CN104592232A - 8,9-dihydro-2,4,7,9a-tetrazine benyoayulene-6(7H)-ketone derivatives - Google Patents
8,9-dihydro-2,4,7,9a-tetrazine benyoayulene-6(7H)-ketone derivatives Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to 8,9-dihydro-2,4,7,9a-tetrazine benyoayulene-6(7H)-ketone derivatives, preparation methods thereof, and a restraining effect of the 8,9-dihydro-2,4,7,9a-tetrazine benyoayulene-6(7H)-ketone derivatives on poly adenosine diphosphate-ribose polymerase (PARP). Pharmacodynamic experiments prove that the compounds disclosed by the invention have the efficacy of resisting tumors. The compounds can also be combined with other antitumor medicines so as to achieve the effects of improving the curative effect of existing antitumor medicines and reducing dosage and toxicity.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to class 8, a 9-dihydro-2,4,7, the 9a-tetrazine Azulene-6 (7H)-one derivative, its preparation method and the medicinal use as PARP inhibitor, and comprise the pharmaceutical composition of this compounds.
Background technology
PARP (Poly adenosine diphosphate-ribose polymerase-1) is present in eukaryotic cell the ribozyme with notable biological activity, the hypotype totally 18 that this family current has been found, wherein PARP-1 proportion is maximum, and play the function of more than 90%, relate to the treatment to diseases such as apoplexy, nerve degenerative diseases, myocardial ischemia, cancer, inflammation and diabetes, play a leading role in DNA damage reparation.PARP-1 can identify and be attached to the gap portions that damage occurs DNA, and rapid catalyzing N AD
+resolve into nicotinamide and ADP-ribose, then with ADP-ribose for substrate, make nuclear receptor protein and ADP-ribose form polymer thus start the injury repairing of DNA.PARP-1 inhibitor improves antitumor drug curative effect as sensitizer and has good prospect, because most of antitumour drug is all the growth causing the mechanism of DNA damage to carry out inhibition tumor cell, and the DNA that PARP-1 can repair damage makes repressed cell produce certain resistance, therefore can reach by the coupling of PARP-1 inhibitor and chemotherapeutics the effect reducing dosage He heighten the effect of a treatment.Simultaneously, preclinical study is had to show, PARP-1 inhibitor has played the effect of synthetic lethal in BRCA1/2 mutated tumor, makes PARP-1 inhibitor except the chemicotherapy sensitizer that can be used as general tumour, is also hopeful as some single therapy agent as BRCA1/2 mutated tumor.
Summary of the invention
The object of the invention is to find novel structure, activity is high and side effect is little antitumor candidate compound.These compounds by with other antitumor drug couplings, thus reach and improve existing antitumor drug curative effect and reduce the effect of dosage and toxicity.
The invention discloses compound or its pharmacy acceptable salt of logical formula I.
Wherein R representative
r
1represent hydrogen, C
1~ C
6alkyl, benzyl; R
2representative
or C
1~ C
6alkylamino methyl.
The compound of logical formula I can form acid salt with pharmaceutically acceptable acid, and described acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, carbonic acid, citric acid, succsinic acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetic acid, toxilic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or forulic acid.
Preferred compound of the present invention is as follows:
1-(4-piperidyl)-8,9-dihydro-2,4,7, the 9a-tetrazine Azulene-6 (7H)-one hydrochloride (I-1)
1-(N-n-propyl-4-piperidyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-2)
1-(N-sec.-propyl-4-piperidyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-3)
1-(N-normal-butyl-4-piperidyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-4)
1-(N-isobutyl--4-piperidyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-5)
1-(N-benzyl-4-piperidyl)-8,9-dihydro-2,4,7, the 9a-tetrazine Azulene-6 (7H)-one (I-6)
1-((4-(pyrroles-1-base) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-7)
1-((4-(piperidin-1-yl) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-8)
1-(4-((methylamino-) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-9)
1-(4-((dimethylamino) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-10)
1-(4-((ethylamino) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-11)
1-(4-((isopropylamino) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-12)
1-(4-((tertiary fourth amino) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-13)
When R representative
time, the available following method preparation of part of compounds of the present invention (I):
Prepare b by compound a, be compound a is dissolved in anhydrous methanol under the effect of chlorizating agent, first generate 4-chloro-5-nitro nicotinoyl chlorine, then obtain b with methanol esterification under acid binding agent effect.Chlorizating agent is selected from sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride, preferred sulfur oxychloride.Solvent is selected from methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, N ' dinethylformamide, ethylene glycol monomethyl ether or glycol dimethyl ether, preferred methylene dichloride or chloroform.Acid binding agent is selected from triethylamine, N ' N-diisopropylethylamine, pyridine, salt of wormwood, saleratus, sodium carbonate or sodium bicarbonate, preferred triethylamine.
