CN105001203A - Bcr-Abl amphiploid inhibitor and preparation method and application thereof - Google Patents
Bcr-Abl amphiploid inhibitor and preparation method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The invention discloses a Bcr-Abl amphiploid inhibitor and a preparation method and application thereof. The structural formula of compound or pharmaceutically acceptable salt of the compound is shown in the specification as I. The compound or pharmaceutically acceptable salt of the compound in the formula I serves as the Bcr-Abl amphiploid inhibitor, can effectively restrain activity of tyrosine kinase, can effectively used for treating diseases related to kinase abnormal excitation and has a good treatment effect on the malignant tumor. The preparation method of the Bcr-Abl amphiploid inhibitor is simple, convenient to implement and low in cost and has good application prospects.
Description
Technical field
The present invention relates to a kind of Bcr-Abl amphiploid inhibitor and its production and use.
Background technology
Chronic myelocytic leukemia is that karyomit(e) produces transgenation [t (9:22) (q34; Q11)] transposition mutually, the abl gene that karyomit(e) is 9 and the BCR gene of chromosome 22 position merge generation BCR-ABL mutually, a kind of 210kDa Tyrosylprotein kinase of this genes encoding merged Bcr-Abl, this albumen is the major cause causing chronic myelocytic leukemia.C-Abl is the monoploid Tyrosylprotein kinase be present in endochylema in normal cell, and after merging with Bcr, form changes, and become the tetramer by monoploid, this kinases is in the state of being activated all the time thus, leads oncogenic generation.Existing in Bcr protein sequence to cause the aminoacid sequence of multimerization to cause Bcr-Abl tetra-dimerization.Because c-Abl plays an important role in the normal cells such as cardiac muscle, if exploitation Selective depression carinogenicity Bcr-Abl but not the inhibitor of Abl, be then expected to greatly to reduce the side effects widely such as the cardiac toxic of this type of inhibitor.
Calendar year 2001, FDA ratifies the listing of first tyrosine kinase inhibitor (TKI) imatinib (Imatinib) 1, for the treatment of chronic myelocytic leukemia (CML).As first-generation Bcr-Abl inhibitor, imatinib has become the first-line drug for the treatment of CML.But finally all there is resistance to imatinib in Most patients.Research subsequently shows, the generation of IM resistance may be relevant with the transgenation in the Abl kinase activity districts such as G250E, Q252H, Y253F, Y253H, E255K, E355G, E255V, T315A, T315I, F317L, F317V, M351T, F359V, H396P, M244V, and transgenation causes imatinib and the kinase whose affinity of Abl to decline.Most transgenation makes the affinity decline 5-30 of imatinib doubly, and this is the major cause producing resistance.Wherein T315I is more special, reduces the most obvious, IC
50be down to about 6400nM, that is not only effective to T315I for Buddhist nun on the slope of recently exploitation, to wild-type and most mutant strain all effective.
From the x-Ray eutectic structure of the kinases part of imatinib and Abl albumen, the n-formyl sarcolysine base section of the first class piperazine moiety in structure exposes in a solvent, and the slant range between two these nitrogen-atoms of inhibitor is about 24 peaces.Bcr-Abl is owing to being the tetramer, can combine with 4 inhibitor simultaneously, if two inhibitor are coupled together by chain, then be expected to the affinity of the Bcr-Abl greatly improved four dimerizations, thus play the effect of Selective depression Bcr-Abl, and Abl is owing to being monoploid, can only combine with an inhibitor, amphiploid inhibitor does not have large impact to the affinity of enzyme.
Summary of the invention
The object of the present invention is to provide a kind of Bcr-Abl amphiploid inhibitor and its production and use.
Type I compound provided by the invention or its pharmacy acceptable salt, its structural formula is as follows:
In the present invention, Linker represents connection molecule.
Further, in formula I, Linker is (Z
1)
a– (Z
2)
b– (Z
3)
c;
Wherein, Z
1, Z
2, Z
3separately be selected from C (O) (CH
2)
dnH, CO (CH
2)
ec (O), (CH
2cH
2)
fnHC (O), (CH
2cH
2)
g-C (O) NH, (CH
2)
hc (O) (OCH
2cH
2)
inHC (O) (CH
2)
jc (O), NH (CH
2)
k(OCH
2cH
2)
l-O (CH
2)
mnH, (CH
2)
nc (O) (OCH
2cH
2)
onH (C (O) (CH
2)
pnH)
qc (O)-alkyl, C (O) NH (CH
2)
rnHC (O)-(CH
2)
sc (O) (NHCH
2cH
2)
tnH (C (O) (CH
2)
unH)
v-C (O)-alkyl;
A ~ v is separately selected from arbitrary numerical value in 1 ~ 20.
