CN103204851A - Benzamide derivative containing fused heterocyclic group and therapeutic use thereof - Google Patents
Benzamide derivative containing fused heterocyclic group and therapeutic use thereof Download PDFInfo
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- CN103204851A CN103204851A CN 201310003861 CN201310003861A CN103204851A CN 103204851 A CN103204851 A CN 103204851A CN 201310003861 CN201310003861 CN 201310003861 CN 201310003861 A CN201310003861 A CN 201310003861A CN 103204851 A CN103204851 A CN 103204851A
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- amino
- pyrimidine
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- 0 *c1c(-c2ccnc(N)n2)[n](cccc2)c2n1 Chemical compound *c1c(-c2ccnc(N)n2)[n](cccc2)c2n1 0.000 description 7
- GEYOCULIXLDCMW-UHFFFAOYSA-N Nc(cccc1)c1N Chemical compound Nc(cccc1)c1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 2
- OYGLGKGUYPGHSC-UHFFFAOYSA-N CC(C)(CC(C)(C)N/C(/N)=N/C)c1cccc(C(O)=O)c1 Chemical compound CC(C)(CC(C)(C)N/C(/N)=N/C)c1cccc(C(O)=O)c1 OYGLGKGUYPGHSC-UHFFFAOYSA-N 0.000 description 1
- FJBZKIMRCLIYCE-KHPPLWFESA-N CCC(C)/N=C1\N(C)C=CC=C1 Chemical compound CCC(C)/N=C1\N(C)C=CC=C1 FJBZKIMRCLIYCE-KHPPLWFESA-N 0.000 description 1
- FCFIERCLOMNJSR-UHFFFAOYSA-N CCCC(C)(C)c1cccc(C(O)=O)c1 Chemical compound CCCC(C)(C)c1cccc(C(O)=O)c1 FCFIERCLOMNJSR-UHFFFAOYSA-N 0.000 description 1
- PUMYPORBYBAZNV-SOFGYWHQSA-N CN(C)/C=C/C(c1cnc2[n]1cccc2)=O Chemical compound CN(C)/C=C/C(c1cnc2[n]1cccc2)=O PUMYPORBYBAZNV-SOFGYWHQSA-N 0.000 description 1
- YRWPFXPJPBKOSS-FCQHKQNSSA-N C[C@@H](CC=C1N)C=C1NC(c1ccc(C(C)(C)CC(C)(C)Nc2nccc([AlH2])n2)cc1)=O Chemical compound C[C@@H](CC=C1N)C=C1NC(c1ccc(C(C)(C)CC(C)(C)Nc2nccc([AlH2])n2)cc1)=O YRWPFXPJPBKOSS-FCQHKQNSSA-N 0.000 description 1
- KEDAOPOHNRSLMW-UHFFFAOYSA-N Cc1c(-c2ccnc(NCc(cc3)ccc3C(Nc(cc(cc3)F)c3N)=O)n2)[n](cccc2)c2n1 Chemical compound Cc1c(-c2ccnc(NCc(cc3)ccc3C(Nc(cc(cc3)F)c3N)=O)n2)[n](cccc2)c2n1 KEDAOPOHNRSLMW-UHFFFAOYSA-N 0.000 description 1
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a benzamide derivative containing a fused heterocyclic group. The benzamide derivative is a compound as presented by formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X, n and Ar are specifically defined in the specification. Furthermore, the invention further discloses a drug using the compound or the salt thereof as an active component, and the drug can be used for treating hyperplastic diseases like a cancer.
Description
Technical field
The present invention relates to a kind of be used for the treatment of with propagation relative disease contain benzamide derivatives of fused heterocycle base and preparation method thereof, the salt of this derivative and the medicine that is activeconstituents with this compound or its salt class.
Background technology
NSC 630176 mainly contains benzamides and hydroxamic acid; existing result of study shows; benzamide compound is than the hydroxamic acid compound couple histon deacetylase (HDAC) (HDAC1 relevant with cell proliferation; 2; 3,8) have higher selectivity and lower side effect.The benzamides medicine that is in clinical study has MS-275, CS055, MGCD0103, wherein MGCD0103 has higher anti-cancer activity, but it is water-soluble lower, the dog bioavailability is 1-90%, big (the Nancy Zhou et al. of the variation coefficient, 2008, J.Med.Chem., 51:4072-4075).Urgent need will be developed has water-soluble height, the new benzamides compounds that pharmacokinetics character is good.
Summary of the invention
The invention provides a kind of benzamide derivatives that contains fused heterocycle, it is NSC 630176, and their main effect is to bring into play its antitumous effect by the activity of inhibition of histone deacetylase (HDAC1,2,3,8).
The purpose of this invention is to provide fused heterocycle benzamide derivatives and its esters or their solvated compounds.
Another object of the present invention provides the preparation method of this derivative.
The 3rd purpose of the present invention provides the pharmaceutical composition of this derivative.
