CN106349224A - JAK kinase inhibitor with 4-amino-(1H)-pyrazole structure and preparation method and application thereof - Google Patents
JAK kinase inhibitor with 4-amino-(1H)-pyrazole structure and preparation method and application thereof Download PDFInfo
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- CN106349224A CN106349224A CN201610630147.8A CN201610630147A CN106349224A CN 106349224 A CN106349224 A CN 106349224A CN 201610630147 A CN201610630147 A CN 201610630147A CN 106349224 A CN106349224 A CN 106349224A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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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
Abstract
The invention discloses a JAK kinase inhibitor with 4-amino-(1H)-pyrazole structure and a preparation method and application thereof. The compound has a structure shown in general formula (I) or (II), and the invention provides a specific preparation method of the compound and application of the compound in preventing or treating inflammation, tumor and blood related diseases; the inflammation, tumor and blood related diseases include psoriasis, rheumatic arthritis, polycythemia vera, cicatricial alopecia, primary thrombocythemia, ulcerative colitis, myelofibrosis with myeloid metaplasia, severe combined immune deficiency, various leukemia, various solid tumors and the like.
Description
Technical field
The present invention relates to one kind contains jak kinase inhibitor of 4- amino-(1h)-pyrrazole structure and preparation method thereof and answers
With belonging to organic compound synthesis and medical applications technical field.
Background technology
Jak/stat signal path serves critically important physiology in autoimmune, blood generation and tumor occur and makees
With.The exception of jak/stat signal path will induce the diseases such as immunodeficiency, inflammation and tumor.During some tumors occur
Sustained activation with jaks kinases.The imbalance of jak2 hypotype is usually found in the t cell acute in hyperosteogeny tumor and childhood
With the patient of Lymphocytic leukemia.The malignant hematologic disease such as malignant lymphoma and myeloproliferative disorder and the mutation of jak2 hypotype
Related.Some somatomedin and cytokine can stimulate jaks to make stat3 phosphorylation with its receptor binding.Through pertinent literature report
Road stat3 target is related to tumor generation.The jak/stat3 signal path of sustained activation can promote propagation and the life of cancerous cell
Long.The inhibitor of therefore effect jak/stat signal path can be applied in anti-tumor disease.
Jaks inhibitor is widely used in the treatment of the diseases such as immunodeficiency, inflammation and tumor.So far, it is used for
Oncotherapy be in shown in the following structural formula of jaks inhibitor of clinic and listing:
Lu Suo replaces Buddhist nun (ruxolitinib) to be used for treating myelofibrosises tumor by fda approval listing in 2013, and this is one
Plant rare myeloma.Additionally, it be additionally operable to treat transitivity cancer of pancreas (clinical three phases) and multiple myeloma, leukemia,
Colon cancer (clinical second phase).Jak2 inhibitor azd1480 can suppress stat5 signal path thus treating carcinoma of prostate.jak2
Inhibitor tg101348 can block jak/stat signal path thus suppressing the growth of tumor cell and inducing its apoptosis, now uses
In treatment myelofibrosises.Jaks inhibitor momelotinib and pacritinib also researches and develops for treating myelofibrosises.This
Front we have synthesized potent jak kinase inhibitor, and this potent inhibitor prior art is simultaneously not disclosed.Later stage, our heres were basic
A kind of jak kinase inhibitor containing 4- amino-(1h)-pyrrazole structure of enterprising one-step synthesis.
Content of the invention
For the deficiencies in the prior art, the invention provides a kind of jak containing 4- amino-(1h)-pyrazoles ring skeleton swashs
Enzyme inhibitor, present invention also offers the preparation method of above-claimed cpd and purposes.
The technical scheme is that
First, contain the jak kinase inhibitor of 4- amino-(1h)-pyrazoles ring structure
The present invention contains the jak kinase inhibitor of 4- amino-(1h)-pyrazole ring, its pharmaceutically acceptable salt, and solvent closes
Thing or prodrug, have below formula or a shown structure:
Wherein:
r1It is hydrogen, alkyl, halogen, nitro or trifluoromethyl；
r2、r3、r4It is independently selected from halogen, hydrogen, the substituent group of ether, alkane or substituted-amino；
N is 0,1,2 or 3；
Ring is five yuan of heteroaromatics, hexa-atomic aromatic ring or hexa-atomic heteroaromatic.
Preferably, r1It is hydrogen, c1-c6 alkyl, fluorine, chlorine or trifluoromethyl；r2、r3、r4Be independently selected from hydrogen, fluorine,
Chlorine, methyl or methoxy；N is 0 or 1；Ring is pyrrole ring, pyrazole ring, phenyl ring or quinoline ring.
