CN105037398B - A kind of Bcr Abl amphiploid inhibitor and its production and use - Google Patents
A kind of Bcr Abl amphiploid inhibitor and its production and use Download PDFInfo
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- CN105037398B CN105037398B CN201510180857.0A CN201510180857A CN105037398B CN 105037398 B CN105037398 B CN 105037398B CN 201510180857 A CN201510180857 A CN 201510180857A CN 105037398 B CN105037398 B CN 105037398B
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Classifications
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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
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of Bcr Abl amphiploid inhibitor and its production and use.The invention discloses type I compound or its pharmaceutically acceptable salt, its structural formula is as follows.Type I compound or its pharmaceutically acceptable salt that the present invention is provided; it is used as Bcr Abl amphiploid inhibitor; tyrosine kinase activity can effectively be suppressed; it can be effectively used for the related disease treatment of such kinases abnormal activation; there is good therapeutic action to malignant tumour; the preparation method of such inhibitor is easy, with low cost, has a good application prospect.
Description
Technical field
The present invention relates to a kind of Bcr-Abl amphiploids inhibitor and its production and use.
Background technology
Chronic myelocytic leukemia is that chromosome produces gene mutation [t (9:22)(q34；Q11)] mutually transposition, chromosome
The BCR genes of abl gene and the chromosome 22 position of 9 blend generation BCR-ABL, a kind of 210kDa of gene code of this fusion
EGFR-TK Bcr-Abl, this albumen is to cause the main cause of chronic myelocytic leukemia.C-Abl is in normal cell
It is the monoploid EGFR-TK being present in endochylema, form generation changes after being merged with Bcr, and the tetramer is become by monoploid,
Thus the kinases leads oncogenic generation all the time in the state that is activated.Presence can cause multimerization in Bcr protein sequences
Amino acid sequence causes Bcr-Abl tetramerizations.Because c-Abl plays an important role in the normal cells such as cardiac muscle, if opened
Selective depression carcinogenicity Bcr-Abl rather than Abl inhibitor are sent out, then is expected to substantially reduce cardiac toxic of such inhibitor etc.
Extensive side effect.
2001, FDA ratified first tyrosine kinase inhibitor (TKI) Imatinib (Imatinib) 1 and listed, and is used for
The treatment of chronic myelocytic leukemia (CML).As first generation Bcr-Abl inhibitor, Imatinib has turned into the one for the treatment of CML
Line medicine.But finally all there is resistance to Imatinib in Most patients.Then research shows, the generations of IM drug resistances may be with
G250E、Q252H、Y253F、Y253H、E255K、E355G、E255V、T315A、T315I、F317L、F317V、M351T、
The gene mutation in the Abl kinase activities such as F359V, H396P, M244V area is relevant, and gene mutation causes Imatinib and Abl kinases
Compatibility decline.Most gene mutations make the compatibility of Imatinib decline 5-30 times, and this is the master for producing drug resistance
Want reason.Wherein T315I is more special, reduces the most obvious, IC50Be down to 6400nM or so, the slope developed recently that for Buddhist nun not
It is only effective to T315I, it is effective to wild type and most mutant strains.
From slope, that is replaced from x-Ray eutectic structures of the Buddhist nun with the kinases part of Abl albumen, the first class piperazine moiety in structure
N-methyl be partially exposed in solvent, the air line distance between two inhibitor nitrogen-atoms is 24 peace left and right.Bcr-Abl by
Then the tetramer, can be combined with 4 inhibitor, if connected two inhibitor by chain, be expected to simultaneously
The compatibility to the Bcr-Abl of tetramerization is greatly improved, so that play a part of selective depression Bcr-Abl, and Abl is due to being
Monoploid, can only be combined, amphiploid inhibitor does not have big influence to the compatibility of enzyme with an inhibitor.
The content of the invention
It is an object of the invention to provide a kind of Bcr-Abl amphiploids inhibitor and its production and use.
Compound of formula I or its pharmaceutically acceptable salt that the present invention is provided, its structural formula are as follows：
Further, in Formulas I, Linker is (Z1)a–(Z2)b–(Z3)c；
Wherein, Z1、Z2、Z3Separately it is selected from C (O) (CH2)dNH、CO(CH2)eC(O)、(CH2CH2)fNHC(O)、
(CH2CH2)g-C(O)NH、(CH2)hC(O)(OCH2CH2)iNHC(O)(CH2)jC(O)、NH(CH2)k(OCH2CH2)l-O(CH2)mNH、
(CH2)nC(O)(OCH2CH2)oNH(C(O)(CH2)pNH)qC(O)-alkyl、C(O)NH(CH2)rNHC(O)-(CH2)sC(O)
(NHCH2CH2)tNH(C(O)(CH2)uNH)v-C(O)-alkyl；
A~v separately any values in 1~20.
Further, its structural formula is：
Present invention also offers the method for preparing above-claimed cpd BP.