Specifically, the invention provides a kind of benzamide derivatives that contains fused heterocycle, it has formula I structure:
Or its pharmacy acceptable salt or solvate
Wherein:
Ar is selected from following groups:
R
1, R
2Be hydrogen or halogen atom (fluorine, chlorine, bromine), or C
1-C
4Alkyl, or C
1-C
4Alkoxyl group, or halo C
1-C
4Alkyl;
N=1,2 or 3;
X is hydrogen or halogen atom (fluorine, chlorine, bromine), or C
1-C
4Alkyl or C
1-C
4Alkoxyl group;
Preferably, the invention provides the compound of (II) structure that has formula, or its pharmacy acceptable salt or solvated compounds:
N wherein, Ar is described suc as formula (I) structure.
More specifically, the invention provides following compound with formula (II) structure, or its pharmacy acceptable salt or solvated compounds
N-(2-aminophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(1H-imidazo [1,2-a] pyridin-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyrimidin-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(imidazo [1,2-a] pyrimidin-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyrazine-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(glyoxal ethyline is [1,2-b] pyridazine-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(imidazo [1,2-a] pyrazine-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(imidazo [1,2-b] pyridazine-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(6-bromo-glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-(2-(4-(imidazo [1,2-a] pyrimidin-3-yl) pyrimidine-2-amino) ethyl) benzamide;
N-(2-aminophenyl)-4-(2-(4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) ethyl) benzamide;
Preferably, the invention provides the compound of (III) structure that has formula, or its pharmacy acceptable salt or solvated compounds:
Ar wherein, n is described suc as formula (I).
Ground is more specifically arranged, the invention provides following compound with formula (III) structure, or its pharmacy acceptable salt or solvated compounds:
N-(2-amino-5-fluorophenyl) 4-((4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(imidazo [1,2-a] pyridin-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(imidazo [1,2-b] pyridazine-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(glyoxal ethyline is [1,2-b] pyridazine-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(imidazo [1,2-a] pyrimidin-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyrimidin-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyrazine-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(imidazo [1,2-a] pyrazine-3-yl) pyrimidine-2-amino) methyl) benzamide;
The compounds of this invention is as containing basic group, then can with sour salify.
Common salt has organic acid salt, inorganic acid salt etc.Usually organic acid salt relatively more commonly used has citrate, fumarate, oxalate, malate, lactic acid salt, camsilate, tosilate, mesylate etc.; Inorganic acid salt has halogen acid salt, vitriol, phosphoric acid salt, nitrate etc.
For example, with low alkyl group sulfonic acid, as methylsulfonic acid, trifluoromethanesulfonic acid etc. can form mesylate, fluoroform sulphonate; With aryl sulfonic acid, can form tosilate, benzene sulfonate as Phenylsulfonic acid or tosic acid etc.; With organic carboxyl acid, as acetic acid, fumaric acid, tartrate, oxalic acid, toxilic acid, oxysuccinic acid, succsinic acid or citric acid etc. can form corresponding salt; With amino acid, can form glutaminate or aspartate as L-glutamic acid or aspartic acid.With mineral acid, as haloid acid (as hydrofluoric acid, Hydrogen bromide, hydroiodic acid HI, spirit of salt), nitric acid, carbonic acid, sulfuric acid or phosphoric acid etc. also can form corresponding salt.
Second purpose of the present invention provided the method for one or more preparation formulas (I) compounds.
Particularly, for the compound of formula (II), adopt following route synthetic:
Compound for formula (III) adopts following route synthetic:
The 3rd purpose of the present invention provides the salt that utilizes benzamide derivatives of the present invention or this compound for the medicine of activeconstituents, is used for the treatment of diseases such as proliferative disease such as cancer.
The inventor confirms that by experiment The compounds of this invention has anti-increment restraining effect to human breast carcinoma (MCF-7), but in the medicine of the solid tumor that application for the treatment of human or animal cell proliferative is correlated with or leukemia.
Can also contain one or more pharmaceutically acceptable carriers in said medicine, described carrier comprises the conventional thinner of pharmaceutical field, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant etc., can also add flavouring agent, sweeting agent etc. in case of necessity.Medicine of the present invention can be made tablet, pulvis, and granula, capsule, various ways such as oral liquid and injecting drug use, the medicine of above-mentioned each formulation all can be according to the ordinary method preparation of pharmaceutical field.
The inventor confirms that by experiment The compounds of this invention has anti-increment restraining effect to human breast carcinoma (MCF-7), but in the medicine of the solid tumor that application for the treatment of human or animal cell proliferative is correlated with or leukemia.
