CN109422664A - A kind of interferon regulation agent and its preparation method and application - Google Patents

A kind of interferon regulation agent and its preparation method and application Download PDF

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Publication number
CN109422664A
CN109422664A CN201711408870.2A CN201711408870A CN109422664A CN 109422664 A CN109422664 A CN 109422664A CN 201711408870 A CN201711408870 A CN 201711408870A CN 109422664 A CN109422664 A CN 109422664A
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alkyl
aryl
coo
heteroaryl
compound
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CN109422664B (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 present invention relates to a kind of logical formula (I) compound and its raceme, stereoisomer, tautomer, polymorph, solvate or their pharmaceutically acceptable salts.The invention further relates to the preparation method of above-mentioned logical formula (I) compound and contain its compositions.Compound of the present invention can be used for treating disease, such as systemic loupus erythematosus, polyneuritis, adolescent diabetes, autoimmune hemolytic anemia, ulcerative colitis or rheumatoid arthritis caused by beta interferon is lacked of proper care etc..

Description

A kind of interferon regulation agent and its preparation method and application
Technical field
The invention belongs to field of medicinal chemistry, are related to a kind of interferon regulation agent and preparation method thereof and purposes.
Background technique
Interferon is the important immunity of organism signal protein of a major class, and effect is infected in Infected with Pathogenic Fungi host cell Cell meeting release signal improves the immune defense of peripheral cell.Including I type, II type and type III three classes, I type and II type are dry It disturbs element and is responsible for activation or regulation immune response.Beta interferon (IFN β) is one kind important in I type interferon, is usually used in research and exempts from Epidemic disease responsing reaction and immunoregulation: when host cell is by immunostimulation (Virus entry or cancer occurrence and development), body Immune response can secrete a large amount of beta interferon to recruit the immune defense cells such as macrophage and establish immune defense；For this Class disease, the raising of beta interferon facilitate the treatment of disease.For certain immune deficiency disorders, body is easy a large amount of β of release Interferon recruits macrophage and causes the accidental injury to normal cell and then lead to disease；The treatment of this kind of disease needs to inhibit β dry Disturb the secretion of element.Therefore, the direct activation and regulation and upstream regulation of beta interferon are of great significance for the treatment of disease.
Summary of the invention
The object of the present invention is to provide a kind of formula (I) compounds and preparation method thereof.
Another object of the present invention is to provide the purposes of above compound.The compound is for beta interferon (IFN in cell β) there is the activity for inhibiting or enhancing.
The present invention is achieved through the following technical solutions:
A kind of logical formula (I) compound and its raceme, stereoisomer, tautomer, polymorph, solvate, Or their pharmaceutically acceptable salts, the structure of the compound are as follows:
Wherein, R1For aryl, heteroaryl, the aryl, heteroaryl are optionally by one or more RaSubstituent group replaces, described RaAre as follows: halogen, alkyl, alkenyl, alkynyl, naphthenic base, aryl, heteroaryl, heterocycle ,-CN ,-NO2, oxo ,-CO-R10、-COO- R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15, boronate, silylation；Above-mentioned RaIn substituent group Alkyl, alkenyl, alkynyl, naphthenic base, aryl, heteroaryl, heterocycle can optionally be replaced by following group: halogen, alkyl, virtue Base, heteroaryl ,-CN ,-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、- SO2-R15；
R2For-(CH2)0-4CO-R7,-SO2-R8,-PO- (R9)2,-CN ,-NO2, R7、R8、R9For alkyl, alkenyl, alkynyl, ring Alkyl, aryl, heteroaryl, heterocycle ,-NR12R13、-NH-CO-R10、-NH-COO-R11、-OR14, wherein the alkyl, alkenyl, Alkynyl, naphthenic base, aryl, heteroaryl, heterocycle can optionally be replaced by following group: halogen, alkyl, aryl, heteroaryl, miscellaneous Ring group ,-CN ,-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15；
R4For halogen, alkyl, alkenyl, alkynyl ,-alkyl-O-CO- alkyl ,-alkyl-O- alkyl ,-alkyl-CO- alkyl, alkane Base-COO- alkyl, abovementioned alkyl, alkenyl, at least one H atom is optionally substituted by halogen in alkynyl；
R3、R6It is identical or different, it is independent to be selected from H, halogen, hydroxyl, alkyl, aryl, alkyl, aryl in above-mentioned group Can be replaced by following one or more substituent groups: halogen, hydroxyl, alkyl, alkoxy ,-CO- alkyl ,-O-CO- alkyl ,- COO- alkyl；
R5For N3OrR5' it is halogen, alkyl, alkenyl, alkynyl, naphthenic base, aryl, heteroaryl, heterocycle Base ,-CN ,-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15, boron Acidic group, silylation；Wherein the alkyl, alkenyl, alkynyl, naphthenic base, aryl, heteroaryl, heterocycle can be optionally as follows Group replaces: halogen, alkyl, aryl, heteroaryl, heterocycle ,-CN ,-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO- R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15；