The method that the present invention prepares above-claimed cpd BP, it includes following operating procedure：
A, prepare compound 12：
B, prepare compound BP：
Further, it includes following operating procedure：
I, prepare compound 4：
(1), 2- methyl-5-nitros benzotrifluoride is in carbon tetrachloride, nitrogen protection is lower add N-bromosuccinimide,
Azodiisobutyronitrile, back flow reaction 24h, obtains reaction solution；Reaction solution is separated, compound 2 is obtained；
(2), compound 2, N-Boc- piperazines, triethylamine are in dichloromethane, and stirring reaction 3h, is reacted at room temperature
Liquid；Reaction solution is separated, purified, compound 3 is obtained；
(3), in the in the mixed solvent of water and ethanol, reduced iron powder, ammonium chloride, compound 3 are added, back flow reaction 1h is obtained
To reaction solution；Reaction solution is separated, purified, compound 4 is obtained；
Ii, prepare compound 8：
(4), the iodo- 4- methyl benzoic acids of 3- and thionyl chloride are in tetrahydrofuran and the mixed solvent of N,N-dimethylformamide
In, 1h is reacted in 60 DEG C, reaction solution is obtained；Reaction solution removes solvent, obtains compound 12；
(5), compound 4, triethylamine, compound 6 after reacting completely at room temperature, obtain reaction solution in dichloromethane；
Reaction solution is separated, purified, compound 7 is obtained；
(6), compound 7 in methyl alcohol, is passed through HCl gases, and reaction is complete, obtains reaction solution；Reaction solution removes solvent, obtains
To compound 8；
Iii, prepare compound 11：
(7), 3- bromines imidazo [1,2-b] pyridazine is in acetonitrile, and nitrogen protection is lower to add bi triphenyl phosphorus palladium chloride, iodine
Change cuprous, dicyclohexylamine, trimethylsilyl acetylene, in reacting complete at 80 DEG C, obtain reaction solution；Reaction solution is separated,
Purifying, obtains compound 10；
(8), compound 10 and methanol, saturation potassium fluoride solution, react complete, obtain reaction solution at room temperature；To reaction
Liquid is separated, purified, and obtains compound 11；
Iv, prepare compound 12：
(9), compound 8, compound 11 are in DMF, and nitrogen protection is lower to add bi triphenyl phosphorus dichloro
Change palladium, cuprous iodide, diisopropylethylamine, stirring reaction completely, obtains reaction solution at room temperature；Reaction solution is separated,
Purifying, obtains compound 12；
V, prepare compound 17：
(10), compound 13, BOC acid anhydrides react completely in dichloromethane, obtain reaction solution；Reaction solution is divided
From, purifying, obtain compound 14；
(11), compound 14, triethylamine, glutaryl chlorine stirring reaction 3h in dichloromethane, obtain reaction solution；To reaction
Liquid is separated, purified, and obtains compound 15；
(12), compound 15 is in HCl/ ethyl acetate, and stirring reaction 3h, obtains reaction solution at room temperature；Reaction solution is removed
Solvent is removed, compound 16 is obtained；
(13), compound 16, diisopropylethylamine, 3- chlorpromazine chlorides be in dichloromethane, at room temperature stirring reaction 3h,
Obtain reaction solution；Reaction solution removes solvent, obtains compound 17；
Vi, prepare compound BP：
(14), compound 12, compound 17, triethylamine are in tetrahydrofuran, and back flow reaction 24h obtains reaction solution；To anti-
Answer liquid to be separated, purified, obtain compound BP.
Further,
In step i (1), the 2- methyl-5-nitros benzotrifluoride, N-bromosuccinimide, azodiisobutyronitrile
Mol ratio be 0.15：0.16：0.01；The molal volume ratio of the 2- methyl-5-nitros benzotrifluoride and carbon tetrachloride is
0.15：200mmol/ml；
In step i (2), the compound 2, N-Boc- piperazines, the mol ratio of triethylamine are 0.146：0.16：0.22；
The molal volume ratio of the compound 2 and dichloromethane is 14.6：200mmol/ml；
In step i (3), the reduced iron powder, ammonium chloride, the mol ratio of compound 3 are 0.5：0.3：0.1；Describedization
The molal volume ratio of compound 3 and mixed solvent is 0.1：200mmol/ml；The volume ratio of the in the mixed solvent, water and ethanol is
1：1；
In step ii (4), the molal volume ratio of the iodo- 4- methyl benzoic acids of 3- and mixed solvent is 0.09：
101mmol/ml；The volume ratio of the in the mixed solvent, tetrahydrofuran and DMF is 100：1；
In step ii (5), the compound 4, triethylamine, the mol ratio of compound 6 are 0.08：0.12：0.088；Institute
The molal volume ratio for stating compound 4 and dichloromethane is 0.08：250mmol/ml；
In step ii (6), the molal volume ratio of the compound 7 and methanol is 0.03：100mmol/ml；
In step iii (7), the molal volume ratio of 3- bromines imidazo [1, the 2-b] pyridazine and acetonitrile is 0.05：
100mmol/ml；3- bromines imidazo [1,2-b] pyridazine, bi triphenyl phosphorus palladium chloride, cuprous iodide, dicyclohexylamine,
The mol ratio of trimethylsilyl acetylene is 0.05：0.0014：0.0014：0.06：0.6；
In step iii (8), the molal volume ratio of the compound 10 and methanol is 0.04：50mol/ml；The methanol
Volume ratio with saturation potassium fluoride solution is 50：20；
In step iv (9), the compound 8, compound 11, bi triphenyl phosphorus palladium chloride, cuprous iodide, diisopropyl
The mol ratio of base ethamine is 17.3：19：1：1：38；The compound 8 and the molal volume ratio of N,N-dimethylformamide are
17.3：150mmol/ml；
In step v (10), the compound 13, the mol ratio of BOC acid anhydrides are 45.5：43.18；The compound 13 with
The molal volume ratio of dichloromethane is 45.5：600mmol/ml；
In step v (11), the compound 14, triethylamine, the mol ratio of glutaryl chlorine are 8.42：14.85：4.17；
The molal volume ratio of the compound 14 and dichloromethane is 8.42：120mmol/ml；
In step v (12), the molal volume ratio of the compound 15 and HCl/ ethyl acetate is 3.8：100mmol/ml；
Described HCl/ ethyl acetate, its concentration is 2M；
In step v (13), the compound 16, diisopropylethylamine, the mol ratio of 3- chlorpromazine chlorides are 0.90：
6.15：1.81；The molal volume ratio of the compound 16 and dichloromethane is 0.90：50mmol/ml；
In step vi (14), the compound 12, compound 17, the mol ratio of triethylamine are 0.2：0.1：0.3；It is described
The molal volume ratio of compound 12 and tetrahydrofuran is 0.2：10mmol/ml.