Embodiment:
Below by embodiment exploitativeness of the present invention is described, it will be understood by those of skill in the art that the instruction according to prior art, corresponding technical characterictic is made amendment or replaced, still belong to the scope of protection of present invention
Embodiment 1.N-(2-aminophenyl)-4-((4-(2-methyl isophthalic acid H-imidazo [1,2-a] pyridin-3-yl) pyrimidine-2-amino) methyl) benzamide (compound 1)
Synthesizing of step 1.1-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) ethyl ketone
With 10g2-aminopyridine, 10.7g sodium bicarbonate, 22g3-chloro-2, the 4-diacetylmethane joins 100ml1, in the 4-dioxane, 80-90 ℃ of reacting by heating 13h, solution by colourless become orange, the vacuum rotary steam solvent, add methylene dichloride and water extraction three times, merge organic layer, drying, filter, concentrating under reduced pressure with ethyl acetate and sherwood oil crystallization, namely gets white solid 13g, productive rate 70.2%, mp:102-105 ℃.
Step 2. (E)-3,3-(dimethylamino)-1-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) acrylketone synthetic
Step 1 product 13g is joined among the 100ml DMFDMA, and 100 ℃ of reflux 30h are spin-dried for solvent, add the ethyl acetate of 70ml, filter, and filter cake washes twice with ethyl acetate, dry khaki color solid 8.7g, productive rate 50.91%, mp:146-148 ℃ of getting.
Step 3.4-((4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) methyl) phenylformic acid
With 4.7g step 2 product, 4.0g4-guanidine tolyl acid, 5.7g salt of wormwood join in the 80ml propyl carbinol, 130 ℃ of heating reflux reaction 15h, the thin-layer chromatography demonstration reacts completely the vacuum rotary steam solvent, cooling is dissolved in water, and removes by filter insolubles, the aqueous solution adds ethyl acetate extraction 1 time, and the water intaking layer adds dilute hydrochloric acid and transfers pH to 5-6, separate out Off-white solid, filter, the flushing of filter cake water, dry, namely get faint yellow solid 3.5g.
Step 4.N-(2-aminophenyl)-4-((4-(2-methyl isophthalic acid H-imidazo [1,2-a] pyridin-3-yl) pyrimidine-2-amino) methyl) benzamide
In the dry three-necked bottle of 100ml, N
2Protection adds 2g step 3 product, 1.6gEDCI down; 0.9gHOBt 80ml heavily steams THF, under the condition of ice bath; drip 1.7gTEA, react 1h with this understanding after, add the 0.72g O-Phenylene Diamine in it; room temperature reaction spends the night, and the vacuum rotary steam solvent adds saturated aqueous sodium carbonate in residue; ultrasonic 10min separates out solid, filters; obtain Off-white solid, recrystallization namely gets compound 0.8g.
1HMR(DMSO-d6)(ppm):δ2.502-2.510(s,3H),4.635-4.650(d,2H),4.892(s,1H),6.572-6.590(t,1H),6.765-6.783(d,1H),6.874-6.944(s,1H),6.948-6.965(t,1H),7.350(s,1H)7.488-7.508(d,2H)7.577(s,1H)7.693-7.980(d,2H),8.052-8.082(t,1H),8.378(s,1H),8.997(s,1H),9.639(s,1H),9.950(s,1H)。
Embodiment 2.4-((4-(1H-imidazo [1,2-a] pyridin-3-yl) pyrimidine-2-amino) methyl) N-(2-aminophenyl) benzamide (compound 2)
Synthesizing of step 1.1-(imidazo [1,2-a] pyridin-3-yl) ethyl ketone
4g 2-aminopyridine is joined among the 70mlDMFDMA, 100 ℃ of reflux 14h, decompression is spin-dried for solvent, cooling, add the 8g1-monochloroacetone in it, methylene dichloride 70ml, 50 ℃ of heating reflux reaction 24h, decompression is spin-dried for solvent, cross silicagel column, obtain white solid 3g, productive rate 40.5%, mp:94-96 ℃.
Step 2. (E)-3,3-dimethylamino-1-(imidazo [1,2-a] pyridin-3-yl) acrylketone synthetic
Synthesis step reference example 1
Product fusing point: mp:185-190 ℃.
Step 3.4-((4-(imidazo [1,2-a] pyridin-3-yl) pyrimidine-2 amino) methyl) is benzoic synthetic
Synthesis step reference example 1
Step 4.4-((4-(1H-imidazo [1,2-a] pyridin-3-yl) pyrimidine-2-amino) methyl) N-(2-aminophenyl) benzamide
Synthesis step reference example 1
1HMR(DMSO-d6)(ppm):δ4.657-4.670(d,2H),4.875(s,2H),6.563-6.599(t,1H),6.753-6.773(d,1H),6.939-6.975(t,1H),7.129-7.193(m,2H),7.518(m,3H),7.735(s,1H),7.949-7.968(d,2H),8.081(s,1H),8.292(s,1H),8.502(m,1H),9.378(s,1H),9.617(s,1H),10.238(s,1H)。
Embodiment 3.N-(2-aminophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyrimidin-3-yl also) pyrimidine-2-amino) methyl) benzamide (compound 3)
Step 1.1-(glyoxal ethyline is [1,2-a] pyrimidin-3-yl also) ethyl ketone
With the 9.0g2-aminopyrimidine, 15g 3-chloro-2, the 4-diacetylmethane joins 100ml1, in the 4-dioxane, 85 ℃ of reflux 30h, the vacuum rotary steam solvent adds ethanol and acetic acid ethyl dissolution impurity, filters, and obtains brick-red crude product 3.4g, mp:85-90 ℃.
