病症的症状，此外，该术语包含预防的目的。该术语还包括获得治疗效果和/或预防效果。所述治疗效果是指治愈或改善所治疗的潜在疾病。此外，对与潜在疾病相关的一种或多种生理症状的治愈或改善也是治疗效果，例如尽管患者可能仍然受到潜在疾病的影响，但观察到患者情况改善。就预防效果而言，可向具有患特定疾病风险的患者施用所述组合物，或者即便尚未做出疾病诊断，但向出现该疾病的一个或多个生理症状的患者施用所述组合物。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、外用和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术。在优选的实施方式中，本文讨论的化合物和组合物通过口服施用。
本文针对制剂、组合物或成分所用术语“可接受的”是指对接受治疗的受试者的一般健康情况没有长期的有害影响。
本文所用术语“药学上可接受的”是指不影响本申请化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
本文所用术语“药物组合物”是指任选地混合有至少一种药学上可接受的化学成分的生物活性化合物，所述药学上可接受的化学成分包括但不限于载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂和/或赋形剂。
本文所用术语“载体”是指相对无毒的化学化合物或试剂，其有助于将化合物引入到细胞或组织中。
本文所用术语“药学上可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力，并且在生物学或其它方面上没有不良作用的盐。药学上可接受的盐的实例包括但不限于，碱性残基(如胺类)的无机酸盐或有机酸盐，酸性残基(如羧酸)的碱性盐或有机盐，等。药学上可接受的盐包括由诸如无毒性的无机或有机酸形成的母体化合物的常规无毒性的盐或季铵盐。例如，这些常规的无毒性盐包括那些源自无机酸的盐，如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等；以及由有机酸制备的盐，如，乙酸、丙酸、琥珀酸、羟基乙酸、乳酸、苹果酸、酒石酸、柠檬酸、延胡索酸、甲磺酸、甲苯磺酸、水杨酸、对氨基苯磺酸等。
本发明的药学上可接受的盐可以通过常规的化学方法从含有碱性或酸性部分的母体化合物合成。通常，这种盐可以通过使这些化合物的游离酸或碱形式与化学计量的适当的碱或酸在水或有机溶剂或二者的混合物中反应制备。
具体实施方式
下面结合实施例对本发明作进一步的说明。需要说明的是，下述实施例不能作为对本发明保护范围的限制，任何在本发明基础上做出的改进都不违背本发明的精神。
其中，中间体和目标化合物的合成过程均以实施例中的代表说明，其余的中间体和目标化合物的合成过程同代表化合物。
TMS为三甲基硅基，TBPB为苯甲酸过氧叔丁酯，Tf为三氟甲磺酸根，DCM为二氯甲烷。
实施例1
Figure PCTCN2018101899-appb-000012
在氮气保护下，将Fe(OTf) 2(0.025mmol)加入25mL的反应管中，抽真空，氮气置换三次，将乙二醇二甲醚(2ml)、1-苯基-丙烯酸甲酯(0.5mmol)、三氟碘甲烷(1.5mmol)、TMSN 3(1.7mmol)、TBPB(1.75mmol)加入反应管中，室温下反应2小时，反应完毕后，乙酸乙酯稀释，硅胶快速过滤，旋转蒸发仪减压除去溶剂后，柱层析分离，得产物(CS-1)。理化数据参见表1。
实施例2
Figure PCTCN2018101899-appb-000013
在氮气保护下，将Fe(OTf) 2(0.025mmol)加入25mL的反应管中，抽真空，氮气置换三次，将乙二醇二甲醚(2ml)，1-(3,4-二氯苯基)-丙烯酸甲酯(0.5mmol),九氟碘丁烷(1.5mmol)，TMSN 3(1.7mmol)，TBPB(1.75mmol)加入反应管中，室温下反应2小时，反应完毕后，乙酸乙酯稀释，硅胶快速过滤，旋转蒸发仪减压除去溶剂后，柱层析分离，得产物样品记为CS-9。理化数据参见表1。
实施例3
Figure PCTCN2018101899-appb-000014
在氮气保护下，将Fe(OTf) 2(0.025mmol)加入25mL的反应管中，抽真空，氮气置换三次，将乙二醇二甲醚(2ml)，苯基苯乙烯酮(0.5mmol)，五氟碘乙烷(1.5mmol)，TMSN 3(1.7mmol)，TBPB(1.75mmol)加入反应管中，室温下反应2小时，反应完毕后，乙酸乙酯稀释，硅胶快速过滤，旋转蒸发仪减压除去溶剂后，柱层析分离，得产物CS-48。理化参数见下面的表1。
按照上述实施例1类似的方法，制备优选的式(I)所示的化合物，优选的化合物以及其NMR数据见下表：
表1-优选化合物结构、编号及理化数据
Figure PCTCN2018101899-appb-000015
Figure PCTCN2018101899-appb-000016
Figure PCTCN2018101899-appb-000017
Figure PCTCN2018101899-appb-000018
Figure PCTCN2018101899-appb-000019
Figure PCTCN2018101899-appb-000020
Figure PCTCN2018101899-appb-000021
Figure PCTCN2018101899-appb-000022
Figure PCTCN2018101899-appb-000023
Figure PCTCN2018101899-appb-000024
Figure PCTCN2018101899-appb-000025
Figure PCTCN2018101899-appb-000026
实施例4
Figure PCTCN2018101899-appb-000027
在氮气保护下，将Cu(OAc) 2·H 2O(0.01mmol)和2-氨基苯酚(0.005mmol)加入到10mL的反应瓶中，抽真空，氮气置换三次，将DCM(0.2ml)，H 2O(0.2ml)，化合物(CS-34)(0.1mmol)，苯乙炔(0.1mmol)加入反应瓶中，室温下反应12小时，反应完毕后，乙酸乙酯萃取后，用硫酸镁干燥，过滤，旋转蒸发仪减压除去溶剂后，柱层析分离，得产物CS-58。数据参见表2。
