CN107827837A - Phosphate receptor modulators compound of sphingol 1 and preparation method and application - Google Patents
Phosphate receptor modulators compound of sphingol 1 and preparation method and application Download PDFInfo
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- 0 *Cc(cc1)ccc1-c1n[o]c(-c(cc2)cc(*)c2OI)n1 Chemical compound *Cc(cc1)ccc1-c1n[o]c(-c(cc2)cc(*)c2OI)n1 0.000 description 1
- BRYSNQPDBAGQEQ-UHFFFAOYSA-N N#Cc(cc(cc1)-c2nc(-c3ccc(CN4CCC(CC(O)=O)CC4)cc3)n[o]2)c1OC1CCCC1 Chemical compound N#Cc(cc(cc1)-c2nc(-c3ccc(CN4CCC(CC(O)=O)CC4)cc3)n[o]2)c1OC1CCCC1 BRYSNQPDBAGQEQ-UHFFFAOYSA-N 0.000 description 1
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- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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Abstract
The present invention relates to phosphate receptor modulators compound of sphingol 1 and preparation method and application.Specifically provide compound shown in lower formula (I), its raceme, stereoisomer, dynamic isomer, solvate, hydrate or their pharmaceutically acceptable salts：
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to sphingosine-1-phosphate receptor modulators compound and its preparation
Method and application.
Background technology
Sphingosine-1-phosphate (Sphingosine-1-phosphate, S1P) is the metabolite of sphingomyelins, participates in cell
Growth, propagation, the process such as migration.S1P acceptors belong to g protein coupled receptor, including S1P1、S1P2、S1P3、S1P4、S1P5Five
Kind hypotype.Wherein, S1P1Receptor stimulating agent can reduce PBLC quantity, play immunoregulation effect.First listing
S1P receptor stimulating agent medicine FTY720s (Fingolimod, FTY720) in the pathology mould of various autoimmune disease
It is proved to validity, the clinical granted treatment for multiple sclerosis in type.But the medicine is for the multiple of S1P acceptors
Hypotype is respectively provided with agonism, and it is to S1P3The agonism of acceptor has triggered the side effect of bradycardia, causes it in clinic
On application be restricted.Therefore, it is necessary to develop with S1P1The immunomodulator of receptor-selective.
The content of the invention
In order to solve the above problems, the present invention provides compound shown in a kind of formula (I), its raceme, stereoisomer, mutually
Tautomeric, solvate, hydrate or their pharmaceutically acceptable salts：
Wherein, R1Selected from H, unsubstituted or by one or more RaSubstituted following groups：C1-8Alkyl, C3-8It is cycloalkyl, miscellaneous
Ring group, aryl or heteroaryl；
R2For-CN；
R3Selected from-NR '2Or azepine C3-8Cycloalkyl；Wherein, the azepine C3-8Cycloalkyl is by one or more-R6COOR7
Substituted；R ' may be the same or different, optionally：H、C1-8Alkyl ,-R6COOR7, wherein, at least one in R ' is-R6COOR7；
Wherein, R6Selected from chemical bond or C1-8Alkylidene, R7Selected from H or C1-8Alkyl；
RaSelected from-F ,-Cl ,-Br ,-I ,-CN ,-OH ,=O or under being substituted by-F ,-Cl ,-Br ,-I ,-CN ,-OH ,=O
Row group：C1-8Alkyl, C3-8Cycloalkyl, heterocyclic radical, aryl or heteroaryl.
According to the embodiment of the compounds of this invention, wherein R1Selected from unsubstituted or by one or more RaWhat is substituted is following
Group：C1-6Alkyl, C3-6Cycloalkyl；The RaSelected from-F ,-Cl ,-Br ,-I ,-CN or by-F ,-Cl ,-Br ,-I ,-CN substitution
Following groups：C1-6Alkyl, C3-6Cycloalkyl；
As example, R1Selected from unsubstituted or by one or more RaSubstituted following groups：Methyl, ethyl, n-propyl,
Isopropyl, cyclopropyl, normal-butyl, isobutyl group, the tert-butyl group, cyclobutyl, n-pentyl, isopentyl, cyclopenta, n-hexyl, isohesyl,
Cyclohexyl；The RaSelected from-F ,-Cl ,-Br ,-I or-CN；
As example, R3It is selected fromWherein R4、R5Selected from H or C1-6Alkyl；L
Selected from C1-6Alkylidene, m and n are identical or different, are independently from each other 1-3 integer, R6Selected from chemical bond or C1-8Alkylidene；
As example, R3Selected from-azelidinyl-R6COOR7,-azepine cyclopenta-R6COOR7Or-piperidyl-
R6COOR7。
According to the embodiment of the compounds of this invention, the compound pharmaceutically acceptable salt is selected from inorganic acid or organic
Acid and the salt that can be formed in compound into salt site (such as on salifiable N)；
The inorganic acid includes but is not limited to：Hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, hydrofluoric acid, hydroiodic acid, pyrosulfuric acid or nitre
Acid；
The organic acid includes but is not limited to：Citric acid, maleic acid, butanedioic acid, acetic acid, malic acid, tartaric acid, first sulphur
Acid, benzene sulfonic acid, formic acid, acetoacetate, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, hendecanoic acid, laurate,
Benzoic acid, salicylic acid, 2- (4- hydroxy benzoyls) benzoic acid, camphoric acid, cinnamic acid, pentamethylene propionic acid, didextrose acid, 3- hydroxyls
Base -2- naphthoic acids, nicotinic acid, flutter acid, pectinic acid, persulfuric acid, 3- phenylpropionic acids, picric acid, pivalic acid, 2- ethylenehydrinsulfonic acids,
Itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulphate, ethyl sulfonic acid, p-methyl benzenesulfonic acid, 2- naphthalene sulfonic acids, naphthalenedisulfonic acid,
Camphorsulfonic acid, stearic acid, lactic acid, oxalic acid, malonic acid, adipic acid, alginic acid, fumaric acid, D- gluconic acids, mandelic acid, ascorbic acid,
Glucoheptose, phosphoglycerol, aspartic acid, sulfosalicylic acid, hemisulfic acid or thiocyanic acid.
Preferably, the compound pharmaceutically acceptable salt is selected from hydrochloride.
As the present invention a kind of embodiment, formula (I) compound be selected from including but not limited to following compound or
Its salt：
The present invention also provides the preparation method of compound shown in the formula (I), and the preparation method comprises the following steps：Will
Formula (I-4) compound reacts to obtain formula (I) compound with formula (I-5) compound
Wherein, R1、R2、R3With definition described above.
Preferably, R is worked as3In group R7For alkyl when, resulting formula (I) compound can be hydrolyzed, reaction obtains
R7For H formula (I) compound.
Preferably, formula (I-4) compound can be prepared by the following method, including：
Wherein, R1、R2、R3With definition described above；
1) by 4- cyanobenzaldehydes and glycol reaction, formula (I-1) compound is obtained；
2) formula (I-1) compound obtained step 1) is reacted with hydroxylamine hydrochloride, obtains formula (I-2) compound；
3) formula (I-2) compound obtained step 2) is reacted with formula (II) compound, obtains formula (I-3) compound, so
Reaction obtains formula (I-4) compound in acid condition afterwards.