Step 2. (E)-3,3-(dimethylamino)-1-(glyoxal ethyline is [1,2-a] pyrimidin-3-yl also) acrylketone
Synthesis step reference example 1
Step 3.4-((4-(glyoxal ethyline is [1,2-a] pyrimidin-3-yl also) pyrimidine-2-amino) methyl) phenylformic acid
Synthesis step reference example 1
Step 4.N-(2-aminophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyrimidin-3-yl also) pyrimidine-2-amino) methyl) benzamide
Synthesis step reference example 1
1HMR(DMSO-d6)(ppm):δ2.499-2.208(s,3H),4.659(d,2H),4.879(s,2H),6.564-6.601(t,1H),6.754-6.774(d,1H),6.938-6.976(t,1H),7.102-7.151(m,2H),7.354-7.366(d,1H),7.462-7.502(s,2H),7.917-7.969(d,3H),8.394(d,1H),8.568-8.575(d,1H),8.787-8.802(d,1H),9.603-9.625(d,1H)。
Embodiment 4.N-(2-aminophenyl)-4-((4-(imidazo [1,2-a] pyrimidin-3-yl) pyrimidine-2-amino) methyl) benzamide (compound 4)
Step 1.1-(imidazo [1,2-a] pyrimidin-3-yl) ethyl ketone
The 10g2-aminopyrimidine is joined among the 80mlDMFDMA, 100 ℃ of reflux 15h, decompression is spin-dried for solvent, cooling adds 1-monochloroacetone 20g, methylene dichloride 100ml, 50 ℃ of about 30h of reflux, solution becomes brown solution by orange, and decompression is spin-dried for solvent, adding ethanol 80ml stirs, filter, the filter cake ethyl acetate rinse obtains white solid 12.3g, productive rate 72.3%, mp:200-203 ℃.
Step 2. (E)-3,3-(dimethylamino)-1-(imidazo [1,2-a] pyrimidin-3-yl) acrylketone
Synthesis step reference example 1
Step 3.4-((4-(imidazo [1,2-a] pyrimidin-3-yl) pyrimidine-2-amino) methyl) phenylformic acid
Synthesis step reference example 1
Step 4.N-(2-aminophenyl)-4-((4-(imidazo [1,2-a] pyrimidin-3-yl) pyrimidine-2-amino) methyl) benzamide
Synthesis step reference example 1
1HMR(DMSO-d6)(ppm):δ4.647-4.662(d,2H),4.886(s,2H),6.564-6.600(t,1H),6.753-6.773(d,1H),6.940-6.957(t,1H),7.107-7.153(m,2H),7.292-7.305(d,1H),7.524(s,2H),7.905-7.942(d,3H),8.401-8.414(m,2H),8.600-8.614(d,1H),9.042-9.056(d,1H),9.610(s,1H)。
Embodiment 5.N-(2-aminophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyrazine-3-yl also) pyrimidine-2-amino) methyl) benzamide (compound 5)
Synthesis step reference example 1
1HMR(DMSO-d6)(ppm):δ2.505-2.699(m,3H),4.643-4.651(d,2H),4.894(s,2H),6.571-6.607(t,1H),6.763-6.781(d,1H),6.947-6.981(t,1H),7.138-7.158(d,1H),7.492-7.512(d,2H),7.440(s,1H),7.984(s,2H),8.193-8.224(t,2H),8.466(s,1H),8.710(s,1H),9.051-9.077(m,1H),9.669(s,1H)。
Embodiment 6.N-(2-aminophenyl)-4-((4-(imidazo [1,2-a] pyrazine-3-yl) pyrimidine-2-amino) methyl) benzamide (compound 6)
Step 1.1-(imidazo [1,2-a] pyrazine-3-yl) ethyl ketone
The amino pyrazine of 10g2-is joined among the 70mlDMFDMA, 100 ℃ of reflux 18h, the vacuum rotary steam solvent, cooling adds the 25g1-monochloroacetone, heavily steam methylene dichloride 100ml, 50 ℃ of reflux 30h, the vacuum rotary steam solvent is crossed silicagel column (developping agent: ethyl acetate: sherwood oil=4: 1), get faint yellow solid 2.0g with alcohol crystal, productive rate 11.8%.Fusing point: 165-170 ℃.
Step 2 (E)-3,3-(dimethylamino)-1-(imidazo [1,2-a] pyrazine-3-yl) acrylketone
Synthesis step reference example 1
Product fusing point: 193-196 ℃.