Prepare c by compound b, be that compound b is dissolved in solvent under the effect of acid binding agent, obtain c with quadrol cyclization.Solvent is selected from methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, N ' dinethylformamide, ethylene glycol monomethyl ether or glycol dimethyl ether, preferred acetonitrile.Acid binding agent is selected from triethylamine, N ' N-diisopropylethylamine, pyridine, salt of wormwood, saleratus, sodium carbonate or sodium bicarbonate, preferred sodium carbonate or salt of wormwood.
Preparing d by compound c, is be dissolved in by compound c in solvent reducing under the effect of reductive agent obtaining d.Reductive agent is selected from iron powder/concentrated hydrochloric acid, iron powder/ammonium chloride, zinc powder/concentrated hydrochloric acid, tin protochloride, hydrogen/palladium carbon, ammonium formiate/palladium carbon, hydrogen/Raney's nickel or hydrazine hydrate/Raney's nickel, preferred hydrogen/palladium carbon.Solvent selected from methanol, ethanol, ethyl acetate, tetrahydrofuran (THF), acetonitrile or both mixed solvents any, particular methanol.
Prepare e by compound d, be compound d to be dissolved in solvent under 5% palladium carbon or 10% palladium carbon effect, obtain e with the cyclization of N-Boc-4-piperidinealdehyde.Solvent selected from methanol, ethanol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile, N ' dinethylformamide or N ' N-N,N-DIMETHYLACETAMIDE, particular methanol.
I (R is prepared by Verbindung
1=H), be Verbindung is dissolved in solvent removing tertbutyloxycarbonyl in acid condition and obtaining I (R
1=H).Acid is selected from hydrochloric acid, trifluoroacetic acid or hydrogen chloride gas, preferred hydrogen chloride gas.Solvent is selected from methylene dichloride, methyl alcohol, ethanol, ethyl acetate, tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane, preferred tetrahydrofuran (THF).
By chemical compounds I (R
1=H) prepare target compound I, be by chemical compounds I (R
1=H) carry out reductive amination process obtain I with aldehydes or ketones.Reductive agent is selected from sodium cyanoborohydride, sodium triacetoxy borohydride, sodium borohydride or POTASSIUM BOROHYDRIDE, preferred sodium cyanoborohydride.Solvent is selected from methylene dichloride, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), methyltetrahydrofuran or methyl tertiary butyl ether, particular methanol.
When R representative
time, the available following method preparation of part of compounds of the present invention (I):
Preparing compound f by compound d, is be dissolved in solvent by compound d, under 5% palladium carbon or 10% palladium carbon effect, obtains f with to two formal benzaldehydes.Solvent selected from methanol, ethanol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile, N ' dinethylformamide or N ' N-N,N-DIMETHYLACETAMIDE, particular methanol.
Preparing g by compound f, is compound f to be dissolved in solvent hydrolysis of acetals in acid condition to obtain g.Acid is selected from hydrochloric acid, Hydrogen bromide or trifluoroacetic acid, preferred hydrochloric acid.Solvent is selected from methylene dichloride, methyl alcohol, ethanol, ethyl acetate, tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane, preferred tetrahydrofuran (THF).
Preparing target compound I by compound g, is compound g and morpholine, piperazine, 4-methylpiperazine, piperidines or Pyrrolidine are carried out reductive amination process obtain I.Reductive agent is selected from sodium cyanoborohydride, sodium triacetoxy borohydride, sodium borohydride or POTASSIUM BOROHYDRIDE, preferred sodium cyanoborohydride.Solvent is selected from methylene dichloride, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), methyltetrahydrofuran or methyl tertiary butyl ether, particular methanol.
