CN107698484A - A kind of preparation method of derivative of lenalidomide and application - Google Patents
A kind of preparation method of derivative of lenalidomide and application Download PDFInfo
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- CN107698484A CN107698484A CN201711113856.XA CN201711113856A CN107698484A CN 107698484 A CN107698484 A CN 107698484A CN 201711113856 A CN201711113856 A CN 201711113856A CN 107698484 A CN107698484 A CN 107698484A
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- PNHIPVUMZYARBM-UHFFFAOYSA-N COC(CC(c(cc1OCC(F)(F)F)ccc1OC)N(Cc1c2cccc1N)C2=O)=O Chemical compound COC(CC(c(cc1OCC(F)(F)F)ccc1OC)N(Cc1c2cccc1N)C2=O)=O PNHIPVUMZYARBM-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
Abstract
The invention discloses a kind of lenalidomide derivative and preparation method and application.Its structural formula of lenalidomide derivative provided by the present invention is shown in formula I.Lenalidomide derivative shown in Formulas I provided by the invention has obvious antiinflammatory action, and impassivity toxicity, is had a good application prospect in anti-inflammatory drug design research and development field.The compound also has obvious antitumaous effect simultaneously, is also had a good application prospect in the research and development field of cancer therapy drug.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of preparation method of derivative of lenalidomide and application.
Background technology
Lenalidomide is the antineoplastic developed by Celgene biopharmaceutical companys of the U.S., chemical constitution and Sha Lidu
Amine is similar, has the multiple actions such as antitumor, immunological regulation and anti-angiogenesis.In vitro test shows that lenalidomide can suppress certain
A little cell line such as Namalwa hyperplasias.Lenalidomide can suppress the growth of patient multiple myeloma's cell and MM1S cells.
In addition, lenalidomide may also suppress cyclooxygenase 2 (COX-2) expression, but to COX-1 without effect.Short Term Clinical result of study
It has been shown that, lenalidomide is in addition to it can be used for treating MDS and MM, to myeloma, leukaemia, metastatic renal cell carcinoma, solid tumor, primary
Property the denaturation of systemic starch ocean and there is the effect of certain with the systemic myeloproliferative disorders of marrow metaplasia.
The content of the invention
It is an object of the present invention to provide a kind of lenalidomide derivative or its pharmaceutically acceptable salt.
The general structure of lenalidomide derivative provided by the present invention is shown in formula I：
In Formulas I, R1 is：H or-C=OR5, wherein, R5 is substituted or unsubstituted following radicals：The C1- of straight or branched
C20 alkyl, aryl, heteroaryl, cycloalkyl, aryl alkyl, cycloheteroalkylalkyl or C1-C8 alkyl-OR6；R6 is for substitution or not
Substituted following radicals：C1-C20 alkyl, aryl alkyl or cycloheteroalkylalkyl；
R2 is：The C1-C20 alkyl of substituted or unsubstituted straight or branched, substituted or unsubstituted aryl alkyl, substitution
Or unsubstituted cycloheteroalkylalkyl；
R3 is：The C1-C20 alkyl of substituted or unsubstituted straight or branched；
R4 is：The C1-C20 alkyl of substituted or unsubstituted straight or branched.
Wherein, the substituent in the alkyl, aryl, heteroaryl, cycloalkyl, aryl alkyl and the cycloheteroalkylalkyl that each substitute
Independently optionally from following radicals：Halogen, hydroxyl, amino and nitro.The halogen refers to F, Cl, Br or I.
The above-mentioned group containing substituent can have a substituent to be substituted in each commutable position of group.Work as institute
More than one position can be substituted by one or more substituents selected from specific group in the structural formula provided, then substituent
With identical or different it can substitute in each position.
Further, above-mentioned cycloalkyl can be C3-C20 cycloalkyl, and above-mentioned aryl alkyl can be C6-C20 virtue
Base alkyl, above-mentioned cycloheteroalkylalkyl can be C3-C20 cycloheteroalkylalkyl.
In some of these embodiments,
In Formulas I, R1 is：H or-C=OR5, R5 are substituted or unsubstituted C1-C20 alkyl, or, substituted or unsubstituted
Phenyl (C1-C5) alkyl；
R2 is：Substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted phenyl (C1-C5) alkyl, or, substitution or
Unsubstituted morpholinyl (C1-C5) alkyl；
R3 is：Substituted or unsubstituted C1-C5 alkyl；
R4 is：Substituted or unsubstituted C1-C5 alkyl.
In some of these embodiments,
In Formulas I, R1 is：H or-C=OR5, R5 are C1-C20 alkyl or benzyl；
R2 is：C1-C5 alkyl, benzyl or 2- morpholinyl ethyls；
R3 is：C1-C5 alkyl or the C1-C5 alkyl of halogen substitution.
R4 is：C1-C5 alkyl or the C1-C5 alkyl of halogen substitution.
In some of these embodiments, lenalidomide derivative of the present invention, can enumerate and be as follows knot
Structure, but it is not limited to following structure：
The term " alkyl " used in the present invention refers to degree of unsaturation is only made up of and do not had carbon atom and hydrogen atom
The group of (such as double bond, three keys or ring), it covers various possible geometrical isomerism groups and alloisomerism group.The group
It is connected by singly-bound with the remainder of molecule.As the non-limiting examples of alkyl, following straight or branched can be enumerated
Group：Methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl and its it is other seven kinds it is different
Structure body, n-hexyl and its other 16 kinds of isomers, n-heptyl and its various isomers, n-octyl and its various isomers, just
Nonyl and its various isomers, positive decyl and its various isomers.
