CN107556311A - A kind of lenalidomide analog - Google Patents
A kind of lenalidomide analog Download PDFInfo
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- CN107556311A CN107556311A CN201711049481.5A CN201711049481A CN107556311A CN 107556311 A CN107556311 A CN 107556311A CN 201711049481 A CN201711049481 A CN 201711049481A CN 107556311 A CN107556311 A CN 107556311A
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- alkyl
- unsubstituted
- substituted
- circle heterocycles
- lenalidomide
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Abstract
The invention provides the compound or its pharmaceutically acceptable salt that one kind has following formula (I) expression；
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to a kind of lenalidomide analog.
Background technology
Lenalidomide is the 2nd generation oral immunity regulating drug of Celgene companies research and development.On lenalidomide phthalyl ring
The amino of C4 positions make it that its chemical property is more more stable than Thalidomide, and there is stronger suppression angiogenesis and immunological regulation to make
With；And Thalidomide is compared, its clinical practice is safer, and adverse reaction is smaller, almost without neurotoxicity and teratogenesis.
Food and drug administration (FDA) ratifies it in December, 2005 and is used for myelodysplastic syndrome
(MDS) treatment, ratify it in June, 2006 and be applied to the treatment of Huppert's disease (MM), ratify it in March, 2013 and be used to cover
The treatment of cell lymphoma (MCL).
At present clinically, lenalidomide is mainly used in the treatment of Huppert's disease, its immunosuppressive action need into
One step is developed.We carry out the modification and transformation of structure to the medicine, it is desirable to obtain new compound in immunization therapy, such as class
There is more preferable clinical effectiveness in terms of the diseases such as rheumatic arthritis.
The content of the invention
Enter to advance it is an object of the invention to disclose a kind of lenalidomide analog, and to lenalidomide of the prior art
One step is modified, and to strengthen target-oriented drug, is improved and is realized more preferable therapeutic effect to diseases such as Huppert's disease and arthritis.
To achieve the above object, the invention provides one kind the compound or its is pharmaceutically acceptable that following formula (I) represents
Salt；
Wherein, in formula (I)：
A be selected from singly-bound-C (=O)-,-C (=O) O- ,-S (=O)2- ,-C (=O) NH- ,-NH- ,-S (=O) NH- ,-S
(=O)2NH-；
B is selected from C and N；
R is selected from H, CN, OH, NH2、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2Or halogen；
R1Selected from OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, substituted C3-C6First cycloalkanes
Base, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl, unsubstituted C3-C6Member
Cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl；
R2And R3Simultaneously or it is respectively selected from H, OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl,
Substituted C3-C6First cycloalkyl, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6It is miscellaneous
Alkyl, unsubstituted C3-C6First cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl.
Compared with prior art, the beneficial effects of the invention are as follows：A kind of lenalidomide analog of announcement of the present invention,
JAK3 can effectively and selectively be suppressed and block the gene expression of cytokine signaling and cytokine induction, through experiment
Prove, more good therapeutic effect is achieved to diseases such as arthritis, Huppert's diseases, and improve the security of medication
With reliability.
Embodiment
With reference to each embodiment, the present invention is described in detail, but it should explanation, these embodiments are simultaneously
Non- limitation of the present invention, those of ordinary skill in the art are according in these embodiment institute work energy, method or structures
Equivalent transformation or replacement, belong within protection scope of the present invention.
Unless otherwise specified, the term " room temperature " in each embodiment of this specification is specially 23 DEG C；When term " h " is specially
Between measurement unit：Hour；Term " min " is specially time measurement unit：Minute；Term " ml " is specially volume unit：Milliliter；
Term " L " is specially volume unit：Rise；Term " mol/L " is specially concentration unit.Term " mmol " is specially the amount of material
Unit, i.e., mM；Term " mg " is unit of weight, i.e. milligram.
Present embodiment discloses a kind of lenalidomide analog, its have following formula (I) represent compound or its
Pharmaceutically acceptable salt；
Wherein, in formula (I)：
A be selected from singly-bound-C (=O)-,-C (=O) O- ,-S (=O)2- ,-C (=O) NH- ,-NH- ,-S (=O) NH- ,-S
(=O)2NH-；
B is selected from C and N；
R is selected from H, CN, OH, NH2、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2Or halogen；
R1Selected from OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, substituted C3-C6First cycloalkanes
Base, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl, unsubstituted C3-C6Member
Cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl；
R2And R3Simultaneously or it is respectively selected from H, OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl,
Substituted C3-C6First cycloalkyl, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6It is miscellaneous
Alkyl, unsubstituted C3-C6First cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl.