Treatment cell breeding disease is being prepared present invention also offers above-claimed cpd and its pharmaceutically acceptable salt
Purposes in medicine.
The purposes of above-claimed cpd and its pharmaceutically acceptable salt in the medicine for preparing treatment cell breeding disease.
Further, the medicine is tyrosine kinase inhibitor.
Further, the medicine is ABL inhibitor class medicines.
Further, the medicine is BCR-ABL or its mutant strain inhibitor class medicine.
Further, the BCR-ABL mutant strains are T315I mutant strains.
Further, the cell breeding disease is cancer.
Further, the cancer is chronic myelocytic leukemia, intestines mesenchymoma, gynaecology's knurl, knuckle skin fiber meat
Knurl, Ph+ALL.
Compound of formula I or its pharmaceutically acceptable salt that the present invention is provided, are used as Bcr-Abl amphiploid inhibitor, energy
It is enough effectively to suppress tyrosine kinase activity, the related disease treatment of such kinases abnormal activation is can be effectively used for, to malignant tumour
With good therapeutic action, the preparation method of such inhibitor is easy, with low cost, has a good application prospect.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification of other diversified forms can also be made, replaces or changes.
The embodiment of form, remakes further specifically to the above of the invention by the following examples
It is bright.But the scope that this should not be interpreted as to above-mentioned theme of the invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Embodiment
The raw material that is used in the specific embodiment of the invention, equipment are known product, are obtained by buying commercially available prod.
The Chinese of abbreviation：
AIBN：Azodiisobutyronitrile；DMF：N,N-dimethylformamide；TLC：Thin-layer chromatography；DCM：Dichloromethane；
(Boc)2O：BOC acid anhydrides；DMSO：Dimethyl sulfoxide (DMSO).
The compounds of this invention BP of embodiment 1 preparation
Synthetic route is as follows：
A, prepare compound 12：
B, prepare compound BP：
Prepare compound 4
2- methyl-5-nitros benzotrifluoride (compound 1) (30g, 0.15mol) is added in carbon tetrachloride (200ml),
Under nitrogen protection, addition N-bromosuccinimide (28.8g, 0.16mol), AIBN (2.5g, 0.01mol), electromagnetic agitation,
It is warming up to after back flow reaction 24h and stops reaction, be cooled to room temperature, by reacting liquid filtering, solid is washed with ethyl acetate, merges second
Acetoacetic ester phase, and washed with saturated sodium bicarbonate aqueous solution, then washed with saturated sodium-chloride water solution (10ml × 2), anhydrous sulphur
Sour sodium is dried, and solvent evaporated obtains yellow oil, as compound 2, without purifying, is directly used in next step.
Prepare compound 3
Compound 2 prepared by previous step is dissolved in dichloromethane (200ml), and add N-Boc- piperazines (29.7g,
0.16mol), triethylamine (30ml, 0.22mol), is stirred at room temperature reaction 3h；After reaction completely, water is added into reaction solution
100ml, pH to 2-3 is adjusted with 1N hydrochloric acid, and layering, aqueous phase dichloromethane (100ml) extraction removes unreacted complete raw material and impurity, water
Mutually adjusted after pH to 9-10, extracted with dichloromethane (50ml × 3) after product, organic phase uses saturation again with 1N sodium hydrate aqueous solutions
Sodium-chloride water solution (10ml × 2) is washed, and anhydrous sodium sulfate drying, solvent evaporated obtains pale yellow oily liquid, as chemical combination
(the 48.1g of thing 3；In terms of compound 1,84.4%) yield is.
ESI-MS m/z：390.2[M+H]+；
1HNMR(CDCl3,500MHz)δ:8.52 (d, J=1.5Hz, 1H), 8.39 (d, J=8.5Hz, 1H), 8.12 (d, J
=8.5Hz, 1H), 3.75 (s, 2H), 3.47 (s, 4H), 2.45 (s, 4H), 1.47 (s, 9H).
Prepare compound 4：
To the in the mixed solvent of water (100ml), ethanol (50ml), reduced iron powder (28g, 0.50mol), ammonium chloride are added
(15.9g, 0.30mol), is heated to after backflow, reaction 30min, compound 3 (38.9g, 0.10mol) is dissolved in into ethanol
In (50ml), it is added dropwise in reaction bulb, 1h is reacted after finishing, TLC (thin-layer chromatography) detection reactions, reaction is complete；System is cold
But to room temperature, filtering is washed solid with ethanol, is evaporated after ethanol, and product is extracted with ethyl acetate (50ml × 3), and organic phase is used again
Saturated sodium-chloride water solution (10ml × 2) is washed, and anhydrous sodium sulfate drying, solvent evaporated obtains pale yellow oil, as changed
(the 34.9g of compound 4；97.3%) yield is.
ESI-MS m/z:360.2[M+H]+；
1HNMR(d6-DMSO,500MHz)δ:7.29 (d, J=8.5Hz, 1H), 6.86 (d, J=2Hz, 1H), 6.75 (dd, J
=2,8.5Hz, 1H), 5.45 (s, 2H), 3.29 (br s, 4H), 2.26-2.28 (m, 4H), 1.38 (s, 9H).
