CN108467397A - A kind of tricyclic compounds containing cyano and its purposes in antitumor drug - Google Patents

A kind of tricyclic compounds containing cyano and its purposes in antitumor drug Download PDF

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CN108467397A
CN108467397A CN201810510067.8A CN201810510067A CN108467397A CN 108467397 A CN108467397 A CN 108467397A CN 201810510067 A CN201810510067 A CN 201810510067A CN 108467397 A CN108467397 A CN 108467397A
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alk
tricyclic compounds
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陈海鹏
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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
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Abstract

The tricyclic compounds formula containing cyano that the invention discloses a kind of（Ⅰ）And its purposes in the preparation of antitumor drugs,, wherein：R1、R2、R3、R4It is independently selected from H, F or CH3.The invention also discloses the tricyclic compounds formulas containing nitrile（Ⅰ）Synthetic method.It finds that the compounds of this invention has good ALK kinase inhibiting activities in external ALK kinase inhibiting activities experiment, more deep research and development can be carried out as antitumor drug.

Description

A kind of tricyclic compounds containing cyano and its purposes in antitumor drug
Technical field
The invention belongs to chemical medicine, it is related to a kind of tricyclic compounds containing cyano and its in antitumor drug In purposes.
Background technology
Anaplastic lymphoma kinase（ALK）It expresses, is recognized in the primary systemic primary cutaneous types of 60%-80% To be primary cutaneous type（ALCL）Compare special marker.Soda in 2007 etc. is in non-small cell lung cancer （NSCLC）ALK and spine skin microtubule associated protein IV are found that in sample for the first time（EML4）Fusion（EML4-ALK）.ALK Albumen belongs to insulin receptor superfamily, can improve ALK expressions after fusion with several genes fusion, activate ALK With abnormal activation downstream phosphatidylinositol3 3 kinase protein kinase B signal transduction pathway, causes growth of tumour cell, proliferation, resists and wither It dies.EML4 belongs to echinoderm micro-pipe associated class protein family, and in NSCLC, EML4 is with ALK gene sequence on chromosome 2p It is separated by 12mb, through that can detect a variety of EML4-ALK fusions types, has largely been proved that tumour is promoted to generate activity. If the target spot in this, as drugs block tumour growth can become another new target therapeutic agent.
ALECENSA（Ai Le replaces Buddhist nun, A Lei to replace Buddhist nun, Alectinib）The molecular targeted medicine of anti-ALK, in December, 2015 quilt U.S. Food and Drug Administration（FDA）ALK positive lung cancers after approval replaces Buddhist nun drug resistant for gram azoles, according to the data of announcement From the point of view of, effect is very good, is no lack of favorable comment always in recent medicine news.
Alectinib is a kind of tyrosine kinase inhibitor targeting ALK and RET.In non-clinical study, alectinib suppressions The activation for the downstream signaling proteins STAT3 and AKT that ALK phosphorylations processed and ALK- are mediated, and ALK fusions, amplification are being sheltered, or swash Tumor cell activity is lowered in mutation various kinds of cell system living.The main active metabolites of Alectinib, M4, display analogue are imitated outside Power and activity.Alectinib and M4 show in vitro and in vivo to a variety of ALK enzyme mutants types, including some with Crizotinib The mutant identified in the patient NSCLC tumours that are in progress is given Ai Le and is replaced in the mouse model that transplanting carries that ALK merges tumour Buddhist nun alectinib leads to antitumor activity and extending life, including encephalic implantation to have ALK- tumor cell line mouse moulds by oneself Type.
Invention content
The tricyclic compounds formula containing cyano that the invention discloses a kind of（Ⅰ）, structure is：
, wherein：R1、R2、R3、R4It is independently selected from H, F or CH3.The present invention also relates to And the tricyclic compounds formula containing cyano（Ⅰ）Pharmaceutically acceptable salt or solvate.
Further, the tricyclic compounds formula containing cyano described in some preferred schemes（Ⅰ）For：
Another object of the present invention discloses the tricyclic compounds formula containing cyano（Ⅰ）Synthetic route be：
。
Specifically synthetic method is：
1) in a low temperature of suitable, 3- methyl benzofuran -2- formyl chlorides (compound 1) and malononitrile generation nucleophilic displacement of fluorine are anti- 2- (methoxyl group (3- methyl benzofuran -2- bases) methylene) malononitrile (compound 2) should be generated；2) under heating condition, chemical combination Object 2 again with CH (OMe)3Reaction generates 2- (methoxyl group (3- methyl benzofuran -2- bases) methylene) malononitrile (compound 3)； 3) in a suitable solvent, with hydrazine hydrate cyclization generation 5- amino -3- (3- methyl benzofurans -2- occur for compound 3 Base) -1H- pyrazoles -4- formonitrile HCNs (compound 4)；4) substitution reaction generation 7- (2- chlorphenyls) -2- (3- of amine occur for compound 4 Methyl benzofuran -2- bases) -5,6,7,8- tetrahydrochysene -4H- benzos [4,5] imidazo [1,2-b] pyrazoles -3- nitriles (compound 5)； 5) in the presence of catalyst and inorganic base, compound 5 undergoes coupling reaction to produce corresponding nitrile with boronic acid derivatives and derives Object.
Further, the synthesis step 1) in low temperature refer to -5-5 DEG C, preferably 0-5 DEG C.