Optionally, the preparation method, which also includes with salt-forming reagent reacting formula (I) compound, to form it and can pharmaceutically connect
By salt.
Preferably, the salt-forming reagent can be organic acid or inorganic acid；
The organic acid or inorganic acid have definition described above, such as the inorganic acid is selected from hydrochloric acid or its solution.
, can be by any functional group in formula (II), formula (I-3), formula (I-4), formula (I-5) compound if necessary to protect
Protected, afterwards if it is necessary, removing protection group again.
Heretofore described " the compounds of this invention " includes formula (I) compound, its raceme, stereoisomer, change
One or more in isomers, solvate, hydrate or its pharmaceutically acceptable salt.
The present invention also provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the chemical combination of the present invention of therapeutically effective amount
Thing.
Preferably, described pharmaceutical composition also includes pharmaceutical acceptable carrier.
Described pharmaceutical acceptable carrier includes but is not limited to：Filler, diluent, disintegrant, lubricant, glidant, adhesive,
Solubilizer, surfactant, emulsifying agent, preservative, antioxidant, flavouring, colouring agent, osmotic pressure regulator, pH adjusting agent, branch
Support the one or more in agent.
Preferably, in described pharmaceutical composition, the quality of the compounds of this invention accounts for the 0.01- of pharmaceutical composition gross mass
99.99%.
Preferably, described pharmaceutical composition can be used alone, and can also be used in conjunction with other therapies or pharmaceutical preparation,
Its dosage and the frequency according to method of administration, the type of illness, patient age and whether take the factors such as other drugs
It is comprehensive to determine.In general, dosage range is daily per kilogram of body weight 0.001mg to 100mg, required dosage is with daily single agent
Amount or fractionated dose form provide.
Described pharmaceutical composition can by it is oral, the mode such as inject, infuse, instill, suck or stick and be administered.
The present invention also provides a kind of preparation for including pharmaceutical composition as described above.
The formulation of the preparation includes but is not limited to：Liquid dosage form, solid dosage forms or semisolid dosage form.
The liquid dosage form can be oral solution formulation, injection, infusion solution, lotion, drops, liniment, aerosol etc.；
The solid dosage forms can be tablet, capsule, granule, powder, pulvis, pill, suppository, patch etc.；The semi-solid agent
Type can be ointment, gel, paste etc..
The formulation also includes ordinary preparation, sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery systems.
The present invention also provides one kind and treats S1P1The method of the related illness of acceptor, including individuals in need is given
The compounds of this invention of therapeutically effective amount or its pharmaceutical composition.
The S1P1The related illness of acceptor includes but is not limited to：Autoimmune disease, the disease of cell mediated,
Inflammatory disease, bacterium infection, fungal infection, virus infection or cancer etc..
As an example, the treatment method is by the compounds of this invention of therapeutically effective amount as described above or its medicine group
Compound be applied to multiple sclerosis, and/or inflammatory enteritis, and/or Crohn disease, and/or ulcerative colitis,
And/or systemic loupus erythematosus, and/or rheumatoid arthritis, and/or the individual of psoriasis, and/or graft rejection.
It is described that to have individual can be the mankind or other mammals.
The present invention also provides the compounds of this invention or its pharmaceutical composition and prepared for treating S1P1Receptor associate disorder
Medicine in purposes.
The S1P1The related illness of acceptor includes but is not limited to：Autoimmune disease, the disease of cell mediated,
Inflammatory disease, bacterium infection, fungal infection, virus infection or cancer etc..
Preferably, the purposes can be to prepare treatment inflammatory enteritis, and/or Crohn disease, and/or exedens knot
Enteritis, and/or systemic loupus erythematosus, and/or rheumatoid arthritis, and/or psoriasis, and/or multiple sclerosis,
And/or the purposes in graft rejection medicine.
Beneficial effect：
The invention provides a kind of S1P with brand new1Receptor modulators, such compound and have been reported
S1P1Receptor modulator compounds are compared, for S1P1The exciting intensity and selectivity of acceptor are improved, and to S1P3Almost do not have
There is agonist activity, and there is higher immunosuppressive activity and metabolic stability, such as the percentage that lymphocyte reduces can be with
More than 60%.In biological activity test, the compound is proved to have obvious therapeutic effect for ulcerative colitis
And there is bioavilability inside suitable, S1P can be turned into1The medicine of receptor associated diseases.
Term defines and explanation：
Unless otherwise defined, the connotation that otherwise all scientific and technical terminologies have herein and claim theme art technology
The connotation that personnel are generally understood that is identical.It should be understood that above-mentioned summary and being specified as exemplary and being only used for explaining hereafter, without right
Subject matter imposes any restrictions.In this application, unless otherwise stated, "or" used, "or" represent "and/or".
In addition, term " comprising " used and other forms, for example, it is "comprising", " containing " and " containing " and non-limiting.
Term " alkyl " refers to, the straight or branched alkyl of preferably 1-6 carbon atom individual with 1-8, and the alkyl is, for example,
Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl.
Term " aryl " is interpreted as the preferred monovalence armaticity represented with 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 represent with 6,7,8,9,
10th, 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 "), particularly the ring (" C with 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
Naphthyl, ihydro naphthyl or naphthyl, or the ring (" C with 13 carbon atoms13Aryl "), such as fluorenyl, or with 14
The ring (" C of individual 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-
10 annular atoms, or monocyclic, the bicyclic and three-ring system of 5-6 annular atom, wherein at least one member ring systems are aromatic, and
At least one member ring systems include one or more hetero atoms (such as N, O, S, Se etc.), and each of which member ring systems include 5-7
Former molecular ring, and there are one or more tie points to be connected with molecule remainder.The heteroaryl groups are optionally by one
Individual or multiple substituents described in the invention are substituted.In some embodiments, 5-10 former molecular heteroaryl bag
Containing 1,2,3 or 4 hetero atoms for being independently selected from O, S, Se and N.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, oxazolyls, thiazole
Base, imidazole radicals, pyrazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, triazolyl, thiadiazolyl group, thiophene -4H- pyrazolyls etc. with
And their benzo derivative, such as benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazole base, benzimidazole
Base, BTA base, indazolyl, indyl, isoindolyl etc.；Or pyridine radicals, 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 cinnolines base, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridines base, pteridyl, carbazole
Base, acridinyl, phenazinyl, phenothiazinyl, phenoxazine groups etc..
Term " heterocyclic radical " means monocyclic, bicyclic or three-ring system, and one or more atoms are individually optionally in its middle ring
Substituted by hetero atom, ring can be fully saturated or comprising one or more degrees of unsaturation, but not be the fragrant same clan, there is one
Individual or multiple tie points are connected to other molecules up.One or more ring hydrogen atoms can it is independently unsubstituted or by
One or more substituents described in the invention are substituted.Some of embodiments are that " heterocyclic radical " is 3-7 atom composition
It is monocyclic or 7-10 former molecular bicyclic, it includes 1-5, the preferably 1-3 hetero atoms for being selected from N, O, S and Se.It is special
Not, the heterocyclic radical can include but is not limited to：4 yuan of rings, such as azetidinyl, oxetanyl；5 yuan of rings, such as four
Hydrogen furyl, dioxa cyclopentenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl；Or 6 yuan of rings, such as tetrahydrochysene pyrrole
Mutter base, piperidyl, morpholinyl, dithiane base, thio-morpholinyl, piperazinyl or trithiane base；Or 7 yuan of rings, such as diaza cycloheptyl
Alkyl.Optionally, the heterocyclic radical can be benzo-fused.The heterocyclic radical can be it is bicyclic, such as, but not limited to 5,5
Yuan of rings, 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 undersaturated, i.e., it can 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-oxazoles 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- benzoxazolyls, 1,3- benzo dioxas
Cyclopentenyl.