Prepare compound 6：
The iodo- 4- methyl benzoic acids (compound 5) (23.6g, 0.09mol) of 3- are added in THF (100ml), DMF is added
(1ml), then adds thionyl chloride (11.78g, 0.099mol), is warming up to 60 DEG C of reaction 1h, after reaction completely, solvent evaporated,
The iodo- 4- methyl benzoyl chlorides (compound 6) of 3- are obtained, next step is directly used in；
Prepare compound 7：
Compound 4 (28.7g, 0.08mol) is dissolved in dichloromethane (200ml), addition triethylamine (17ml,
0.12mol), it is standby；The iodo- 4- methyl benzoyl chlorides (compound 6) of 3- obtained in the previous step are diluted with dichloromethane (50ml)
Afterwards, it is slowly added dropwise under condition of ice bath into above-mentioned standby reaction solution, TCL detections after room temperature reaction, 1h is warming up to after finishing anti-
Should, after reaction completely, reaction solution is washed with saturated sodium bicarbonate solution (20ml × 3), organic phase uses saturated sodium-chloride water again
Solution (20ml × 2) is washed, and anhydrous sodium sulfate drying, solvent evaporated obtains faint yellow solid, the as (39.7g of compound 7；Receive
82.5%) rate is.
ESI-MS m/z:604.2[M+H]+；
1HNMR(CDCl3,500MHz)δ:8.32 (s, 1H), 7.91 (s, 2H), 7.88~7.92 (m, 2H), 7.75~7.79
(m, 2H), 7.30 (d, J=8Hz, 1H), 3.62 (s, 2H), 3.42-3.44 (m, 4H), 2.48 (s, 2H), 2.39-2.41 (m,
4H),1.46(s,9H)。
Prepare compound 8：
Compound 7 (18g, 0.03mol) is dissolved in methanol (100ml), HCl gases is passed through, after reaction completely, is evaporated
Solvent, obtains compound 8, is directly used in next step；
Prepare compound 10
3- bromines imidazo [1,2-b] pyridazine (compound 9) (10g, 0.05mol) is dissolved in acetonitrile (100ml), in nitrogen
Under gas shielded, bi triphenyl phosphorus palladium chloride (1.0g, 1.4mmol), cuprous iodide (0.3g, 1.4mmol), dicyclohexyl are added
Amine (11ml, 0.06mol), is warming up to 80 DEG C, and trimethylsilyl acetylene (8ml, 0.6mol) is slowly added dropwise into reaction solution, finished
Reaction 1h TLC detections afterwards, reaction is complete, and reaction solution is cooled into room temperature, filtered, solid is washed with dichloromethane (200ml),
Merge organic phase, residue is added dichloromethane (100ml), organic phase uses saturated sodium-chloride water solution again by solvent evaporated
(20ml × 2) are washed, anhydrous sodium sulfate drying, and solvent evaporated obtains crude product, and crude product is crystallized with ethyl acetate/petroleum ether system, obtained
To brown-black powder shape solid, the as (8.9g of compound 10；81.8%) yield is.
1HNMR(CDCl3,400MHz)δ:8.47 (dd, J=1.6,4.4Hz, 1H), 7.99 (s, 1H), 7.96 (dd, J=
1.6,9.2Hz, 1H), 7.10 (dd, J=4.4,9.2Hz, 1H), 0.33 (s, 9H).
Prepare compound 11：
By compound 10 (8g, 0.04mol) methanol (50ml) dissolving, saturation potassium fluoride solution (20ml) is added, in room
After lower reaction 20min, the TLC detection reactions completely of temperature, methanol is evaporated, residue dichloromethane (100m) dissolves, and organic phase is again
Washed with saturated sodium-chloride water solution (30ml × 3), sodium sulphate is dried, solvent evaporated obtains brown-black powder shape solid, be
(the 5.2g of compound 11；98.4%) yield is.
ESI-MS m/z:144.1[M+H]+；
1HNMR(CDCl3,400MHz)δ:8.48 (dd, J=1.6,4.4Hz, 1H), 8.02 (s, 1H), 8.00 (dd, J=
1.6,9.2Hz, 1H), 7.12 (dd, J=4.4,9.2Hz, 1H), 3.82 (s, 1H).
Prepare compound 12
Compound 8 (10g, 17.3mmol) is added in DMF (100ml), under nitrogen protection, bi triphenyl phosphorus two is added
Palladium bichloride (0.7g, 1mmol), cuprous iodide (0.2g, 1mmol), diisopropylethylamine (6.6ml, 38mmol), are stirred at room temperature,
By compound 11 (2.7g, 19mmol) with after DMF (50ml) dilutions, it is slowly added dropwise into reaction solution, TLC detections reaction after 1h,
After reaction completely, reaction solution is poured into water (300ml), product is extracted with dichloromethane (50ml × 3), organic phase uses saturation again
Sodium-chloride water solution (20ml × 2) is washed, and sodium sulphate is dried, and solvent evaporated obtains crude product；Crude product ethanol/petroleum ether system
Recrystallization, obtains pale yellow powder shape solid, the as (7.7g of compound 12；85.7%) yield is.
ESI-MS m/z:519.2[M+H]+；
1HNMR(d6-DMSO,500MHz)δ:10.57 (s, 1H), 8.73 (dd, J=1.5,4.5Hz, 1H), 8.28 (dd, J
=1.5,9.5Hz, 1H), 8.24 (s, 1H), 8.22 (d, J=1.5,2H), 8.07 (d, J=8Hz, 1H), 7.95 (dd, J=
1.5,8Hz, 1H), 7.73 (d, J=8.5Hz, 1H), 7.55 (d, J=8.5Hz, 1H), 7.40 (dd, J=4.5,9.5Hz, 1H),
3.54 (s, 2H), 2.75 (br s, 4H), 2.61 (s, 3H), 2.34 (br s, 4H), 1.23 (br s, 1H).