The term " cycloalkyl " used in the present invention refers to the non-aromatic ring system of saturation being made up of at least three carbon atom, should
Ring system can be monocyclic, bicyclic, polycyclic or condensed ring, bridged ring, loop coil., can be with as the non-limiting examples of cycloalkyl
Enumerate following group：Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl；And by two
Individual or multiple above-mentioned monocyclic condensed ring, bridged ring or spiro-cyclic groups formed by common edge and public carbon atom.
The term " aryl " used in the present invention can be used alone or the part as " aryl alkyl ", refers to contain altogether
There is the monocyclic of 6-14 yuan of rings, it is bicyclic, and the carbocyclic ring system of three rings, wherein, at least one member ring systems are aromatic, each of which
Individual member ring systems include 3-7 yuan of rings, and only an attachment point is connected with the remainder of molecule.Term " aryl " can and term
" aromatic rings ", which exchanges, to be used, as aromatic rings can include phenyl, naphthyl and anthryl.
The term " heteroaryl " used in the present invention refers to one or more hetero atoms independently selected from N, O or S
5-14 member heteroaromatic ring systems, the ring system can be it is monocyclic, bicyclic, polycyclic, wherein it is bicyclic and it is polycyclic can be by monocyclic logical
Cross singly-bound connected mode or fusion mode is formed.As the non-limiting examples of heteroaryl, following group can be enumerated：Oxazole
Base, isoxazolyls, imidazole radicals, furyl, indyl, isoindolyl, pyrrole radicals, triazolyl, triazine radical, tetrazole radical, thienyl,
Thiazolyl, isothiazolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl,
Benzimidazolyl, benzothienyl, benzopyranyl, carbazyl, quinolyl, isoquinolyl, quinazolyl, cinnolines base, naphthyridines
Base, pteridyl, purine radicals, quinoxalinyls, thiadiazolyl group, indolizine base, acridinyl, phenazinyl, phthalazinyl, cumarin base, pyrrole
Azoles and pyridine radicals, pyrido pyridazinyl, pyrrolopyridinyl, imidazopyridyl, pyrazolo pyridazine base；And by above-mentioned heteroaryl
The group that base is formed by way of singly-bound connected mode or fusion.
The term " aryl alkyl " used in the present invention refers to the alkyl that one or more hydrogen atoms are independently substituted by aryl,
Wherein described aryl and alkyl are as hereinbefore defined.Example includes benzyl, phenylethyl etc..
The term " heteroaryl alkyl " used in the present invention refers to what one or more hydrogen atoms were independently substituted by heteroaryl
Alkyl, wherein described heteroaryl and alkyl are as hereinbefore defined.Example includes 2- morpholinyl ethyls etc..
The compounds of this invention can also be used in the form of its pharmaceutically acceptable salt or solvate.Formulas I shownization
The physiologically receivable salt of compound is included by pharmaceutically acceptable inorganic acid or organic acid or inorganic base or organic base
The conventional salt of formation and the acid-addition salts of quaternary ammonium.The more specifically example of suitable hydrochlorate includes hydrochloric acid, hydrobromic acid, sulphur
Acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, butanedioic acid, hydroxyacetic acid, formic acid, lactic acid, maleic acid, tartaric acid,
Citric acid, flutter acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, first
The salt of sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, steroic, tannic acid etc..Suitable alkali salt
More specifically example include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, two
Monoethanolamine, ethylenediamine, N-METHYL-ALPHA-L-GLUCOSAMINE and procaine salt.
It is also another object of the present invention to provide the preparation method of above-mentioned compound of formula I.
The preparation method of R1=H provided by the present invention compound of formula I, comprises the steps：
1) compound shown in formula II is reacted with 2- amino phenyl acetyls amine, form the schiff base compounds shown in formula III；
Wherein, in formula II, formula III R3, R4 definition with R3, R4 in Formulas I；
2) bromacetate shown in formula IV is carried out catalytic addition reaction with the schiff base compounds shown in formula III, obtain formula
Compound shown in V；
Wherein, in formula IV R2 definition with the R2 in Formulas I；The same Formulas I of R2, R3, R4 definition in formula V；
3) compound shown in formula V is subjected to hydro-reduction, obtains the amino-compound shown in formula VI；
The same Formulas I of R2, R3, R4 definition in formula VI；
4) 2- bromomethyl -3- nitrobenzene methyls is carried out ring closure reaction with the amino-compound shown in formula VI, obtain
Compound shown in VII；
The same Formulas I of R2, R3, R4 definition in formula VII；
5) reduce the nitro in the compound shown in VII, obtain compound shown in R1=H Formulas I.
Wherein, the reaction condition reacted described in step 1) is：Reaction temperature is spent to 30 degree for -10, and the reaction time is 8 small
When -20 hours, the mol ratio of compound shown in the formula II and 2- amino phenyl acetyl amine is 1：1.0-1.5；The reaction exists
Carried out in solvent, the solvent is preferably methanol.