R10、R11、R12、R13、R14、R15It may be the same or different, independently selected from H, alkyl, aryl, heteroaryl, heterocycle； Abovementioned alkyl, aryl, heteroaryl, heterocycle can also be replaced following groups: halogen, alkyl, aryl, heteroaryl, heterocycle Base ,-CN ,-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15；
The compound is not following particular compound:
According to the present invention, R1For aryl, such as phenyl, naphthalene etc.；Or R1For heteroaryl, such as thienyl, benzothiophene Base, furyl, benzofuranyl.The aryl, heteroaryl are optionally by 1-5 RaSubstituent group replaces, the RaSuch as are as follows: halogen, Alkyl, alkenyl, alkynyl, naphthenic base, aryl, heteroaryl, heterocycle ,-CN ,-NO2, oxo ,-CO- alkyl ,-CO- aryl ,- COO- alkyl ,-COO- aryl ,-NH-CO- alkyl ,-NH-CO- aryl ,-NH2,-NH- alkyl ,-N (alkyl)2,-OH ,-O- alkane Base ,-O- aryl ,-O- heteroaryl, boronate, silylation；Above-mentioned RaAlkyl, alkenyl, alkynyl, naphthenic base, virtue in substituent group Base, heteroaryl, heterocycle can optionally be replaced by following group: halogen, alkyl, aryl, heteroaryl ,-CN ,-NO2, oxo ,- 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 present invention, R2For-(CH2)0-4CO-R7, for example,-CO-R7、-CH2-CO-R7、-CH2-CH2-CO-R7。
According to the present invention, R7For alkyl, aryl, heteroaryl ,-O- alkyl ,-O- aryl ,-O- heteroaryl, wherein the alkane Base, aryl, heteroaryl can optionally be replaced by following group: halogen, alkyl, aryl, heteroaryl, heterocycle ,-CN ,-NO2, oxygen Generation ,-CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14；
According to the present invention, R4For perfluoroalkyl ,-perfluoroalkyl-O-CO- alkyl ,-perfluoroalkyl-O- alkyl ,-perfluor alkane Base-CO- alkyl ,-perfluoroalkyl-COO- alkyl；
According to the present invention, R5For N3OrThe R5' it is halogen, alkyl, aryl, heteroaryl ,-CN ,-NO2、 Oxo ,-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, silylation, alkyl among the above, aryl, Heteroaryl can optionally be replaced by following group: halogen, alkyl, aryl, heteroaryl ,-CN ,-NO2, oxo ,-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 present invention, formula (I) compound is selected from following particular compound:
The present invention also provides a kind of preparation methods of above-mentioned logical formula (I) compound, comprising:
Wherein, X is halogen, and R ' is identical or different, is optionally alkyl, R1-R4、R5’、R6As defined above；
1) formula (II) compound is reacted with formula (III) compound, formula (IV) compound, obtains general formula (I-1) change Close object, i.e. R5For N3Logical formula (I) compound；
2) optionally, general formula (I-1) compound is reacted with formula (V) compound, obtains general formula (I-2) compound, i.e. R5 ForLogical formula (I) compound；
Optionally, the formula (I) compound and pharmaceutically acceptable organic acid or inorganic acid reaction are obtained into formula (I) institute The pharmaceutically acceptable salt shown.
According to the present invention, in the step 1),
Preferably, the reaction carries out in the presence of catalyst and radical initiator.
Preferably, the catalyst in ferrous metal catalyst and trifluoromethanesulfonic acid root anionic metallic catalysts extremely Few one kind；
It is further preferred that the catalyst be selected from trifluoromethanesulfonic acid ferrous iron, frerrous chloride, ferrous acetate, to methylbenzene Sulfonic acid iron, trifluoromethanesulfonic acid palladium, trifluoromethanesulfonic acid indium, trifluoromethanesulfonic acid neodymium, trifluoromethanesulfonic acid yttrium, trifluoromethanesulfonic acid iron, trifluoro At least one of methanesulfonic acid, copper trifluoromethanesulfcomposite, silver trifluoromethanesulfonate, trifluoromethanesulfonic acid lanthanum, trifluoromethanesulfonic acid cerium；
Preferably, the radical initiator is selected from least one of organic peroxide；
It is further preferred that the radical initiator is selected from acyl class peroxide, hydroperoxides, dialkyl group peroxidating At least one of object, esters peroxide, ketone peroxide, two carbonic ester peroxide；
It is further preferred that the radical initiator is selected from benzoyl peroxide, lauroyl peroxide, isopropylbenzene mistake Hydrogen oxide, tert-butyl hydroperoxide, di-t-butyl peroxide, peroxide acetic acid butyl ester, cumyl peroxide, benzoyl peroxide T-butyl formate, peroxidating trimethylacetic acid tertiary butyl ester, methyl ethyl ketone peroxide, cyclohexanone peroxide, dicetyl peroxydicarbonate diisopropyl At least one of ester, di-cyclohexylperoxy di-carbonate；
Preferably, the radical initiator is peroxidized t-butyl perbenzoate；
Preferably, the molar ratio of compound (II), compound (III), compound (IV), radical initiator, catalyst Example are as follows: 1:1~2:2~3:2~3:0.03~0.07；
Preferably, the reaction temperature of the reaction is -20 DEG C to 80 DEG C, and the reaction time is 0.5h to 12h；
Preferably, the temperature of the reaction is 0 DEG C to 50 DEG C, and the reaction time is 0.5h to 3h.