Prepare compound 14：
Compound 13 (10g, 45.5mmol) is dissolved in 500ml DCM, at room temperature, by (Boc)2O (9.4g,
43.18mmol) it is dissolved in 100ml DCM, is slowly added dropwise into reaction bulb, reaction is stayed overnight；Water is added into reaction solution
200ml, is adjusted after pH to 3-4, and extraction removes organic phase impurity, and aqueous phase adjusts pH to 10, adds sodium chloride saturation, extract and product, organic
The complete raw material of unreacted is mutually washed away with saturated sodium-chloride water solution (10ml × 6) again, sodium sulphate is dried, and solvent evaporated obtains nothing
Color grease, the as (4.7g of compound 14；34.1%) yield is.
1H NMR(400MHz,CDCl3):δ 5.11 (br s, 1H), 3.63-3.45 (m, 12H), 3.21 (t, J=6.0Hz,
2H), (s, the 9H) of 2.81 (t, J=6.4Hz, 2H), 1.77-1.42 (m, 6H), 1.42
Prepare compound 15：
At room temperature, compound 14 (2.7g, 8.42mmol), triethylamine (1.5g, 14.85mmol) are dissolved in dichloromethane
In alkane (100ml), compound glutaryl chlorine (0.7g, 4.17mmol) is dissolved in dichloromethane (20ml), into reaction solution
It is added dropwise, more than 1h reaction 3h is stirred at room temperature, then with saturated sodium-chloride water solution (100ml × 2) in time for adding after finishing
Organic phase is washed, organic phase dried with sodium sulphate, be concentrated in vacuo solvent evaporated, residue purifies (dichloro with silica gel column chromatography
Methane/methanol=20/1) obtains colorless oil, the as (3.1g of compound 15；Yield 100%).
ESI-MS m/z:737.4[M+H]+；
1H NMR(400MHz,CDCl3):δ6.55(br s,2H),5.06(br s,2H),3.63-3.49(m,24H),
3.34 (m, 4H), 3.20 (m, 4H), 2.22 (t, J=7.2Hz, 4H), 1.93 (m, 2H), 1.78-1.70 (m, 8H), 1.41 (s,
18H)。
Prepare compound 16：
Compound 15 (2.8g, 3.80mmol) is added in HCl/ ethyl acetate (2M, 100ml), stirs anti-at room temperature
3h is answered, solvent evaporated is concentrated in vacuo, obtains colourless oil liquid, as compound 16 (2.6g, yield:~100%), without entering
One step is purified, and is directly used in next step reaction；
Prepare compound 17：
At room temperature, by compound 16 (484mg, 0.90mmol), diisopropylethylamine (DIPEA) (800mg,
6.15mmol) it is dissolved in dichloromethane (40ml), by 3- chlorpromazine chlorides (230mg, 1.81mmol) dichloromethane (10ml)
After dilution, it is added dropwise into reaction solution, time for adding is stirred at room temperature reaction 3h, then uses saturation chlorination more than 1h after finishing
Sodium water solution (50ml × 2) washs organic phase, and organic phase is dried with sodium sulphate, and be concentrated under reduced pressure solvent evaporated, adds into residue
Enter n-hexane to stir, filter, obtain white solid, the as (330mg of compound 17；50.9%) yield is.
1H NMR(400MHz,CDCl3):δ 6.85 (bs, 2H), 6.58 (bs, 2H), 3.81 (t, J=6.4Hz, 4H),
3.66-3.53 (m, 24H), 3.39-3.31 (m, 8H), 2.64 (m, 4H), 2.24 (t, J=7.2Hz, 4H), 1.81 (m, 2H),
1.55-1.47(m,8H)。
Prepare compound BP
By compound 12 (0.1g, 0.2mmol), compound 17 (0.07g, 0.1mmol), triethylamine (42 μ l, 0.3mmol)
It is added in 10ml tetrahydrofurans, is warming up to after back flow reaction 24h, solvent evaporated, yellow powder is prepared with preparation liquid phase
Shape solid, as compound BP (63mg；37.5%) yield is.
ESI-MS m/z:1681.8[M+H]+；
1HNMR(D2O,400MHz)δ:8.48 (dd, J=1.6,4.4Hz, 2H), 8.03 (dd, J=1.6,9.6Hz, 2H),
7.99 (s, 2H), 8.97 (d, J=1.6,4H), 7.82 (d, J=8Hz, 2H), 7.71 (dd, J=1.6,8Hz, 2H), 7.48 (d,
J=8.8Hz, 2H), 7.31 (d, J=8.8Hz, 2H), 7.15 (dd, J=4.4,9.6Hz, 2H), 3.66-3.44 (m, 44H),
3.34 (s, 4H), 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).
Beneficial effects of the present invention are illustrated below by way of test example.
The medical active of the compounds of this invention of test example 1
1st, tyrosine kinase inhibitory activity
Reference：Amy Card et al.,Journal of Biomolecular Screening 14(1)2009；Jude
Dunne et al.,Assay&Drug Development Technologies Vol.2,No.2,2004。
Using Mobility Shift Assay method, the compounds of this invention BP screening is carried out to vitro kinase Abl,
Compound BP concentration is diluted to 0.005 μM with 100%DMSO successively by 100 μM of three times dilution methods, and totally 10 concentration points, are examined
Survey (2 multiple holes), using compound staurosporine as standard control, if Vehicle controls (10%DMSO) and negative control
(EDTA)。
By enzyme linked immunoassay on 384 hole reaction plates, suppression feelings of the compound BP to kinases Abl of each concentration are detected
Condition, the upper reading and converting rate data of Caliper, and conversion into inhibiting rate.