Unless otherwise indicated, heterocyclic radical, heteroaryl include its all possible isomeric form, such as its position isomer.
Therefore, for some illustrative non-limiting examples, pyridine radicals or sub- pyridine radicals include pyridine -2- bases, sub- pyridine -2- bases,
Pyridin-3-yl, sub- pyridin-3-yl, pyridin-4-yl and sub- pyridin-4-yl；Thienyl or sub- thienyl include thiophene -2- bases, Asia
Thiophene -2- bases, thiene-3-yl and sub- thiene-3-yl.
Relevant 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 into
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..Provided herein is a method and composition implementation
In mode, the mammal is behaved.
Term " treatment " used herein includes alleviating, mitigate or improving disease or illness disease with other similar synonyms
Shape, prevent other symptoms, improve or prevent the potential metabolism reason for causing symptom, suppress disease or illness, such as prevent disease
Or the development of illness, alleviate disease or illness, disease or illness is taken a turn for the better, alleviate 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 also include obtain therapeutic effect and/or
Preventive effect.The therapeutic effect refers to cure or improves treated potential disease.In addition, pair related to potential disease one
The healing of kind or a variety of physiological signs or improvement and therapeutic effect, such as although patient may nevertheless suffer from the shadow of potential disease
Ring, but observe that patient profiles improve.For preventive effect, described group can be applied to the patient for suffering from specified disease risk
Compound, even if or 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 dose ", " therapeutically effective amount " or " pharmacy effective dose " used herein refers to take metapedes with certain
Alleviate at least one medicament of one or more symptoms or the amount of compound of treated disease or illness in degree.Its result
Can be sign, the abatement of symptom or the cause of disease and/or alleviation, or biosystem it is any other needed for change.For example, for controlling
" effective dose " treated is clinically to provide the composition for including compound disclosed herein needed for significant remission effect
Amount.The technology of such as dose escalation trial can be used to determine the effective dose being suitable in any individual case.
Terms used herein " taking ", " administration ", " administration ", " giving " etc. are referred to compound or composition delivering
To the method in the required site for carrying out biological agent.These methods include but is not limited to oral route, through intraduodenal routes, stomach
Parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), external application and per rectum administration.Ability
The known application technique available for Compounds and methods for described herein of field technique personnel.In a preferred embodiment, beg for herein
The compound and composition of opinion are by orally administering.
Refer to dock the one of treated subject herein for term " acceptable " used in preparation, composition or composition
As health condition there is no long-term adverse effect.
Terms used herein " pharmaceutically acceptable " refers to the bioactivity for not influenceing the application compound or property
Material (such as carrier or diluent), and relative nontoxic, the i.e. material can be applied to individual without causing bad biological respinse
Or interacted in a manner of bad with any component included in composition.
Terms used herein " pharmaceutical composition " refer to be optionally mixed with least one pharmaceutically acceptable chemistry into
Point bioactive compound, the pharmaceutically acceptable chemical composition include but is not limited to carrier, stabilizer, diluent,
Dispersant, suspending agent, thickener and/or excipient.
Terms used herein " carrier " refers to the chemical compound or reagent of relative nontoxic, and it helps to introduce compound
Into cell or tissue.
Embodiment
Further detailed description is done to technical scheme below in conjunction with specific embodiment.It should be appreciated that
The following example is merely illustrative the ground description and interpretation present invention, and is not necessarily to be construed as limiting the scope of the invention.
In the range of all technologies realized based on the above of the present invention are encompassed by it is contemplated that protecting.
Unless otherwise indicated, the raw material and reagent used in following examples is commercial goods, or can be by
It is prepared by perception method.
The positive control drug used in embodiment 2 to 6 is the Ozanimod of homemade Receptos companies exploitation.
Ozanimod is a kind of selective S1P developed by Receptos companies1Receptor modulators.It is currently in multiple immunity diseases
The clinical investigation phase of disease, data show that it has higher S1P1Receptor-selective and good pharmacokinetic property.
Ozanimod structure is as follows：
The preparation method and structure elucidation data of the compound of embodiment 1
(1) preparation of intermediate compound I -1
Intermediate compound I -1：By intermediate 4- formylbenzonitriles (6.0g, 45.76mmol), ethylene glycol (9.32ml,
183.02mmol), p-methyl benzenesulfonic acid (626mg, 3.66mmol) is dissolved in 240ml toluene, is heated to reflux 2h, is entered using water knockout drum
Row divides water.Room temperature is cooled to, solvent is evaporated off, residue is dissolved with 300ml ethyl acetate, is washed, and is dried, column chromatography, eluant, eluent
For petroleum ether：Dichloromethane=20：1, obtain white solid 5.8g, yield 71.2%.1H NMR(400MHz,DMSO-d6)δ7.87
(d, J=8.4Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 5.83 (s, 1H), 3.94-4.08 (m, 4H) .MS (ESI) m/z (M+
H)+176.8。
(2) preparation of intermediate compound I -2
Intermediate compound I -2：Intermediate compound I -1 (5.60g, 31.96mmol) is dissolved in 240ml absolute methanols, under stirring
Hydroxylamine hydrochloride (7.78g, 111.88mmol), sodium acid carbonate (10.74g, 127.86mmol) are sequentially added, is heated to reflux 10h.It is cold
But, filter, filter cake is washed with absolute methanol, merging filtrate.Distilled water is added in filtrate, ethyl acetate extraction, washes, dries,
Column chromatography, eluant, eluent are dichloromethane：Methanol=20：1, obtain white solid 4.3g, yield 65.4%.1H NMR(400MHz,
DMSO-d6)δ9.66(s,1H),7.67-7.69(m,2H),7.41-7.43(m,2H),5.82(s,2H),5.74(s,1H),
3.93-4.07(m,4H).MS(ESI)m/z(M+H)+209.4。
(3) intermediate compound I -3-1, I-3-2 preparation
Intermediate compound I -3-1 (R1=isopropyl, R2=CN)：By 3- cyano group -4- isopropoxies benzoic acid (4.84g,
23.58mmol), I-hydroxybenzotriazole (2.9g, 21.42mmol), 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide salt
Hydrochlorate (4.1g, 21.42mmol), potassium carbonate (4.44g, 32.14mmol) are dissolved in 240ml DMF, are stirred at room temperature, and add middle
Body I-2 (5.2g, 21.42mmol), heating response.Cooling, filter, filter cake is washed with ethyl acetate, merging filtrate.Add in filtrate
Enter distilled water, ethyl acetate extraction, wash, dry, concentration, column chromatography, eluant, eluent is petroleum ether：Ethyl acetate=4:1, obtain white
Color solid 3.58g, yield 53.1%.1H NMR(400MHz,DMSO-d6) δ 8.46 (s, 1H), 8.37 (d, J=8.9Hz, 1H),
8.10 (s, 2H), 7.64 (d, J=8.2Hz, 2H), 7.52 (d, J=9.1Hz, 1H), 5.82 (s, 1H), 4.96 (p, J=
6.0Hz, 1H), 3.93-4.16 (m, 4H), 1.38 (d, J=6.0Hz, 6H)；MS(ESI)m/z 378.4.