按照上述实施例4类似的方法，制备优选的式(I)所示的化合物，优选的化合物以及其理化数据见下表2：
表2-优选化合物结构、编号及其理化数据
Figure PCTCN2018101899-appb-000028
Figure PCTCN2018101899-appb-000029
实施例5 生物活性测定
在高通量实时荧光定量PCR仪(QuantStudio 6Flex，ABI)上对上述实施例1至4制备得到的化合物的生物活性进行了测定，采用RAWBlue细胞，用以检测β干扰素(IFNβ)活性变化。具体步骤为：
(1)取用1mM(DMSO为溶剂)的上述化合物1ul对提前铺板的细胞(含1mL的培养液)进行预处理60min。
(2)更换培养液后分别用HT-DNA或Poly(I:C)刺激细胞6小时。
(3)对刺激后的细胞提取RNA并将其反转录为cDNA。
(4)利用QRT-PCR检测细胞中IFN-β及CXCL10在mRNA水平的相对表达。
结果参见下述表3。
表3 化合物的应激炎症水平
Figure PCTCN2018101899-appb-000030
Figure PCTCN2018101899-appb-000031
Figure PCTCN2018101899-appb-000032

Claims (10)

  1. 一种通式(I)化合物，及其消旋体、立体异构体、互变异构体、多晶型物、溶剂化物、或它们药学上可接受的盐，所述化合物的结构如下：
    Figure PCTCN2018101899-appb-100001
    其中，R 1为芳基，杂芳基，所述芳基、杂芳基任选被一个或多个R a取代基取代，所述R a为：卤素、烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15、硼酸基、硅烷基；上述R a取代基中的烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基可以任选被如下基团取代：卤素、烷基、芳基、杂芳基、-CN，-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15；
    R 2为-(CH 2) 0-4CO-R 7，-SO 2-R 8，-PO-(R 9) 2，-CN，-NO 2，R 7、R 8、R 9为烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基、-NR 12R 13、-NH-CO-R 10、-NH-COO-R 11、-OR 14，其中所述烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基可以任选被如下基团取代：卤素、烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15；
    R 4为卤素、烷基、烯基、炔基、-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、烯基、炔基中至少有一个H原子被卤素取代；
    R 3、R 6相同或不同，独立的选自H、卤素、羟基、烷基、芳基，上述基团中的烷基、芳基可以被如下一个或多个取代基取代：卤素、羟基、烷基、烷氧基、-CO-烷基、-O-CO-烷基、-COO-烷基；
    R 5为N 3、或
    Figure PCTCN2018101899-appb-100002
    R 5’为卤素、烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15、硼酸基、硅烷基；其中所述的烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基可以任选被如下基团取代：卤素、烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15；
    R 10、R 11、R 12、R 13、R 14、R 15可相同或不同，独立地选自H、烷基、芳基、杂芳基、杂环基；上述烷基、芳基、杂芳基、杂环基还可以被如下基团所取代：卤素、烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15；
    所述化合物不为如下具体化合物：
    Figure PCTCN2018101899-appb-100003
  2. 根据权利要求1所述的化合物，其中，R 1为芳基，例如苯基、萘基等；或者R 1为杂芳基，例如噻吩基、苯并噻吩基、呋喃基、苯并呋喃基。
    优选的，R 2为-(CH 2) 0-4CO-R 7，例如为-CO-R 7、-CH 2-CO-R 7、-CH 2-CH 2-CO-R 7；
    优选的，R 7为烷基、芳基、杂芳基、-O-烷基、-O-芳基、-O-杂芳基，其中所述烷基、芳基、杂芳基可以任选被如下基团取代：卤素、烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14；
    优选的，R 4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。
  3. 根据权利要求1所述的化合物，其中，R 5为N 3、或
    Figure PCTCN2018101899-appb-100004
    所述R 5’为卤素、取代或未取代的烷基、取代或未取代的芳基、取代或未取代的杂芳基、-CN、-NO 2、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14，所述取代基为卤素、烷基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14。
  4. 根据权利要求1所述的化合物，其中，所述化合物选自如下具体化合物：