Percent inhibition=(max-conversion)/(max-min) * 100.Wherein max refers to DMSO pairs
According to conversion ratio, min refers to the conversion ratio of no enzyme activity control.BP pairs of the compounds of this invention is calculated according to the inhibiting rate of each concentration
The enzymatic activity half-inhibition concentration IC of c-Abl EGFR-TKs50。
Histamine result is as follows：
Compound BP IC50：0.01μM；
Result of the test illustrates that the compounds of this invention BP has stronger inhibitory activity to c-Abl EGFR-TKs.
2nd, the compounds of this invention BP increases in vitro to KBM5 (Bcr-Abl is positive) with KBM5R (T315I mutant strains) tumour cell
Grow suppression experiment
The cytotoxicity of BP series compounds of the present invention is determined with ATP methods, KBM5 and KBM5R cells are adjusted suitable thin
Born of the same parents' density, with every orifice plate of hole 140ul cell suspension inoculations 96, the inoculum density of every kind of cell is：2000-6000；Will be above-mentioned
Tissue Culture Plate is placed 24 hours in incubator makes it be adhering completely on hole wall, using three times dilution method by chemical combination of the present invention
Each compound is configured to suitable various concentrations respectively in thing BP series, is added to advance 96 orifice plates for being vaccinated with cell corresponding
Hole in, per the μ L of hole 10, make its ultimate density be respectively：100μM、33.3μM、11.1μM、3.70μM、1.23μM、0.41μM、
0.14μM、0.046μM、0.015μM.Each concentration is set respectively be incubated 72 hours in three multiple holes, 37 DEG C of incubators after, ATP methods
Each hole cell proliferative conditions are determined, inhibiting rate and median lethal that each drug concentration is bred to KBM5 and KBM5R cells is calculated
Concentration (IC50)。
Result of the test：
Compound BP is as follows to the cytotoxicity of KBM5 (people source wild type Bcr-Abl) tumour cell：
Compound BP IC50：2μM；
Compound BP is to KBM5R (Bcr-AblT315IMutant strain) tumour cell cytotoxicity it is as follows：
Compound BP IC50：5μM；
Result of the test illustrates that the compounds of this invention BP has stronger inhibitory activity on cellular level in vitro.
3rd, the compounds of this invention BP internal leukaemia Subcutaneous Xenograft Proliferation Ability experiment
Suppress the result of experiment according to in-vitro multiplication, IC is selected in BP series compounds of the present invention50Minimum inhibitor,
BP be have evaluated in C57BL/6 (Es-1c) nude mice by subcutaneous transplanting people source leukaemia KBM5 and KBM5R cells growth inhibitory effect.
The compounds of this invention BP dosage is respectively：80mg/Kg, 160mg/Kg, 350mg/Kg, while setting positive right
According to group (160mg/Kg Imatinib Imatinib) and blank control group (physiological saline), one is administered daily after mice with tumor packet
Secondary, continuous intraperitoneal injection detects the volume of tumour after two weeks.
Investigate whether tumour growth can be suppressed, delays or cure.It is twice a week or swollen with vernier caliper measurement every other day
Knurl diameter.The calculation formula of gross tumor volume is：V=0.5a × b2, a and b represent the major diameter and minor axis of tumour respectively.
Data analysis：T is examined for comparing between two groups；Three groups or multigroup are compared and use one-way ANOVA.If F values
There is significant difference, Multiple range test should be carried out again after ANOVA analyses.Two-way ANOVA are used for analysis joint administration group
Potential synergy.All data analyses are carried out with SPSS 17.0；p<0.05 thinks there is significant difference.
Result of the test：For people source leukaemia KBM5 (Bcr-Abl is positive) subcutaneous transplantation knurl model, the compounds of this invention BP
It is suitable with Imatinib 160mg/kg inhibition under 80mg/kg dosage with antitumor drug effect.For people source leukaemia
KBM5R (Bcr-AblT315I mutant strains) subcutaneous transplantation knurl model, the compounds of this invention BP have with to KBM5 subcutaneous transplantation knurls
Suitable inhibition, Imatinib has no obvious inhibition.
4th, the compounds of this invention BP Initial pharmacokinetic research
Female C57BL/6 (Es-1c) after the tested the compounds of this invention BP of nude mice Single-dose intravenous, use liquid chromatography tandem matter
Spectrometry quantitative determines its concentration and blood concentration in Main Tissues, investigates test medicine in female C57BL/6 (Es-1c) naked
Blood and the distributional difference in Main Tissues in mouse body；With Imatinib as a comparison.