Intermediate compound I -3-2 (R1=cyclopenta, R2=CN)：By foregoing intermediate compound I -3-1 identical preparation methods, with 3- cyanogen
Base -4- cyclopentyloxies benzoic acid replaces 3- cyano group -4- isopropoxy benzoic acid, obtains white solid 6.7g, yield 61.1%.1H
NMR(400MHz,DMSO-d6) δ 8.50 (d, J=2.4Hz, 1H), 8.41 (dd, J=9.0,2.2Hz, 1H), 8.10-8.12 (m,
2H), 7.65-7.67 (m, 2H), 7.52 (d, J=8.8Hz, 1H), 5.84 (s, 1H), 5.14-5.18 (m, 1H), 3.96-4.12
(m,4H),1.99-2.06(m,2H),1.63-1.82(m,6H).MS(ESI)m/z(M+H)+404.5。
(4) intermediate compound I -4-1, I-4-2 preparation
Intermediate compound I -4-1 (R1=isopropyl, R2=CN)：Intermediate compound I -3-1 (4.60g, 12.18mmol) is dissolved in 60ml
In acetone, 2N hydrochloric acid solutions are added under stirring, 3h is heated at 45 DEG C.Reaction is cooled to room temperature, decompression filters, and dries,
Obtain white solid 2.28g, yield 56.3%.1H NMR(400MHz,DMSO-d6) δ 10.11 (s, 1H), 8.48 (d, J=2.4Hz,
1H), 8.39 (dd, J=9.0,2.2Hz, 1H), 8.28 (d, J=8.4Hz, 2H), 8.10 (d, J=8.0Hz, 2H), 7.54 (d, J
=9.2Hz, 1H), 4.97 (hept, J=6.0Hz, 1H), 1.38 (d, J=6.0Hz, 6H) .MS (ESI) m/z (M+H)+334.1。
Intermediate compound I -4-2 (R1=cyclopenta, R2=CN)：By foregoing intermediate compound I -4-1 identical preparation methods, with centre
Body 1-3-2 replaces intermediate compound I -3-1, obtains white solid 4.45g, yield 48.5%.11H NMR(400MHz,DMSO-d6)δ
10.12 (s, 1H), 8.52 (d, J=2.4Hz, 1H), 8.42 (dd, J=8.8,2.4Hz, 1H), 8.29-8.32 (m, 2H),
8.10--8.14 (m, 2H), 7.53 (d, J=9.2Hz, 1H), 5.15-5.19 (m, 1H), 1.98-2.07 (m, 2H), 1.63-
1.83(m,6H).MS(ESI)m/z(M+H)+360.8。
(5) target compound LK-S1P-001 preparation
(4- (5- (3- cyano group -4- isopropyl phenyls) -1,2,4- oxadiazoles -3- bases) benzyl) glycine hydrochloride
Intermediate compound I -4-1 (400mg, 1.2mmol) is dissolved in 70ml dichloromethane, adds glycine methyl ester hydrochloride
(222mg, 1.8mmol), glacial acetic acid (0.28ml, 4.80mmol) and DIPEA (0.3ml, 1.8mmol),
15ml methanol, itrile group sodium borohydride (76mg, 1.2mmol), the lower reaction 10h of argon gas protection are added after reacting at room temperature 3h.Add full
And sodium bicarbonate solution, dichloromethane extraction 3 times (3 × 50mL), wash, dry, column chromatography for separation, eluant, eluent is dichloromethane
Alkane：Methanol=20:1, obtain white solid 298mg, yield 61.1%.1H NMR(400MHz,DMSO-d6)δ8.49(m,1H),
8.39 (dt, J=9.2,1.7Hz, 1H), 8.03 (d, J=8.0Hz, 2H), 7.53-7.56 (m, 3H), 4.97 (hept, J=
6.0Hz, 1H), 3.81 (s, 2H), 3.63 (s, 3H), 3.36 (s, 2H), 2.73 (s, 1H), 1.38 (d, J=6.0Hz, 6H) .MS
(ESI)m/z(M+H)+407.4。
By upper step products therefrom N- (4- (5- (3- cyano group -4- isopropyl phenyls) -1,2,4- oxadiazoles -3- bases) benzyls
Base)-glycine methyl ester (200mg, 49.24mmol) is dissolved in 5ml methanol, add lithium hydroxide (6mg, 246.2mmol), heating
3-5h is reacted, cooling, 1mol/L concentrated hydrochloric acid solutions is added dropwise to pH=3, solvent is evaporated off, adds distilled water, filters, washs, dries
Obtain white solid 115mg.Yield 59.3%.1H NMR(400MHz,DMSO-d6) δ 8.49 (d, J=2.0Hz, 1H), 8.39 (dd,
J=8.8,2.4Hz, 1H), 8.11 (d, J=8.4Hz, 2H), 7.70 (d, J=8.4Hz, 2H), 7.56 (d, J=9.2Hz, 1H),
4.97 (hept, J=6.0Hz, 1H), 4.18 (s, 2H), 3.66 (s, 2H), 1.38 (d, J=6.0Hz, 6H) .MS (ESI) m/z (M
+H)+393.7。
(6) target compound LK-S1P-002 preparation
N- (4- (5- (3- cyano group -4- isopropyl phenyls) -1,2,4- oxadiazoles -3- bases) benzyl)-sarcosine
Hydrochloride
By preceding aim compound L K-S1P-001 identical preparation methods, glycine is replaced with hydrochloride ethyl sarcosnate
Methyl ester hydrochloride, N- (4- (5- (3- cyano group -4- isopropyl phenyls) -1,2,4- oxadiazoles -3- bases) benzyls are prepared first
Base)-sarcosine ethyl ester, it is white solid 170mg, yield 65.4%.1H NMR(400MHz,DMSO-d6)δ8.47(d,
J=2.0Hz, 1H), 8.38 (dd, J=9.0,1.8Hz, 1H), 8.03 (d, J=8.0Hz, 2H), 7.53 (t, J=7.8Hz,
3H), 4.97 (hept, J=5.8Hz, 1H), 4.10 (q, J=7.1Hz, 2H), 3.73 (s, 2H), 3.33 (s, 2H), 2.28 (s,
3H), 1.38 (d, J=6.0Hz, 6H), 1.20 (t, J=7.0Hz, 3H) .MS (ESI) m/z (M+H)+421.7.