Step 3.4-((4-(imidazo [1,2-a] pyrazine-3-yl) pyrimidine-2-amino) methyl) phenylformic acid
Synthesis step reference example 1
Step 4.N-(2-aminophenyl)-4-((4-(imidazo [1,2-a] pyrazine-3-yl) pyrimidine-2-amino) methyl) benzamide
Synthesis step reference example 1
1HMR(DMSO-d6)(ppm):δ4.6678-4.6825(d,2H),4.8702(s,2H),6.5629-6.6000(t,1H),6.7562-6.7758(d,1H),6.9405-6.9762(t,1H),7.1289-7.1457(s,1H),7.2732-7.2859(d,1H),7.5255(s,2H),7.9661(s,3H),8.2064(s,1H),8.3942(s,1H),8.6618-8.7431(d,1H),9.1907-9.2342(m,1H),9.6258(s,1H),10.1120(s,1H)。
Embodiment 7.N-(2-aminophenyl)-4-((4-(glyoxal ethyline is [1,2-b] pyridazine-3-yl also) pyrimidine-2-amino) methyl)
Benzamide (compound 7)
Synthesizing of step 1.3-amino pyridazine
With 40g3 amino-6-chlorine pyridazine, 4g palladium carbon, 37.4g triethylamine, 3000ml methyl alcohol join in the autoclave of 5L, react 6h under 1.5atm, 60 ℃ of conditions, filter, and filtrate decompression concentrates, and gets white powder 16.7g with ethyl alcohol recrystallization.
Product fusing point: 167-169 ℃.
Step 2.1-(glyoxal ethyline is [1,2-b] pyridazine-3-yl also) ethyl ketone
Under nitrogen protection, with the 10g3-amino pyridazine, 18.4g3-chloro-2,4-diacetylmethane join in the 80ml ethanol, 80 ℃ of reflux 10h, and the vacuum rotary steam solvent is crossed silicagel column (developping agent: ethyl acetate: sherwood oil=1: 2), obtain brown solid 1.4g.
Product fusing point: 130-133 ℃.
Step 3. (E)-3,3-(dimethylamino)-1-(glyoxal ethyline is [1,2-b] pyridazine-3-yl also) acrylketone
Synthesis step reference example 1
Product fusing point: 128-131 ℃.
Step 4.4-((4-(glyoxal ethyline is [1,2-b] pyridazine-3-yl also) pyrimidine-2-amino) methyl) phenylformic acid
Synthesis step reference example 1
Synthesizing of step 5.N-(2-aminophenyl)-4-((4-(glyoxal ethyline is [1,2-b] pyridazine-3-yl also) pyrimidine-2-amino) methyl) benzamide
Synthesis step reference example 1
1HMR(DMSO-d6)(ppm):δ2.500-2.652(s,3H),4.665-4.679(d,2H),4.866(s,2H),6.567-6.605(t,1H),6.761-6.781(d,1H),6.937-6.928(t,1H),7.144-7.163(d,1H),7.330-7.365(t,1H),7.456-7.476(d,2H),7.762-7.935(m,4H),8.128-8.155(dd,1H),8.428-8.441(d,1H),8.645-8.656(dd,1H),9.584(s,1H)。
Embodiment 8.N-(2-aminophenyl)-4-((4-(imidazo [1,2-b] pyridazine-3-yl) pyrimidine-2-amino) methyl) benzamide (compound 8)
Step 1.1-(imidazo [1,2-b] pyridazine-3-yl) acetone
10g 3-amino pyridazine is joined among the 80mlDMFDMA, reflux 18h, the vacuum rotary steam solvent, cooling adds the 20g1-monochloroacetone in it, heavily steams methylene dichloride 100ml, 50 ℃ of reaction 30h, the vacuum rotary steam solvent is crossed silicagel column (developping agent: ethyl acetate: be raw material sherwood oil=2: 1), obtain safran solid 0.8g.
Product fusing point: 126-133 ℃.