The reaction condition of catalytic addition reaction described in step 2) is：Reaction temperature is spent for 0 to -50, reaction time 2-8
Hour；The mol ratio of schiff base compounds shown in the formula III and the bromacetate shown in formula IV is 1:1-1.5；The catalysis
The catalyst that addition reaction uses is selected from following at least one：Diethyl zinc and diacetyl acetone nickel, the addition of the catalyst
Measure as 0.05-1 equivalents.The reaction is carried out in a solvent, and the solvent is preferably dichloromethane.
The reaction condition of hydro-reduction described in step 3) is：Reaction temperature 20-80 degree, hour in reaction time 3-10, instead
Answer pressure 1-10bar Hydrogen Vapor Pressures；The hydrogenation is carried out in a solvent, and the solvent is preferably methanol or ethanol.
Ring closure reaction described in step 4) is carried out in a solvent, and the solvent is preferably toluene；The ring closure reaction it is anti-
The condition is answered to be：3-10 hours are heated under reflux conditions；2- bromomethyls -3- the nitrobenzene methyls and the ammonia shown in formula VI
The mol ratio of based compound is 1.0-1.5:1.The ring closure reaction is carried out in the presence of alkalescence condition, and alkali used can be three
Ethamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylamino naphthyridine or sodium acetate etc., preferably triethylamine.The alkali with
The mol ratio of amino-compound shown in formula VI is 1-5：1.
Nitro described in step 5) reduction reaction condition be：Answer temperature 20-80 degree, hour in reaction time 3-10, reaction
Pressure 1-10bar Hydrogen Vapor Pressures；The hydrogenation is carried out in a solvent, and the solvent is preferably methanol or ethanol.
The preparation method of R1=-C=OR5 provided by the present invention compound of formula I, comprises the steps：
Amino in compound shown in R1=H Formulas I is acylated, obtains R1=-C=OR5 compound of formula I.
Another object of the present invention is to provide the application of above-mentioned compound of formula I.
The application of compound of formula I provided by the present invention includes following aspects：1) compound of formula I prepare prevention and/or
Treat the application in the medicine of inflammation；2) application of the compound of formula I in the medicine of prevention and/or treating cancer is prepared；3) Formulas I
Compound is preparing the application in suppressing cancer cell multiplication medicine.
Described inflammation includes acute inflammation, subacute inflammation and immune inflammation.
Described cancer includes various cancers (solid carcinoma or non-physical cancer) as known in the art, includes but is not limited to：
Lymph cancer, myeloma, liver cancer, cervical carcinoma, colon cancer, non-small cell lung cancer, breast cancer, the cancer of the esophagus, leukaemia.
Described cancer cell include lymphoma cell, myeloma cell, liver cancer cells, cervical cancer cell, colon cancer cell,
Non-small cell lung cancer cell, breast cancer cell, esophageal cancer cell, leukaemia.
The lymphoma cell concretely lymphoma cell P388D1 or NHL cell Raji
The myeloma cell concretely multiple myeloma cells ARH77.
The prevention that is prepared using the lenalidomide derivative shown in Formulas I as active component and/or treat inflammation medicine and
The medicine of prevention and/or treating cancer falls within protection scope of the present invention.
The medicine and the medicine of prevention and/or treating cancer of prevention and/or the treatment inflammation can be by injecting, spraying
Penetrate, collunarium, eye drip, infiltration, absorption, the method that physically or chemically mediates import body such as muscle, intracutaneous, subcutaneous, vein, mucous membrane
Tissue；Or imported body after other material mixings or parcel.
When needs, one or more pharmaceutically acceptable carriers can also be added in said medicine.The load
Body includes the conventional diluent of pharmaceutical field, excipient, filler, adhesive, wetting agent, disintegrant, sorbefacient, surface
Activating agent, absorption carrier, lubricant etc..
A variety of shapes such as parenteral solution, tablet, pulvis, granule, capsule, oral liquid, paste, creme can be made in said medicine
Formula.The medicine of above-mentioned various formulations can be prepared according to the conventional method of pharmaceutical field.
Lenalidomide derivative shown in Formulas I provided by the invention has obvious antiinflammatory action, and impassivity toxicity,
Anti-inflammatory drug design research and development field has a good application prospect.And the lenalidomide derivative shown in Formulas I has obvious resist
Cancer acts on, and is also had a good application prospect in the research and development field of cancer therapy drug.
Brief description of the drawings
Fig. 1 is the reacting flow chart of compound 6 prepared by embodiment 1.
Embodiment
The method of the present invention is illustrated below by specific embodiment, but the invention is not limited in this, it is all at this
All any modification, equivalent and improvement done within the spirit and principle of invention etc., should be included in the protection model of the present invention
Within enclosing.
Experimental method used in following embodiments is conventional method unless otherwise specified.
Material used, reagent etc., unless otherwise specified, are commercially obtained in following embodiments.