Further, its structural formula is:
Present invention also offers the method for the above-mentioned formula I of preparation or its pharmacy acceptable salt.
The present invention prepares the method for above-mentioned type I compound, and it comprises following operation steps:
Further, it comprises following operation steps:
(1) compound 2 is prepared:
(2) prepare compd B GC, be type I compound:
Further, it comprises following operation steps:
I, prepare compound 2:
Compound 1, triethylamine, 4-(chloromethyl) Benzoyl chloride, in methylene dichloride, in stirred at ambient temperature reaction 18h, obtain reaction solution; Reaction solution is separated, purifying, obtain compound 2;
Ii, prepare compound 6:
1. compound 4, is prepared
Compound 3, triethylamine, glutaryl chlorine, in methylene dichloride, react 6 hours in stirred at ambient temperature, obtain reaction solution; Reaction solution is separated, purifying, obtain compound 4;
2. compound 6, is prepared
Compound 4, I-hydroxybenzotriazole, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-methylmorpholine are in methylene dichloride, react under condition of ice bath after 0.5 hour, add compound 5, react completely under room temperature, obtain reaction solution; Reaction solution is separated, purifying, obtain compound 6;
Iii, prepare compd B GC
Compound 2, compound 6, salt of wormwood, in DMF, in 100 DEG C of stirring reaction 18h, obtain reaction solution; Reaction solution is separated, purifying, obtain compd B GC.
Further,
In step I, the mol ratio of described compound 1, triethylamine, 4-(chloromethyl) Benzoyl chloride is 18:35.6:21.3; Described compound 1 is 18:400mmol/ml with the molecular volume ratio of methylene dichloride;
Step I i 1. in, the mol ratio of described compound 3, triethylamine, glutaryl chlorine is 45.4:68.1:22.7; Described compound 3 is 45.4:300mmol/ml with the molecular volume ratio of methylene dichloride;
Step I i 2. in, the mol ratio of described compound 4, I-hydroxybenzotriazole, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-methylmorpholine, compound 5 is: 1:1.2:1.2:3:2.1; Described compound 4 is 1:20mmol/ml with the molecular volume ratio of methylene dichloride;
In step I ii, the mol ratio of described compound 2, compound 6, salt of wormwood is 0.28:0.09:2.69; Described compound 2 is 0.28:20mmol/ml with the molecular volume ratio of DMF.
Invention additionally provides above-claimed cpd and the purposes of pharmacy acceptable salt in the medicine of preparation treatment cell breeding disease thereof.
Above-claimed cpd and pharmacy acceptable salt thereof the purposes in the medicine of preparation treatment cell breeding disease.
Further, described medicine is tyrosine kinase inhibitor.
Further, described medicine is ABL inhibitor class medicine.
Further, described medicine is BCR-ABL or its mutant strain inhibitor class medicine.
Further, described BCR-ABL mutant strain is T315I mutant strain.
Further, described cell breeding disease is cancer.
Further, described cancer is chronic myelocytic leukemia, intestines mesenchymoma, gynaecology's knurl, dermatofibrosarcoma protuberans, Ph+ALL.
Type I compound provided by the invention or its pharmacy acceptable salt; as Bcr-Abl amphiploid inhibitor; effectively can suppress tyrosine kinase activity; the disease treatment that such kinases abnormal activation is relevant can be effective to; to malignant tumour, there is good therapeutic action; the preparation method of such inhibitor is easy, with low cost, has a good application prospect.
Obviously, according to foregoing of the present invention, according to ordinary technical knowledge and the customary means of this area, not departing under the present invention's above-mentioned basic fundamental thought prerequisite, the amendment of other various ways, replacement or change can also be made.
The embodiment of form by the following examples, is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
Accompanying drawing explanation
Fig. 1, BGC are on the impact of KBM5 mice with tumor knurl volume.
Embodiment
The raw material used in the specific embodiment of the invention, equipment are known product, obtain by buying commercially available prod.
The Chinese of abbreviation:
HOBT:1-hydroxybenzotriazole; EDC:1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride; NMM:N-methylmorpholine; DMSO: dimethyl sulfoxide (DMSO).