Experimental method is as follows with process：Female C57BL/6 (Es-1c) nude mice, body weight 18-25g, 6-8 week old, in addition, 3
Female C57BL/6 (Es-1c) nude mice is used to gather blank sample, prepares the standard curve needed for analysis.It is injected intravenously to medicament
Measure as 1mg/kg, administered volume is 5mL/kg.Intravenous injection administration solvent：DMSO:Solutol HS15:Saline=5:5:
90,v/v/v.LC-MS/MS methods are set up, test medicine blood concentration and tissue concentration, the range of linearity are determined with inner mark method ration
1~1000ng/mL, lower limit of quantitation scope is generally 1ng/mL.Female C57BL/6 (Es-1c) nude mice intravenous administration administration after
In 0.25h, 2h, 8h and 24h singles gather the μ L of whole blood about 20 from mouse tail vein, use K2EDTA anti-freezings, 3 are added according to volume ratio
Times redistilled water dilute after blood sample, be stored in -70 DEG C until analyze.The heart is gathered simultaneously, and liver, spleen, lung, kidney, stomach is small
Intestines, the tissue sample such as pancreas is cleaned, filter paper is weighed and recorded after blotting with physiological saline, be then stored in -70 DEG C until point
Analysis.After weighed organs and tissues are thawed, the heart, liver, spleen, lung, kidney, stomach, small intestine, pancreas adds 3 times of PBS buffer salts and used
Beadbeater is homogenized；Rinsed when bone marrow specimens are gathered using 0.3mL PBS buffer salts, then 12000 leave the heart 5 minutes, moved
0.25mL supernatants are removed, remaining cell sample adds the homogenate of 150LPBS buffer salts.
Data analysis：Using WinNonlin (version 6.2) software, pharmacokinetic parameters are calculated by non-compartment model.
Test result indicates that, the compounds of this invention BP half-life period (t1/2) it is 3.5 hours, it is far longer than Imatinib
Half-life period (t1/2For 1.5h)；Compared with Imatinib, the compounds of this invention BP is special in the pharmacokinetics after intravenous injection
Property on there is obviously advantage.
In summary, the present invention is provided type I compound or its pharmaceutically acceptable salt, are used as Bcr-Abl amphiploids
Inhibitor, can effectively suppress tyrosine kinase activity, can be effectively used for the related disease treatment of such kinases abnormal activation, right
Malignant tumour has good therapeutic action, and the preparation method of such inhibitor is easy, with low cost, before good application
Scape.
Claims (12)
1. type I compound or its pharmaceutically acceptable salt, its structural formula are as follows：
In Formulas I, Linker is (Z1)a–(Z2)b–(Z3)c；
Wherein, Z1、Z2、Z3Separately it is selected from C (O) (CH2)dNH、CO(CH2)eC(O)、(CH2CH2)fNHC(O)、
(CH2CH2)g-C(O)NH、(CH2)hC(O)(OCH2CH2)iNHC(O)(CH2)jC(O)、NH(CH2)k(OCH2CH2)l-O(CH2)mNH、
(CH2)nC(O)(OCH2CH2)oNH(C(O)(CH2)pNH)qC(O)-alkyl、C(O)NH(CH2)rNHC(O)-(CH2)sC(O)
(NHCH2CH2)tNH(C(O)(CH2)uNH)v-C(O)-alkyl；
A~v separately any values in 1~20.
2. type I compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that：Its structural formula is：
3. prepare claim 2 compound BP method, it is characterised in that：It includes following operating procedure：
A, prepare compound 12：
B, prepare compound BP：
。
4. preparation method according to claim 3, it is characterised in that：It includes following operating procedure：
I, prepare compound 4：
(1), 2- methyl-5-nitros benzotrifluoride (compound 1) is in carbon tetrachloride, and nitrogen protection is lower to add N- bromo succinyls
Imines, azodiisobutyronitrile, back flow reaction 24h, obtain reaction solution；Reaction solution is separated, compound 2 is obtained；
(2), compound 2, N-Boc- piperazines, triethylamine are in dichloromethane, and stirring reaction 3h, obtains reaction solution at room temperature；
Reaction solution is separated, purified, compound 3 is obtained；
(3), in the in the mixed solvent of water and ethanol, reduced iron powder, ammonium chloride, compound 3 are added, back flow reaction 1h obtains anti-
Answer liquid；Reaction solution is separated, purified, compound 4 is obtained；
Ii, prepare compound 8：
(4), the iodo- 4- methyl benzoic acids of 3- and thionyl chloride tetrahydrofuran and DMF in the mixed solvent,
1h is reacted in 60 DEG C, reaction solution is obtained；Reaction solution removes solvent, obtains compound 6；
(5), compound 4, triethylamine, compound 6 after reacting completely at room temperature, obtain reaction solution in dichloromethane；To anti-
Answer liquid to be separated, purified, obtain compound 7；
(6), compound 7 in methyl alcohol, is passed through HCl gases, and reaction is complete, obtains reaction solution；Reaction solution removes solvent, is changed
Compound 8；
Iii, prepare compound 11：
(7), 3- bromines imidazo [1,2-b] pyridazine is in acetonitrile, and nitrogen protection is lower to add bi triphenyl phosphorus palladium chloride, iodate Asia
Copper, dicyclohexylamine, trimethylsilyl acetylene, in reacting complete at 80 DEG C, obtain reaction solution；Reaction solution is separated, purified,
Obtain compound 10；
(8), compound 10 and methanol, saturation potassium fluoride solution, react complete, obtain reaction solution at room temperature；Reaction solution is entered
Row separation, purifying, obtain compound 11；
Iv, prepare compound 12：
(9), compound 8, compound 11 are in DMF, and nitrogen protection is lower to add bi triphenyl phosphorus dichloride
Palladium, cuprous iodide, diisopropylethylamine, stirring reaction is complete at room temperature, obtains reaction solution；Reaction solution is separated, it is pure
Change, obtain compound 12；
V, prepare compound 17：
(10), compound 13, BOC acid anhydrides react completely in dichloromethane, obtain reaction solution；Reaction solution is separated, it is pure
Change, obtain compound 14；
(11), compound 14, triethylamine, glutaryl chlorine stirring reaction 3h in dichloromethane, obtain reaction solution；Reaction solution is entered
Row separation, purifying, obtain compound 15；
(12), compound 15 is in HCl/ ethyl acetate, and stirring reaction 3h, obtains reaction solution at room temperature；Reaction solution removes molten
Agent, obtains compound 16；
(13), compound 16, diisopropylethylamine, 3- chlorpromazine chlorides are in dichloromethane, and stirring reaction 3h, is obtained at room temperature
Reaction solution；Reaction solution removes solvent, obtains compound 17；
Vi, prepare compound BP：
(14), compound 12, compound 17, triethylamine are in tetrahydrofuran, and back flow reaction 24h obtains reaction solution；To reaction solution
Separated, purified, obtain compound BP.