Meanwhile this specification also discloses a kind of compound of formula (I) expression or the synthesis of its pharmaceutically acceptable salt
Method.The synthetic method is that 10 steps react (i.e. step a~step j), the following institute of reaction equation involved by its synthetic route
Show：
Step a
Dichloromethane 10ml, 2- amino -4- nitropyridines (215mg, 1.4mmol) starting material is added into 50ml reaction bulbs
Bromo- 2 oxo-acetic acid ethyl esters (280ml, 1.4mmol) of 1 and 2-, room temperature magnetic agitation react 1~2h, are concentrated under reduced pressure and remove solvent,
Residue is heated to reflux 3h after being dissolved with 10ml ethanol, TLC detection reactions are complete.Reaction solution is concentrated under reduced pressure after naturally cooling to room temperature
Remove ethanol.Residue is washed with saturated sodium bicarbonate solution, and water layer is extracted with dichloromethane, and organic layer solution uses anhydrous sulphur
Sour sodium is dried overnight, and is filtered and is concentrated, and residue is separated using silica gel column chromatography, obtains yellow solid, produces intermediate 2.
Step b
Under normal temperature condition, 150mg intermediates 2 are dissolved in the absolute ethyl alcohol that 20ml concentration is 1mol/L, it is dense gradually to add 2ml
Spend and protected for 1mol/L hydrochloric acid and 15mg platinum dioxides, nitrogen, be passed through hydrogen (50psi) and react 16h in 50 DEG C of magnetic agitations,
TLC detection reactions are complete, reaction solution concentrated half, filter, obtain white solid 120mg, produce intermediate 3.
Step c
100mg intermediates 3 and the chloro- 7- nitros of 2- (p-toluenesulfonyl) -4--isoindoline -3- ketone 185mg are dissolved in
5ml n-butanols, 158mgDIEA (DIPEA) is continuously added, magnetic agitation, is heated to back flow reaction 16h, TLC
Detection reaction is complete, and reaction solution pressurization concentration, residue is diluted with 10ml water, and aqueous phase ethyl acetate extracts 3 times, each 20ml, closes
And organic layer solution and stayed overnight using anhydrous sodium sulfate drying, filter, be concentrated under reduced pressure, residue uses silica gel column chromatography separation (PE:
EA=1：2) light yellow solid 68mg, is obtained, produces intermediate 4.
Wherein, PE is petroleum ether, and EA is ethyl acetate.To washing used in the separation of residue silica gel column chromatography in step c
De- liquid is selected from the mixed solution of petroleum ether and ethyl acetate, and the mol ratio of eluent petrochina ether and ethyl acetate is 1:2.
Step d
Condition of ice bath, nitrogen protection, adds 3.1g intermediates 4 into 250ml there-necked flasks and THF120ml is (specially anhydrous
Tetrahydrofuran), magnetic agitation, NaH about 500mg, insulation reaction 1h is added portionwise, iodomethane about 7.5g, drop is then gradually added dropwise
Adding complete, warm naturally to room temperature, react 1h, TLC detection reactions are complete, add 10ml saturated ammonium chloride solutions extraction and go out reaction,
Then frozen water 50ml, DCM/MeOH (3 is added:1) extract 3 times, each 50ml, merge organic layer solution, and to organic layer solution
Stayed overnight, filtered using anhydrous sodium sulfate drying, obtain intermediate 5 after filtrate concentration, intermediate 5 is not purified, is directly used in down
Single step reaction.
Step e
Room temperature condition, intermediate 5 obtained by step d is dissolved in the ethanol solution that 20ml concentration is 1mol/L, adds ethanol
Sodium 1.0g, insulated and stirred 16~20h, TLC detection reaction is complete, and reaction solution concentration, residue is diluted with 50ml water, layering, water layer
Extracted 3 times with dichloromethane 30ml, merge organic layer solution, and organic layer solution is stayed overnight using anhydrous sodium sulfate drying, taken out
Filter, filtrate concentration, residue are obtained using silica gel column chromatography separation (DCM/MeOH=1/1~10/1, mol ratio in eluent)
The about 58.9mg of intermediate 6, yield 58.2%.
Step f
Condition of ice bath, 500mg intermediates 6 are dissolved in 10mlTHF (anhydrous tetrahydro furan), 111mg tetrahydrochysene lithiums are added portionwise
Aluminium, warm naturally to react at room temperature 2h after adding, TLC detection reactions are complete, are cooled to 0 DEG C, add frozen water 10ml extractions and go out, mistake
Filter, water layer DCM/MeOH (10:1) extract 3 times, each 20ml, merge organic layer solution, and organic layer solution is used anhydrous
Sodium sulphate is dried overnight, and is filtered, and filtrate decompression concentration, obtains the crude product of intermediate 7, the crude product of intermediate 7 is not purified to be directly used in down
Single step reaction.