The preparation of embodiment 1 the compounds of this invention BGC
Synthetic route is as follows:
(2) compd B GC is prepared:
Concrete synthesis step is as follows:
A) compound 2 is prepared
By compound 1 (5.0g, 18.0mmol; Manufacturer: Xu Gang bio tech ltd, Shanghai), triethylamine (3.6g, 35.6mmol) be dissolved in methylene dichloride (400ml), by 4-(chloromethyl) Benzoyl chloride (4.0g, 21.3mmol) be dissolved in methylene dichloride (100ml), at 0 DEG C, drip in reaction solution, finish the rear stirring at room temperature that naturally rises to and react 18h, solid is separated out in reaction flask, reaction mixture is filtered, the solid with methylene chloride collected, water washing, obtain yellow solid compound 2 (5.3g; Yield 68%).
1H NMR(400MHz,DMSO-d6):δ10.23(s,1H),9.28(s,1H),8.97(s,1H),8.69(d,J＝4.4Hz,1H),8.52(m,2H),8.09(s,1H),7.97(d,J＝7.6Hz,2H),7.59-7.42(m,5H),7.22(d,J＝8.0Hz,1H),4.84(s,2H),2.23(s,3H).MS(ESI+)m/z:430[M+1]
+。
B) compound 4 is prepared
At room temperature, by compound 3 (10.0g, 45.4mmol; Manufacturer: Sigma-Aldrich.) be dissolved in methylene dichloride (250ml), add triethylamine (6.9g, 68.1mmol), again glutaryl chlorine (3.8g, 22.7mmol) is dissolved in methylene dichloride (50ml), and drips in reaction solution lentamente, at room temperature stirring reaction 6h after finishing, then use water (200ml × 2) washing reaction liquid, organic phase with sodium sulfate is dry, vacuum concentration solvent evaporated.Residue over silica gel column chromatography purification (methylene chloride/methanol=20/1) obtains compound 4.(4.3g; Yield 35.4%).
C) compound 6 is prepared
Under ice bath, by compound 4 (2.7g, 5.0mmol) be dissolved in methylene dichloride (100ml), add HOBT (0.81g, 6.0mmol), EDC (0.59g, 6.0mmol), NMM (1.52g, 15mmol) react half an hour, by compound 5 (1.67g, 10.5mmol, manufacturer: lark prestige Science and Technology Ltd.) join in reaction solution in batches, after finishing, rise to room temperature gradually, reaction is spent the night, reaction solution saturated sodium-chloride water solution (100ml × 2) washing organic phase, organic phase with sodium sulfate is dry, vacuum concentration solvent evaporated, residue over silica gel column chromatography purification obtains compound 6 (1.3g, yield 31.8%).
1H NMR(400MHz,D
2O)3.62(30H,m),3.53(14H,m),3.21(8H,q,J＝7,2Hz).2.77(4H,t,J＝6.8Hz).2.21(4H,t,J＝7.6Hz).1.82(2H,m)。
D) compd B GC is prepared
By compound 6 (72mg, 0.09mmol), compound 2 (120mg, 0.28mmol), K
2cO
3(350mg, 2.69mmol), N, dinethylformamide (20ml) joins in round-bottomed flask, at 100 DEG C of stirring reaction 18h, after question response liquid is cooled to room temperature, reaction solution is poured in the frozen water of vigorous stirring, separate out solid, filter, collect solid, resistates obtains orange solids BGC (18mg by preparing high performance liquid phase purifying; Yield 12%).
1H NMR(400MHz,D
2O):δ9.40(s,2H),9.12(d,J＝8Hz，2H,),8.87(d,J＝5.2Hz,2H),8.50(bs,2H),8.13(t,J＝6.8Hz,2H),7.95(d,J＝7.6Hz,4H),7.90(s,2H),7.65(d,J＝8Hz,4H),7.45(d,J＝5.2Hz,2H),7.36(d,J＝8Hz,2H),7.24(d,J＝7.6Hz,2H),4.43(s,4H),3.66-3.44(m,44H),3.28(t,J＝6.8Hz,4H),3.22(t,J＝6.8Hz,4H),2.78(t,J＝6.8Hz,4H),2.26(s,6H),2.22(t,J＝7.2Hz,4H),1.87-1.70(m,10H).MS(ESI+)m/z:1604[M+1]
+。
Beneficial effect of the present invention is illustrated below by way of test example.