It is more highly preferred to, above-claimed cpd is one of following:
The chloro- n of 5-4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3a),
The chloro- n of 5-4- (4- phenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3b),
The chloro- n of 5-4- (4- fluorophenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3c),
The chloro- n of 5-4- (4- methoxyphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3d),
The chloro- n of 5-4- (2- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3e),
The chloro- n of 5-4- (3- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3f),
n4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3g),
n4- (2- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3h),
2- ((2- ((1h- pyrazoles -4- alkane)-amino) pyrimidine -4- alkane) amino) cyanophenyl (3i),
n4- (3- acetylene phenyl)-n2- (1h- pyrazoles -4- alkane)-amino) pyrimidine -2,4- diamidogen (3j),
n4- (4- chlorphenyl) the fluoro- n of -5-2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3k),
n4The fluoro- n of-phenyl -5-2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3l),
n4- (4- methoxyphenyl) the fluoro- n of -5-2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3m),
n4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6a),
n4- phenyl-n2- (1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6b),
n4- (4- methoxyphenyl)-n2- (1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6c),
n4- (3- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6d),
n4- (3- acetylene phenyl)-n2- (1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6e),
n4- (2- chlorobenzyl)-n2- (1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6f),
n4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) -7h- pyrroles [2,3-d] pyrimidine -2,4- diamidogen (11a),
n4- phenyl-n2- (1h- pyrazoles -4- alkane) -7h- pyrroles [2,3-d] pyrimidine -2,4- diamidogen (11b),
n4- (4- methoxyphenyl)-n2- (1h- pyrazoles -4- alkane) -7h- pyrroles [2,3-d] pyrimidine -2,4- diamidogen (11c) or
n4- (2- chlorobenzyl)-n2- (1h- pyrazoles -4- alkane) -7h- pyrroles [2,3-d] pyrimidine -2,4- diamidogen (11d).
2nd, contain the preparation method of the jak kinase inhibitor of 4- amino-(1h)-pyrazoles ring structure
The present invention contains the preparation method of the jak kinase inhibitor of 4- amino-(1h)-pyrazoles ring structure, is following method
One of:
(1) -2,4- dichloro pyrimidine is replaced with the aromatic amine replacing for initiation material with 5-, generate through under the conditions of acid or alkali
Midbody compound 2, midbody compound 2 can get end-product 3 with the generation nucleophilic displacement of fluorine of 4- amino-pyrazol；
Reaction equation one is as follows:
Wherein, r1、r2、r3、r4As described in above-mentioned formula i；
Reagent in above-mentioned reaction equation and condition: (a), for 2a, the synthesis of 2b, 2d, n, n- diisopropylethylamine, n, n-
Dimethylformamide, room temperature, 16h；For the synthesis of 2c, sodium carbonate, ethanol, room temperature, reaction is overnight；For the synthesis of 2e, n,
N- diisopropylethylamine, n- N-methyl 2-pyrrolidone N-, 100 DEG C, 12h；For 2f, the synthesis of 2g, triethylamine, ethanol, 50-80 DEG C, instead
Should overnight；For the synthesis of 2h, hcl, h2O, room temperature, 5 days；For 2i, the synthesis of 2l, hcl, h2O, 50 DEG C, 5h；For 2j's
Synthesis, n, n- diisopropylethylamine, isopropanol, 60 DEG C, reaction is overnight；For 2k, the synthesis of 2m, mol ratio h2o/ch3Oh=3:
1,50℃,5h；(b), 4- amino-pyrazol, trifluoroacetic acid, n-butyl alcohol, 120 DEG C, 2-3h.
, concrete preparation process is as follows taking compound 3a as a example:
The chloro- n of 5-4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2, the preparation method of 4- diamidogen (3a), step is such as
Under:
(1) preparation of the chloro- n- of 2,5- bis- (4- chlorphenyl) pyrimidine -4- amine (2a)
At ambient temperature, by 2,4,5- trichloropyrimidine 0.65g and parachloroanilinum 0.5g are dissolved in n, n- dimethylformamide
In 30ml, continue Deca n, n- diisopropylethylamine 1.3g in above-mentioned solution, mixed solution is stirred at room temperature reaction overnight；Reaction
After the completion of, add ethyl acetate 150ml, organic phase washed with water, aqueous citric acid solution, each 100ml of common salt aqueous solution in reactant liquor
Washing three times；Organic faciess anhydrous magnesium sulfate is dried overnight, and sucking filtration removes solvent under reduced pressure, obtains crude product；With petroleum ether: second
The silica gel column chromatography purification of acetoacetic ester=10:1 volume ratio can get intermediate 2a；
(2) the chloro- n of 5-4- (4- chlorphenyl)-n2The preparation of-(1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3a)
Intermediate 2a 0.3g and 4- amidopyrazole 0.18g is dissolved in n-butyl alcohol, adds 2-3 to drip trifluoroacetic acid in the solution,
React 2-3h at 150 DEG C of microwave, after reaction terminates, solvent decompression Rotary Evaporators are evaporated and obtain crude product；To obtain
Crude product by column purification dichloromethane: methanol=30:1 volume ratio obtains compound 3a.
(2) with the aromatic amine of 2,4- dichloroquinazoline and replacement for initiation material, in generating under the conditions of alkali is made with sodium acetate
Intermediate compounds therefor 5, midbody compound 5 can get end-product 6 with the generation nucleophilic displacement of fluorine of 4- amino-pyrazol；
Reaction equation two is as follows:
Wherein, r2、r3、r4, n is as described in above-mentioned formula；
Reagent in above-mentioned reaction equation and condition: (a), sodium acetate, oxolane/water=3:1 (v/v), room temperature, reacted
Night；(b), 4- amino-pyrazol, n-butyl alcohol, 120 DEG C, 1h.