According to the present invention, in the step 2), it is preferred that the reaction carries out under catalyst, such as Cu (OAc)2Or Ortho-Aminophenol, the reaction carry out in a solvent, and the solvent may be, for example, methylene chloride or water etc..
The compounds of this invention is the regulator of beta interferon (IFN β), can increase or inhibit the secretion of beta interferon.With In adjusting immune system.
The present invention also provides a kind of pharmaceutical composition, comprising the logical formula (I) compound represented of the present invention and its raceme, Stereoisomer, tautomer, polymorph, solvate, its pharmaceutically acceptable salt.
According to the present invention, described pharmaceutical composition can also optionally include at least one pharmaceutically acceptable auxiliary material, such as Carrier, excipient etc..As example, the auxiliary material can be for selected from one of the following or a variety of: disintegrating agent, glidant, profit Lubrication prescription, diluent, filler, adhesive, colorant, effervescent agent, corrigent, preservative, coating material etc..
According to the present invention, described pharmaceutical composition can for include but is not limited to peroral dosage form, it is parenteral dosage forms, outer With the form of dosage form and forms for rectal administration.
In some embodiments, described pharmaceutical composition can be oral tablet, capsule, pill, pulvis, sustained release system Agent, solution and suspension, for the sterile solution, suspension or lotion of parental injection, or the suppository for rectally.
In other embodiments, described pharmaceutical composition is the unit dosage forms for being suitble to single to bestow exact dose.
In other embodiments, the amount of the compound about 0.001mg/kg body weight/day-about 1000mg/kg weight/ In the range of it.
In other embodiments, the range of the amount of the compound is about 0.1mg/kg body weight/day-about 50mg/kg body Weight/day.
In other embodiments, the range of the amount of the compound is about 0.1mg/kg body weight/day-about 10mg/kg body Weight/day.
In some embodiments, the compound is applied with single dose, once a day.
In other embodiments, the compound is applied with multi-dose, daily more than once.
In some embodiments, the compound twice is applied daily.
In other embodiments, the three times or more than three times compound of application daily.
In some embodiments, the individual that described pharmaceutical composition is applied to is mammal.
In other embodiments, the mammal is people.
In other embodiments, described pharmaceutical composition also includes that at least another therapeutic agent (is made a kind of dose Type).
In some embodiments, described pharmaceutical composition and at least one therapeutic agent respectively with independent dosage form combination at Combination product such as covers containing medicines (kit of part).
In some embodiments, described pharmaceutical composition contains the compound of the present invention and one or more interferon Regulator drug.
In some embodiments, the pharmaceutical composition is set with the pharmaceutical composition containing two or more independent packagings, The pharmaceutical composition of one of independent packaging contains new general formula compound, the pharmaceutical composition difference of remaining independent packaging Contain one or more interferon adjustment agent drug.
The present invention also provides logical formula (I) compound as above and its raceme, stereoisomer, tautomer, polymorphics Disease caused by object, solvate and its pharmaceutically acceptable salt or aforementioned pharmaceutical compositions are lacked of proper care in preparation treatment beta interferon Purposes in the drug of disease.According to the present invention, the disease is systemic loupus erythematosus, polyneuritis, teenager's glycosuria Disease, autoimmune hemolytic anemia, ulcerative colitis or rheumatoid arthritis etc..
The present invention also provides it is a kind of treat beta interferon imbalance method, including by interferon and it is a effective amount of on State compound or its pharmaceutically acceptable salt contact.
Preferably, this method can be used in vivo, can be used for external.
Specific dosage is selected and is adjusted according to patient's body tumour cell state and whole physical condition.
Term definition and explanation
Unless otherwise defined, the connotation that all scientific and technical terminologies have herein and claim theme fields technology The normally understood connotation of personnel is identical.Unless otherwise indicated, all patents, patent application, the public material being cited in full text herein It is integrally incorporated by reference herein.If there are multiple definition to term herein, it is subject to the definition of this chapter.
It should be understood that above-mentioned summary and being specified as exemplary and being only used for explaining hereafter, without appointing to subject matter What is limited.In this application, unless otherwise stated, "or" used, "or" indicate "and/or".In addition, term used " comprising " and other forms, for example, it is "comprising", " containing " and " containing " and non-limiting.
Term " alkyl " refers to 1-10 carbon atom, the linear or branched alkyl group of preferably 1-6 carbon atom, the alkyl For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, sec-butyl, amyl, neopentyl.
Term " alkenyl " refers to 2-10 carbon atom, the linear chain or branched chain alkenyl of preferably 2-6 carbon atom, the alkenyl For example, vinyl, acrylic, isopropenyl.
Term " alkynyl " refers to 2-10 carbon atom, the linear chain or branched chain alkynyl of preferably 2-6 carbon atom, the alkynyl For example, acetenyl, propinyl, butynyl.
Term " alkoxy " refers to 1-10 carbon atom, the straight or branched alkoxyl of preferably 1-6 carbon atom, such as Methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy.
Term " halogen " is fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine, bromine.