The medical active of test example 1 the compounds of this invention
1, tyrosine kinase inhibitory activity
Reference: Amy Card et al., Journal of Biomolecular Screening 14 (1) 2009; JudeDunne et al., Assay & Drug Development Technologies Vol.2, No.2,2004.
Utilize the method for Mobility Shift Assay, vitro kinase Abl is carried out to the screening of the compounds of this invention BGC, compd B GC concentration is diluted to 0.005 μM successively by 100 μMs of three times of dilution method 100%DMSO, totally 10 concentration point, carry out detecting in (2 multiple hole), adopt compound staurosporine as standard control, if Vehicle controls (10%DMSO) and negative control (EDTA).
By enzyme linked immunoassay on 384 hole Sptting plates, detect the suppression situation of compd B GC to kinases Abl of each concentration, Caliper upper reading and converting rate data, and conversion is become inhibiting rate.
Percent inhibition＝(max-conversion)/(max-min)*100。Wherein max refers to that the transformation efficiency that DMSO contrasts, min refer to the transformation efficiency without enzyme contrast alive.According to the inhibiting rate computerized compound BGC of each concentration to the half-inhibition concentration IC of SRCA bl
50.
Suppress result as follows:
The IC of compd B GC
50: 0.02 μM;
Test-results illustrates, the compounds of this invention BGC has stronger inhibit activities to c-Abl Tyrosylprotein kinase.
2, the compounds of this invention BGC is to KBM5 (Bcr-Abl is positive) Proliferation of Tumor Cells In Vitro inhibition test
Measure the cytotoxicity of BGC series compound of the present invention by ATP method, KBM5 cell is adjusted suitable cell density, with every hole 140ul cell suspension inoculation 96 orifice plate, the inoculum density of often kind of cell is: 2000-6000; Placing in above-mentioned Tissue Culture Plate incubator makes it be attached to completely on hole wall for 24 hours, adopt three times of dilution methods that the compounds of this invention BGC is mixed with suitable different concns respectively, join and be vaccinated with in the 96 corresponding holes of orifice plate of cell in advance, every hole 10 μ L, makes its ultimate density be respectively: 100 μMs, 33.3 μMs, 11.1 μMs, 3.70 μMs, 1.23 μMs, 0.41 μM, 0.14 μM, 0.046 μM, 0.015 μM.Each concentration establishes three multiple holes respectively, and after hatching 72 hours in 37 DEG C of incubators, ATP method measures each porocyte proliferative conditions, calculates the median lethal concentration IC of each drug level to KBM5 cell proliferation
50.
Test-results:
The cytotoxicity of compd B GC to KBM5 (people source wild-type Bcr-Abl) tumour cell is as follows:
The IC of compd B GC
50: 9 μMs;
Test-results illustrates, the compounds of this invention BGC in vitro cell levels has stronger inhibit activities.
Leukemia Subcutaneous Xenograft Proliferation Ability test in the body of 3, the compounds of this invention BGC
According to the result of in-vitro multiplication inhibition test, BGC is at C57BL/6 (Es-1 in assessment
c) growth inhibitory effect of nude mice by subcutaneous Transplanted Human source leukemia KBM5 cell.
The dosage of the compounds of this invention BGC is respectively: 80mg/Kg, 160mg/Kg, 350mg/Kg, establish positive controls (the imatinib Imatinib of 160mg/Kg) and blank group (physiological saline) simultaneously, after mice with tumor grouping daily once, successive administration, after two weeks, detects the volume of tumour.
Investigate tumor growth whether can suppressed, delay or cure.Twice or use vernier caliper measurement diameter of tumor every other day weekly.The calculation formula of gross tumor volume is: V=0.5a × b
2, a and b represents major diameter and the minor axis of tumour respectively.
Data analysis: T compares between checking and being used for two groups; Compare between three groups or many groups and use one-wayANOVA.If F value has significant difference, after ANOVA analyzes, multiple comparisons should be carried out again.Two-way ANOVA is used for the potential synergy of analysis joint administration group.All data analyses are carried out with SPSS 17.0; P<0.05 thinks significant difference.
Test-results: the compounds of this invention BGC, to pharmacodynamic study result in the body of KBM5 cell subcutaneous transplantation tumor model, is shown in Fig. 1.
Under subcutaneous tumors model, the compounds of this invention BGC has antitumor drug effect, suitable with the inhibition of imatinib 160mg/kg under 350mg/kg dosage.
