CN108456212A - A kind of compound or its solvate or precursor or their pharmaceutically acceptable salt, drug and application thereof - Google Patents
A kind of compound or its solvate or precursor or their pharmaceutically acceptable salt, drug and application thereof Download PDFInfo
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- CN108456212A CN108456212A CN201810536871.3A CN201810536871A CN108456212A CN 108456212 A CN108456212 A CN 108456212A CN 201810536871 A CN201810536871 A CN 201810536871A CN 108456212 A CN108456212 A CN 108456212A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Abstract
The invention discloses a kind of compound or its solvates or precursor or their pharmaceutically acceptable salt, drug and application thereof.The compound of the present invention can directly act on Janus kinases, have remarkable result to treatment tumour and autoimmune disease.
Description
Technical field
The invention belongs to pharmaceutical fields;More particularly it relates to a kind of compound or its solvate or precursor,
Or their pharmaceutically acceptable salt, drug and application thereof.
Background technology
Over nearly more than 20 years, majority state tumor incidence is in rising trend in the world.As the improvement of people's living standards,
The change of eating habit and structure, in addition aging of population tendency influence, global tumor invasion number and death toll are also in increase
Long situation.According to statistics, 2012, world wide is interior, and there are about 14,000,000 new cancer cases, it is contemplated that 20 years new cases from now on
Number will increase about 70%.Tumour in 2015 causes 8,800,000 people dead.In terms of global picture, nearly 1/6th death is by cancer
It causes.The economic impact that cancer is brought is very big and is constantly aggravating.Estimate the annual economical total cost caused by cancer in 2010
About 1.16 trillion dollars.
JAK is the abbreviation of English Janus kinase, is the tyrosine kinase of a kind of non-transmembrane.JAK can phosphorylation
Cytokine receptor combined with it, and can the multiple signaling molecules containing specific SH2 structural domains of phosphorylation.JAK protein families
Include 4 members altogether:JAK1, JAK2, JAK3 and Tyk2, they have 7 JAK homeodomains (JAK in structure
Homology domain, JH), wherein JH1 structural domains be kinases area, JH2 structural domains be "false" kinases area, JH6 and JH7 be by
Body calmodulin binding domain CaM.
JAK-STAT signal paths are a signal transduction pathways stimulated by cell factor, participate in the proliferation of cell, divide
Many important biological processes such as change, apoptosis and immunological regulation.JAK-STAT signal path functions are extensive, participate in cell
Many important biological processes such as proliferation, differentiation, apoptosis and immunological regulation, at present with disease and New drug discovery are relevant grinds
Study carefully and all concentrates on autoimmune disease and tumour.Wherein, and tumour relates generally to myelofibrosis, polycythemia vera
And primary thrombocytosis.In addition, the mutation of itself of JAK molecules also result in acute myeloid leukemia (AML),
Acute lymphatic leukemia (ALL), breast ductal cancer and non-small cell lung cancer (NSCLC) etc..
Invention content
The purpose of the present invention is to provide 7H- pyrrolo-es [2,3-d] miazines derivatives with Janus kinase inhibitory activities
Object and application thereof.
Another object of the present invention is to provide such Indolinyl derivative or its pharmaceutically acceptable equivalents
It is used alone or the application in treatment tumour, autoimmune disease or central nervous system is used in combination with other drugs.
The purpose of the present invention can be achieved by the following measures:
One kind has the compound or its solvate or precursor or theirs is pharmaceutically acceptable of following general formula (I)
Salt:
Wherein,
N is the integer of 0-6;
R1 be hydrogen, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxies, C1-6 alkyl aminos, halogenated C1-6 alkyl,
Halogenated C1-6 alkoxies or C3-6 naphthenic base;
R2 be hydrogen, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxies, C1-6 alkyl aminos, halogenated C1-6 alkyl,
Halogenated C1-6 alkoxies or C3-6 naphthenic base.
R3 is hydrogen, halogen, the phenyl arbitrarily replaced, naphthalene, C5-7 cycloalkadienyls or the list or fused ring heterocycle arbitrarily replaced
Base, the heterocycle have armaticity, containing 5 to 12 annular atoms and in the ring or each ring containing at most four selected from S,
The hetero atom of O and N.
In a preferred embodiment of the present invention:
N be 0-3 integer, further preferably 0 or 1;
R1 is hydrogen, C1-6 alkyl or halogen, further preferably hydrogen, C1-4 alkyl or fluorine;
R2 be hydrogen, C1-6 alkyl aminos, cyano or halogen, further preferably hydrogen, C1-4 alkyl aminos, cyano, chlorine or
Fluorine;
R3 is hydrogen, halogen or the phenyl arbitrarily replaced, the further preferably phenyl of alkoxy substitution.