Step 2. (E)-3,3-(dimethylamino)-1-imidazo [1,2-b] pyridazine-3-yl) acrylketone
Synthesis step reference example 1
Step 3 4-((4-(imidazo [1,2-b] pyridazine-3-yl) pyrimidine-2-amino) methyl) phenylformic acid
Synthesis step reference example 1
Step 4.N-(2-aminophenyl)-4-((4-(imidazo [1,2-b] pyridazine-3-yl) pyrimidine-2-amino) methyl) benzamide
Synthesis step reference example 1
MS(FAB):437(M+1)
Embodiment 9.N-(2-aminophenyl)-4-((4-(6-bromo-2-methyl isophthalic acid H-imidazo [1,2-a] pyridin-3-yl) pyrimidine-2-amino) methyl) benzamide (compound 9)
Synthesis step reference example 1
1HMR(DMSO-d6)(ppm):δ2.500-2.509(m,3H),4.664-4.678(d,2H),4.877(s,1H),6.564-6.600(t,3H),6.754-6.773(d,1H),6.898-6.976(m,2H),7.124-7.139(s,1H),7.918-7.938(d,2H),8.123-8.224(m,1H),8.398(s,1H),9.610(s,1H),9.817-9.995(d,1H)。
Embodiment 10.N-(2-amino-4-fluorophenyl)-4-((4-(2-methyl isophthalic acid H-imidazoles [1,2-a] pyridin-3-yl) pyrimidine-2-amino) methyl) benzamide (compound 10)
Reference example 1 synthetic 4-((4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) methyl) phenylformic acid; With 1.5g4-((4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) methyl) phenylformic acid, 1.0gN, N-phosphinylidyne diimidazole is dissolved in the 70ml anhydrous tetrahydro furan, 60 ℃ of reaction 24h, cooling, standby.Get another dry 100ml three-necked bottle, under nitrogen protection, with 0.58g4-fluoro-1; the 2-phenylenediamine is dissolved in the 20ml anhydrous tetrahydro furan, under the condition of ice bath, drips the 0.52g trifluoroacetic acid; drip standby reaction solution again, 40 ℃ of stirrings are spent the night, and TCL shows that reaction finishes; decompression and solvent recovery, residue are poured in the unsaturated carbonate aqueous solutions of potassium, ethyl acetate and three times (80ml*3) of water extraction; merge organic layer; drying concentrates and obtains oily matter, gets compound 0.56g with ethyl alcohol recrystallization.
1HMR(DMSO-d6)(ppm):δ2.500-2.590(s,3H),4.625-4.640(d,2H),5.209(s,2H),6.341-6.348(t,1H),6.507-6.542(dd,1H),6.865-6.876(d,1H),7.073-7.111(t,1H),7.457-7.581(m,4H),7.946-8.056(m,3H),8.379(s,1H),9.005(s,1H),9.553(s,1H),9.959(s,1H)。
Embodiment 11.N-(2-amino-5-fluorophenyl) 4-((4-(2-methyl isophthalic acid H-imidazo [1,2-a] pyridin-3-yl) pyrimidine-2-amino) methyl) benzamide (compound 11)
Reference example 1 synthetic 4-((4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) methyl) phenylformic acid; In the 100ml of drying three-necked bottle; under the nitrogen protection, add 1.4g4-((4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) methyl) phenylformic acid; EDCI1.1g; HOBt0.63g, anhydrous THF40ml, DMF10ml; drip triethylamine 0.78g under the condition of ice bath; behind the room temperature reaction 2h, add 1.0gN-Boc-2-amino-4-fluoroaniline then, room temperature reaction spends the night; the vacuum rotary steam solvent; residue adds ethyl acetate and three times (80ml*3) of water extraction, merges organic layer, concentrates; cross silicagel column; eluent ethyl acetate/petroleum ether=2: 1 and methylene chloride=20: 1, elutriant concentrates, and obtains solid chemical compound 0.7g with alcohol crystal.
0.7g is gone up the step product to be suspended in the 50ml methylene dichloride, add the 20ml concentrated hydrochloric acid, room temperature reaction 3h, TLC show that reaction finishes the vacuum rotary steam solvent, residue adds sodium carbonate solution and transfers pH to 8, separate out white solid, filter, filter cake washes with water twice, use then ethyl acetate and sherwood oil (2: 1) mixed solution wash-out 2 times, alcohol crystal gets solid 0.5g.
MS(FAB):468(M+1)
Embodiment 12.4-((4-(1-H-imidazo [1,2-a] pyridin-3-yl) pyrimidine-2 amino) methyl) N-(2-amino-4-fluorophenyl) benzamide (compound 14)
Synthesis step reference example 2 and embodiment 10
MS(FAB):454(M+1)
Embodiment 13.N-(2-amino-4-fluorophenyl)-4-((4-(imidazo [1,2-b] pyridazine-3-yl) pyrimidine-2-amino) methyl) benzamide (compound 12)
Synthesis step reference example 8 and embodiment 10
MS(FAB):455(M+1)
Embodiment 14.N-(2-amino-4-fluorophenyl)-4-((4-(glyoxal ethyline is [1,2-b] pyridazine-3-yl also) pyrimidine-2-amino) methyl) benzamide (compound 13)
Synthesis step reference example 7 and embodiment 10
MS(FAB):469(M+1)
Embodiment 15.N-(2-amino-4-fluorophenyl)-4-((4-(imidazo [1,2-a] pyrimidin-3-yl) pyrimidine-2-amino) methyl) benzamide (compound 15)
Synthesis step reference example 4 and embodiment 10
MS(FAB):455(M+1)