4, the Initial pharmacokinetic research of the compounds of this invention BGC
Female C57BL/6 (Es-1
c) after the tested the compounds of this invention BGC of nude mice Single-dose intravenous, by its concentration in Main Tissues of liquid chromatography tandem mass spectrometry quantitative assay and Plasma Concentration, investigate test medicine at female C57BL/6 (Es-1
c) distributional difference in nude mouse inner blood and Main Tissues; With imatinib as a comparison.
Experimental technique and process as follows: female C57BL/6 (Es-1
c) nude mice, body weight 18-25g, 6-8 week age, in addition, 3 female C57BL/6 (Es-1
c) nude mice for gathering blank sample, preparation analyze needed for typical curve.Intravenous administration dosage is 1mg/kg, and administration volume is 5mL/kg.Intravenous administration solvent: DMSO:Solutol HS15:Saline=5:5:90, v/v/v.Set up LC-MS/MS method, measure test medicine Plasma Concentration and tissue concentration with inner mark method ration, linearity range 1 ~ 1000ng/mL, lower limit of quantitation scope is generally 1ng/mL.Female C57BL/6 (Es-1
c) nude mice gathers whole blood about 20 μ L at 0.25h, 2h, 8h and 24h single from mouse tail vein after intravenous administration, uses K
2eDTA anti-freezing, the redistilled water adding 3 times according to volume ratio obtains the blood sample after diluting, and is stored in-70 DEG C until analyze.Gather the heart, liver, spleen, lung, kidney, stomach, small intestine, the tissue samples such as pancreas simultaneously, clean with physiological saline, weigh and record after filter paper blots, be then stored in-70 DEG C until analyze.After weighed organs and tissues is thawed, the heart, liver, spleen, lung, kidney, stomach, small intestine, pancreas adds 3 times of PBS buffering salt Beadbeater homogenate; Adopt the PBS buffering salt of 0.3mL to rinse when bone marrow specimens gathers, then 12000 leave the heart 5 minutes, remove 0.25mL supernatant liquor, remaining cell sample adds the PBS damping fluid homogenate of 150mL.
Data analysis: adopt WinNonlin (version 6.2) software, calculates pharmacokinetic parameters by non-compartment model.
Experimental result shows, the transformation period (t of the compounds of this invention BGC
1/2) be 3.5 hours, be far longer than the transformation period (t of imatinib
1/2for 1.5h); Compared with imatinib, the compounds of this invention BGC has obviously advantage on the pharmacokinetic properties after intravenous injection.
In sum; type I compound provided by the invention or its pharmacy acceptable salt; as Bcr-Abl amphiploid inhibitor; effectively can suppress tyrosine kinase activity; can be effective to the disease treatment that such kinases abnormal activation is relevant, have good therapeutic action to malignant tumour, the preparation method of such inhibitor is easy; with low cost, have a good application prospect.
Claims (14)
1. type I compound or its pharmacy acceptable salt, its structural formula is as follows:
2. type I compound according to claim 1 or its pharmacy acceptable salt, is characterized in that: in formula I, Linker is (Z
1)
a– (Z
2)
b– (Z
3)
c;
Wherein, Z
1, Z
2, Z
3separately be selected from
C(O)(CH
2)
dNH、CO(CH
2)
eC(O)、
(CH
2CH
2)
fNHC(O)、(CH
2CH
2)
g-C(O)NH、
(CH
2)
hC(O)(OCH
2CH
2)
iNHC(O)(CH
2)
jC(O)、
NH(CH
2)
k(OCH
2CH
2)
l-O(CH
2)
mNH、
(CH
2)
nC(O)(OCH
2CH
2)
oNH(C(O)(CH
2)
pNH)
qC(O)-alkyl、
C(O)NH(CH
2)
rNHC(O)-(CH
2)
sC(O)(NHCH
2CH
2)
tNH(C(O)(CH
2)
uNH)
v-C(O)-alkyl；
A ~ v is separately selected from arbitrary numerical value in 1 ~ 20.