Further as foregoing LK-S1P-001 identicals preparation method, hydrolysis, acidification reaction obtain target compound LK-
S1P-002, is white solid 102mg, yield 55.9%.1H NMR(400MHz,DMSO-d6) δ 8.50 (d, J=2.4Hz, 1H),
8.40 (dd, J=9.0,2.2Hz, 1H), 8.16 (d, J=8.4Hz, 2H), 7.79 (d, J=8.4Hz, 2H), 7.56 (d, J=
9.2Hz, 1H), 4.98 (hept, J=6.1Hz, 1H), 4.45 (s, 2H), 4.07 (s, 2H), 2.79 (s, 3H), 1.38 (d, J=
6.0Hz,6H).MS(ESI)m/z(M+H)+407.7。
(7) target compound LK-S1P-003 preparation
(4- (5- (- cyano group -4- (cyclopentyloxy) phenyl) -1,2,4- oxadiazoles -3- bases) benzyl) glycine hydrochloride
By preceding aim compound L K-S1P-001 identical preparation methods, intermediate compound I -4- is replaced with intermediate compound I -4-2
1, (4- (5- (3- cyano group -4- (cyclopentyloxy) phenyl) -1,2,4- oxadiazoles -3- bases) benzyl) glycine first is prepared first
Ester, is white solid 144mg, yield 59.6%.1H NMR(400MHz,DMSO-d6) δ 8.47 (d, J=2.4Hz, 1H), 8.37
(dd, J=9.0,2.2Hz, 1H), 8.02-8.00 (m, 2H), 7.54-7.48 (m, 3H), 5.16-5.12 (m, 1H), 3.80 (s,
2H),3.63(s,3H),3.36(s,2H),2.66(s,1H),1.96-2.05(m,2H),1.62-1.81(m,6H).MS(ESI)
m/z(M+H)+433.9。
Further as foregoing LK-S1P-001 identicals preparation method, hydrolysis, acidification reaction obtain target compound LK-
S1P-003, is white solid 112mg, yield 70.9%.1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.48(s,
1H), 8.39 (dd, J=9.2,2.0Hz, 1H), 8.11 (d, J=8.0Hz, 2H), 7.70 (d, J=8.0Hz, 2H), 7.52 (d, J
=9.2Hz, 1H), 5.14-5.17 (m, 1H), 4.19 (s, 2H), 3.69 (s, 2H), 1.97-2.06 (m, 2H), 1.64-1.80
(m,6H)；MS(ESI)m/z(M+H)+419.2。
(8) target compound LK-S1P-004 preparation
N- (4- (5- (3- cyano group -4- (cyclopentyloxy) phenyl) -1,2,4- oxadiazoles -3- bases) benzyl) sweet ammonia of-N- methyl
Acid hydrochloride
By preceding aim compound L K-S1P-001 identical preparation methods, intermediate compound I -4- is replaced with intermediate compound I -4-2
1, glycine methyl ester hydrochloride is replaced with hydrochloride ethyl sarcosnate, prepares N- (4- (5- (3- cyano group -4- (cyclopentyloxy) first
Phenyl) -1,2,4- oxadiazoles -3- bases) benzyl)-sarcosine ethyl ester, it is white solid 126mg, yield 49.2%.1H
NMR(400MHz,DMSO-d6) δ 8.46 (d, J=2.4Hz, 1H), 8.38 (dd, J=9.0,2.2Hz, 1H), 8.04-8.02 (m,
2H), 7.53-7.48 (m, 3H), 5.16-5.12 (m, 1H), 4.10 (q, J=7.2Hz, 2H), 3.72 (s, 2H), 3.32 (s,
2H), 2.28 (s, 3H), 2.06-1.96 (m, 2H), 1.62-1.82 (m, 6H), 1.20 (t, J=7.2Hz, 3H) .MS (ESI) m/z
(M+H)+447.1。
Further as foregoing LK-S1P-001 identicals preparation method, hydrolysis, acidification reaction obtain target compound LK-
S1P-004, is white solid 111mg, yield 58.9%.1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.37(d,J
=8.0Hz, 1H), 8.05 (d, J=6.8Hz, 2H), 7.58 (d, J=6.4Hz, 2H), 7.50 (d, J=8.4Hz, 1H), 5.14
(s,1H),3.91(s,2H),3.42(s,2H),2.41(s,3H),2.00(m,2H),1.80-1.65(m,6H)；MS(ESI)m/z
(M+H)+433.6。
(9) target compound LK-S1P-005 preparation
1- (4- (5- (3- cyano group -4- isopropyl phenyls) -1,2,4- oxadiazoles -3- bases) benzyl) pyrrolidines -3- formic acid
Hydrochloride
By preceding aim compound L K-S1P-001 identical preparation methods, replaced with pyrrolidines -3- methyl formate hydrochlorides
Glycine methyl ester hydrochloride is changed, prepares 1- (4- (5- (3- cyano group -4- isopropyl phenyls) -1,2,4- oxadiazoles -3- bases) first
Benzyl) pyrrolidines -3- methyl formates, it is white solid 161mg, yield 61.2%.1H NMR(400MHz,DMSO-d6)δ8.48
(d, J=2.0Hz, 1H), 8.39 (dd, J=8.8,2.4Hz, 1H), 8.02-8.04 (m, 2H), 7.51-7.56 (m, 3H), 4.97
(hept, J=6.0Hz, 1H), 3.63-3.70 (m, 2H), 3.61 (s, 3H), 3.02-3.10 (m, 1H), 2.75 (t, J=
8.6Hz, 1H), 2.64-2.68 (m, 1H), 2.53-2.56 (m, 2H), 1.94-2.07 (m, 2H), 1.38 (d, J=6.0Hz,
6H).MS(ESI)m/z(M+H)+447.1。
Further as foregoing LK-S1P-001 identicals preparation method, hydrolysis, acidification reaction obtain target compound LK-
S1P-005, is white solid 118mg, yield 61.4%.1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.50(d,
J=2.4Hz, 1H), 8.40 (dd, J=9.0,2.2Hz, 1H), 8.13 (d, J=8.4Hz, 2H), 7.78 (d, J=8.0Hz,
2H), 7.56 (d, J=9.2Hz, 1H), 4.98 (hept, J=6.0Hz, 1H), 4.34 (s, 2H), 3.26-3.16 (m, 5H),
2.29-2.10 (m, 2H), 1.38 (d, J=6.0Hz, 6H)；MS(ESI)m/z(M+H)+433.6。
(10) target compound LK-S1P-006 preparation
1- (4- (5- (3- cyano group -4- (cyclopentyloxy) phenyl) -1,2,4- oxadiazoles -3- bases) benzyl) pyrrolidines -3- first
Acid hydrochloride
By preceding aim compound L K-S1P-001 identical preparation methods, intermediate compound I -4- is replaced with intermediate compound I -4-2
1, glycine methyl ester hydrochloride is replaced with pyrrolidines -3- methyl formates hydrochloride, prepares 1- (4- (5- (3- cyano group -4- (rings first
Amoxy) phenyl) -1,2,4- oxadiazoles -3- bases) benzyl) pyrrolidines -3- methyl formates, it is white solid 144mg, yield
54.8%.1H NMR(400MHz,DMSO-d6) δ 8.48 (d, J=2.0Hz, 1H), 8.39 (dd, J=9.0,2.2Hz, 1H),
8.03 (d, J=8.1Hz, 2H), 7.51 (d, J=8.0Hz, 3H), 5.14-5.17 (m, 1H), 3.66 (m, 2H), 3.60 (s,
3H), 3.02-3.10 (m, 1H), 2.74 (t, J=8.8Hz, 1H), 2.63-2.67 (m, 1H), 2.52-2.57 (m, 2H), 1.94-
2.06(m,4H),1.60-1.81(m,6H)。