Composite part embodiment
Embodiment 1：3- (4- amino -1- isoindolinone -2- bases) -3- (3- ethoxy-4-methoxyphenyls) propionic acid first
Ester (compound 6)
1.1 steps 1, (E) -2- ((3- ethyoxyl -4- methoxybenzylidenes) amino) -2- phenyl acetamides (compound 2)
Preparation
The methoxybenzaldehyde of 3- ethyoxyls -4 (compound 1,31.0g, 172mmol) is dissolved in 200mL methanol, then
2- amino phenyl acetyls amine (25.8g, 172mmol) is added, is stirred at room temperature 18 hours.After reaction terminates, concentration of reaction solution, ethanol weight
Crystallization obtain white solid (E) -2- ((3- ethyoxyl -4- methoxybenzylidenes) amino) -2- phenyl acetamides (23.6g,
44.0%).1H NMR(DMSO-d6,400MHz)δ8.74(s,1H),7.58-6.95(m,8H),5.36(s,1H),4.09(m,
2H),3.83(s,3H),1.32(m,3H).ESI-MS m/z:313.4[M+H]+.
1.2 steps 2,3- ((2- amino -2- oxygen -1- phenylacetylaminos) -3- (3- ethoxy-4-methoxyphenyls) propionic acid
The preparation of methyl esters (compound 3)
By (E) -2- ((3- ethyoxyl -4- methoxybenzylidenes) amino) -2- phenyl acetamides (compound 2,23.6g,
75.6mmol) it is dissolved in 150mL dichloromethane, cools to -30 degree, add diethyl zinc to reaction solution respectively
(121mL, 21mmol, 1M hexane solution), diacetyl acetone nickel (0.646g, 2.52mmol), bromoacetate (13.8g,
90.7mmol), constant temperature stirs 3 hours.Reaction adds frozen water and reaction, organic phase concentration is quenched after terminating, Liquid Residue column chromatography obtains
To transparent yellow liquid 3- ((2- amino -2- oxygen -1- phenylacetylaminos) -3- (3- ethoxy-4-methoxyphenyls) methyl propionates
(12.0g, 41.3%).1H NMR(DMSO-d6,400MHz)δ7.33-6.83(m,8H),4.85(s,1H),4.54(m,1H),
4.09(m,2H),3.83(s,3H),3.68(s,3H),2.75(m,2H),1.33(m,3H).ESI-MS m/z:387.4[M+H
]+.
The preparation of 1.3 steps 3,3- amino -3- (3- ethoxy-4-methoxyphenyls) methyl propionates (compound 4)
By 3-, ((2- amino -2- oxygen -1- phenylacetylaminos) -3- (3- ethoxy-4-methoxyphenyls) methyl propionate (is changed
Compound 3,12.0g, 31.0mmol) it is dissolved in 80mL methanol, add 10% palladium carbon (1.90g, H20w/w=50%), mixed liquor
In 9bar hydrogen environments high-pressure stirring 16 hours.Reacting liquid filtering, mother liquor are concentrated under reduced pressure.Residual grease is recrystallized to give pale yellow
Color solid 3- amino -3- (3- ethoxy-4-methoxyphenyls) methyl propionate (5.00g, 64.1%).1H NMR(DMSO-d6,
400MHz)δ6.96-6.83(m,3H),4.54(m,1H),4.09(m,2H),3.83(s,3H),3.68(s,3H),2.88(m,
2H),1.32(m,3H).ESI-MS m/z:276.3[M+Na]+.
1.4 steps 4,3- (3- ethoxy-4-methoxyphenyls) -3- (4- nitro -1- isoindolinone -2- bases) propionic acid
The preparation of methyl esters (compound 5)
3- amino -3- (3- ethoxy-4-methoxyphenyls) methyl propionate (compound 4,5.00g, 19.7mmol) is molten
Solution is separately added into triethylamine (2.00g, 19.7mmol), 2- bromomethyl -3- nitrobenzene methyls in 80mL toluene
(4.83g, 17.8mmol), mixed liquor flow back 5 hours in 110 degree.Reaction solution is concentrated under reduced pressure, and residue column chromatography obtains yellow
Solid 3- (3- ethoxy-4-methoxyphenyls) -3- (4- nitro -1- isoindolinone -2- bases) methyl propionate (4.00g,
49.0%).1H NMR(DMSO-d6,400MHz)δ8.33-6.83(m,6H),5.54(m,1H),4.22(s,2H),4.09(m,
2H),3.83(s,3H),3.68(s,3H),2.92(m,2H),1.32(m,3H).ESI-MS m/z:415.3[M+H]+.
1.5 steps 5,3- (4- amino -1- isoindolinone -2- bases) -3- (3- ethoxy-4-methoxyphenyls) propionic acid
The preparation of methyl esters (compound 6)
By 3- (3- ethoxy-4-methoxyphenyls) -3- (4- nitro -1- isoindolinone -2- bases) methyl propionate (chemical combination
Thing 5,4.00g, 9.66mmol) it is dissolved in 80mL tetrahydrofurans, add 10% palladium carbon (1.0g, H20w/w=50%), react
Liquid high-pressure stirring 16 hours under 9bar hydrogen environments.Reacting liquid filtering, mother liquor are concentrated under reduced pressure, and Liquid Residue is recrystallized to give white
Solid 3- (4- amino -1- isoindolinone -2- bases) -3- (3- ethoxy-4-methoxyphenyls) methyl propionate (2.20g,
59.2%).1H NMR(DMSO-d6,400MHz)δ7.27-6.72(m,6H),6.27(s,2H),5.54(m,1H),4.22(S,
2H),4.09(m,2H),3.83(s,3H),3.68(s,3H),2.92(m,2H),1.32(m,3H).ESI-MS m/z:385.3[M
+H]+.