Preparing target compound I by compound d, is be dissolved in solvent by compound d, under 5% palladium carbon or 10% palladium carbon effect, with C
1~ C
6the condensation of alkylamino tolyl aldehyde obtains I.Solvent selected from methanol, ethanol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile, N ' dinethylformamide or N ' N-N,N-DIMETHYLACETAMIDE, particular methanol.
Another object of the present invention is to provide a kind of pharmaceutical composition, it comprises the compound or its salt of the present invention of medicine effective dose and pharmaceutically acceptable carrier.
Compound of the present invention can add pharmaceutically acceptable carrier and make common medicinal preparations, as tablet, capsule, pulvis, syrup, liquor, suspension agent, injection, the common medicinal supplementary material such as spices, sweeting agent, liquid or solid filler or thinner can be added.
Compound of the present invention administering mode clinically can adopt the modes such as oral, injection.
Usually, when compound of the present invention is used for the treatment of, people's dosage range is 1mg ~ 1000mg/ days.Also can according to the difference of formulation and disease severity, using dosage exceeds this scope.
Pharmacological experiment and the result of part of compounds of the present invention are as follows:
Detection compound suppresses the IC of PARP-1 at enzyme level
50value
Experimental technique
Take out in 96 orifice plates of pre-coated histone, every hole adds the inhibitor of following enzyme reaction system and different concns, comprising: the reaction buffer (Tris*HCl, pH 8.0) of 50 μ l, NAD
+, biotin labeled activated dna, PARP-1 enzyme and inhibitor; At room temperature react after 1h, add the HRP of 50 μ l avidin marks in every hole, reaction 30min; Add the HRP substrate of 100 μ l again, SpectraMax M5 instrument detects values of chemiluminescence.
Drug level dilutes according to three times of concentration gradients, and each concentration all detects two multiple holes.Using drug level as X-coordinate, enzymic activity percentage corresponding to each concentration is ordinate zou, uses GRAPHPAD PRISM 5 to do non-linear regression, calculates the IC of the suppression PARP-1 of each compound
50value.
Experimental result is in table 1
Table 1, test-compound suppress the IC of PARP-1
50
| Compound | IC 50(nM) | Compound | IC 50(nM) |
| Ⅰ-1 | 54 | Ⅰ-8 | 29 |
| Ⅰ-2 | 19 | Ⅰ-9 | 13 |
| Ⅰ-3 | 92 | Ⅰ-10 | 28 |
| Ⅰ-4 | 21 | Ⅰ-11 | 11 |
| Ⅰ-5 | 28 | Ⅰ-12 | 58 |
| Ⅰ-6 | 103 | Ⅰ-13 | 75 |
| Ⅰ-7 | 20 |
Embodiment
Embodiment 1
The synthesis (b) of chloro-5 nitronicotinic acid methyl ester of 4-
14g (76.0mmol) 4-hydroxyl-5-nitronicotinic acid (a) and 200ml chloroform are added in 500ml single port bottle, add 40ml sulfur oxychloride and 1ml N ' dinethylformamide again, 80 DEG C of back flow reaction 24h are warming up under drying conditions, reaction solution becomes clarification gradually by white opacity, and TLC monitors raw material complete reaction.Reaction solution is let cool to room temperature, remove solvent under reduced pressure, obtain yellow oil.Above-mentioned oily matter is dissolved in 25ml methylene dichloride, is slowly added drop-wise in the mixing solutions of 200ml anhydrous methanol and 10ml triethylamine at-10 DEG C, drip and finish, insulation reaction 1.5h.Add 300ml methylene dichloride and 100ml moisture liquid, water layer adds 50ml × 3 dichloromethane extraction again, merges organic phase, and organic phase washing twice, saturated common salt washes one time, anhydrous magnesium sulfate drying 2h.Suction filtration, filtrate concentrates to obtain faint yellow solid 12.8g, yield 77.8%.
1H-NMR(300MHz,CDCl
3),δ(ppm):9.13(s,1H,ArH),9.06(s,1H,ArH),4.03(s,3H,CH
3).
The synthesis (c) of 9-nitro-3,4-dihydro-1H-pyridine [4,3-e] [Isosorbide-5-Nitrae] diaza Azulene-5 (2H)-one
By 8g (36.9mmol) b, 4g (37.7mmol) sodium carbonate solid and 140ml acetonitrile add in 250ml single port bottle, 2.7ml (40.8mmol) quadrol is slowly instilled under stirring at room temperature, khaki color muddiness is produced gradually in reaction solution, drip and finish, be warming up to 90 DEG C of back flow reaction 24h.Suction filtration, filter cake acetonitrile wash, dries to obtain khaki color solid 6.2g, yield 80.7%.