Term " aryl " is interpreted as the preferred monovalence armaticity for indicating to have 6~20 carbon atoms or partial aromatic Monocyclic, bicyclic or tricyclic hydrocarbon ring, preferably " C6-14Aryl ".Term " C6-14Aryl " be interpreted as it is preferred indicate to have 6,7,8,9, 10, monocyclic, bicyclic or tricyclic the hydrocarbon ring (" C of the monovalence armaticity of 11,12,13 or 14 carbon atoms or partial aromatic6-14Virtue Base "), especially with the ring (" C of 6 carbon atoms6Aryl "), such as phenyl；Or xenyl, or there are 9 carbon atoms Ring (" C9Aryl "), such as indanyl or indenyl, or the ring (" C with 10 carbon atoms10Aryl "), such as tetrahydro Naphthalene, ihydro naphthyl or naphthalene, or the ring (" C with 13 carbon atoms13Aryl "), such as fluorenyl, or have 14 The ring (" C of a carbon atom14Aryl "), such as anthryl.
Term " heteroaryl " is interpreted as containing 5-20 annular atom, 5-14 annular atom or 5-12 annular atom or 5- The monocycle of 10 annular atoms or 5-6 annular atom, bicyclic and three-ring system, wherein at least one ring system is aromatic, and At least one ring system includes one or more hetero atoms (such as N, O, S, Se etc.), and wherein each ring system includes 5-7 Former molecular ring, and there are one or more tie points to be connected with molecule rest part.The heteroaryl groups are optionally by one Replaced a or multiple substituent groups described in the invention.In some embodiments, 5-10 former molecular heteroaryl packet The hetero atom of O, S, Se and N are independently selected from containing 1,2,3 or 4.In other embodiments, 5-6 former molecular heteroaryl Base includes 1,2,3 or 4 hetero atoms for being independently selected from O, S, Se and N.
The Monocyclic examples of heteroaryl groups include, but is not limited to, thienyl, furyl, pyrrole radicals, oxazolyl, thiazole Base, imidazole radicals, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazoles base, triazolyl, thiadiazolyl group, thiophene -4H- pyrazolyl etc. with And their benzo derivative, such as benzofuranyl, benzothienyl, benzoxazolyl, benzo isoxazolyl, benzimidazole Base, benzotriazole base, indazolyl, indyl, isoindolyl etc.；Or pyridyl group, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical Deng and their benzo derivative, such as quinolyl, quinazolyl, isoquinolyl etc.；Or azocine base, indolizine base, purine Base etc. and their benzo derivative；Or cinnoline base, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridines base, pteridyl, carbazole Base, acridinyl, phenazinyl, phenothiazinyl, phenoxazine base etc..
Term " heterocycle " means monocycle, bicyclic or three-ring system, and one or more atoms are individually optionally in middle ring Replaced hetero atom, ring can be fully saturated or comprising one or more degrees of unsaturation, but is not aromatic, there is one A or multiple tie points are connected to other molecules up.Hydrogen atom on one or more rings can it is independently unsubstituted or by Replaced one or more substituent groups described in the invention.Some of embodiments are that " heterocycle " is 3-7 atom composition Monocycle or 7-10 it is former molecular bicyclic, it includes 1-5, preferably 1-3 are selected from the hetero atoms of N, O, S and Se.It is special Not, the heterocycle can include but is not limited to: 4 member rings, such as azetidinyl, oxetanyl；5 member rings, such as four Hydrogen furyl, dioxa cyclopentenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl；Or 6 member rings, such as tetrahydro pyrrole It mutters base, piperidyl, morpholinyl, dithianyl, thio-morpholinyl, piperazinyl or trithiane base；Or 7 member rings, such as diaza cycloheptyl Alkyl.Optionally, the heterocycle can be benzo-fused.The heterocycle can be it is bicyclic, such as, but not limited to 5,5 Member ring, such as hexahydro cyclopentano [c] pyrroles -2 (1H)-basic ring or 5,6 membered bicyclics, such as hexahydropyrrolo simultaneously [1,2-a] pyrazine -2 (1H)-basic ring.The ring of nitrogen atom can be that part is unsaturated, i.e., it may include one or more double bonds, such as but not It is limited to 2,5- dihydro -1H- pyrrole radicals, 4H- [1,3,4] thiadiazine base, 4,5- dihydro-oxazole base or 4H- [Isosorbide-5-Nitrae] thiazinyl, or Person, it can be benzo-fused, such as, but not limited to dihydro-isoquinoline base, 1,3- benzoxazolyl, 1,3- benzo dioxa Cyclopentenyl.
Unless otherwise indicated, heterocycle, heteroaryl include its all possible isomeric form, such as its position isomer. Therefore, for some illustrative non-limiting examples, pyridyl group or sub-pyridyl group include pyridine -2- base, Asia pyridine -2- base, Pyridin-3-yl, sub- pyridin-3-yl, pyridin-4-yl and sub- pyridin-4-yl；Thienyl or sub- thienyl include thiophene -2- base, Asia Thiophene -2- base, thiene-3-yl and sub- thiene-3-yl.