Embodiment 2：3- (4- acetylaminohydroxyphenylarsonic acid 1- isoindolinone -2- bases) -3- (3- ethoxy-4-methoxyphenyls) third
Sour methyl esters (compound 7)
By 3- (4- amino -1- isoindolinone -2- bases) -3- (3- ethoxy-4-methoxyphenyls) methyl propionate
(1.0g, 2.6mmol) is dissolved in 10mL tetrahydrofurans, respectively into reaction add dicyclohexylcarbodiimide (0.54g,
2.6mmol), DMAP (0.32g, 2.6mmol), acetic acid (0.16g, 2.6mmol), are stirred at room temperature 10 hours.Cross
Reaction solution is filtered, is concentrated under reduced pressure, column chromatography obtains white solid 3- (4- acetylaminohydroxyphenylarsonic acid 1- isoindolinone -2- bases) -3- (3- second
Epoxide -4- methoxyphenyls) methyl propionate (0.97g, 88.2%).1H NMR(DMSO-d6,400MHz)δ7.65-6.74(m,
6H),5.51(m,1H),4.22(S,2H),4.09(m,2H),3.83(s,3H),3.68(s,3H),2.92(m,2H),2.04(s,
2H),1.32(m,3H).ESI-MS m/z:449.5[M+Na]+.
Embodiment 3：3- (1- oxygen -4- pentanamide isoindolinone -2- bases) -3- (3- ethoxy-4-methoxyphenyls) third
Sour methyl esters (compound 8)
For method with embodiment 2, raw material is 3- (4- amino -1- isoindolinone -2- bases) -3- (3- ethyoxyl -4- methoxyl groups
Phenyl) methyl propionate and valeric acid, obtain white solid powder, yield：92.5%.1H NMR(DMSO-d6,400MHz)δ7.65-
6.74(m,6H),5.51(m,1H),4.22(S,2H),4.09(m,2H),3.83(s,3H),3.68(s,3H),2.92(m,2H),
2.39(m,2H),1.63(m,2H),1.32(m,2H),0.90(m,3H).ESI-MS m/z:469.5[M+H]+.
Embodiment 4：3- (4- decanamido -1- isoindolinone -2- bases) -3- (3- ethoxy-4-methoxyphenyls) third
Sour methyl esters (compound 9)
For method with embodiment 2, raw material is 3- (4- amino -1- isoindolinone -2- bases) -3- (3- ethyoxyl -4- methoxyl groups
Phenyl) methyl propionate and capric acid, obtain white solid powder, yield：85.6%.1H NMR(DMSO-d6,400MHz)δ7.65-
6.74(m,6H),5.51(m,1H),4.22(S,2H),4.09(m,2H),3.83(s,3H),3.68(s,3H),2.92(m,2H),
2.39(m,2H),1.63-1.29(m,14H),0.88(m,3H).ESI-MS m/z:539.5[M+H]+.
Embodiment 5：3- (4- stearoylketene amino -1- isoindolinone -2- bases) -3- (3- ethoxy-4-methoxyphenyls)
Methyl propionate (compound 10)
For method with embodiment 2, raw material is 3- (4- amino -1- isoindolinone -2- bases) -3- (3- ethyoxyl -4- methoxyl groups
Phenyl) methyl propionate and Eighteen alkyl acid, obtain white solid powder, yield：80.6%.1H NMR(DMSO-d6,400MHz)
δ7.65-6.74(m,6H),5.51(m,1H),4.22(S,2H),4.09(m,2H),3.83(s,3H),3.68(s,3H),2.92
(m,2H),2.39(m,2H),1.63-1.26(m,30H),0.88(m,3H).ESI-MS m/z:673.7[M+Na]+.
Embodiment 6：3- (4- phenylacetylamino -1- isoindolinone -2- bases) -3- (3- ethoxy-4-methoxyphenyls)
Methyl propionate (compound 11)
For method with embodiment 2, raw material is 3- (4- amino -1- isoindolinone -2- bases) -3- (3- ethyoxyl -4- methoxyl groups
Phenyl) methyl propionate and phenylacetic acid, obtain white solid powder, yield：80.6%.1H NMR(DMSO-d6,400MHz)δ
7.65-6.74(m,11H),5.51(m,1H),4.22(s,2H),4.09(m,2H),3.90(s,2H),3.83(s,3H),3.68
(s,3H),2.92(m,2H),1.32(m,3H).ESI-MS m/z:503.5[M+H]+.
Embodiment 7：3- (4- amino -1- isoindolinone -2- bases) -3- (3- (2,2,2- trifluoro ethoxies) -4- methoxyl groups
Phenyl) methyl propionate (compound 12)
The methoxybenzaldehyde of raw material 3- ethyoxyls -4 in its step 1.1 need to only be replaced with 4- first by method with embodiment 1
Epoxide -3- (2,2,2- trifluoro ethoxy) benzaldehyde, obtains white solid powder, total recovery：4.25%.1H NMR(DMSO-
d6,400MHz)δ7.27-6.74(m,6H),6.27(s,2H),5.51(m,1H),4.46(s,2H),3.83(s,3H),3.68
(s,3H),2.92(m,2H).ESI-MS m/z:439.5[M+H]+.