, concrete preparation process is as follows taking compound 6a as a example:
n4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) quinazoline -2, the preparation method of 4- diamidogen (6a), step is as follows:
(1) preparation of the chloro- n- of 2- (4- chlorphenyl) quinazoline -4- amine (5a)
Under condition of ice bath, 2,4- dichloroquinazoline 0.50g and sodium acetate 0.80g is dissolved in thf/ water=3:1 (v/v)
In mixed solvent, more slowly to Deca parachloroanilinum 0.30g in above-mentioned solution, mixed solution is stirred at room temperature reaction overnight；Reaction
After the completion of, filter out insoluble sodium acetate, solvent evaporated obtains crude product；The crude product obtaining is passed through column purification dichloromethane: first
Alcohol=50:1 volume ratio obtains compound 5a；
(2)n4- (4- chlorphenyl)-n2The preparation of-(1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6a)
Intermediate 5a 0.30g is dissolved in n-butyl alcohol 12ml, adds 4- amidopyrazole 0.12g to above-mentioned solution, micro-
React 1h at 120 DEG C of ripple, after reaction terminates, solvent decompression Rotary Evaporators are evaporated and obtain crude product；By the crude product obtaining
By column purification dichloromethane: methanol=20:1 volume ratio obtains compound 6a.
(3) with the aromatic amine of 2,4- bis- chloro- 7h- pyrroles [2,3-d] pyrimidine and replacement for initiation material, first with to first
Base benzene sulfonyl chloride and the reaction of 2,4- bis- chloro- 7h- pyrroles [2,3-d] pyrimidine thus protecting n to obtain intermediate 8, intermediate 8 with various
The aromatic amine replacing occurs nucleophilic substitution to obtain intermediate 9, and intermediate 9 continues to occur nucleophilic displacement of fluorine anti-with 4- amino-pyrazol
Key intermediate 10 should be obtained, intermediate 10 removes protection group under strongly alkaline conditions and can get target product 11；
Reaction equation three is as follows:
Wherein, r2、r3、r4, n is as described in above-mentioned formula；
Reagent in above-mentioned reaction equation and condition: (a), mesyl chloride, triethylamine, DMAP, dichloromethane,
Room temperature, 5h；(b) n, n- diisopropylethylamine, n-butyl alcohol, 100 DEG C, reaction is overnight；(c) trifluoroacetic acid, n-butyl alcohol, 120 DEG C,
1h, microwave reaction；(d) cesium carbonate, water: methanol: dioxane=1:3:3 (v/v/v), 80 DEG C, 6h.
, concrete preparation process is as follows taking compound 11a as a example:
n4- (4- chlorphenyl)-n2The preparation of-(1h- pyrazoles -4- alkane) -7h- pyrroles [2,3-d] pyrimidine -2,4- diamidogen (11a)
Method, step is as follows:
(1) preparation to Methyl benzenesulfonyl base -7h- pyrazoles [2,3-d] pyrimidine (8) for the chloro- 7- of 2,4- bis-
Under condition of ice bath, chloro- for 2,4- bis- 7h- pyrroles [2,3-d] pyrimidine 1.0g is dissolved in dichloromethane 50ml, to
Above-mentioned mixed solution is slowly added to p-methyl benzene sulfonic chloride 1.06g, triethylamine 1.08g, n, n- lutidines -4- amine
0.019g, mixed solution is stirred at room temperature 5h, after the completion of waiting reaction, pours 150ml, organic phase washed with water, Fructus Citri Limoniae into in above-mentioned solution
Aqueous acid, each 100ml of common salt aqueous solution washs three times；Organic faciess anhydrous magnesium sulfate is dried overnight, sucking filtration, removes under reduced pressure molten
Agent, obtains crude product, can get white sterling with petroleum ether recrystallization；
(2) preparation to methyl sulphonyl -7h- pyrroles [2,3-d] pyrimidine -4- amine (9a) for the chloro- n- of 2- (4- the chlorphenyl) -7-
Compound 8 0.5g is dissolved in n-butyl alcohol 20ml, above-mentioned solution adds parachloroanilinum 0.35g, n, n- bis- is different
Propylethylamine 0.55g, mixed solution is heated to 100 DEG C of stirring reactions overnight；After the completion of reaction, solvent evaporated, use ethyl acetate
Organic phase washed with water after 100ml dissolving, aqueous citric acid solution, each 100ml of common salt aqueous solution washs three times；Organic faciess anhydrous slufuric acid
Magnesium is dried overnight, sucking filtration, removes solvent under reduced pressure, that is, obtain crude product；The crude product obtaining is passed through column purification petroleum ether: ethyl acetate
=10:1 volume ratio obtains compound 6a；
(3)n4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) -7- to methyl sulphonyl -7h- pyrroles [2,3-d] pyrimidine -
The preparation of 2,4- diamidogen (10a)
Intermediate 9a 0.6g and 4- amidopyrazole 0.23g is dissolved in n-butyl alcohol, adds 2-3 to drip trifluoroacetic acid in the solution,
React 1h at 120 DEG C of microwave, after reaction terminates, solvent decompression Rotary Evaporators are evaporated and obtain crude product；By obtain
Crude product is by column purification dichloromethane: methanol=100:1 volume ratio obtains compound 10a；
(4)n4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) -7h- pyrroles [2,3-d] pyrimidine -2,4- diamidogen (11a)
Preparation
By 10a 0.14g be dissolved in water (5ml), methanol (15ml), in dioxane (15ml) mixed system, molten to mixing
Liquid adds cesium carbonate 0.9g, and mixed solution is heated to 80 DEG C of stirring reactions 6h；After the completion of reaction, solvent evaporated, use ethyl acetate
Organic phase washed with water after 100ml dissolving, aqueous citric acid solution, each 100ml of common salt aqueous solution washs three times；Organic faciess anhydrous slufuric acid
Magnesium is dried overnight, sucking filtration, removes solvent under reduced pressure, that is, obtain crude product；By the crude product obtaining by column purification dichloromethane: methanol=
20:1 volume ratio obtains compound 11a.