" halogen " indicates fluorine, chlorine, bromine or iodine.
" C1-6 alkyl " indicates the branch with 1-6 carbon atom or direct-connected alkyl, including but not limited to methyl, ethyl,
Propyl- 1- bases, propyl- 2- bases, 2- methyl -propyl- 1- bases, 2- methyl -propyl- 2- bases, 2,2- dimethyl -propyl- 1- bases, butyl- 1- bases, butyl-
2- bases, 3- methyl-butyl- 1- bases, 3- methyl-butyl- 2- bases, amyl- 1- bases, amyl- 2- bases, amyl- 3- bases, hex- 1- bases, hex- 2- bases,
Hex- 3- bases.
" C1-3 alkyl " indicates the branch with 1-3 carbon atom or direct-connected alkyl, including but not limited to methyl, ethyl,
Propyl- 1- bases, propyl- 2- bases.
" halogenated C1-6 alkyl " indicates the C1-6 alkyl replaced by one or more halogen atoms, including but not limited to trifluoro
Tri- fluoro- 1- propyl of methyl and 3,3,3-.
" C3-6 naphthenic base " indicates the monocycle alkyl with 3-6 carbon atom, and the ring does not have the π electricity being fully connected
Subsystem, including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclopentenyl, cyclohexenyl group.
" C1-6 alkoxies " expression-O- (unsubstituted C1-6 alkyl) and-O- (unsubstituted C3-6 naphthenic base), including but
It is not limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy.
" halogenated C1-6 alkoxies " indicates the C1-6 alkoxies replaced by one or more halogen atoms, including but not limited to
Tri- fluoro- 1- propoxyl group of trifluoromethoxy and 3,3,3-.
" C1-6 alkyl aminos " expression-NH- (unsubstituted C1-6 alkyl) and-NH- (unsubstituted C3-6 naphthenic base), packet
Include but be not limited to methylamino, ethylamino, propylcarbamic, butylamino, cyclopropylamino, Cyclobutylamino, cyclopenta ammonia
Base, Cyclohexylamino.
" pharmaceutically acceptable salt " refers to that the acid salt or basic salt of the compounds of this invention, the salt have desired
Pharmaceutical active and biologically and in other aspects without nonconforming place.Acid salt include inorganic acid salt and
Acylate.Inorganic acid includes but not limited to hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, and organic acid includes but not limited to acetic acid, trichlorine
Acetic acid, propionic acid, butyric acid, maleic acid, p-methyl benzenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, two
Gluconic acid, aspartic acid, tartaric acid.
The present invention also provides a kind of pharmaceutical compositions, it is with any one compound or its solvent of the above-mentioned protection of the present invention
It is active constituent to close object or precursor or their pharmaceutically acceptable salt, can pharmaceutically be connect containing one or more simultaneously
The carrier or diluent received.
Meaning " pharmaceutically acceptable carrier or diluent " of the invention common excipient, auxiliary in pharmaceutical preparation
Material or solvent, including but not limited to lactose, sucrose, talcum powder, gelatin, agar, pectin, gum arabic, magnesium stearate, tristearin
Acid, the lower alkyl ether of cellulose, cornstarch, potato starch, natural gum, aliphatic acid, fatty acid amine, glycerol monostearate or
Glycerol disterate fat, phosphatide, olive oil, peanut oil, syrup, colorant, corrigent, preservative, water, ethyl alcohol, propyl alcohol, physiology
Brine, glucose solution.
The compounds of this invention as effective administration dosage of active constituent can be with administration pattern and disease to be treated
Severity and change.However, usually when the compound of the present invention is daily with about 0.05-500mg/kg, preferably 0.1-
When the dosage of 300mg/kg, more preferably 1-200mg/kg the weight of animals are given, satisfactory effect can be obtained, preferably daily
It is given with 1-3 separated dosage, or is administered with sustained release forms.This dosage is adjusted to provide optimal treatment response.Example
Such as, by an urgent demand for the treatment of situation, dosage separated several times can be given once daily, or dosage is reduced pari passu.