Further as foregoing LK-S1P-001 identicals preparation method, hydrolysis, acidification reaction obtain target compound LK-
S1P-006, is white solid 123mg, yield 63.7%.1H NMR(400MHz,DMSO-d6)δ12.94-11.36(m,1H),
8.51 (d, J=2.0Hz, 1H), 8.41 (dd, J=9.0,2.2Hz, 1H), 8.15 (d, J=8.4Hz, 2H), 7.82 (d, J=
8.0Hz, 2H), 7.54 (d, J=9.2Hz, 1H), 5.15-5.18 (m, 1H), 4.46 (s, 2H), 3.35 (s, 5H), 2.16-2.33
(m,2H),1.97-2.06(m,2H),1.61-1.82(m,6H)；MS(ESI)m/z(M+H)+459.4。
(11) target compound LK-S1P-007 preparation
2- (1- (4- (5- (3- cyano group -4- isopropyl phenyls) -1,2,4- oxadiazoles -3- bases) benzyl) piperidin-4-yl)
Acetic acid hydrochloride
By preceding aim compound L K-S1P-001 identical preparation methods, sweet ammonia is replaced with piperidineacetate hydrochloride
Acid methyl ester hydrochloride salt, (1- (4- (5- (3- cyano group -4- isopropyl phenyls) -1,2,4- oxadiazoles -3- bases) benzyl) is prepared first
Piperidin-4-yl) methyl acetate, it is white solid 145mg, yield 51.2%.1H NMR(400MHz,DMSO-d6)δ8.49(d,J
=2.4Hz, 1H), 8.39 (dd, J=9.0,2.2Hz, 1H), 8.02-8.04 (m, 2H), 7.55 (d, J=9.2Hz, 1H), 7.50
(d, J=8.0Hz, 1H), 4.97 (hept, J=6.1Hz, 1H), 3.58 (s, 3H), 3.52 (s, 2H), 2.78 (d, J=
11.6Hz, 2H), 2.24 (d, J=6.8Hz, 2H), 1.93-1.99 (m, 2H), 1.60-1.63 (m, 3H), 1.38 (d, J=
6.0Hz,6H),1.17-1.27(m,2H)；MS(ESI)m/z(M+H)+475.8。
Further as foregoing LK-S1P-001 identicals preparation method, hydrolysis, acidification reaction obtain target compound LK-
S1P-007, is white solid 154mg, yield 673%.1H NMR (400MHz, DMSO-d6) δ 12.24 (s, 1H), 10.78 (s,
1H), 8.50 (d, J=2.3Hz, 1H), 8.40 (dd, J=9.0,2.3Hz, 1H), 8.14 (d, J=8.3Hz, 2H), 7.83 (d, J
=8.2Hz, 2H), 7.57 (d, J=9.3Hz, 1H), 4.98 (p, J=6.1Hz, 1H), 4.35 (d, J=4.1Hz, 2H), 3.31
(s, 2H), 3.04-2.89 (m, 2H), 2.18 (d, J=6.6Hz, 2H), 1.86 (t, J=15.1Hz, 3H), 1.58 (q, J=
13.0,12.2Hz, 2H), 1.38 (d, J=6.0Hz, 6H)；MS(ESI)m/z(M+H)+461.6。
(12) target compound LK-S1P-008 preparation
2- (1- (4- (5- (3- cyano group -4- (cyclopentyloxy) phenyl) -1,2,4- oxadiazoles -3- bases) benzyl) piperidines -4-
Base) acetic acid hydrochloride
By preceding aim compound L K-S1P-001 identical preparation methods, intermediate compound I -4- is replaced with intermediate compound I -4-2
1, glycine methyl ester hydrochloride is replaced with piperidineacetate hydrochloride, prepares (1- (4- (5- (3- cyano group -4- (the oxygen of ring penta first
Base) phenyl) -1,2,4- oxadiazoles -3- bases) benzyl) piperidin-4-yl) methyl acetate, it is white solid 140mg, yield
50.8%.1H NMR(400MHz,DMSO-d6) δ 8.48 (d, J=2.0Hz, 1H), 8.39 (dd, J=9.0,2.2Hz, 1H),
8.02 (d, J=8.4Hz, 2H), 7.49-7.52 (m, 3H), 5.13-5.17 (m, 1H), 3.57 (s, 3H), 3.51 (s, 2H),
2.78 (d, J=11.2Hz, 2H), 2.24 (d, J=6.8Hz, 2H), 1.92-2.06 (m, 4H), 1.60-1.82 (m, 9H),
1.17-1.25(m,2H).MS(ESI)m/z(M+H)+501.2。
Further as foregoing LK-S1P-001 identicals preparation method, hydrolysis, acidification reaction obtain target compound LK-
S1P-008, is white solid 143mg, yield 63.9%.1H NMR(400MHz,DMSO-d6)δ12.17(s,1H),10.58-
10.43 (m, 1H), 8.47 (d, J=2.4Hz, 1H), 8.37 (dd, J=9.0,2.2Hz, 1H), 8.12 (d, J=8.0Hz, 2H),
7.77 (d, J=8.0Hz, 2H), 7.50 (d, J=9.2Hz, 1H), 5.11-5.15 (m, 1H), 4.31-4.32 (m, 2H), 3.32
(s, 2H), 2.88-2.98 (m, 2H), 2.15 (d, J=6.8Hz, 2H), 1.94-2.03 (m, 2H), 1.45-1.83 (m, 11H)；
MS(ESI)m/z(M+H)+487.3。
The exemplary embodiments of the present invention compound of embodiment 2 is to S1P1And S1P3The external agonist activity of acceptor
Use [35S] GTP γ S Binding experiments evaluation the present invention be performed as described above example 1 preparation compound to S1P1And S1P3By
The external agonist activity of body.By 5 μ g memebrane proteins (S1P1Memebrane protein HTS176M, S1P3Memebrane protein HTS097M, Merck
Millipore, USA) with the compounds of various concentrations in buffer solution (20mM HEPES, pH7.4,100mM NaCl, 10mM
MgCl2, 5 μ g Saponin, 0.5 μM of GDP, 0.3nm [35S] the middle incubations of GTP γ S (1200Ci/mmol), incubation temperature 30
DEG C, the time is 30 minutes.Reaction solution is moved into the pretreated GF/B filters (Millipore MAHFB1H) of deionized water.
Washed 3 times with the 10mM sodium radio-phosphate,P-32 solutions (pH7.4) of precooling, radionuclide detection, the parallel survey of each compound are carried out after drying
It is fixed 3 times, average, as a result as shown in table 1.
As a result show, compound prepared by the embodiment of the present invention 1 is for S1P1The external agonist activity of acceptor is significantly excellent
In positive control drug Ozanimod, particularly compound L K-S1P-005, LK-S1P-006 is for S1P1The external excitement of acceptor
Activity value is substantially higher by two orders of magnitude compared with Ozanimod；And such compound is for S1P3Acceptor is without agonism, table
Bright the compounds of this invention is for S1P1The exciting intensity and selectivity of acceptor are superior to Ozanimod.
The compound of table 1 is to S1P1And S1P3The external agonist activity of acceptor
Note："/" represents external agonist activity>5000nM.