3. type I compound according to claim 1 and 2 or its pharmacy acceptable salt, is characterized in that: its structural formula is:
4. prepare the method for claim 1 type I compound, it is characterized in that: it comprises following operation steps:
5. preparation method according to claim 4, is characterized in that: it comprises following operation steps:
(1) compound 2 is prepared:
(2) prepare compd B GC, be type I compound:
6. preparation method according to claim 5, is characterized in that: it comprises following operation steps:
I, prepare compound 2:
Compound 1, triethylamine, 4-(chloromethyl) Benzoyl chloride, in methylene dichloride, in stirred at ambient temperature reaction 18h, obtain reaction solution; Reaction solution is separated, purifying, obtain compound 2;
Ii, prepare compound 6:
1. compound 4, is prepared
Compound 3, triethylamine, glutaryl chlorine, in methylene dichloride, react 6 hours in stirred at ambient temperature, obtain reaction solution; Reaction solution is separated, purifying, obtain compound 4;
2. compound 6, is prepared
Compound 4, I-hydroxybenzotriazole, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-methylmorpholine are in methylene dichloride, react under condition of ice bath after 0.5 hour, add compound 5, react completely under room temperature, obtain reaction solution; Reaction solution is separated, purifying, obtain compound 6;
Iii, prepare compd B GC
Compound 2, compound 6, salt of wormwood, in DMF, in 100 DEG C of stirring reaction 18h, obtain reaction solution; Reaction solution is separated, purifying, obtain compd B GC.
7. preparation method according to claim 6, is characterized in that:
In step I, the mol ratio of described compound 1, triethylamine, 4-(chloromethyl) Benzoyl chloride is 18:35.6:21.3; Described compound 1 is 18:400mmol/ml with the molecular volume ratio of methylene dichloride;
Step I i 1. in, the mol ratio of described compound 3, triethylamine, glutaryl chlorine is 45.4:68.1:22.7; Described compound 3 is 45.4:300mmol/ml with the molecular volume ratio of methylene dichloride;
Step I i 2. in, the mol ratio of described compound 4, I-hydroxybenzotriazole, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-methylmorpholine, compound 5 is: 1:1.2:1.2:3:2.1; Described compound 4 is 1:20mmol/ml with the molecular volume ratio of methylene dichloride;
In step I ii, the mol ratio of described compound 2, compound 6, salt of wormwood is 0.28:0.09:2.69; Described compound 2 is 0.28:20mmol/ml with the molecular volume ratio of DMF.
8. compound described in claims 1 to 3 any one and pharmacy acceptable salt thereof the purposes in the medicine of preparation treatment cell breeding disease.
9. purposes according to claim 8, is characterized in that: described medicine is tyrosine kinase inhibitor.
10. purposes according to claim 8 or claim 9, is characterized in that: described medicine is ABL inhibitor class medicine.
11. purposes according to claim 8 or claim 9, is characterized in that: described medicine is BCR-ABL or its mutant strain inhibitor class medicine.
12. purposes according to claim 11, is characterized in that: described BCR-ABL mutant strain is T315I mutant strain.
13. the purposes described according to Claim 8 ~ 12 any one, is characterized in that: described cell breeding disease is cancer.
14. purposes according to claim 13, is characterized in that: described cancer is chronic myelocytic leukemia, intestines mesenchymoma, gynaecology's knurl, dermatofibrosarcoma protuberans, Ph+ALL.
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- 2015-04-16 CN CN201510180997.8A patent/CN105001203B/en active Active
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| WO2003037384A2 (en) * | 2001-10-29 | 2003-05-08 | Nektar Therapeutics Al, Corporation | Polymer conjugates of protein kinase c inhibitors |
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| WO2010120386A1 (en) * | 2009-04-17 | 2010-10-21 | Nektar Therapeutics | Oligomer-protein tyrosine kinase inhibitor conjugates |
| US20150073006A1 (en) * | 2009-04-17 | 2015-03-12 | Nektar Therapeutics | Oligomer-protein tyrosine kinase inhibitor conjugates |
| CN103113355A (en) * | 2013-02-27 | 2013-05-22 | 无锡爱内特生物科技有限公司 | Bcr/Abl tyrosine kinase inhibitor as well as preparation method and application thereof in treating chronic granulocytic leukemia |
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| CN105037398A (en) | 2015-11-11 |
| CN105037398B (en) | 2017-10-24 |
| CN105001203B (en) | 2017-03-01 |
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Effective date of registration: 20170406 Address after: 518000 Jiangsu building, Yitian Road, Guangdong, Shenzhen, A3504, Patentee after: Shenzhen pharmaceutical Limited by Share Ltd Address before: Outside the East Shiling Town of Longquanyi District of Chengdu city of Sichuan Province in 610106 Patentee before: Chengdu University |