    Figure PCTCN2018101899-appb-100005
    Figure PCTCN2018101899-appb-100006
    Figure PCTCN2018101899-appb-100007
    Figure PCTCN2018101899-appb-100008
  5. 一种权利要求1-4任一项所述化合物的制备方法，包括：
    Figure PCTCN2018101899-appb-100009
    Figure PCTCN2018101899-appb-100010
    其中，X为卤素，R’相同或不同，任选的为烷基，R 1-R 4、R 5’、R 6如上述所定义；
    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R 5为N 3的通式(I)化合物；
    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R 5为
    Figure PCTCN2018101899-appb-100011
    的通式(I)化合物；
    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；
  6. 一种药物组合物，包含如下通式(I)所示的化合物、及其消旋体、立体异构体、互变异构体、多晶型物、溶剂化物、或它们药学上可接受的盐，所述化合物的结构如下：
    Figure PCTCN2018101899-appb-100012
    其中，R 1为芳基，杂芳基，所述芳基、杂芳基任选被一个或多个R a取代基取代，所述R a为：卤素、烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15、硼酸基、硅烷基；上述R a取代基中的烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基可以任选被如下基团取代：卤素、烷基、芳基、 杂芳基、-CN，-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15；
    R 2为-(CH 2) 0-4CO-R 7，-SO 2-R 8，-PO-(R 9) 2，-CN，-NO 2，R 7、R 8、R 9为烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基、-NR 12R 13、-NH-CO-R 10、-NH-COO-R 11、-OR 14，其中所述烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基可以任选被如下基团取代：卤素、烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15；
    R 4为卤素、烷基、烯基、炔基、-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、烯基、炔基中至少有一个H原子被卤素取代；
    R 3、R 6相同或不同，独立的选自H、卤素、羟基、烷基、芳基，上述基团中的烷基、芳基可以被如下一个或多个取代基取代：卤素、羟基、烷基、烷氧基、-CO-烷基、-O-CO-烷基、-COO-烷基；
    R 5为N 3、或
    Figure PCTCN2018101899-appb-100013
    R 5’为卤素、烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15、硼酸基、硅烷基；其中所述的烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基可以任选被如下基团取代：卤素、烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15；
    R 10、R 11、R 12、R 13、R 14、R 15可相同或不同，独立地选自H、烷基、芳基、杂芳基、杂环基；上述烷基、芳基、杂芳基、杂环基还可以被如下基团所取代：卤素、烷基、芳基、杂芳基、杂环基、-CN、-NO 2、氧代、-CO-R 10、-COO-R 11、-NH-CO-R 10、-NH-COO-R 11、-NR 12R 13、-OR 14、-SO 2-R 15。
  7. 如权利要求6所述的药物组合物，其中，所述药物组合物还可任选包含至少一种药学上可接受的辅料，例如载体、赋形剂等；所述辅料例如为选自下 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、包衣材料等。
  8. 如权利要求7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、外用剂型和直肠给药剂型的形式；
    优选的，所述药物组合物为口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液和悬浮液，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；
    优选的，所述化合物的量在约0.001mg/kg体重/天-约1000mg/kg体重/天的范围内。
    优选的，所述化合物的量的范围为约0.1mg/kg体重/天-约50mg/kg体重/天。
    优选的，所述药物组合物还包含另一种或多种干扰素调节剂药物。
  9. 权利要求5中所述的通式(I)化合物及其消旋体、立体异构体、互变异构体、多晶型物、溶剂化物、其药学可接受的盐、或权利要求5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。
  10. 根据权利要求9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等。
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