Immunosupress is tested inside the exemplary embodiments of the present invention compound of embodiment 3
Use the immune suppression of Peripheral Lymphocytes of Rat quantitative index evaluation exemplary embodiments of the present invention compound
Make and use.From by healthy male SD rat (body weight 200-220g), random packet, every group 3.Overnight fasting.Next day endocanthion
Venous blood sampling, basic Number of haemocytes detection is carried out using the full-automatic blood cell analysis machines of ADVIA2120.Every group according to 1mg/
Kg doses give medicine to be measured, and angular vein takes blood to 24h again after administration, carries out Number of haemocytes detection, calculates leaching
Bar cell reduces percentage, takes the average value of 3 zoometry results, as a result as shown in table 2.
Immunosuppressive action inside the compound of table 2
As a result showing, immunosuppressive action is totally better than positive control drug Ozanimod inside the compounds of this invention, its
The reduction percentage of middle chemical combination LK-S1P-004, LK-S1P-006, LK-S1P-008 for lymphocyte quantity is higher, it is shown that
Immunosuppressive activity inside relatively strong.
The metabolic stability in vitro experiment of the exemplary embodiments of the present invention compound of embodiment 4
The metabolism of system appraisal preliminary assessment exemplary embodiments of the present invention compound is incubated using rat liver microsomes body temperature
Stability.By testing compound (1 μ L, 400 μm of ol/L DMSO solutions), rat liver microsomes body protein (5 μ L, 20mg/mL) and
Tris-HCl buffer solutions (50mM, pH=7.4) add 20 μ L NADPH (10mM) and start reaction after 37 DEG C of pre-temperatures incubate 5min,
Reaction cumulative volume is that (organic solvent content is 200 μ L<0.5%), final concentration of 2 μm of ol/L of compound.After temperature incubates 0h, 1h,
Ice acetonitrile (400 μ L) terminating reaction.13000g × the 5min after mixing that is vortexed is centrifuged, and is taken the μ L sample introductions of supernatant 5, is carried out LC-MS/MS
Analysis detection.It is metabolized percentage (%)=(1-Q1h/Q0h) × 100%；Q1h/Q0h is that temperature incubates testing compound after 1h/0h
Surplus, as a result as shown in table 3.
The Compound ira vitro metabolic stability of table 3
As a result show, the compounds of this invention has preferable metabolic stability in vitro, the 1h in liver particle body temperature incubates system
The medicine for generally having more than 85% afterwards maintains original form, better than positive control drug Ozanimod.
Therapeutic action of the exemplary embodiments of the present invention compound of embodiment 5 to chronic ulcerative colitis
The amount of activated compound of the chronic evaluation present invention of chronic ulcerative colitis pathology induced using OXZ is for chronic
The therapeutic action of ulcerative colitis.From male mouse of kunming (28-32g), random packet, every group 6.Normal group is small
Mouse smears 0.2ml sensitization, model group and each administration group mouse 3%4- ethoxymeyhylene -2- phenyl with 100% ethanol belly
Oxazoline -5- ketone (OXZ, E0753) ethanol solutions belly smear 0.2ml sensitization, second day repetition sensitization once, from mould after 5 days
Type group and administration group mouse anus pour into 0.15ml 2%OXZ ethanol (50%) solution, and Normal group pours into from anus
The ethanol of 0.15ml 50%.In experiment screening in the 3rd day into mould mice group, it is administered once a day as follows：(1) it is normal right
According to group (Control)：Directly give 1% sodium carboxymethylcellulose gavage.(2) UC model groups (Model)：Directly give 1% carboxylic
Sodium carboxymethylcellulose pyce gavage.(3) positive drug SASP group (SASP)：Gavage after being prepared with 1% sodium carboxymethylcellulose.
(4) compound group (the compounds of this invention and control compound Ozanimod)：1mg/kg, prepared with 1% sodium carboxymethylcellulose
Gavage afterwards.After administration 8 days, take off neck and put to death each group animal, and detect the related indices of colitis.Every group 6 calculate averagely
Value, as a result as shown in table 4.
Influence of the compound of table 4 to colitis mice body weight and colon lengths
As a result show, in experimentation, no animal dead, reactive compound of the present invention has to chronic ulcerative colitis
Certain therapeutic action, and compared with positive drug SASP and Ozanimod, the influence for mouse weight is smaller, curative effect and peace
Full property is higher.
The pharmacokinetic parameter evaluation of the compounds of this invention of embodiment 6
Healthy male SD rat (body weight 200-220g) is grouped, every group of 5 parallel samples.(1) use physiological saline will
Medicine to be measured and control drug are configured to solution, according to 3mg/kg/10ml dosage gastric infusions；(2) will be treated using physiological saline
Survey medicine and control drug is configured to solution, according to 0.3mg/kg/5ml dose intravenous drug administration by injection；By pharmacokinetics
Conventional method is studied to carry out time segment blood sampling, plasma treatment, draw standard curve, carry out UPLC-MS/MS analyses to sample,
Calculate bioavilability.Pharmacokinetic parameter analysis is carried out using Phoenix softwares.As a result as shown in table 5, chemical combination of the present invention
Thing is respectively provided with suitable bioavilability.
The non-atrioventricular model parameter of pharmacokinetics of the part of compounds of table 5
More than, embodiments of the present invention are illustrated.But the present invention is not limited to above-mentioned embodiment.It is all
Within the spirit and principles in the present invention, any modification, equivalent substitution and improvements done etc., it should be included in the guarantor of the present invention
Within the scope of shield.
Claims (10)
1. compound, its raceme, stereoisomer, dynamic isomer, solvate, hydrate or their medicines shown in formula (I)
Acceptable salt on：
Wherein, R1Selected from H, unsubstituted or by one or more RaSubstituted following groups：C1-8Alkyl, C3-8Cycloalkyl, heterocycle
Base, aryl or heteroaryl；
R2For-CN；
R3Selected from-NR '2Or azepine C3-8Cycloalkyl；Wherein, the azepine C3-8Cycloalkyl is by one or more-R6COOR7Taken
Generation；R ' may be the same or different, optionally：H、C1-8Alkyl ,-R6COOR7, wherein, at least one in R ' is-R6COOR7；Its
In, R6Selected from chemical bond or C1-8Alkylidene, R7Selected from H or C1-8Alkyl；
RaSelected from-F ,-Cl ,-Br ,-I ,-CN ,-OH ,=O or the following base substituted by-F ,-Cl ,-Br ,-I ,-CN ,-OH ,=O
Group：C1-8Alkyl, C3-8Cycloalkyl, heterocyclic radical, aryl or heteroaryl.