1H-NMR(300MHz,DMSO),δ(ppm):8.83(s,1H,ArH),8.54(s,1H,ArH),3.77(s,2H,CH
2),3.38(s,2H,CH
2).
The synthesis (d) of amino-3,4-dihydro-1H-pyridine [4,3-e] [Isosorbide-5-Nitrae] diaza Azulene-5 (2H)-one of 9-
3g (14.4mmol) c and 300ml methyl alcohol is added in 500ml single port bottle, then adds 0.75g 10%Pd/C, hydrogenation under normal temperature and pressure.After reaction solution is placed stirring at room temperature 16h, TLC monitors raw material complete reaction, stops hydrogenation.Suction filtration, filtrate concentrates to obtain yellow solid.Column chromatography for separation (eluent methylene dichloride: methyl alcohol=10:1), obtains yellow solid 2.3g, yield 89.6%.
1H-NMR(300MHz,DMSO),δ(ppm):8.33(s,1H,ArH),8.24(s,1H,ArH),3.77(s,2H,CH
2),3.38 (s,2H,CH
2).
1-(N-Boc-4-piperidyl)-8,9-dihydro-2,4,7, the 9a-tetrazine the synthesis (e) of Azulene-6 (7H)-one
Be dissolved in 60ml methyl alcohol by 1.0g (5.6mmol) d, 0.60g (5.6mmol) N-Boc-4-piperidinealdehyde, then add 130mg10%Pd/C, tube sealing is heated to 120 DEG C of reaction 16h.Be cooled to room temperature, suction filtration, filtrate concentrates to obtain pale solid.Column chromatography for separation (eluent methylene dichloride: methyl alcohol=30:1), obtains white solid 0.9g, yield 43.3%.
1H-NMR(300MHz,DMSO),δ(ppm):8.99(s,1H,ArH),8.79(s,1H,ArH),8.48(t,J＝4.4Hz,1H,CONH),4.41(br s,2H,CH
2),4.04(d,J＝11.9Hz,2H,CH
2),3.62(d,J＝2.9Hz,2H,CH
2),3.24(dd,J＝12.0,4.8Hz,1H,CH),3.02–2.85(m,2H,CH
2),1.96(d,J＝11.9Hz,2H,CH
2),1.78–1.61(m,2H,CH
2),1.42(s,9H,3CH
3).
MS(ESI(+)70V)m/z:372[M+H]
+.
1-(4-piperidyl)-8,9-dihydro-2,4,7, the 9a-tetrazine the synthesis (I-1) of Azulene-6 (7H)-one hydrochloride
0.2g (0.54mmol) e is dissolved in 5ml tetrahydrofuran (THF), under room temperature, slowly drips the tetrahydrofuran (THF) saturated solution of 5ml hydrogenchloride.Drip and finish, after placing stirring at room temperature 4h, suction filtration, filter cake tetrahydrofuran (THF) washs, and dries to obtain white solid 0.13g, yield 78.2%.m.p.>300℃。
1H-NMR(300MHz,DMSO),δ(ppm):9.47(s,1H,ArH),9.16(br s,1H,NH),9.00–8.86(m,2H,CONH,ArH),4.52(br s,2H,CH
2),3.71(d,J＝3.9Hz,2H,CH
2),3.58–3.37(m,3H,CH,CH
2),3.06(dd,J＝19.9,10.1Hz,2H,CH
2),2.19–1.92(m,4H,2CH
2).
MS(ESI(+)70V)m/z:272[M+H]
+.