Embodiment 16.N-(2-amino-4-fluorophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyrimidin-3-yl also) pyrimidine-2-amino) methyl) benzamide (compound 16)
Synthesis step reference example 3 and embodiment 10
MS(FAB):469(M+1)
Embodiment 17.N-(2-amino-4-fluorophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyrazine-3-yl also) pyrimidine-2-amino) methyl) benzamide (compound 17)
Synthesis step reference example 5 and embodiment 10
MS(FAB):469(M+1)
Embodiment 18.N-(2-amino-4-fluorophenyl)-4-((4-(imidazo [1,2-a] pyrazine-3-yl) pyrimidine-2-amino) methyl) benzamide (compound 18)
Synthesis step reference example 6 and embodiment 10
MS(FAB):455(M+1)
Embodiment 19.N-(2-aminophenyl)-4-(2-(4-(imidazo [1,2-a] pyrimidin-3-yl) pyrimidine-2-amino) ethyl) benzamide (compound 19)
Step 1 4-((4-(imidazo [1,2-a] pyrimidin-3-yl) pyrimidine-2-amino) ethyl) phenylformic acid
Reference example 4 synthetic (E)-3,3-(dimethylamino)-1-(imidazo [1,2-a] pyrimidin-3-yl) acrylketone; With 4.3g (E)-3,3-(dimethylamino)-1-(imidazo [1,2-a] pyrimidin-3-yl) acrylketone, 5.9g guanidine ethylamino benzonitrile tert-butyl acrylate and 5.5 salt of wormwood join in the 100ml propyl carbinol, 130 ℃ of reflux 15h, cooling is filtered, and filtrate decompression is spin-dried for, add dilute hydrochloric acid and transfer pH to 4-5, with ethyl acetate extraction 3 times, merge organic layer, use anhydrous Na SO
4Drying is filtered, and is spin-dried for, and obtains oily matter, adds the 50ml concentrated hydrochloric acid in it, 100ml water, and heating reflux reaction 3h, vacuum rotary steam part water is transferred pH to 3-4 with the NaOH aqueous solution, uses K again
2CO
3Transfer pH to 6-7, separate out solid, filter, obtain the about 3.1g of compound.
Step 4.N-(2-aminophenyl)-4-(2-(4-(imidazo [1,2-a] pyrimidin-3-yl) pyrimidine-2-amino) ethyl) benzamide
Synthesis step reference example 1
1HMR(DMSO-d6)(ppm):δ3.001(s,2H),3.617-3.631(d,2H),4.896(s,2H),6.579-6.615(t,1H),6.768-6.788(d,1H),6.952-6.987(t,1H),7.110-7.167(m,2H),7.280-7.292(d,2H),7.423-7.440(d,2H),7.793-7.950(d,2H),8.417(m,2H),8.603-8.613(t,1H),9.044-9.061(dd,1H),9.628(s,1H)。
Embodiment 20.N-(2-aminophenyl)-4-(2-(4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) ethyl) benzamide (compound 20)
Synthesis step reference example 1, embodiment 10 and embodiment 19
1HMR(DMSO-d6)(ppm):δ3.014(s,2H),3.653(s,2H),4.911(s,2H),6.585-6.622(t,1H),6.778-6.798(dd,1H),6.955-6.997(t,1H),7.127-7.185(m,3H),7.422-7.574(m,4H),7.759-7.781(d,1H),7.905-7.965(d,2H),8.299(s,1H),8.556(s,1H),9.647(s,1H),10.020-10.176(d,1H)。
Embodiment 21: compound in-vitro multiplication restraining effect
Mtt assay is measured compound to the growth-inhibiting effect of MCF-7 (MCF-7).Compound is dissolved cryopreservation with DMSO.To be grown in the cell of logarithmic phase, the trysinization through 0.01%, counting is with 2.0 * 10
3The cell density of/well is seeded in 100ml in 96 orifice plates, places 5%CO
237 ℃ of overnight incubation in the incubator.Each compound is established six concentration gradients, and each concentration is established three multiple holes, and each concentration joins respectively in the corresponding aperture, 5%CO
2Cultivated 72 hours in 37 ℃ of incubators, add the 5mg/mlMTT of 20ml.37 ℃ hatch 3 hours after, inhale and to abandon supernatant, add the DMSO dissolving of 100ml, use SpectraMAX340 to survey 550nm (L1) absorbance value, reference wavelength 690nm (L2) maps (L1-L2) value to the inhibitor different concns, get IC through formula fitting
50
Table 1 compound is to MCF-7 MCF-7 inhibited proliferation
Compound | IC 50 | Error |
MGCD0103 | 4.807 | 0.181 |
Compound 1 | 2.088 | 0.626 |
Compound 2 | 0.661 | 0.156 |
Compound 3 | 4.111 | 1.186 |
Compound 4 | 0.856 | 0.271 |
Compound 5 | 3.741 | 1.265 |
Compound 6 | 2.178 | 0.801 |
Compound 7 | 7.155 | 1.821 |
Compound 8 | 8.347 | 1.521 |
Compound 9 | 2.359 | 0.148 |
Compound 10 | 2.400 | 0.934 |
Compound 11 | 1.004 | 0.265 |
Compound 12 | 5.467 | 1.747 |
Compound 13 | 1.478 | 1.168 |
Compound 14 | 2.896 | 0.784 |
Compound 15 | 3.763 | 0.832 |
Compound 16 | 7.498 | 1.636 |
Compound 17 | 8.129 | 1.763 |
Compound 18 | 3.468 | 1.076 |
Compound 19 | 1.723 | 0.893 |
Compound 20 | 4.119 | 0.579 |
Conclusion: the inhibition activity of compound 2,3 pairs of tumours is about 6 times of positive control MGCD0103, and the inhibition activity of compound 1,4,5,6,10 pairs of tumours is compared the raising that significance is also arranged with positive control MGCD0103.