Step g
By 128mg intermediates 7,50wt% ethanol 10ml, 2 drop hydrochloric acid and 4mg iron powders are added to hydriding reactor, reacted at room temperature
8h, filter, filtrate concentration, obtain colourless oil liquid 100mg, produce intermediate 8.
Step h
Under normal temperature condition, 150mg intermediates 8 are dissolved in 10ml anhydrous methylene chlorides, add thionyl chloride 300mg, 70 DEG C
Magnetic agitation reacts 1h, and TLC detection reactions are complete, and reaction solution is concentrated under reduced pressure, and obtains the crude product of intermediate 9, the crude product of intermediate 9 is not
It is purified, it is directly used in and reacts in next step.
Step i
150mg intermediates 9 are dissolved in 10mlDMSO (dimethyl sulfoxide (DMSO)), 41mg Cymags is added, is warming up to 40 DEG C of reactions
10h, TLC detection reaction terminate, and are naturally cooling to room temperature, add 10ml frozen water extraction and go out, solution dichloromethane extraction 2 times, often
Secondary 20ml, merge organic layer solution, and organic layer solution is washed 2 times using saturated brine, each 10ml, then using anhydrous
Sodium sulphate is dried overnight, and is filtered, filtrate concentration, and residue uses silica gel column chromatography separation (PE:EA=1：2) white solid, is obtained
60mg, produce intermediate 10.
Step j
500mg racemate intermediates 10 are split by hand-type post, then respectively with isopropanol 35 DEG C recrystallize white
Solid, target product 11 and target product 12 are produced, optical purity is above 99.5%.
The arthritis model test of pesticide effectiveness of rat adjuvant induction
The treatment of arthritis of the arthritis model checking the compounds of this invention induced with rat adjuvant acts on.Female, body weight
After 160-180g Lewis rat isoflurane anesthesias, 0.1ml mycobacterium tuberculosis suspension is registered under left back foot skin.Making
Mould is grouped after 13 days and gives corresponding test-compound, and the test-compound for such as giving 10mpk respectively to rat is dissolved in
In DMSO/PEG400/H2O mixed solvents, and orally give Female Lewis rats (animal subject of each dosage group be 10
Only), successive administration 2 weeks, rat state is during which observed, sufficient volume swelling situation is recorded and scores.Tested experiment shows compound
WXFQ-0104 etc. is respectively provided with good arthritis inhibitory activity.
| Compound | AUC (%) |
| Vehicle control group | |
| WXFQ-0101 | 56 |
| WXFQ-0102 | 58 |
| WXFQ-0103 | 61 |
| WXFQ-0104 | 75 |
| WXFQ-0105 | 45 |
| WXFQ-0106 | 49 |
| WXFQ-0107 | 50 |
| WXFQ-0108 | 41 |
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit requires rather than described above limits, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.
Moreover, it will be appreciated that although the present specification is described in terms of embodiments, not each embodiment is only wrapped
Containing an independent technical scheme, this narrating mode of specification is only that those skilled in the art should for clarity
Using specification as an entirety, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
It is appreciated that other embodiment.
Claims (1)
1. one kind has the compound or its pharmaceutically acceptable salt of following formula (I) expression；
Wherein, in formula (I)：
A be selected from singly-bound-C (=O)-,-C (=O) O- ,-S (=O)2- ,-C (=O) NH- ,-NH- ,-S (=O) NH- ,-S (=O)2NH-；
B is selected from C and N；
R is selected from H, CN, OH, NH2、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2Or halogen；
R1Selected from OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, substituted C3-C6First cycloalkyl, quilt
Substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl, unsubstituted C3-C6First cycloalkanes
Base or unsubstituted C3-C6Circle heterocycles alkyl；
R2And R3Simultaneously or it is respectively selected from H, OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, taken
The C in generation3-C6First cycloalkyl, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl,
Unsubstituted C3-C6First cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711049481.5A CN107556311A (en) | 2017-10-31 | 2017-10-31 | A kind of lenalidomide analog |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711049481.5A CN107556311A (en) | 2017-10-31 | 2017-10-31 | A kind of lenalidomide analog |
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| Publication Number | Publication Date |
|---|---|
| CN107556311A true CN107556311A (en) | 2018-01-09 |
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ID=61032634
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| Application Number | Title | Priority Date | Filing Date |
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| CN201711049481.5A Pending CN107556311A (en) | 2017-10-31 | 2017-10-31 | A kind of lenalidomide analog |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1696127A (en) * | 2005-04-18 | 2005-11-16 | 中国科学院长春应用化学研究所 | Analogue of thalidomide and preparation method |
-
2017
- 2017-10-31 CN CN201711049481.5A patent/CN107556311A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1696127A (en) * | 2005-04-18 | 2005-11-16 | 中国科学院长春应用化学研究所 | Analogue of thalidomide and preparation method |
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Application publication date: 20180109 |