Embodiment 2
1-(N-n-propyl-4-piperidyl)-8,9-dihydro-2,4,7, the 9a-tetrazines the synthesis (I-2) of Azulene-6 (7H)-one
0.17g (0.55mmol) I-1 and 10ml methyl alcohol are added in 50ml single port bottle, slowly regulate pH to 7 in instillation triethylamine to reaction solution, reaction solution becomes clarification by white opacity.After adding 58 μ l (0.81mmol) positive propionic aldehyde placement stirring at room temperature 10min, then add 0.07g (1.08mmol) sodium cyanoborohydride placement stirred overnight at room temperature.Decompression steams solvent, obtains pale yellow oil.Column chromatography for separation (eluent methylene dichloride: methyl alcohol=20:1), obtains white solid 90mg, yield 52.3%.m.p.256-258°℃。
1H-NMR(300MHz,DMSO),δ(ppm):8.99(s,1H,ArH),8.78(s,1H,ArH),8.51(t,J＝5.3Hz,1H,CONH),4.39(br s,2H,CH
2),3.61(d,J＝3.5Hz,2H,CH
2),2.98(d,J＝10.5Hz,3H,CH,CH
2),2.32–2.26(m,2H,CH
2),2.06(t,J＝11.1Hz,2H,CH
2),1.95(d,J＝10.2Hz,2H,CH
2),1.84(br s,2H,CH
2),1.51–1.42(m,2H,CH
2),0.87(t,J＝7.3Hz,3H,CH
3).
MS(ESI(+)70V)m/z:314[M+H]
+.
Embodiment 3
1-(N-sec.-propyl-4-piperidyl)-8,9-dihydro-2,4,7, the 9a-tetrazines the synthesis (I-3) of Azulene-6 (7H)-one
With 0.17g (0.55mmol) I-1,59 μ l (0.81mmol) acetone, 0.07g (1.08mmol) sodium cyanoborohydride for raw material, utilize the method being similar to embodiment 2, obtained white solid 100mg, yield 58.1%.m.p.261-263℃。
1H-NMR(300MHz,DMSO),δ(ppm):8.99(s,1H,ArH),8.78(s,1H,ArH),8.50(t,J＝5.4Hz,1H,CONH),4.38(br s,2H,CH
2),3.61(d,J＝3.7Hz,2H,CH
2),2.99–2.88(m,3H,CH,CH
2),2.75(dd,J＝12.2,6.1Hz,1H,CH),2.31(t,J＝10.8Hz,2H,CH
2),1.96(d,J＝11.4Hz,2H,CH
2),1.80(br s,2H,CH
2),1.01(d,J＝6.5Hz,6H,2CH
3).
MS(ESI(+)70V)m/z:314[M+H]
+.
Embodiment 4
1-(N-normal-butyl-4-piperidyl)-8,9-dihydro-2,4,7, the 9a-tetrazines the synthesis (I-4) of Azulene-6 (7H)-one
With 0.25g (0.81mmol) I-1,110 μ l (1.22mmol) butyraldehyde-n, 0.1g (1.62mmol) sodium cyanoborohydride for raw material, utilize the method being similar to embodiment 2, obtained white solid 130mg, yield 49.1%.m.p.268-270℃。
1H-NMR(300MHz,DMSO),δ(ppm):8.99(s,1H,ArH),8.78(s,1H,ArH),8.52(t,J＝5.4Hz,1H,CONH),4.40(br s,2H,CH
2),3.61(d,J＝3.6Hz,2H,CH
2),2.97(d,J＝6.6Hz,3H,CH,CH
2),2.31(d,J＝5.3Hz,2H,CH
2),2.10–1.84(m,6H,3CH
2),1.43(d,J＝6.6Hz,2H,CH
2),1.28(dd,J＝14.5,7.3Hz,2H,CH
2),0.90(t,J＝6.5Hz,3H,CH
3).
MS(ESI(+)70V)m/z:328[M+H]
+.
Embodiment 5
1-(N-isobutyl--4-piperidyl)-8,9-dihydro-2,4,7, the 9a-tetrazines the synthesis (I-5) of Azulene-6 (7H)-one
With 0.25g (0.81mmol) I-1,110 μ l (1.22mmol) isobutyric aldehyde, 0.1g (1.62mmol) sodium cyanoborohydride for raw material, utilize the method being similar to embodiment 2, obtained white solid 120mg, yield 45.3%.m.p.275-277℃。
1H-NMR(300MHz,DMSO),δ(ppm):8.98(s,1H,ArH),8.78(s,1H,ArH),8.52(t,J＝5.3Hz,1H,CONH),4.38(br s,2H,CH
2),3.61(d,J＝3.6Hz,2H,CH
2),2.99–2.90(m,3H,CH,CH
2),2.05(t,J＝10.6Hz,4H,2CH
2),1.95(d,J＝16.0Hz,4H,2CH
2),1.83–1.79(m,1H,CH),0.87(d,J＝6.4Hz,6H,2CH
3).