According to molecular structure, the compound of the present invention can be chiral, it is thus possible to which there are the various enantiomerism bodily forms Formula.Thus these compounds can exist with racemate form or optical active forms.The compound of the present invention or in which mesosome It can be by the way that well known to a person skilled in the art chemically or physically methods to be separated into enantiomter compound, or in this format For synthesizing.In the case where racemic, by reacting with optically active resolution reagent, diastereo-isomerism is made from mixture Body.The example of resolution reagent appropriate is optically active acid, such as R and the tartaric acid of S-shaped formula, diacetyl tartaric acid, hexichol Formyl tartaric acid, mandelic acid, malic acid, lactic acid, N-protected appropriate amino acid (such as N- benzoyl proline or N- benzene sulphur Acyl-proline) or various optically active camphorsulfonic acids.By optically active resolution reagent (such as it is fixed on silica gel The derivative or chiral derivatizing different of dinitrobenzoyl phenylglycine, cellulose triacetate or other carbohydrate Butenoate polymer), it can also advantageously carry out chromatography Chiral Separation.Eluant, eluent appropriate for this purpose be it is aqueous or The solvent mixture of alcohol-containing, for example, hexane/isopropyl alcohol/acetonitrile.
Term " tautomer " refers to the functional group because atom a certain in molecule generates due to two positions are moved rapidly Isomers.The compounds of this invention can express tautomerism.Tautomeric compound can there may be two or more The type mutually converted.The migration of prototropictautomer hydrogen atom of covalent bonding between two atoms.Interconversion Isomers generally exists with equilibrium form, attempts to generally produce a kind of mixture, physics and chemistry when separating single tautomer The mixture of matter and compound is consistent.The position of balance depends on the chemical characteristic of intramolecular.For example, in many aliphatic aldehydes In ketone such as acetaldehyde, ketone type is dominant；And in phenol, enol form is dominant.The present invention includes all tautomerisms of compound Form.
Term " solvate ", " polymorphic " refer to any possible solvate and polymorphic.Form the molten of solvate There is no particular limitation for agent type, as long as the solvent is pharmacologically acceptable.For example, water, ethyl alcohol, propyl alcohol, acetone etc. Similar solvent can use.
Related term " subject ", " patient " or " individual " used herein refers to disease, illness or the patient's condition etc. Individual, including mammal and nonmammalian.The embodiment of mammal include but is not limited to class of mammals it is any at Member: people, inhuman primate (such as chimpanzee and other apes and monkey)；Domestic animal, such as ox, horse, sheep, goat, pig； Domestic animal, such as rabbit, dog and cat；Laboratory animal, including rodent, such as rat, mouse and cavy etc..The inhuman food in one's mouth The embodiment of newborn animal includes but is not limited to birds and fish etc..In the implementation of a method and composition provided herein In mode, the mammal is behaved.
The term as used herein " treatment " includes alleviating, mitigate or improving disease or illness disease with other similar synonyms Shape prevents other symptoms, improves or prevents the potential metabolism reason for leading to symptom, inhibit disease or illness, such as prevent disease Or the development of illness, alleviate disease or illness, disease or illness is made to improve, alleviates the symptom as caused by disease or illness, or Stop the symptom of disease or illness, in addition, the term includes the purpose of prevention.The term further include obtain therapeutic effect and/or Preventive effect.The therapeutic effect refers to the potential disease that healing or improvement are treated.In addition, to relevant to potential disease one The healing or improvement of kind or a variety of physiological signs are also therapeutic effect, such as although patient may nevertheless suffer from the shadow of potential disease It rings, but observes that patient profiles improve.For preventive effect, described group can be applied to the patient for suffering from specified disease risk Close object, even if not yet make medical diagnosis on disease, but apply institute to the patient for one or more physiological signs of the disease occur State composition.
Term " effective quantity ", " therapeutically effective amount " or " pharmacy effective dose " used herein, which refers to, takes metapedes at certain Alleviate at least one medicament of one or more symptoms of treated disease or illness or the amount of compound in degree.Its result It can be sign, the abatement of symptom or the cause of disease and/or alleviation or any other required variation of biosystem.For example, for controlling " effective quantity " treated is the composition needed for clinically providing significant remission effect comprising compound is disclosed herein Amount.The technology of such as dose escalation trial can be used to measure the effective quantity being suitable in any individual case.
Terms used herein " taking ", " application ", " administration " etc. are to refer to for compound or composition to be delivered to progress The method in the required site of biological effect.These methods include but is not limited to oral route, through intraduodenal routes, parenteral note Penetrate (including in intravenous, subcutaneous, peritonaeum, intramuscular, intra-arterial injection or infusion), external application and per rectum administration.Art technology It can be used for the application technique of Compounds and methods for described herein known to personnel.In a preferred embodiment, the change being discussed herein It closes object and composition passes through oral administration.
Refer to herein for term used in preparation, composition or ingredient " acceptable " and docks the one of treated subject As the not long-term adverse effect of health condition.
Terms used herein " pharmaceutically acceptable " refers to the bioactivity or property for not influencing the application compound Substance (such as carrier or diluent), and relative nontoxic, the i.e. substance can be applied to individual without causing undesirable biological respinse Or it is interacted in a manner of bad with any component for including in composition.
Terms used herein " pharmaceutical composition " refer to be optionally mixed at least one pharmaceutically acceptable chemistry at Point bioactive compound, the pharmaceutically acceptable chemical component include but is not limited to carrier, stabilizer, diluent, Dispersing agent, suspending agent, thickener and/or excipient.