2. compound, its raceme, stereoisomer, dynamic isomer, solvate, water shown in formula described in claim 1 (I)
Compound or their pharmaceutically acceptable salts, it is characterised in that R1Selected from unsubstituted or by one or more RaWhat is substituted is following
Group：C1-6Alkyl, C3-6Cycloalkyl；The RaSelected from-F ,-Cl ,-Br ,-I ,-CN or by-F ,-Cl ,-Br ,-I ,-CN substitution
Following groups：C1-6Alkyl, C3-6Cycloalkyl；
Preferably, R1Selected from unsubstituted or by one or more RaSubstituted following groups：Methyl, ethyl, n-propyl, isopropyl
Base, cyclopropyl, normal-butyl, isobutyl group, the tert-butyl group, cyclobutyl, n-pentyl, isopentyl, cyclopenta, n-hexyl, isohesyl, hexamethylene
Base；The RaSelected from-F ,-Cl ,-Br ,-I or-CN；
Preferably, R3It is selected fromWherein R4、R5Selected from H or C1-6Alkyl；L is selected from C1-6
Alkylidene, m and n are identical or different, are independently from each other 1-3 integer, R6Selected from chemical bond or C1-8Alkylidene；
It is further preferred that R3Selected from-azelidinyl-R6COOR7,-azepine cyclopenta-R6COOR7Or-piperidyl-R6COOR7。
3. compound, its raceme, stereoisomer, dynamic isomer, solvation shown in the formula of claim 1 or 2 (I)
Thing, hydrate or their pharmaceutically acceptable salts, it is characterised in that the compound pharmaceutically acceptable salt is selected from inorganic
The salt that can be formed in acid or organic acid and compound into salt site (such as on salifiable N)；
The inorganic acid includes but is not limited to：Hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, hydrofluoric acid, hydroiodic acid, pyrosulfuric acid or nitric acid；
The organic acid includes but is not limited to：Citric acid, maleic acid, butanedioic acid, acetic acid, malic acid, tartaric acid, methanesulfonic acid, benzene
Sulfonic acid, formic acid, acetoacetate, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, hendecanoic acid, laurate, benzene first
Acid, salicylic acid, 2- (4- hydroxy benzoyls) benzoic acid, camphoric acid, cinnamic acid, pentamethylene propionic acid, didextrose acid, 3- hydroxyls-
2- naphthoic acids, nicotinic acid, flutter acid, pectinic acid, persulfuric acid, 3- phenylpropionic acids, picric acid, pivalic acid, 2- ethylenehydrinsulfonic acids, clothing health
Acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulphate, ethyl sulfonic acid, p-methyl benzenesulfonic acid, 2- naphthalene sulfonic acids, naphthalenedisulfonic acid, camphor
Sulfonic acid, stearic acid, lactic acid, oxalic acid, malonic acid, adipic acid, alginic acid, fumaric acid, D- gluconic acids, mandelic acid, ascorbic acid, Portugal heptan
Acid, phosphoglycerol, aspartic acid, sulfosalicylic acid, hemisulfic acid or thiocyanic acid；
Preferably, the compound pharmaceutically acceptable salt is selected from hydrochloride.
It is 4. compound shown in any one of the claim 1-3 formulas (I), its raceme, stereoisomer, dynamic isomer, molten
Agent compound, hydrate or their pharmaceutically acceptable salts, it is characterised in that compound shown in the formula (I) is selected from followingization
Compound or its salt：
It is 5. compound shown in any one of the claim 1-4 formulas (I), its raceme, stereoisomer, dynamic isomer, molten
The preparation method of agent compound, hydrate or their pharmaceutically acceptable salts, it is characterised in that comprise the following steps：By formula (I-
4) compound is reacted with formula (I-5) compound, obtains formula (I) compound,
Wherein, R1、R2、R3With any one of the claim 1-4 definition；
Optionally, the preparation method also includes reacting to form its pharmaceutically-acceptable salts by formula (I) compound and salt-forming reagent；
Preferably, R is worked as3In group R7For alkyl when, resulting formula (I) compound can be hydrolyzed, reaction obtain R7For
H formula (I) compound.
6. the preparation method described in claim 5, it is characterised in that formula (I-4) compound is prepared by the following method, bag
Include：
Wherein, R1、R2、R3With any one of the claim 1-4 definition；
1) by 4- cyanobenzaldehydes and glycol reaction, formula (I-1) compound is obtained；
2) formula (I-1) compound obtained step 1) is reacted with hydroxylamine hydrochloride, obtains formula (I-2) compound；
3) formula (I-2) compound obtained step 2) is reacted with formula (II) compound, obtains formula (I-3) compound, Ran Hou
Reaction obtains formula (I-4) compound under acid condition.
A kind of 7. pharmaceutical composition, it is characterised in that any one of claim 1-4 comprising therapeutically effective amount formulas (I) institute
Show compound, its raceme, stereoisomer, dynamic isomer, solvate, hydrate or their pharmaceutically acceptable salts
In one or more；
Preferably, described pharmaceutical composition also includes pharmaceutical acceptable carrier；
Described pharmaceutical acceptable carrier includes but is not limited to：Filler, diluent, disintegrant, lubricant, glidant, adhesive, solubilising
Agent, surfactant, emulsifying agent, preservative, antioxidant, flavouring, colouring agent, osmotic pressure regulator, pH adjusting agent, proppant
In one or more；
Preferably, it is compound shown in formula (I), its raceme, stereoisomer, dynamic isomer, molten in described pharmaceutical composition
One or more in agent compound, hydrate or their pharmaceutically acceptable salts account for the 0.01- of pharmaceutical composition gross mass
99.99%.
A kind of 8. preparation for including claim 7 described pharmaceutical composition；
Preferably, the formulation of the preparation includes but is not limited to：Liquid dosage form, solid dosage forms or semisolid dosage form；
Preferably, the liquid dosage form is oral solution formulation, injection, infusion solution, lotion, drops, liniment, aerosol etc.；
The solid dosage forms can be tablet, capsule, granule, powder, pulvis, pill, suppository, patch etc.；The semi-solid agent
Type can be ointment, gel, paste etc.；
Preferably, the formulation also includes ordinary preparation, sustained release preparation, controlled release preparation, targeting preparation and various particulates administration system
System.
9. compound, its raceme, stereoisomer, dynamic isomer, solvate described in claim any one of 1-4,
Hydrate or their pharmaceutically acceptable salts, or claim 7 described pharmaceutical composition are being prepared for treating S1P1By
Purposes in the medicine of body phase related disorders；
Preferably, the S1P1The related illness of acceptor includes but is not limited to：Autoimmune disease, the disease of cell mediated
Disease, inflammatory disease, bacterium infection, fungal infection, virus infection or cancer etc..
10. the pharmaceutical composition described in claim 9 is being prepared for treating S1P1Purposes in the medicine of receptor associate disorder；
Characterized in that, the purposes be prepare treatment inflammatory enteritis, and/or Crohn disease, and/or ulcerative colitis and/
Or systemic loupus erythematosus, and/or rheumatoid arthritis, and/or psoriasis, and/or multiple sclerosis, and/or transplanting
Repel the purposes in medicine.
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| CN201711168722.8A CN107827837B (en) | 2017-11-21 | 2017-11-21 | Sphingosine-1-phosphate receptor modulator compounds, and preparation method and application thereof |
| PCT/CN2018/116258 WO2019101045A1 (en) | 2017-11-21 | 2018-11-19 | Sphingosine-1-phosphate receptor modulator compound, preparation method therefor and application thereof |
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Cited By (2)
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| WO2019101045A1 (en) * | 2017-11-21 | 2019-05-31 | 苏州朗科生物技术股份有限公司 | Sphingosine-1-phosphate receptor modulator compound, preparation method therefor and application thereof |
| CN109956912A (en) * | 2017-12-26 | 2019-07-02 | 中国医学科学院药物研究所 | Carboxylic acid compound, preparation method and the medical usage of the oxadiazoles containing diphenyl |
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| WO2019101045A1 (en) | 2019-05-31 |
| CN107827837B (en) | 2021-09-24 |
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