Embodiment 22: the test of rat pharmacokinetics
Precision takes by weighing a certain amount of compound, with dissolution with solvents or make suspension, give the SD rat oral gavage or and tail vein injection, irritating the stomach amount is every about 0.5ml of animal, the about 0.3ml of every animal of intravenous injection.Different time points blood sampling after the administration, anticoagulant heparin, the centrifugal 10min of 8000rpm, separated plasma, interior mensuration with the good HPLC-MS quantivative approach of foundation finishes on the same day.
The about 0.5ml of amount for taking blood separates obtaining the about 0.2ml of blood plasma.
Before the getting the blood time point and be administration of gastric infusion, 5min after the administration, 15min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24h.Before the getting the blood time point and be administration of intravenously administrable, 1min after the administration, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h.
Compound solvent and the dosage of each experiment are different.
6 rats are divided into 2 groups at random, and 3 every group, vein and filling stomach give compound (1) respectively, and intravenously administrable dosage 5mg/kg uses N, the dinethylformamide dissolving; Gastric infusion dosage 50mg/kg is made into suspension with (containing 0.5%CMC-Na, 1% tween-80,0.1mol/L HCl) physiological saline.
Pharmacokinetic parameter (50mg/kg) in the blood plasma of the oral single-dose compound of table 2 (1) back
Pharmacokinetic parameter in table 3 (MGCD0103) document
Document (Nancy Zhou et al., 2008, J.Med.Chem., 51:4072-4075) bioavailability of report N-(2-aminophenyl)-4-((4-pyridin-3-yl-pyrimidine-2-amino) methyl) benzamide (MGCD0103) rat is 47%, the bioavailability of comparing our compound with it is 81%, and the bioavailability of the former dog is 1-92, and the variation coefficient is bigger.Therefore, our designed target compound has pharmacokinetic property preferably.
Claims (8)
1. general formula (I) structural compounds, or its pharmacy acceptable salt or solvated compounds:
Wherein:
X is hydrogen or halogen atom (fluorine, chlorine, bromine), or C
1-C
4Alkyl or C
1-C
4Alkoxyl group;
N=1,2 or 3;
Ar is selected from following groups:
R
1, R
2Be hydrogen or halogen atom (fluorine, chlorine, bromine), or C
1-C
4Alkyl, or C
1-C
4Alkoxyl group, or halo C
1-C
4Alkyl.
2. in the compound according to claim 1, wherein, X is hydrogen.
3. according to the described compound of arbitrary right among the claim 1-2, it is characterized in that described compound has following formula structure (II):
Or its pharmacy acceptable salt or solvated compounds
N wherein, Ar such as according to arbitrary requirement among the claim 1-2 definition.
4. compound according to claim 3 is characterized in that described compound is:
N-(2-aminophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(1H-imidazo [1,2-a] pyridin-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyrimidin-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(imidazo [1,2-a] pyrimidin-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyrazine-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(glyoxal ethyline is [1,2-b] pyridazine-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(imidazo [1,2-a] pyrazine-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(imidazo [1,2-b] pyridazine-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-((4-(6-bromo-glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-aminophenyl)-4-(2-(4-(imidazo [1,2-a] pyrimidin-3-yl) pyrimidine-2-amino) ethyl) benzamide;
N-(2-aminophenyl)-4-(2-(4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) ethyl) benzamide.
6. compound according to claim 5 is characterized in that described compound is:
N-(2-amino-5-fluorophenyl) 4-((4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyridin-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(imidazo [1,2-a] pyridin-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(imidazo [1,2-b] pyridazine-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(glyoxal ethyline is [1,2-b] pyridazine-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(imidazo [1,2-a] pyrimidin-3-yl) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyrimidin-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(glyoxal ethyline is [1,2-a] pyrazine-3-yl also) pyrimidine-2-amino) methyl) benzamide;
N-(2-amino-4-fluorophenyl)-4-((4-(imidazo [1,2-a] pyrazine-3-yl) pyrimidine-2-amino) methyl) benzamide.
7. a pharmaceutical composition contains the described compound of arbitrary claim or its pharmacy acceptable salt and pharmaceutically acceptable carrier among one or more claims 1-6.
8. the described compound of arbitrary claim or its pharmacy acceptable salt application in the medicine for preparing the relevant solid tumor for the treatment of human or animal cell proliferative or leukemia in the claim 1-6 item.
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