The present invention also provides above-mentioned each compound or its solvates or precursor or their pharmaceutically acceptable salt
Purposes in terms of preparing inhibition Janus kinases, especially in the application for preparing treatment tumour and autoimmune disease.It is described
" tumour and autoimmune disease " include but not limited to myelofibrosis, polycythemia vera, essential thrombocythemia
Increase disease, rheumatoid arthritis or psoriasis.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part such as J. Pehanorm Brookers etc. is write, Molecular Cloning:A Laboratory guide, the third edition, Science Press, the condition described in 2002, or
According to the normal condition proposed by manufacturer.
Specific implementation mode
In order to which the present invention is described in more detail, following preparating examples are provided, but the scope of the present invention is not limited to this.
Embodiment one
6- (3- methoxyphenyls)-N- methyl -4- ((tetrahydrofuran -3- bases) oxygroup) -7H- pyrrolo-es [2,3-d] pyrimidine -
The preparation of 2- amine
6- (3- methoxyphenyls) -2- (methylamino) -7H- pyrrolo-es [2,3-d] pyrimidine -4- alcohol
By chloro- 7H- pyrrolo-es [2,3-d] pyrimidine -4- alcohol (583mg) of 6- (3- methoxyphenyls) -2- and methylamine (276mg)
It is dissolved in dimethylformamide (5mL), in reacting 8h under room temperature.Reaction terminates that the dilution of 15mL ethyl acetate is added, and washes,
Organic phase is dried with anhydrous magnesium sulfate.It is filtered to remove solid insoluble, product 6- (3- methoxybenzenes are obtained after filtrate decompression concentration
Base) -2- (methylamino) -7H- pyrrolo-es [2,3-d] pyrimidine -4- alcohol (374mg, 65% yield).MS:270.54[M+H]+。
The chloro- 6- of 4- (3- methoxyphenyls)-N- methyl -7H- pyrrolo-es [2,3-d] pyrimidine -2- amine
By 6- (3- methoxyphenyls) -2- (methylamino) -7H- pyrrolo-es [2,3-d] pyrimidine -4- alcohol (317mg) and trichlorine
Change phosphorus (645mg) to be dissolved in dichloromethane (3mL).Appoint to office be heated to 40 DEG C react 6 hours.It is cooled to room temperature, 15mL second is added
Acetoacetic ester dilutes, and washing, organic phase is dried with anhydrous magnesium sulfate, is concentrated to give the chloro- 6- of product 4- (3- methoxyphenyls)-N- first
Base -7H- pyrrolo-es [2,3-d] pyrimidine -2- amine, crude product direct plunges into reacts in next step.
6- (3- methoxyphenyls)-N- methyl -4- ((tetrahydrofuran -3- bases) oxygroup) -7H- pyrrolo-es [2,3-d] pyrimidine -
2- amine
To the tetrahydrochysene of the chloro- 6- of 4- (3- methoxyphenyls)-N- methyl -7H- pyrrolo-es [2,3-d] pyrimidine -2- amine (330mg)
Potassium hydroxide (193mg) and 3- hydroxyl tetrahydrofurans (202mg) are added in furans (1.5mL) solution, it is small to be heated to 50 DEG C of reactions 5
When.Water quenching is added to go out reaction, ethyl acetate extracts (3 × 10mL), merging organic phase, with saturated common salt water washing, anhydrous slufuric acid
Sodium is dried, and filtering is spin-dried for column chromatography and obtains product 6- (3- methoxyphenyls)-N- methyl -4- ((tetrahydrofuran -3- bases) oxygen
Base) -7H- pyrrolo-es [2,3-d] pyrimidine -2- amine (307mg, yield 79%).
1H NMR(400MHz,CDCl3)δ:11.92(brs,1H),8.07(brs,1H),7.57-7.31(m,3H),7.05
(d,1H),6.57(s,1H),4.31-3.97(m,3H),3.88(s,3H),3.82-3.70(m,2H),2.85(s,3H),2.36-
2.11(m,2H)ppm;13C NMR(100MHz,CDCl3)δ:165.7,161.0,159.1,149.7,138.2,130.3,
129.6,119.8,114.2,113.9,108.1,100.3,81.3,79.4,67.6,55.9,32.3,28.9ppm;MS-ESI:
341.46[M+H]+.