Terms used herein " carrier " refers to the chemical compound or reagent of relative nontoxic, helps to introduce compound Into cell or tissue.
Terms used herein " pharmaceutically acceptable salt " refers to the free acid and free alkali for remaining appointed compound Biopotency, and biologically or otherwise on not no ill-effect salt.The example of pharmaceutically acceptable salt includes But it is not limited to, the inorganic acid salt or acylate of alkaline residue (such as amine), the basic salt or organic of acidic residues (such as carboxylic acid) Salt, etc..Pharmaceutically acceptable salt includes the conventional nothing of the parent compound formed by such as avirulent inorganic or organic acid The salt or quaternary ammonium salt of toxicity.For example, these conventional non-toxic salts include salt that those are originated from inorganic acid, as hydrochloric acid, hydrobromic acid, Sulfuric acid, sulfamic acid, phosphoric acid, nitric acid etc.；And by organic acid prepare salt, e.g., acetic acid, propionic acid, succinic acid, hydroxyacetic acid, Lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, methanesulfonic acid, toluenesulfonic acid, salicylic acid, p-aminobenzene sulfonic acid etc..
Pharmaceutically acceptable salt of the invention can be by conventional chemical method from containing alkaline or acidic moiety Parent compound synthesis.In general, this salt can by make these compounds free acid or alkali form and stoichiometry it is suitable When alkali or acid preparation is reacted in the mixture of water or organic solvent or both.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments cannot function as Limiting the scope of the invention, any improvement made on the basis of the present invention is all without prejudice to spirit of the invention.
Wherein, the synthesis process of intermediate and target compound is with the representative explanation in embodiment, remaining intermediate With the same representation compound of synthesis process of target compound.
TMS is trimethyl silicon substrate, and TBPB is the benzoic acid peroxide tert-butyl ester, and Tf is trifluoromethanesulfonic acid root, and DCM is dichloromethane Alkane.
Embodiment 1
Under nitrogen protection, by Fe (OTf)2(0.025mmol) is added in the reaction tube of 25mL, vacuumizes, nitrogen displacement Three times, by glycol dimethyl ether (2ml), 1- phenyl-acrylic acid methyl esters (0.5mmol), trifluoroiodomethane (1.5mmol), TMSN3 (1.7mmol), TBPB (1.75mmol) are added in reaction tube, react at room temperature 2 hours, and after completion of the reaction, ethyl acetate dilutes, Silica gel quickly filters, and after solvent is removed under reduced pressure in Rotary Evaporators, column chromatography for separation obtains product (CS-1).Physicochemical data is referring to table 1。
Embodiment 2
Under nitrogen protection, by Fe (OTf)2(0.025mmol) is added in the reaction tube of 25mL, vacuumizes, nitrogen displacement Three times, by glycol dimethyl ether (2ml), 1- (3,4- dichlorophenyl)-methyl acrylate (0.5mmol), nine fluorine iodobutanes (1.5mmol), TMSN3(1.7mmol), TBPB (1.75mmol) are added in reaction tube, react 2 hours at room temperature, end of reaction Afterwards, ethyl acetate dilutes, and silica gel quickly filters, and after solvent is removed under reduced pressure in Rotary Evaporators, column chromatography for separation obtains Product samples note For CS-9.Physicochemical data is referring to table 1.
Embodiment 3
Under nitrogen protection, by Fe (OTf)2(0.025mmol) is added in the reaction tube of 25mL, vacuumizes, nitrogen displacement Three times, by glycol dimethyl ether (2ml), chalkone (0.5mmol), pentafluoroiodoethane (1.5mmol), TMSN3 (1.7mmol), TBPB (1.75mmol) are added in reaction tube, react at room temperature 2 hours, and after completion of the reaction, ethyl acetate dilutes, Silica gel quickly filters, and after solvent is removed under reduced pressure in Rotary Evaporators, column chromatography for separation obtains product CS-48.What physical and chemical parameter was seen below Table 1.
Similar method in accordance with the above-mentioned embodiment 1, prepares preferred formula (I) compound represented, preferred compound with And its NMR data see the table below:
Table 1- preferred compound structure, number and physicochemical data
Embodiment 4
Under nitrogen protection, by Cu (OAc)2·H2O (0.01mmol) and Ortho-Aminophenol (0.005mmol) are added to It in the reaction flask of 10mL, vacuumizes, nitrogen is replaced three times, by DCM (0.2ml), H2O (0.2ml), compound (CS-34) (0.1mmol), phenylacetylene (0.1mmol) are added in reaction flask, react 12 hours, after completion of the reaction, ethyl acetate extraction at room temperature It after taking, is dried, filtered with magnesium sulfate, after solvent is removed under reduced pressure in Rotary Evaporators, column chromatography for separation obtains product CS-58.Data ginseng It is shown in Table 2.
According to the similar method of above-described embodiment 4, prepare preferred formula (I) compound represented, preferred compound with And its physicochemical data see the table below 2:
Table 2- preferred compound structure, number and its physicochemical data
5 biological activity determination of embodiment
Above-described embodiment 1 to 4 is made on high-throughput real-time fluorescence quantitative PCR instrument (QuantStudio 6Flex, ABI) The bioactivity of standby obtained compound is determined, using RAWBlue cell, to detect beta interferon (IFN β) activity Variation.Specific steps are as follows:
(1) cell (culture solution containing 1mL) of the above compound 1ul to bed board in advance of 1mM (DMSO is solvent) is taken Carry out pretreatment 60min.