Embodiment 8：3- (4- amino -1- isoindolinone -2- bases) -3- (3- ethyoxyl -4- propoxyphenyls) propionic acid first
Ester (compound 14)
Raw material 3- ethyoxyls -4-methoxybenzaldehyde in its step 1.1 need to only be replaced with 3- by method with embodiment 1
Ethyoxyl -4- propoxybenzaldehydes, obtain white solid powder, total recovery：5.13%.1H NMR(DMSO-d6,400MHz)δ
7.27-6.74(m,6H),6.27(s,2H),5.51(m,1H),4.42(s,2H),4.09(m,4H),3.68(s,3H),2.92
(m,2H),1.74(m,2H),1.32(m,3H),0.90(m,3H).ESI-MS m/z:413.5[M+H]+.
Embodiment 9：3- (4- amino -1- oxoisoindolines -2- bases) -3- (3- ethoxy-4-methoxyphenyls) propionic acid
Benzyl ester (compound 19)
Raw material bromoacetate in its step 1.2 need to only be replaced with benzyl acetate bromide, obtained by method with embodiment 1
White solid powder, total recovery：5.33%.1H NMR(DMSO-d6,400MHz)δ7.47-6.74(m,11H),6.27(s,
2H),5.51(m,1H),5.20(s,2H),4.22(s,2H),4.09(m,2H),3.83(s,3H),2.92(m,2H),1.32(m,
3H).ESI-MS m/z:483.5[M+Na]+.
Embodiment 10：3- (4- amino -1- oxoisoindolines -2- bases) -3- (3- ethoxy-4-methoxyphenyls) third
Acid -2- morpholine ethyl esters (compound 20)
Method only need to replace with the raw material bromoacetate in its step 1.2 bromoacetic acid -2- morpholine second with embodiment 1
Ester, obtain white solid powder, total recovery：3.82%.1H NMR(DMSO-d6,400MHz)δ7.27-6.74(m,6H),6.27
(s,2H),5.51(m,1H),4.35(m,2H),4.22(s,2H),4.09(m,2H),3.83(s,3H),3.65(m,4H),2.97
(m,2H),2.67(m,2H),2.36(m,4H),1.32(m,3H).ESI-MS m/z:506.5[M+Na]+.
According to above-described embodiment, those skilled in the art can be reasonably selected reaction raw materials, so as to synthesize this
The compound of the claimed other similar structures of invention right.
Comparative example 1：3- (5- amino -1- isoindolinone -2- bases) -3- (3- ethoxy-4-methoxyphenyls) propionic acid first
Ester (compound 15)
Method need to only replace with the raw material 2- bromomethyl -3- nitrobenzene methyls in its step 1.4 with embodiment 1
4- nitro -2- bromomethyl-benzoic acid methyl esters, obtain white solid powder, total recovery：4.68%.1H NMR(DMSO-d6,
400MHz)δ7.66-6.35(m,6H),6.27(s,2H),5.51(m,1H),4.42(s,2H),4.09(m,2H),3.83(s,
3H),3.68(s,3H),2.92(m,2H),1.32(m,3H).ESI-MS m/z:407.5[M+Na]+.
Comparative example 2：3- (4- amino -1,3- dioxoisoindolin 2- yls) -3- (3- ethoxy-4-methoxyphenyls) third
Sour methyl esters (compound 16)
It is prepared by the method that its preparation method can refer to known similar compound.
Drug effect section Example
Embodiment 11：Antiinflammatory action effect test
Choose 130 Kunming mouses, SPF levels, male, 15-17g.Quarantine 3 days, quarantine are divided at random after terminating by body weight
Into 13 groups, every group 10, i.e.,：Model group, embodiment compound experimental group be divided into 10 groups, comparative example compound experimental group be divided into 2
Group.Auricle edema is caused in the wide dimethylbenzene (0.03mL/ is only) that applies of each mouse auris dextra during experiment, is compared with left ear, applies dimethylbenzene 30min
Tail vein gives corresponding medicine afterwards, and 10mg/kg body weight is administered, and model group gives the physiological saline of isometric(al).1 hour after administration
De- cervical vertebra puts to death mouse, and ears are cut with position homalographic with diameter 8mm card punch, are weighed with precision electronic balance, right
The difference that auricle subtracts the weight of left auricle weight again is swelling.
The paraxylene of table 1 causes the influence of Kunming mouse ear swelling
Compared with model group：*p<0.05, * * p<0.01.
Embodiment 12：Neurotoxicity compares
Health is taken without pregnant NIH mouse 130,18~22g of body weight, male and female half and half.During experiment by sex, body weight by mouse with
Machine is divided into 3 groups, every group of l0 only, male and female half and half.Experiment same day compound is divided into 12 groups (10mg/kg), and negative control group gavage is given
Isometric sodium chloride injection is given, observes mouse toxicity response situation after administration immediately, the reaction after mouse administration is recorded and holds
The continuous time；Continuous Observation 14d after administration.Enter respectively for the behavior expression after the mouse administration of negative control group, compound group
Go the record of each side, the results are shown in Table 2.
Compound 15 and compound 16 have a neurotoxicity, and the wherein neurotoxicity of compound 16 is larger；And embodiment 1-10
Compound does not have discovery to have neurotoxicity.