Embodiment two
The fluoro- 4- of 2- ((3- isopropyls tetrahydropyran -3-base) oxygroup) -6- (3- methoxyphenyls) -7H- pyrrolo-es [2,3-
D] pyrimidine preparation
The chloro- 2- of 4- fluoro- 6- (3- methoxyphenyls) -7H- pyrrolo-es [2,3-d] pyrimidines (550mg) and 3- hydroxyls -4- is different
Propyl tetrahydrofuran (516mg) is dissolved in dimethylformamide (3mL), and potassium hydroxide (450mg) is added, and is heated to 90 DEG C of reactions
10 hours.Reaction terminates that the dilution of 15mL ethyl acetate, washing is added, and organic phase is dried with anhydrous magnesium sulfate.Filtering, is spin-dried for, column
Chromatography obtains the fluoro- 4- of product 2- ((3- isopropyls tetrahydropyran -3-base) oxygroup) -6- (3- methoxyphenyls) -7H- pyrrolo-es
[2,3-d] pyrimidine (573mg, 78% yield).
MS:372.56[M+H]+.1H NMR(400MHz,CDCl3)δ:11.95(brs,1H),7.55-7.27(m,3H),
7.06(d,1H),6.58(s,1H),4.33-3.99(m,3H),3.84(s,3H),3.78-3.63(m,2H),2.22-2.10(m,
1H),1.45-1.36(m,1H),0.89(d,6H)ppm;13CNMR(100MHz,CDCl3)δ:169.4,161.7,161.1,
149.5,138.2,130.5,130.6,120.4,114.4,113.8,108.6,101.1,80.8,78.9,69.3,56.4,
55.5,22.6,20.9ppm.
All compounds of the present invention are shown in following at least one experiment with physiology and pharmacological activity effect.Below
Embodiment is only used for that the activity of the present invention is described in detail, and is not the restriction of the compounds of this invention to not expressing.
Three enzyme of embodiment is analyzed
(1) test method:JAK1, JAK2 and JAK3 kinase assays utilize baculovirus infection SF9 cells (GST's
The catalyst structure domain of fusion protein and mankind's JAK enzymes) in express protein, by affinity chromatography to Glutathione-agarose
Sugar is purified.The substrate of reaction is polyglutamic acid-tyrosine [PGT (4:1)], with 100 μ g/ on Nunc Maxi Sorp plates
ML is stayed overnight at 37 DEG C.Three times by plate washing, and JAK enzymes are added to containing 100 μ L kinase buffer liquids (50mM HEPES, pH
7.3,125mM NaCl,24mM MgCl2) the positive sodium acetates of+ATP+1mM) and hole in.In hatching 30 minutes under room temperature, by plate
It washes three times.The content of phosphorylated tyrosine is measured using anti-phospho-AB standard ELISA methods.
(2) measurement result:Refer to table 1, wherein IC50It is smaller, indicate that the activity of respective compound is higher.
Example IV cell analysis-inhibition human IL-2's dependent T cell proliferation (IL-2 Blast Assay)
(1) test method:This method measures the inhibiting effect of Compounds in vitro IL-2 dependent T cells proliferation.Due to
Need JAK3, the cell active inhibitors of JAK3 that IL-2 dependent T cells can be inhibited to be proliferated by the signal of IL-2 receptors.For
The cell of the measurement is detached from fresh human blood.Monokaryon is detached using Accuspin System-Histopaque-1077
After cell, primary human T-Cells are detached by Solid phase using Lympho-Kwik T (One Lambda, Inc.).Culture medium
(RPMI+10% heat-inactivated fetal calf serum (Hyclone) × 1% penicillin/streptomycins (P/S;Gibco T cell is cultivated in))
(1-2)*106/ and by the way that 10 μ g/mL PHA (Murex Diagnostics) proliferative inductions are added.At 37 DEG C, 5%CO2In 3 days
Afterwards, cell is washed three times in the medium, and settling flux adds to a concentration of (1-2) × 106 cell/mL in the medium
Upper 100 units/mL people's recombinant il-2 (R&D Systems).After 1 week, cell relies on IL-2, can be added with isometric culture medium
The IL-2 of upper 100 units/mL twice a week, maintains to be up to 3 weeks.
In order to measure the ability that compound inhibits IL-2 dependent T cells proliferation, three times by the washing of IL-2 dependent cells,
It is resuspended in culture medium, (50000 cells/well/0.1mL) microtiter plate is then inoculated in flat 96 orifice plate.From 10mM
In dimethyl sulfoxide (DMSO) (DMSO) storing solution of test compound, by continuous 2 times of diluted compounds with 10 μM of one formulas three of beginning
Part is added.One row is used as 100% proliferation and controls, and is individually incubated with DMSO.After 1 hour, it is single that 10 are added into each test hole
The IL-2 of position/mL, then by plate in 37 DEG C and 5%CO2It is lower to be incubated 72 hours.Then by plate with [3H] thymidine (0.5 holes μ Ci/) arteries and veins
It rushes and is incubated again 18 hours.Culture plate is harvested with 96 orifice plate harvesters, by Packard Top Count scintillation counters
In the determining incorporation proliferative cell of counting [3H] thymidine amount, so that it is determined that IC50It is worth (micromole).