Room temperature of the present invention is 25-30 DEG C.
The structural formula of the target compound of present invention preparation is as follows:
The concrete preparation process of described compound will be described in detail in an embodiment.
Those skilled in the art can be changed to improve yield to above-mentioned steps, and they can knowing according to this area substantially
Know the route determining synthesis, such as selective response thing, solvent and temperature, can be secondary anti-to avoid by using various GPF (General Protection False bases
The generation answered is thus improve yield.These conventional guard methods can be found in such as t.greene, protecting groups
in organic synthesis.
Detailed Description Of The Invention
Term and definition implication used herein is as follows:
" alkane " refers to refer to the aliphatic chain of c1-c6, cyclopropane, Tetramethylene., Pentamethylene., hexamethylene, cycloheptane etc..
" aryl " refers to the group containing aromatic carbon ring and the substituted aryl of the substituted base of ring upper band, and preferred aromatic ring contains
There is 6-10 carbon atom.
Hel cell is human leukemia cancerous cell, and mcf-7 cell is mankind mastopathy cell, and pc-3 cell is prostate
Cancerous cell, k562 is human myeloid leukemic cells, and molt4 cell is mankind's Lymphoma leukemia cell, and these cells are wide
General be applied to tumor research, biotic experiment or cell culture, have become as very important instrument in medical research.
3rd, contain the application of the jak kinase inhibitor of 4- amino-(1h)-pyrazoles ring structure
Screening active ingredients experiment display the compounds of this invention has a good external jak1, the inhibitory activity of jak2, jak3, because
This, the present invention also provides compound in preparation prevention or treatment and application in inflammation, tumor, the medicine of blood-related diseases；Institute
That states is included with inflammation, tumor, blood-related diseases: psoriasiss, rheumatic arthritis, polycythemia vera, limitation
Alopecia, primary thrombocytosiss, ulcerative colitiss, metaplasia myelofibrosises, severe combined immune Defect, various
Leukemia, various solid tumor etc..
A kind of prevention or treatment and inflammation, tumor, the pharmaceutical composition of blood-related diseases, comprise of the present invention containing
The jak kinase inhibitor of 4- amino-(1h)-pyrazoles ring structure or its pharmaceutically acceptable salt and one or more are pharmaceutically
Acceptable carriers or excipient.
Brief description
Fig. 1 is 5 μm of the compounds of this invention to hel cel l proliferation histamine result figure.
Specific embodiment
With reference to embodiment, the present invention is described further, but not limited to this.
Embodiment 1: the synthesis of compound 3a-3m, taking 3a as a example.
(1) preparation of the chloro- n- of 2,5- bis- (4- chlorphenyl) pyrimidine -4- amine (2a)
At ambient temperature, by 2,4,5- trichloropyrimidine 0.65g and parachloroanilinum 0.5g are dissolved in n, n- dimethylformamide
In 30ml, continue Deca n, n- diisopropylethylamine 1.3g in above-mentioned solution, mixed solution is stirred at room temperature reaction overnight.Reaction
After the completion of, add ethyl acetate 150ml, organic phase washed with water, aqueous citric acid solution, each 100ml of common salt aqueous solution in reactant liquor
Washing three times；Organic faciess anhydrous magnesium sulfate is dried overnight, and sucking filtration removes solvent under reduced pressure, obtains crude product.With petroleum ether: second
It is white solid 0.6g that the silica gel column chromatography purification of acetoacetic ester=10:1 volume ratio can get intermediate 2a., yield: 61%；
Esi-ms, m/z=274 [m+h]+.1h nmr(400mhz,dmso-d6)δ9.59(s,1h),8.41(s,1h),7.72–7.56
(m,2h),7.51–7.39(m,2h).
(2) the chloro- n of 5-4- (4- chlorphenyl)-n2The preparation of-(1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3a)
Intermediate 2a 0.3g and 4- amidopyrazole 0.18g is dissolved in n-butyl alcohol, adds 2-3 to drip trifluoroacetic acid in the solution,
React 2h at 150 DEG C of microwave, after reaction terminates, solvent decompression Rotary Evaporators are evaporated and obtain crude product；By obtain
Crude product is by column purification dichloromethane: methanol=30:1 volume ratio obtains compound 3a, is white solid 0.15g, yield:
42%；Esi-ms, m/z=321 [m+h]+.1h nmr(400mhz,dmso-d6)δ12.44(s,1h),9.19(s,1h),8.87
(s,1h),8.11(s,1h),7.97–7.42(m,4h),7.39(s,1h),7.37(s,1h).13c nmr(101mhz,dmso-
d6)δ131.06,128.66,118.58.hrms(ap-esi)m/z calcd for c13h10cl2n6[m+h]+321.0417,
found 321.0441.m.p.246-248℃.
Embodiment 2: the synthesis of compound 6a-f, taking 6a as a example.