Embodiment 13, antitumous effect experiment
Select mouse lymphoma cell P388D1, NHL cell Raji, multiple myeloma cells ARH77
Tumour cell determines the IC of embodiment compound50。
Medicine and preparation of reagents：One liter of one bag of RPMI1640 culture mediums plus water, add 2 grams of sodium acid carbonates, and 100,000 units are blue or green
Mycin and 100mg streptomysins, regulation pH value are degerming with 0.22 μm of degerming membrane filtration to 7.4.95ml culture mediums add inactivation newborn
Cow's serum 5ml is complete culture solution.Trypsase is made into 0.25% solution with D-hanks buffer solutions, 4 DEG C of guarantors after filtration sterilization
Deposit standby.
It is accurate to claim each compound of embodiment and each 100mg of lenalidomide, it is added in the 1.5ml centrifuge tubes of sterilizing, adds
DMSO 1ml, it is made into 100mg/ml stostes, -20 DEG C of freezen protectives.Take after melting before use and be diluted in right amount with complete culture solution
Respective concentration application.
Cell culture and passage：All equal adhere-wall cultures of cell are in the Tissue Culture Flask of complete culture solution containing 10ml, in 37
DEG C, 5%CO2, full close cultivate under humidity.Cell is washed twice after covering with bottom of bottle with sterilizing D-hanks liquid, adds 0.25% trypsase
Vitellophag 2 minutes, outwells trypsase, after jog cell can be completely fallen off, after adding full nutrient solution 30ml, uses pipette
Cell is dispelled, is sub-packed in 3 new Tissue Culture Flasks, continues to cultivate.
Drug-treated：One bottle of the cell just covered with is taken, cell is collected after Trypsin Induced, is blown and beaten with pipette equal
It is even, two drop cell suspension Trypan Blues are taken, the living cell counting number under microscope, cell number are adjusted with complete culture solution
To 1 × 105Individual cells/ml.100 μ l cell suspensions are added per hole in 96 porocyte culture plates, culture plate is placed in CO2Training
Support and cultivate 12 hours in case, taking-up culture plate after the complete culture solution that 100 μ l Experimental agents containing various concentrations are added in every hole,
Each concentration sets 4 parallel holes, and separately setting 4 hole cells additions, drug containing complete culture solution does not make negative control hole, and 4 hole cells, which add, to be contained
The complete culture solution of vincristine makees positive control, the final concentration of 5 μ g/ml of vincristine.Culture plate is in microwell plate after adding medicine
Vibrate and mix on oscillator, be placed in CO2Continue culture 48 hours in incubator.Culture plate is taken out, 10 μ l 5mg/ml are added per hole
MTT liquid, vibration mix, continue culture 4 hours, discard original fluid, in every hole add the μ l of DMSO 150, fully vibration with molten
Bluish violet crystallization is solved, in the light absorbs that each hole is determined on the ELIASAs of Bio-Rad 550, determines wavelength 570nm, reference wavelength
630nm。
The inhibiting rate of medicine cell proliferation is calculated according to each hole OD values：
Inhibiting rate makees linear regression according to corresponding to the logarithm of drug concentration, obtains linear equation, calculates inhibiting rate and exists
Corresponding drug concentration is 503nhibiting concentration (IC of the Experimental agents to tumour cell when 50%50)。
503nhibiting concentration (IC of the compound to different tumor cell lines50, μ g/ml)
Embodiment compound 6-14,19 are better than compound for above-mentioned tumour cell P388D1 and Raji inhibitory action
15th, 16 and lenalidomide, it is better than 15 and 16 for ARH77 tumour cell embodiments 6-14, it is close with lenalidomide.
Claims (10)
1. compound or its pharmaceutically acceptable salt shown in Formulas I：
In Formulas I, R1 is：H or-C=OR5, wherein, R5 is substituted or unsubstituted following radicals：C1-C20 alkyl, aryl,
Heteroaryl, cycloalkyl, aryl alkyl, cycloheteroalkylalkyl or C1-C8 alkyl-OR6；R6 is substituted or unsubstituted following radicals：
C1-C20 alkyl, aryl alkyl or cycloheteroalkylalkyl；
R2 is：Substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted heterocyclic radical
Alkyl；
R3 is：Substituted or unsubstituted C1-C20 alkyl；
R4 is：Substituted or unsubstituted C1-C20 alkyl.
Wherein, the substituent in the alkyl, aryl, heteroaryl, cycloalkyl, aryl alkyl and the cycloheteroalkylalkyl that each substitute is independent
Ground is optionally from following radicals：Halogen, hydroxyl, amino and nitro；The halogen refers to F, Cl, Br or I；The alkyl be straight chain or
The alkyl of side chain.
2. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that：The cycloalkyl is
C3-C20 cycloalkyl, the aryl alkyl are C6-C20 aryl alkyl, and the cycloheteroalkylalkyl is C3-C20 heterocyclic radical
Alkyl.
3. compound according to claim 1 or 2 or its pharmaceutically acceptable salt, it is characterised in that：
In the Formulas I, R1 is：H or-C=OR5, R5 are substituted or unsubstituted C1-C20 alkyl, or, substituted or unsubstituted
Phenyl (C1-C5) alkyl；
R2 is：Substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted phenyl (C1-C5) alkyl, or, substitute or do not take
Morpholinyl (C1-C5) alkyl in generation；
R3 is：Substituted or unsubstituted C1-C5 alkyl；
R4 is：Substituted or unsubstituted C1-C5 alkyl.