(2) measurement result:Refer to table 1, wherein IL-2 blast IC50It is smaller, indicate that the activity of respective compound is higher.
1 part of compounds of the present invention of table and enzyme analysis test and cell analysis measurements determination result
Claims (9)
1. one kind having compound or its solvate or precursor shown in following general formula (I) or theirs is pharmaceutically acceptable
Salt is used to prepare the drug for the treatment of tumour and autoimmune disease;The drug is using Janus kinases as action target spot:
Wherein,
N is the integer of 0-6;
R1For hydrogen, halogen, nitro, cyano, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, halogenated C1-6Alkyl, halogenated C1-6Alkane
Oxygroup or C3-6Naphthenic base;
R2For hydrogen, halogen, nitro, cyano, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, halogenated C1-6Alkyl, halogenated C1-6Alkane
Oxygroup or C3-6Naphthenic base;
R3For hydrogen, halogen, the phenyl arbitrarily replaced, naphthalene or C5-7Cycloalkadienyl, or the list or fused ring heterocycle base that arbitrarily replace,
The heterocycle has armaticity, containing 5 to 12 annular atoms and in the ring or each ring containing at most four selected from S, O and
The hetero atom of N.
2. compound according to claim 1 or its solvate or precursor or their pharmaceutically acceptable salt,
Wherein,
N is the integer of 0-3;
R1For hydrogen, C1-6Alkyl or halogen;
R2For hydrogen, C1-6Alkyl amino, cyano or halogen.
R3For hydrogen, halogen or the phenyl arbitrarily replaced.
3. compound according to claim 2 or its solvate or precursor or their pharmaceutically acceptable salt,
Wherein R1For hydrogen, C1-4Alkyl or fluorine.
4. compound according to claim 2 or its solvate or precursor or their pharmaceutically acceptable salt,
Wherein R2For hydrogen, C1-4Alkyl amino, cyano, chlorine or fluorine.
5. compound according to claim 2 or its solvate or precursor or their pharmaceutically acceptable salt,
Wherein n is 0 or 1.
6. a kind of pharmaceutical composition, the compound as described in any one of claim 1-5 containing medicine effective dose
Or its solvate or precursor or their pharmaceutically acceptable salt and pharmaceutically acceptable carrier or diluent.
7. compound or its hydrate or precursor as described in requiring any one of 1-5 or theirs is pharmaceutically acceptable
Salt, which is characterized in that its purposes is treatment tumour and autoimmune disease.
8. purposes according to claim 7, wherein the tumour relates generally to myelofibrosis, polycythemia vera
And primary thrombocytosis.
9. purposes according to claim 7, wherein the autoimmune disease relate generally to rheumatoid arthritis and
Psoriasis.
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Citations (3)
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CN102372717A (en) * | 2010-08-20 | 2012-03-14 | 和记黄埔医药(上海)有限公司 | Pyrrolopyrimidine compound and use thereof |
CN102574857A (en) * | 2009-07-08 | 2012-07-11 | 利奥制药有限公司 | Heterocyclic compounds as jak receptor and protein tyrosine kinase inhibitors |
CN102740698A (en) * | 2009-11-18 | 2012-10-17 | 普莱希科公司 | Compounds and methods for kinase modulation, and indications therefor |
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2018
- 2018-05-30 CN CN201810536871.3A patent/CN108456212A/en active Pending
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CN102574857A (en) * | 2009-07-08 | 2012-07-11 | 利奥制药有限公司 | Heterocyclic compounds as jak receptor and protein tyrosine kinase inhibitors |
CN102740698A (en) * | 2009-11-18 | 2012-10-17 | 普莱希科公司 | Compounds and methods for kinase modulation, and indications therefor |
CN102372717A (en) * | 2010-08-20 | 2012-03-14 | 和记黄埔医药(上海)有限公司 | Pyrrolopyrimidine compound and use thereof |
Non-Patent Citations (1)
Title |
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MARK E. FLANAGAN,ET AL.,: "Discovery of CP-690,550: A Potent and Selective Janus Kinase (JAK) Inhibitor for the Treatment of Autoimmune Diseases and Organ Transplant Rejection", 《J. MED. CHEM.》 * |
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