(1) preparation of the chloro- n- of 2- (4- chlorphenyl) quinazoline -4- amine (5a)
Under condition of ice bath, 2,4- dichloroquinazoline 0.50g and sodium acetate 0.80g is dissolved in thf/ water (v/v 3:1)
In mixed solvent, more slowly to Deca parachloroanilinum 0.30g in above-mentioned solution, mixed solution is stirred at room temperature reaction overnight.Reaction
After the completion of, filter out insoluble sodium acetate, solvent evaporated obtains crude product；The crude product obtaining is passed through column purification dichloromethane: first
Alcohol=50:1 volume ratio obtains compound 5a, is white solid 0.47g, yield: 70%；Esi-ms, m/z=290 [m+h]+.1h-
Nmr:10.26 (s, 1h), 8.57 (d, j=8.2hz, 1h), 7.91 (t, j=7.6hz, 1h), 7.85 (d, j=8.9hz, 2h),
7.74 (d, j=8.3hz, 1h), 7.68 (t, j=7.6hz, 1h), 7.51 (d, j=8.8hz, 2h).
(2)n4- (4- chlorphenyl)-n2The preparation of-(1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6a)
Intermediate 5a 0.30g is dissolved in n-butyl alcohol 12ml, adds 4- amidopyrazole 0.12g to above-mentioned solution, micro-
React 1h at 120 DEG C of ripple, after reaction terminates, solvent decompression Rotary Evaporators are evaporated and obtain crude product；By the crude product obtaining
By column purification dichloromethane: methanol=20:1 volume ratio obtains compound 6a, it is faint yellow solid 0.07g, yield: 21%；
Esi-ms, m/z=337 [m+h]+.1h-nmr:12.66(s,1h),9.89(s,1h),9.39(s,1h),8.47(s,1h),8.04
(s, 2h), 7.73 (s, 3h), 7.56 (d, j=8.2hz, 1h), 7.45 (d, j=8.7hz, 2h), 7.34 (s, 1h).13c-nmr:
128.8,124.2.hrms(ap-esi)m/z calcd for c17h13cln6[m+h]+337.0963,found
337.0970.m.p.240-242℃.
Embodiment 3: the synthesis of compound 11a-d, taking 11a as a example.
(1) preparation to Methyl benzenesulfonyl base -7h- pyrazoles [2,3-d] pyrimidine (8) for the chloro- 7- of 2,4- bis-
Under condition of ice bath, chloro- for 2,4- bis- 7h- pyrroles [2,3-d] pyrimidine 1.0g is dissolved in dichloromethane 50ml, to
Above-mentioned mixed solution is slowly added to p-methyl benzene sulfonic chloride 1.06g, triethylamine 1.08g, n, n- lutidines -4- amine
0.019g, mixed solution is stirred at room temperature 5h, after the completion of waiting reaction, pours 150ml, organic phase washed with water, Fructus Citri Limoniae into in above-mentioned solution
Aqueous acid, each 100ml of common salt aqueous solution washs three times；Organic faciess anhydrous magnesium sulfate is dried overnight, sucking filtration, removes under reduced pressure molten
Agent, obtains crude product.Can get white sterling 1.6g with petroleum ether recrystallization.Yield 89%.Esi-ms, m/z=342 [m+
h]+.1H-nmr:8.12 (d, j=4.1hz, 1h), 8.03 (d, j=8.5hz, 2h), 7.50 (d, j=8.3hz, 2h), 6.98 (d,
J=4.1hz, 1h), 2.38 (s, 3h).
(2) preparation to methyl sulphonyl -7h- pyrroles [2,3-d] pyrimidine -4- amine (9a) for the chloro- n- of 2- (4- the chlorphenyl) -7-
Compound 8 0.5g is dissolved in n-butyl alcohol 20ml, above-mentioned solution adds parachloroanilinum 0.35g, n, n- bis- is different
Propylethylamine 0.55g, mixed solution is heated to 100 DEG C of stirring reactions overnight.After the completion of reaction, solvent evaporated, use ethyl acetate
Organic phase washed with water after 100ml dissolving, aqueous citric acid solution, each 100ml of common salt aqueous solution washs three times；Organic faciess anhydrous slufuric acid
Magnesium is dried overnight, sucking filtration, removes solvent under reduced pressure, that is, obtain crude product；The crude product obtaining is passed through column purification petroleum ether: ethyl acetate
=10:1 volume ratio obtains compound 6a, is faint yellow solid 0.42g, yield: 67%；Esi-ms, m/z=433 [m+h]+.1h-
Nmr:10.11 (s, 1h), 7.99 (d, j=8.4hz, 2h), 7.76 7.67 (m, 3h), 7.47 (dd, j=14.3,8.6hz,
4h), 7.05 (d, j=3.5hz, 1h), 2.38 (s, 3h).
(3)n4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) -7- to methyl sulphonyl -7h- pyrroles [2,3-d] pyrimidine -
The preparation of 2,4- diamidogen (10a)
Intermediate 9a 0.6g and 4- amidopyrazole 0.23g is dissolved in n-butyl alcohol, adds 2-3 to drip trifluoroacetic acid in the solution,
React 1h at 120 DEG C of microwave, after reaction terminates, solvent decompression Rotary Evaporators are evaporated and obtain crude product；By obtain
Crude product is by column purification dichloromethane: methanol=100:1 volume ratio obtains compound 10a, is pale solid 0.16g, yield:
25%；Esi-ms, m/z=476 [m+h]+.1h-nmr:12.48(s,1h),9.43(s,1h),9.27(s,1h),8.31(s,
1h), 7.93 (s, 4h), 7.65 (s, 1h), 7.43 7.30 (m, 5h), 6.96 (d, j=14.0hz, 1h), 2.32 (s, 3h).