(2) it is stimulated cell 6 hours with HT-DNA or Poly (I:C) respectively after replacing culture solution.
(3) to post-stimulatory cell extraction RNA and by its reverse transcription be cDNA.
(4) using IFN-β and CXCL10 in QRT-PCR detection cell mRNA level in-site relative expression.
As a result referring to following Table 3.
3 compound of table stress level of inflammation

Claims (10)

1. a kind of logical formula (I) compound and its raceme, stereoisomer, tautomer, polymorph, solvate or The structure of their pharmaceutically acceptable salts, the compound is as follows:
Wherein, R1For aryl, heteroaryl, the aryl, heteroaryl are optionally by one or more RaSubstituent group replaces, the RaAre as follows: Halogen, alkyl, alkenyl, alkynyl, naphthenic base, aryl, heteroaryl, heterocycle ,-CN ,-NO2, oxo ,-CO-R10、-COO-R11、- NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15, boronate, silylation；Above-mentioned RaAlkyl in substituent group, Alkenyl, alkynyl, naphthenic base, aryl, heteroaryl, heterocycle can optionally be replaced by following group: halogen, alkyl, aryl, heteroaryl Base ,-CN ,-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15；
R2For-(CH2)0-4CO-R7,-SO2-R8,-PO- (R9)2,-CN ,-NO2, R7、R8、R9For alkyl, alkenyl, alkynyl, naphthenic base, Aryl, heteroaryl, heterocycle ,-NR12R13、-NH-CO-R10、-NH-COO-R11、-OR14, wherein the alkyl, alkenyl, alkynyl, Naphthenic base, aryl, heteroaryl, heterocycle can optionally be replaced by following group: halogen, alkyl, aryl, heteroaryl, heterocycle Base ,-CN ,-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15；
R4For halogen, alkyl, alkenyl, alkynyl ,-alkyl-O-CO- alkyl ,-alkyl-O- alkyl ,-alkyl-CO- alkyl, alkyl- COO- alkyl, abovementioned alkyl, alkenyl, at least one H atom is optionally substituted by halogen in alkynyl；
R3、R6Identical or different, independent to be selected from H, halogen, hydroxyl, alkyl, aryl, alkyl, aryl in above-mentioned group can be with Replaced by following one or more substituent groups: halogen, hydroxyl, alkyl, alkoxy ,-CO- alkyl ,-O-CO- alkyl ,-COO- alkane Base；
R5For N3OrR5' be halogen, alkyl, alkenyl, alkynyl, naphthenic base, aryl, heteroaryl, heterocycle ,- CN、-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15, boric acid Base, silylation；Wherein the alkyl, alkenyl, alkynyl, naphthenic base, aryl, heteroaryl, heterocycle can be optionally by following bases Group replaces: halogen, alkyl, aryl, heteroaryl, heterocycle ,-CN ,-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、- NH-COO-R11、-NR12R13、-OR14、-SO2-R15；
R10、R11、R12、R13、R14、R15It may be the same or different, independently selected from H, alkyl, aryl, heteroaryl, heterocycle；It is above-mentioned Alkyl, aryl, heteroaryl, heterocycle can also be replaced following groups: halogen, alkyl, aryl, heteroaryl, heterocycle ,- CN、-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15；
The compound is not following particular compound:
2. compound according to claim 1, wherein R1For aryl, such as phenyl, naphthalene etc.；Or R1For heteroaryl, Such as thienyl, benzothienyl, furyl, benzofuranyl.
Preferably, R2For-(CH2)0-4CO-R7, for example,-CO-R7、-CH2-CO-R7、-CH2-CH2-CO-R7；
Preferably, R7For alkyl, aryl, heteroaryl ,-O- alkyl ,-O- aryl ,-O- heteroaryl, wherein the alkyl, aryl, miscellaneous Aryl can optionally be replaced by following group: halogen, alkyl, aryl, heteroaryl, heterocycle ,-CN ,-NO2, oxo ,-CO- R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14；
Preferably, R4For perfluoroalkyl ,-perfluoroalkyl-O-CO- alkyl ,-perfluoroalkyl-O- alkyl ,-perfluoroalkyl-CO- alkane Base ,-perfluoroalkyl-COO- alkyl.