MS(ESI(+)70V)m/z:328[M+H]
+.
Embodiment 6
1-(N-benzyl-4-piperidyl)-8,9-dihydro-2,4,7, the 9a-tetrazine the synthesis (I-6) of Azulene-6 (7H)-one
With 0.17g (0.55mmol) I-1,57 μ l (0.65mmol) phenyl aldehyde, 0.05g (0.81mmol) sodium cyanoborohydride for raw material, utilize the method being similar to embodiment 2, obtained white solid 150mg, yield 75.5%.m.p.287-289℃。
1H-NMR(300MHz,DMSO),δ(ppm):8.99(s,1H,ArH),8.78(s,1H,ArH),8.51(t,J＝5.3Hz,1H,CONH),7.30(m,5H,ArH),4.37(br s,2H,CH
2),3.60(s,2H,CH
2),3.53(s,2H,CH
2),3.03–2.91(m,3H,CH,CH
2),2.15–2.06(m,2H,CH
2),1.97–1.81(m,4H,2CH
2).
MS(ESI(+)70V)m/z:362[M+H]
+.
Embodiment 7
1-(4-(dimethoxy-methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazine the synthesis (f) of Azulene-6 (7H)-one
By 0.5g (2.81mmol) d and 0.51g (2.82mmol) to two formal dissolution of benzaldehyde in 30ml methyl alcohol, then add 125mg 10%Pd/C, tube sealing is heated to 120 DEG C of reaction 24h.Be cooled to room temperature, suction filtration, filtrate concentrates to obtain yellow oil.Column chromatography for separation (eluent methylene dichloride: methyl alcohol=20:1), obtains yellow solid 0.59g, yield 62.1%.
1H-NMR(300MHz,CDCl
3),δ(ppm):9.23(s,1H,ArH),9.13(s,1H,ArH),8.41(br s,1H,CONH),7.82(d,J＝8.22Hz,2H,ArH),7.72(d,J＝8.16Hz,2H,ArH),5.60(s,1H,CH),4.55(m,2H,CH
2),3.78(m,2H,CH
2),3.72(m,4H,2CH
2),1.30(q,J
1＝7.02Hz,J
2＝14.07Hz,6H,2CH
3).
MS(ESI(+)70V)m/z:339[M+H]
+.
The synthesis (g) of 4-(6-oxo-6,7,8,9-tetrahydrochysene-2,4,7, the 9a-tetrazine Azulene-1 base-) phenyl aldehyde
0.1g (0.30mmol) f is dissolved in 15ml tetrahydrofuran (THF), adds 12ml 1mol/L hydrochloric acid soln, be warming up to 80 ° of reactions 2h, TLC and monitor raw material complete reaction.Be cooled to room temperature, decompression steams tetrahydrofuran (THF), and in residue, add saturated sodium bicarbonate solution regulate pH to alkalescence, 50ml × 2 extraction into ethyl acetate, organic phase washes one time, and saturated common salt washes one time, and anhydrous sodium sulfate drying spends the night.Suction filtration, filtrate concentrates, and obtains white solid 60mg, yield 68.5%.
1H-NMR(300MHz,CDCl
3),δ(ppm):10.08(s,1H,CHO),9.22(s,1H,ArH),9.12(s,1H,ArH),8.05(m,2H,ArH),7.98(m,2H,ArH),4.48(m,2H,CH
2),3.72(m,2H,CH
2).
MS(ESI(+)70V)m/z:293[M+H]
+.
1-((4-(pyrroles-1-base) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines the synthesis (I-7) of Azulene-6 (7H)-one
0.2g (0.68mmol) g and 0.12g (1.7mmol) tetramethyleneimine is dissolved in 10ml methyl alcohol, after stirring at room temperature 10min, then adds 0.1g (1.6mmol) sodium cyanoborohydride.After placing stirred overnight at room temperature, decompression steams solvent and obtains yellow oil.Column chromatography for separation (eluent methylene dichloride: methyl alcohol=20:1), obtains yellow solid 100mg, yield 42.4%.m.p.118～120℃。
1H-NMR(300MHz,DMSO),δ(ppm):9.13(s,1H,ArH),8.85(s,1H,ArH),8.69(br s,1H,CONH),7.93(d,J＝8.04Hz,2H,ArH),7.73(d,J＝7.56Hz,2H,ArH),4.51(s,2H,CH
2),4.05(s,2H,CH
2),3.62(s,2H,CH
2),2.83(s,4H,2CH
2),1.85(s,4H,2CH
2).