(4)n4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) -7h- pyrroles [2,3-d] pyrimidine -2,4- diamidogen (11a)
Preparation
By 10a 0.14g be dissolved in water (5ml), methanol (15ml), in dioxane (15ml) mixed system, molten to mixing
Liquid adds cesium carbonate 0.9g, and mixed solution is heated to 80 DEG C of stirring reactions 6h.After the completion of reaction, solvent evaporated, use ethyl acetate
Organic phase washed with water after 100ml dissolving, aqueous citric acid solution, each 100ml of common salt aqueous solution washs three times；Organic faciess anhydrous slufuric acid
Magnesium is dried overnight, sucking filtration, removes solvent under reduced pressure, that is, obtain crude product；；The crude product obtaining is passed through column purification dichloromethane: methanol
=20:1 volume ratio obtains compound 11a, is faint yellow solid 0.05g, yield: 54%；Esi-ms, m/z=326 [m+h]+
.1H-nmr:12.34 (s, 1h), 11.08 (s, 1h), 9.16 (s, 1h), 8.63 (s, 1h), 7.97 (t, j=11.4hz, 3h),
7.56 (s, 1h), 7.33 (d, j=8.8hz, 2h), 6.99 6.74 (m, 1h), 6.60 (s, 1h).13c-nmr:156.2,154.0,
153.5,140.3,128.6,125.4,124.3,121.9,119.1,99.41,98.0.hrms(ap-esi)m/z calcd
for c15h12cln7[m+h]+326.0915,found 326.0915.m.p.252-254℃.
Embodiment 4: the test experiments of the external Inhibiting enzyme activity of compound
And then used to jak substrate phosphorylation level by measuring compoundDetection method is detected.
Table 1 compound and positive drug staurosporine are to jak1, the external Inhibiting enzyme activity of jak2, jak3
Experiment conclusion: to jak1, jak2, jak3 all have certain inhibitory action, ic to compound50It is worth in nanomolar range,
Most preferably compound 3a, 3e, 3f.
Embodiment 5: part of compounds inhibiting tumor cell proliferation experiment mtt.
Concentration is inoculated in 96 orifice plates for the cell in 3000-12000/hole, at 37 DEG C, 5%co2Under the conditions of culture 4h after
Add the medicine of variable concentrations.Continue incubation 2 days afterwards.Plus mtt20 μ l, then it is incubated 4h, use microplate reader mensuration absorbance.Calculate
Suppression ratio.It is shown in Table 2 and Fig. 1.
Table 2: part of compounds inhibiting tumor cell proliferation activity
Experiment conclusion:, to hel leukaemia cancer cell, mcf-7 mankind mastopathy cell, pc-3 carcinoma of prostate is thin for each compound
Born of the same parents, k562 human myeloid leukemic cells, molt4 human lymphoma leukaemia etc. has very strong antiproliferative activity,
Show as low micromolar level.Particularly compound 11b shows sub-micromolar level to two plants of cancerous cell of hel and k562.
Claims (9)
1. contain the jak kinase inhibitor of 4- amino-(1h)-pyrazole ring, its pharmaceutically acceptable salt, solvate or front
Medicine, has below formula or a shown structure:
Wherein:
r1It is hydrogen, alkyl, halogen, nitro or trifluoromethyl；
r2、r3、r4It is independently selected from halogen, hydrogen, the substituent group of ether, alkane or substituted-amino；
N is 0,1,2 or 3；
Ring is five yuan of heteroaromatics, hexa-atomic aromatic ring or hexa-atomic heteroaromatic.
2. contain as claimed in claim 1 the jak kinase inhibitor of 4- amino-(1h)-pyrazole ring it is characterised in that r1It is
Hydrogen, c1-c6 alkyl, fluorine, chlorine or trifluoromethyl；r2、r3、r4It is independently selected from hydrogen, fluorine, chlorine, methyl or methoxy；N is 0
Or 1；Ring is pyrrole ring, pyrazole ring, phenyl ring or quinoline ring.
3. compound as claimed in claim 1 or 2 is it is characterised in that be one of following compounds:
The chloro- n of 5-4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3a),
The chloro- n of 5-4- (4- phenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3b),
The chloro- n of 5-4- (4- fluorophenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3c),
The chloro- n of 5-4- (4- methoxyphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3d),
The chloro- n of 5-4- (2- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3e),
The chloro- n of 5-4- (3- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3f),
n4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3g),
n4- (2- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3h),
2- ((2- ((1h- pyrazoles -4- alkane)-amino) pyrimidine -4- alkane) amino) cyanophenyl (3i),
n4- (3- acetylene phenyl)-n2- (1h- pyrazoles -4- alkane)-amino) pyrimidine -2,4- diamidogen (3j),
n4- (4- chlorphenyl) the fluoro- n of -5-2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3k),
n4The fluoro- n of-phenyl -5-2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3l),
n4- (4- methoxyphenyl) the fluoro- n of -5-2- (1h- pyrazoles -4- alkane) pyrimidine -2,4- diamidogen (3m),
n4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6a),
n4- phenyl-n2- (1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6b),
n4- (4- methoxyphenyl)-n2- (1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6c),
n4- (3- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6d),
n4- (3- acetylene phenyl)-n2- (1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6e),
n4- (2- chlorobenzyl)-n2- (1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6f),
n4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) -7h- pyrroles [2,3-d] pyrimidine -2,4- diamidogen (11a),
n4- phenyl-n2- (1h- pyrazoles -4- alkane) -7h- pyrroles [2,3-d] pyrimidine -2,4- diamidogen (11b),
n4- (4- methoxyphenyl)-n2- (1h- pyrazoles -4- alkane) -7h- pyrroles [2,3-d] pyrimidine -2,4- diamidogen (11c) or
n4- (2- chlorobenzyl)-n2- (1h- pyrazoles -4- alkane) -7h- pyrroles [2,3-d] pyrimidine -2,4- diamidogen (11d).