4. compound or its pharmaceutically acceptable salt according to any one of claim 1-3, it is characterised in that：It is described
In Formulas I, R1 is：H or-C=OR5, R5 are C1-C20 alkyl or benzyl；
R2 is：C1-C5 alkyl, benzyl or 2- morpholinyl ethyls；
R3 is：C1-C5 alkyl or the C1-C5 alkyl of halogen substitution
R4 is：C1-C5 alkyl or the C1-C5 alkyl of halogen substitution.
5. compound or its pharmaceutically acceptable salt according to any one of claim 1-4, it is characterised in that：It is described
Compound shown in Formulas I includes following any shown compounds：
6. the preparation method of compound, comprises the steps shown in the Formulas I of the R1=H described in claim 1：
1) compound shown in formula II is reacted with 2- amino phenyl acetyls amine, form the schiff base compounds shown in formula III；
Wherein, in formula II, formula III R3, R4 definition with R3, R4 in Formulas I；
2) bromacetate shown in formula IV is carried out catalytic addition reaction with the schiff base compounds shown in formula III, obtain the institute of formula V
The compound shown；
Wherein, in formula IV R2 definition with the R2 in Formulas I；The same Formulas I of R2, R3, R4 definition in formula V；
3) compound shown in formula V is subjected to hydro-reduction, obtains the amino-compound shown in formula VI；
The same Formulas I of R2, R3, R4 definition in formula VI；
4) 2- bromomethyl -3- nitrobenzene methyls is carried out ring closure reaction with the amino-compound shown in formula VI, obtain VII institute
The compound shown；
The same Formulas I of R2, R3, R4 definition in formula VII；
5) reduce the nitro in the compound shown in VII, obtain compound shown in R1=H Formulas I.
7. the preparation method of compound, comprises the steps shown in the Formulas I of the R1=-C=OR5 described in claim 1：
Amino in compound shown in R1=H Formulas I is acylated, obtains R1=-C=OR5 compound of formula I.
8. compound shown in the Formulas I any one of claim 1-5 or its pharmaceutically acceptable salt are preparing following medicines
Application in thing：1) prevent and/or treat the medicine of inflammation；2) medicine of prevention and/or treating cancer；3) suppress cancer cell to increase
The medicine grown.
9. a kind of medicine, its active component is compound shown in Formulas I described in claim any one of 1-5 or it can pharmaceutically connect
The salt received；The medicine is：1) prevent and/or treat the medicine of inflammation；2) medicine of prevention and/or treating cancer；3) suppress
The medicine of cancer cell multiplication.
10. the medicine described in application according to claim 8 or claim 9, it is characterised in that：The inflammation includes anxious
Property inflammation, subacute inflammation and immune inflammation；
The cancer includes solid carcinoma or non-physical cancer, more specifically including lymph cancer, myeloma, liver cancer, cervical carcinoma, colon
Cancer, non-small cell lung cancer, breast cancer, the cancer of the esophagus and leukaemia；
The cancer cell includes：It is lymphoma cell, myeloma cell, liver cancer cells, cervical cancer cell, colon cancer cell, non-small
Cell lung cancer cell, breast cancer cell, esophageal cancer cell, leukaemia.
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| CN110498759A (en) * | 2019-09-12 | 2019-11-26 | 天津瑞岭化工有限公司 | The synthetic method of isoindoline ketone compound |
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| CN1420889A (en) * | 1999-11-12 | 2003-05-28 | 塞尔基因公司 | Pharmaceutically active isoindoline derivs. |
| WO2006069798A1 (en) * | 2004-12-28 | 2006-07-06 | Dsm Ip Assets B.V. | Process for the preparation of chiral amines |
| CN1802353A (en) * | 2002-12-30 | 2006-07-12 | 细胞基因公司 | Fluoroalkoxy-substituted 1,3-dihydro-isoindolyl compounds and their pharmaceutical uses |
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| US5463063A (en) * | 1993-07-02 | 1995-10-31 | Celgene Corporation | Ring closure of N-phthaloylglutamines |
| CN101074210A (en) * | 1999-11-12 | 2007-11-21 | 塞尔基因公司 | Pharmaceutically active isoindoline derivatives |
| US6326388B1 (en) * | 1999-12-21 | 2001-12-04 | Celgene Corporation | Substituted 1,3,4-oxadiazoles and a method of reducing TNF-alpha level |
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| CN1420889A (en) * | 1999-11-12 | 2003-05-28 | 塞尔基因公司 | Pharmaceutically active isoindoline derivs. |
| CN1802353A (en) * | 2002-12-30 | 2006-07-12 | 细胞基因公司 | Fluoroalkoxy-substituted 1,3-dihydro-isoindolyl compounds and their pharmaceutical uses |
| WO2006069798A1 (en) * | 2004-12-28 | 2006-07-06 | Dsm Ip Assets B.V. | Process for the preparation of chiral amines |
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| CN110498759A (en) * | 2019-09-12 | 2019-11-26 | 天津瑞岭化工有限公司 | The synthetic method of isoindoline ketone compound |
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