3. compound according to claim 1, wherein R5For N3OrThe R5' be halogen, replace or not Substituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl ,-CN ,-NO2、-CO-R10、-COO-R11、- NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14, the substituent group is halogen, alkyl ,-CN ,-NO2, oxo ,-CO- R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14。
4. compound according to claim 1, wherein the compound is selected from following particular compound:
5. a kind of preparation method of any one of claim 1-4 compound, comprising:
Wherein, X is halogen, and R ' is identical or different, is optionally alkyl, R1-R4、R5’、R6As defined above；
1) formula (II) compound is reacted with formula (III) compound, formula (IV) compound, obtains general formula (I-1) compound, That is R5For N3Logical formula (I) compound；
2) optionally, general formula (I-1) compound is reacted with formula (V) compound, obtains general formula (I-2) compound, i.e. R5ForLogical formula (I) compound；
Optionally, the formula (I) compound and pharmaceutically acceptable organic acid or inorganic acid reaction are obtained shown in formula (I) Pharmaceutically acceptable salt；
6. a kind of pharmaceutical composition includes logical formula (I) compound represented as follows and its raceme, stereoisomer, mutually variation Structure body, polymorph, solvate or their pharmaceutically acceptable salts, the structure of the compound are as follows:
Wherein, R1For aryl, heteroaryl, the aryl, heteroaryl are optionally by one or more RaSubstituent group replaces, the RaAre as follows: Halogen, alkyl, alkenyl, alkynyl, naphthenic base, aryl, heteroaryl, heterocycle ,-CN ,-NO2, oxo ,-CO-R10、-COO-R11、- NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15, boronate, silylation；Above-mentioned RaAlkyl in substituent group, Alkenyl, alkynyl, naphthenic base, aryl, heteroaryl, heterocycle can optionally be replaced by following group: halogen, alkyl, aryl, heteroaryl Base ,-CN ,-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15；
R2For-(CH2)0-4CO-R7,-SO2-R8,-PO- (R9)2,-CN ,-NO2, R7、R8、R9For alkyl, alkenyl, alkynyl, naphthenic base, Aryl, heteroaryl, heterocycle ,-NR12R13、-NH-CO-R10、-NH-COO-R11、-OR14, wherein the alkyl, alkenyl, alkynyl, Naphthenic base, aryl, heteroaryl, heterocycle can optionally be replaced by following group: halogen, alkyl, aryl, heteroaryl, heterocycle Base ,-CN ,-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15；
R4For halogen, alkyl, alkenyl, alkynyl ,-alkyl-O-CO- alkyl ,-alkyl-O- alkyl ,-alkyl-CO- alkyl, alkyl- COO- alkyl, abovementioned alkyl, alkenyl, at least one H atom is optionally substituted by halogen in alkynyl；
R3、R6Identical or different, independent to be selected from H, halogen, hydroxyl, alkyl, aryl, alkyl, aryl in above-mentioned group can be with Replaced by following one or more substituent groups: halogen, hydroxyl, alkyl, alkoxy ,-CO- alkyl ,-O-CO- alkyl ,-COO- alkane Base；
R5For N3OrR5' be halogen, alkyl, alkenyl, alkynyl, naphthenic base, aryl, heteroaryl, heterocycle ,- CN、-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15, boric acid Base, silylation；Wherein the alkyl, alkenyl, alkynyl, naphthenic base, aryl, heteroaryl, heterocycle can be optionally by following bases Group replaces: halogen, alkyl, aryl, heteroaryl, heterocycle ,-CN ,-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、- NH-COO-R11、-NR12R13、-OR14、-SO2-R15；
R10、R11、R12、R13、R14、R15It may be the same or different, independently selected from H, alkyl, aryl, heteroaryl, heterocycle；It is above-mentioned Alkyl, aryl, heteroaryl, heterocycle can also be replaced following groups: halogen, alkyl, aryl, heteroaryl, heterocycle ,- CN、-NO2, oxo ,-CO-R10、-COO-R11、-NH-CO-R10、-NH-COO-R11、-NR12R13、-OR14、-SO2-R15。
7. pharmaceutical composition as claimed in claim 6, wherein described pharmaceutical composition can also be optionally comprising at least one pharmacy Upper acceptable auxiliary material, such as carrier, excipient etc.；As example, the auxiliary material can be for selected from one of the following or more Kind: disintegrating agent, glidant, lubricant, diluent, filler, adhesive, colorant, effervescent agent, corrigent, preservative, coating Material etc..
8. pharmaceutical composition as claimed in claim 7, wherein described pharmaceutical composition be peroral dosage form, parenteral dosage forms, The form of exterior-applied formulation and forms for rectal administration；
Preferably, described pharmaceutical composition can be oral tablet, capsule, pill, pulvis, sustained release preparation, solution and suspension Liquid, for the sterile solution, suspension or lotion of parental injection, or the suppository for rectally；
Preferably, the amount of the compound is in the range of about 0.001mg/kg body weight/day-about 1000mg/kg body weight/day.
Preferably, the range of the amount of the compound is about 0.1mg/kg body weight/day-about 50mg/kg body weight/day.
Preferably, described pharmaceutical composition also includes one or more interferon regulation agent drugs.
9. logical formula (I) compound and its raceme, stereoisomer, tautomer, polymorphic described in claim 5 Pharmaceutical composition described in object, solvate, its pharmaceutically acceptable salt or claim 5 is in preparation treatment beta interferon imbalance Purposes in the drug of caused disease.
10. purposes according to claim 9, the disease is systemic loupus erythematosus, polyneuritis, teenager's glycosuria Disease, autoimmune hemolytic anemia, ulcerative colitis or rheumatoid arthritis etc..
CN201711408870.2A 2017-08-23 2017-12-22 Interferon regulator and its prepn and use Active CN109422664B (en)

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CN113354495A (en) * 2021-05-20 2021-09-07 上海应用技术大学 Difluorone carbonyl substituted asymmetric nitrile compound and preparation and application thereof

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