4. the preparation method of compound as claimed in claim 1 or 2 is it is characterised in that be one of following method:
(1) -2,4- dichloro pyrimidine is replaced with the aromatic amine replacing for initiation material with 5-, middle through generating under the conditions of acid or alkali
Body compound 2, midbody compound 2 can get end-product 3 with the generation nucleophilic displacement of fluorine of 4- amino-pyrazol；
Reaction equation one is as follows:
Wherein, r1、r2、r3、r4As described in above-mentioned formula i；
Reagent in above-mentioned reaction equation and condition: (a), for 2a, the synthesis of 2b, 2d, n, n- diisopropylethylamine, n, n- diformazan
Base Methanamide, room temperature, 16h；For the synthesis of 2c, sodium carbonate, ethanol, room temperature, reaction is overnight；For the synthesis of 2e, n, n- bis-
Wopropyl ethyl amine, n- N-methyl 2-pyrrolidone N-, 100 DEG C, 12h；For 2f, the synthesis of 2g, triethylamine, ethanol, 50-80 DEG C, reacted
Night；For the synthesis of 2h, hcl, h2O, room temperature, 5 days；For 2i, the synthesis of 2l, hcl, h2O, 50 DEG C, 5h；For the synthesis of 2j,
N, n- diisopropylethylamine, isopropanol, 60 DEG C, reaction is overnight；For 2k, the synthesis of 2m, mol ratio h2o/ch3Oh=3:1,50
℃,5h；(b), 4- amino-pyrazol, trifluoroacetic acid, n-butyl alcohol, 120 DEG C, 2-3h；
(2) with the aromatic amine of 2,4- dichloroquinazoline and replacement for initiation material, under the conditions of alkali is made with sodium acetate, generate intermediate
Compound 5, midbody compound 5 can get end-product 6 with the generation nucleophilic displacement of fluorine of 4- amino-pyrazol；
Reaction equation two is as follows:
Wherein, r2、r3、r4, n is as described in above-mentioned formula；
Reagent in above-mentioned reaction equation and condition: (a), sodium acetate, oxolane/water=3:1 (v/v), room temperature, reaction is overnight；
(b), 4- amino-pyrazol, n-butyl alcohol, 120 DEG C, 1h；
(3) with the aromatic amine of 2,4- bis- chloro- 7h- pyrroles [2,3-d] pyrimidine and replacement for initiation material, first with to methylbenzene
Sulfonic acid chloride and the reaction of 2,4- bis- chloro- 7h- pyrroles [2,3-d] pyrimidine are thus protect n to obtain intermediate 8, intermediate 8 and various replacements
Aromatic amine occur nucleophilic substitution to obtain intermediate 9, intermediate 9 continues to obtain with 4- amino-pyrazol generation nucleophilic substitution
To key intermediate 10, intermediate 10 removes protection group under strongly alkaline conditions and can get target product 11；
Reaction equation three is as follows:
Wherein, r2、r3、r4, n is as described in above-mentioned formula；
Reagent in above-mentioned reaction equation and condition: (a), mesyl chloride, triethylamine, DMAP, dichloromethane, room
Temperature, 5h；(b) n, n- diisopropylethylamine, n-butyl alcohol, 100 DEG C, reaction is overnight；(c) trifluoroacetic acid, n-butyl alcohol, 120 DEG C, 1h,
Microwave reaction；(d) cesium carbonate, water: methanol: dioxane=1:3:3 (v/v/v), 80 DEG C, 6h.
The chloro- n of 5.5-4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2, the preparation method of 4- diamidogen (3a), step is such as
Under:
(1) preparation of the chloro- n- of 2,5- bis- (4- chlorphenyl) pyrimidine -4- amine (2a)
At ambient temperature, by 2,4,5- trichloropyrimidine 0.65g and parachloroanilinum 0.5g are dissolved in n, n- dimethylformamide 30ml
In, continue Deca n, n- diisopropylethylamine 1.3g in above-mentioned solution, mixed solution is stirred at room temperature reaction overnight；Reaction completes
Afterwards, ethyl acetate 150ml, organic phase washed with water, aqueous citric acid solution are added in reactant liquor, each 100ml of common salt aqueous solution washs
Three times；Organic faciess anhydrous magnesium sulfate is dried overnight, and sucking filtration removes solvent under reduced pressure, obtains crude product；With petroleum ether: acetic acid second
The silica gel column chromatography purification of ester=10:1 volume ratio can get intermediate 2a；
(2) the chloro- n of 5-4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) pyrimidine -2, the preparation of 4- diamidogen (3a)
Intermediate 2a 0.3g and 4- amidopyrazole 0.18g is dissolved in n-butyl alcohol, adds 2-3 to drip trifluoroacetic acid, micro- in the solution
React 2-3h at 150 DEG C of ripple, after reaction terminates, solvent decompression Rotary Evaporators are evaporated and obtain crude product；Thick by obtain
Product are by column purification dichloromethane: methanol=30:1 volume ratio obtains compound 3a.