MS(ESI(+)70V)m/z:348[M+H]
+.
Embodiment 8
1-((4-(piperidin-1-yl) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines the synthesis (I-8) of Azulene-6 (7H)-one
With 0.2g (0.68mmol) g, 0.15g (1.7mmol) piperidines and 0.1g (1.6mmol) sodium cyanoborohydride for raw material, utilize the method being similar in embodiment 7 I-7, obtained yellow solid 110mg, yield 44.8%.m.p.>300℃。
1H-NMR(300MHz,DMSO),δ(ppm):9.16(s,1H,ArH),8.85(s,1H,ArH),8.65(br s,1H,CONH),7.95(d,J＝8.01Hz,2H,ArH),7.83(d,J＝7.59Hz,2H,ArH),4.50(m,2H,CH
2),4.13(s,2H,CH
2),3.59(s,2H,CH
2),3.17(s,2H,CH
2),2.89(m,4H,2CH
2),1.75(m,4H,2CH
2).
MS(ESI(+)70V)m/z:362[M+H]
+.
Embodiment 9
1-(4-((methylamino-) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-9)
0.60g (3.37mmol) d and 0.50g (3.37mmol) 4-((methylamino-) methyl) dissolution of benzaldehyde in 30ml methyl alcohol, then is added 150mg 10%Pd/C, and tube sealing is heated to 120 DEG C of reaction 24h.Be cooled to room temperature, suction filtration, filtrate concentrates to obtain yellow oil.Column chromatography for separation (eluent methylene dichloride: methyl alcohol=10:1), obtains yellow solid 0.24g, yield 23.2%.m.p.252-254℃。
1H-NMR(300MHz,DMSO),δ(ppm):9.12(s,1H,ArH),8.83(s,1H,ArH),8.61(t,J＝5.4Hz,1H,CONH),7.86(d,J＝8.1Hz,2H,ArH),7.56(d,J＝8.1Hz,2H,ArH),4.48(br s,2H,CH
2),3.76(s,2H,CH
2),3.58(br s,2H,CH
2),2.30(s,3H,CH
3).
MS(ESI(+)70V)m/z:308[M+H]
+.
Embodiment 10
1-(4-((dimethylamino) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-10)
With 0.70g (3.93mmol) d, 0.64g (3.93mmol) 4-((dimethylamino) methyl) phenyl aldehyde and 175mg 10%Pd/C for raw material, utilize the method being similar to embodiment 9, obtained yellow solid 0.32g, yield 25.4%.m.p.220-222℃。
1H-NMR(300MHz,DMSO),δ(ppm):9.12(s,1H,ArH),8.84(s,1H,ArH),8.61(t,J＝4.8Hz,1H,CONH),7.87(d,J＝7.7Hz,2H,ArH),7.53(d,J＝7.7Hz,2H,ArH),4.49(s,2H,CH
2),3.58(br s,2H,CH
2),3.51(s,2H,CH
2),2.20(s,6H,2CH
3).
MS(ESI(+)70V)m/z:322[M+H]
+.
Embodiment 11
1-(4-((ethylamino) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-11)
With 0.60g (3.37mmol) d, 0.55g (3.37mmol) 4-((ethylamino) methyl) phenyl aldehyde and 150mg 10%Pd/C for raw material, utilize the method being similar to embodiment 9, obtained yellow solid 0.27g, yield 25.0%.m.p.228-230℃。
1H-NMR(300MHz,DMSO),δ(ppm):9.13(s,1H,ArH),8.84(s,1H,ArH),8.63(t,J＝5.4Hz,1H,CONH),7.89(d,J＝8.1Hz,2H,ArH),7.61(d,J＝8.1Hz,2H,ArH),4.48(br s,2H,CH
2),3.91(s,2H,CH
2),3.59(br s,2H,CH
2),2.66(q,J＝7.1Hz,2H,CH
2),1.11(t,J＝7.1Hz,3H,CH
3).