5. preparation method according to claim 4, it is characterised in that：
In step i (1), the 2- methyl-5-nitros benzotrifluoride, N-bromosuccinimide, azodiisobutyronitrile rub
You are than being 0.15：0.16：0.01；The molal volume ratio of the 2- methyl-5-nitros benzotrifluoride and carbon tetrachloride is 0.15：
200mmol/ml；
In step i (2), the compound 2, N-Boc- piperazines, the mol ratio of triethylamine are 0.146：0.16：0.22；It is described
The molal volume ratio of compound 2 and dichloromethane is 14.6：200mmol/ml；
In step i (3), the reduced iron powder, ammonium chloride, the mol ratio of compound 3 are 0.5：0.3：0.1；The compound 3
Molal volume ratio with mixed solvent is 0.1：200mmol/ml；The volume ratio of the in the mixed solvent, water and ethanol is 1：1；
In step ii (4), the molal volume ratio of the iodo- 4- methyl benzoic acids of 3- and mixed solvent is 0.09：101mmol/
ml；The volume ratio of the in the mixed solvent, tetrahydrofuran and DMF is 100：1；
In step ii (5), the compound 4, triethylamine, the mol ratio of compound 6 are 0.08：0.12：0.088；Describedization
The molal volume ratio of compound 4 and dichloromethane is 0.08：250mmol/ml；
In step ii (6), the molal volume ratio of the compound 7 and methanol is 0.03：100mmol/ml；
In step iii (7), the molal volume ratio of 3- bromines imidazo [1, the 2-b] pyridazine and acetonitrile is 0.05：100mmol/
ml；3- bromines imidazo [1,2-b] pyridazine, bi triphenyl phosphorus palladium chloride, cuprous iodide, dicyclohexylamine, trimethyl silicane
The mol ratio of acetylene is 0.05：0.0014：0.0014：0.06：0.6；
In step iii (8), the molal volume ratio of the compound 10 and methanol is 0.04：50mol/ml；The methanol is with satisfying
Volume ratio with potassium fluoride solution is 50：20；
In step iv (9), the compound 8, compound 11, bi triphenyl phosphorus palladium chloride, cuprous iodide, diisopropyl second
The mol ratio of amine is 17.3：19：1：1：38；The molal volume ratio of the compound 8 and N,N-dimethylformamide is 17.3：
150mmol/ml；
In step v (10), the compound 13, the mol ratio of BOC acid anhydrides are 45.5：43.18；The compound 13 and two
The molal volume ratio of chloromethanes is 45.5：600mmol/ml；
In step v (11), the compound 14, triethylamine, the mol ratio of glutaryl chlorine are 8.42：14.85：4.17；It is described
The molal volume ratio of compound 14 and dichloromethane is 8.42：120mmol/ml；
In step v (12), the molal volume ratio of the compound 15 and HCl/ ethyl acetate is 3.8：100mmol/ml；It is described
HCl/ ethyl acetate, its concentration be 2M；
In step v (13), the compound 16, diisopropylethylamine, the mol ratio of 3- chlorpromazine chlorides are 0.90：6.15：
1.81；The molal volume ratio of the compound 16 and dichloromethane is 0.90：50mmol/ml；
In step vi (14), the compound 12, compound 17, the mol ratio of triethylamine are 0.2：0.1：0.3；The chemical combination
The molal volume ratio of thing 12 and tetrahydrofuran is 0.2：10mmol/ml.
6. compound described in claim 1~2 any one and its pharmaceutically acceptable salt are preparing treatment cell propagation disease
Purposes in the medicine of disease.
7. purposes according to claim 6, it is characterised in that：The medicine is tyrosine kinase inhibitor.
8. the purposes according to claim 6 or 7, it is characterised in that：The medicine is ABL inhibitor class medicines.
9. the purposes according to claim 6 or 7, it is characterised in that：The medicine is BCR-ABL or its mutant strain inhibitor
Class medicine.
10. purposes according to claim 9, it is characterised in that：The BCR-ABL mutant strains are T315I mutant strains.
11. purposes according to claim 6, it is characterised in that：The cell breeding disease is cancer.
12. purposes according to claim 11, it is characterised in that：The cancer is chronic myelocytic leukemia, intestines interstitial
Knurl, gynaecology's knurl, dermatofibrosarcoma protuberans, Ph+ALL.
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| CN103570724A (en) * | 2012-07-27 | 2014-02-12 | 中国科学院广州生物医药与健康研究院 | Synthesis method of ponatinib |
| CN103664951A (en) * | 2012-09-05 | 2014-03-26 | 南京圣和药业有限公司 | Preparation method of drug for treating chronic granulocytic leukemia |
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| US8530492B2 (en) * | 2009-04-17 | 2013-09-10 | Nektar Therapeutics | Oligomer-protein tyrosine kinase inhibitor conjugates |
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| CN103570724A (en) * | 2012-07-27 | 2014-02-12 | 中国科学院广州生物医药与健康研究院 | Synthesis method of ponatinib |
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