6.n4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) quinazoline -2, the preparation method of 4- diamidogen (6a), step is as follows:
(1) preparation of the chloro- n- of 2- (4- chlorphenyl) quinazoline -4- amine (5a)
Under condition of ice bath, 2,4- dichloroquinazoline 0.50g and sodium acetate 0.80g are dissolved in thf/ water=3:1 (v/v) and mix
In solvent, more slowly to Deca parachloroanilinum 0.30g in above-mentioned solution, mixed solution is stirred at room temperature reaction overnight；Reaction completes
Afterwards, filter out insoluble sodium acetate, solvent evaporated obtains crude product；By the crude product obtaining by column purification dichloromethane: methanol=
50:1 volume ratio obtains compound 5a；
(2)n4- (4- chlorphenyl)-n2The preparation of-(1h- pyrazoles -4- alkane) quinazoline -2,4- diamidogen (6a)
Intermediate 5a 0.30g is dissolved in n-butyl alcohol 12ml, adds 4- amidopyrazole 0.12g to above-mentioned solution, in microwave
React 1h at 120 DEG C, after reaction terminates, solvent decompression Rotary Evaporators are evaporated and obtain crude product；The crude product obtaining is led to
Cross column purification dichloromethane: methanol=20:1 volume ratio obtains compound 6a.
7.n4- (4- chlorphenyl)-n2The preparation side of-(1h- pyrazoles -4- alkane) -7h- pyrroles [2,3-d] pyrimidine -2,4- diamidogen (11a)
Method, step is as follows:
(1) preparation to Methyl benzenesulfonyl base -7h- pyrazoles [2,3-d] pyrimidine (8) for the chloro- 7- of 2,4- bis-
Under condition of ice bath, chloro- for 2,4- bis- 7h- pyrroles [2,3-d] pyrimidine 1.0g is dissolved in dichloromethane 50ml, to above-mentioned
Mixed solution is slowly added to p-methyl benzene sulfonic chloride 1.06g, triethylamine 1.08g, n, n- lutidines -4- amine 0.019g, mixes
Close solution and 5h is stirred at room temperature, after the completion of waiting reaction, pour 150ml in above-mentioned solution into, organic phase washed with water, aqueous citric acid solution,
The each 100ml of common salt aqueous solution washs three times；Organic faciess anhydrous magnesium sulfate is dried overnight, and sucking filtration removes solvent under reduced pressure, obtains thick
Product, can get white sterling with petroleum ether recrystallization；
(2) preparation to methyl sulphonyl -7h- pyrroles [2,3-d] pyrimidine -4- amine (9a) for the chloro- n- of 2- (4- the chlorphenyl) -7-
Compound 8 0.5g is dissolved in n-butyl alcohol 20ml, above-mentioned solution adds parachloroanilinum 0.35g, n, n- diisopropyl
Ethamine 0.55g, mixed solution is heated to 100 DEG C of stirring reactions overnight；After the completion of reaction, solvent evaporated, use ethyl acetate 100ml
Organic phase washed with water after dissolving, aqueous citric acid solution, each 100ml of common salt aqueous solution washs three times；Organic faciess are done with anhydrous magnesium sulfate
Dry overnight, sucking filtration, remove solvent under reduced pressure, that is, obtain crude product；By the crude product obtaining by column purification petroleum ether: ethyl acetate=
10:1 volume ratio obtains compound 6a；
(3)n4- (4- chlorphenyl)-n2- (1h- pyrazoles -4- alkane) -7- is to methyl sulphonyl -7h- pyrroles [2,3-d] pyrimidine -2,4-
The preparation of diamidogen (10a)
Intermediate 9a 0.6g and 4- amidopyrazole 0.23g is dissolved in n-butyl alcohol, adds 2-3 to drip trifluoroacetic acid, micro- in the solution
React 1h at 120 DEG C of ripple, after reaction terminates, solvent decompression Rotary Evaporators are evaporated and obtain crude product；By the crude product obtaining
By column purification dichloromethane: methanol=100:1 volume ratio obtains compound 10a；
(4)n4- (4- chlorphenyl)-n2The preparation of-(1h- pyrazoles -4- alkane) -7h- pyrroles [2,3-d] pyrimidine -2,4- diamidogen (11a)
10a 0.14g is dissolved in water 5ml, methanol 15ml, in dioxane 15ml mixed system, adds carbonic acid to mixed solution
Caesium 0.9g, mixed solution is heated to 80 DEG C of stirring reactions 6h；After the completion of reaction, solvent evaporated, after the dissolving of ethyl acetate 100ml
Organic phase washed with water, aqueous citric acid solution, each 100ml of common salt aqueous solution washs three times；Organic faciess anhydrous magnesium sulfate is dried overnight,
Sucking filtration, removes solvent under reduced pressure, that is, obtain crude product；The crude product obtaining is passed through column purification dichloromethane: methanol=20:1 volume ratio
Obtain compound 11a.
8. compound as described in claim 1,2 or 3 is in preparation prevention or treatment and inflammation, tumor, blood-related diseases
Application in medicine；Described is included with inflammation, tumor, blood-related diseases: psoriasiss, rheumatic arthritis, true property are red thin
Born of the same parents' increase disease, alopecia circumscripta, primary thrombocytosiss, ulcerative colitiss, metaplasia myelofibrosises, seriously synthesis
Immunodeficiency symptoms, various leukemia, various solid tumor.
9. a kind of prevention or treatment and inflammation, tumor, the pharmaceutical composition of blood-related diseases, comprise claim 1,2 or 3 institute
The compound stated and one or more pharmaceutically acceptable carrier or excipient.
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Application publication date: 20170125 |