MS(ESI(+)70V)m/z:322[M+H]
+.
Embodiment 12
1-(4-((isopropylamino) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-12)
With 0.30g (1.69mmol) d, 0.30g (1.69mmol) 4-((isopropylamino) methyl) phenyl aldehyde and 75mg 10%Pd/C for raw material, utilize the method being similar to embodiment 9, obtained yellow solid 0.11g, yield 19.4%.m.p.218-220℃。
1H-NMR(300MHz,DMSO),δ(ppm):9.09(s,1H,ArH),8.81(s,1H,ArH),8.65(br s,1H,ArH),7.82(d,J＝5.6Hz,2H,ArH),7.55(d,J＝5.4Hz,2H,ArH),4.46(br s,2H,CH
2),3.77(s,2H,
CH
2),3.56(br s,2H,CH
2),2.70(m,1H,CH),1.00(d,J＝3.4Hz,6H,2CH
3).
MS(ESI(+)70V)m/z:336[M+H]
+.
Embodiment 13
1-(4-((tertiary fourth amino) methyl) phenyl)-8,9-dihydro-2,4,7, the 9a-tetrazines Azulene-6 (7H)-one (I-13)
With 0.44g (2.47mmol) d, 0.47g (2.47mmol) 4-((tertiary fourth amino) methyl) phenyl aldehyde and 110mg 10%Pd/C be for raw material, utilize the method being similar to embodiment 9, obtained yellow solid 0.22g, yield 25.5%.m.p.266-268℃。
1H-NMR(300MHz,DMSO),δ(ppm):9.09(s,1H,ArH),8.82(s,1H,ArH),8.61(br s,1H,ArH),7.81(d,J＝5.2Hz,2H,ArH),7.57(d,J＝4.8Hz,2H,ArH),4.46(br s,2H,CH
2),3.75(s,2H,
CH
2),3.57(br s,2H,CH
2),1.10(s,9H,3CH
3).
MS(ESI(+)70V)m/z:350[M+H]
+。
Claims (6)
1. lead to compound or its pharmacy acceptable salt of formula I:
Wherein R representative
r
1represent hydrogen, C
1~ C
6alkyl, benzyl; R
2representative
or C
1~ C
6alkylamino methyl.
2. the compound of claim 1 or its pharmacy acceptable salt, wherein R
1represent hydrogen or C
1~ C
6alkyl.
3. the compound of claim 1 or its pharmacy acceptable salt, wherein R
2represent C
1~ C
3alkylamino methyl or
4. the compound of claims 1 to 3 or its pharmacy acceptable salt, wherein pharmacy acceptable salt is the acid salt that general formula (I) compound of claim 1 and following acid are formed: hydrochloric acid, Hydrogen bromide, sulfuric acid, carbonic acid, citric acid, succsinic acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetic acid, toxilic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or forulic acid.
5. a pharmaceutical composition, wherein containing the logical formula I compound of claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
6. the compound of claim 1,2 or 3 or its pharmacy acceptable salt are preparing the purposes in antitumor drug.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004087713A1 (en) * | 2003-03-31 | 2004-10-14 | Pfizer Inc. | Salts of tricyclic inhibitors of poly(adp-ribose) polymerases |
| WO2008114114A2 (en) * | 2007-03-16 | 2008-09-25 | Pfizer Products Inc. | Poly(adp-ribose) polymerases inhibitor for treating ophthalmic condition |
-
2015
- 2015-03-02 CN CN201510092804.3A patent/CN104592232A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004087713A1 (en) * | 2003-03-31 | 2004-10-14 | Pfizer Inc. | Salts of tricyclic inhibitors of poly(adp-ribose) polymerases |
| WO2008114114A2 (en) * | 2007-03-16 | 2008-09-25 | Pfizer Products Inc. | Poly(adp-ribose) polymerases inhibitor for treating ophthalmic condition |
Non-Patent Citations (2)
| Title |
|---|
| HUW D. THOMAS ET AL.: ""Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial"", 《MOLECULAR CANCER THERAPEUTICS》 * |
| 耿元硕 等: ""聚腺苷二磷酸核糖聚合酶抑制剂Rucaparib的合成研究"", 《精细化工中间体》 * |
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