Further, the synthesis step 2) in heating temperature be 60-85 DEG C, preferably 75 DEG C.
Further, the synthesis step 3) in reaction dissolvent can be ethyl alcohol, methanol, isopropanol etc., preferred alcohol.
Further, the inorganic base used in the step 5) can be sodium bicarbonate, sodium carbonate, saleratus, carbonic acid The salt such as potassium, preferably potassium carbonate and sodium carbonate, most preferably potassium carbonate.
Another object of the present invention discloses the tricyclic compounds formula containing cyano（Ⅰ）And its it is pharmaceutically acceptable The application as anaplastic lymphoma kinase inhibitor of salt and/or solvate.
Another object of the present invention discloses the tricyclic compounds formula containing cyano（Ⅰ）And its it is pharmaceutically acceptable The application as antitumor drug of salt and/or solvate.
Compound of the present invention uses MTT（Tetrazolium bromide）Method measures thin to NCI-H2228 cells and Karpas-299 The external inhibitory activity of born of the same parents, wherein ALK-N01, ALK-N02, ALK-N03, ALK-N04, ALK-N06, ALK-N10 inhibit in vitro Activity is better than Alectinib, and experiment measures ICs of the Alectinib to NCI-H2228 cells50For 50nM, Alectinib pairs The IC of Karpas-299 cells50For 5nM.
Pharmaceutically acceptable salt of the present invention refers to the organic salt and inorganic salts of the compounds of this invention.Pharmaceutically may be used The salt that the nontoxic acid received is formed includes, but is not limited to, inorganic acid salt, such as hydrochloride, hydrobromate, phosphate, sulfuric acid Salt, perchlorate；Acylate, such as acetate, oxalates, maleate, tartrate, citrate, succinate, the third two Hydrochlorate；Or these salt are obtained by other methods described in the books or literature such as ion-exchange.Other can pharmaceutically connect The salt received includes adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, Borate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, second Sulfonate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, Caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, apple Hydrochlorate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfuric acid Salt, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, 11 Hydrochlorate, valerate, etc..By including alkali metal, alkaline-earth metal, ammonium and N+ (C1-4 alkane with alkali appropriate salt obtained by the reaction Base) 4 salt.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Can with the alkali metal of forming salt or Alkaline-earth metal includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises appropriate, nontoxic ammonium, season The amine cation that ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitre Acidulants, C1-8 azochlorosulfonate acid compounds and aromatic sulphonic acid compound.
Solvate of the present invention refers to that one or more solvent molecules are formed by with the compound of the present invention and form Close object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, Acetic acid and ethylaminoethanol.
Specific embodiment
1 2- of embodiment (3- methyl benzofuran -2- bases) -7- (2- (pyridine -2- bases) phenyl) -5,6,7,8- tetrahydrochysene -4H- benzene And the synthesis of [4,5] imidazo [1,2-b] pyrazoles -3- nitriles
The synthesis of 1.1 2- (hydroxyl (3- methyl benzofuran -2- bases) methylene) malononitrile：
Malononitrile (8.95g, 135.5mmol) and n,N-diisopropylethylamine (DIEA) (35.02g, 271.0mmol) are dissolved in In tetrahydrofuran (THF) (80mL), the 3- methyl benzofurans -2- being dissolved in toluene (80mL) was added dropwise with 1 hour at 0-5 DEG C Formyl chloride (compound 1) (31.5g, 161.86mmol) solution, after being added dropwise, so as to get mixture be warming up to room temperature, stir It mixes 8 hours.Reaction is quenched with water (100mL) and is extracted with ethyl acetate (100mL × 3).By combined organic layer 3mol/L HCl/water solution (100mL) washing, then washed with brine (100mL × 3), then use Na2SO4It is dry, concentration, flash column chromatography Isolated crude product 2- (hydroxyl (3- methyl benzofuran -2- bases) methylene) malononitrile (compound 2), 28.26g, yield 93%。1H-NMR (400 MHz, CDCl3) δ: 2.55(s, 3H), 5.91(s, 1H), 7.22(t, 1H), 7.28(t, 1H), 7.50(d, 1H), 7.59(d, 1H). 13C-NMR (125 MHz, CDCl3) δ: 8.77, 50.36, 110.70, 113.96, 120.25, 121.45, 121.98, 122.84, 125.52, 147.93, 151.19, 167.38. LC-MS(ESI, pos, ion) m/z: 225[M+H].
The synthesis of 1.2 2- (methoxyl group (3- methyl benzofuran -2- bases) methylene) malononitrile：
It is dissolved in CH (OMe)3The solution of compound 2 (28.26g, 126.04mmol) in (100mL) is heated to 75 DEG C and adds Heat 8 hours.Then mixture is concentrated into 50ml, filtered, be used in combination MeOH (50mL) to wash, obtain yellow solid 2- (methoxyl groups (3- methyl benzofuran -2- bases) methylene) malononitrile (compound 3), 14.26g, yield is 47.5%.1H-NMR (400 MHz, CDCl3) δ: 2.55(s, 3H), 3.51(s, 3H), 7.22(t, 1H), 7.28(t, 1H), 7.50(d, 1H), 7.59(d, 1H). 13C-NMR (125 MHz, CDCl3) δ: 8.77, 57.05, 61.51, 110.70, 112.28, 120.25, 121.98, 122.84, 125.52, 126.01, 148.90, 151.19, 152.38. LC-MS (ESI, pos, ion) m/z: 239[M+H].
The synthesis of 1.3 5- amino -3- (3- methyl benzofuran -2- bases) -1H- pyrazoles -4- formonitrile HCNs：
Hydrazine hydrate (20mL) is added into the solution for the compound 3 (14.26g, 59.85mmol) being dissolved in ethyl alcohol (100mL), After mixture is stirred at room temperature 5 hours, it is concentrated to give crude product, then MeOH (30mL) is used to be beaten, it is solid to obtain canescence Body 5- amino -3- (3- methyl benzofuran -2- bases) -1H- pyrazoles -4- formonitrile HCNs (compound 4), 9.81g, yield is 68.8%.1H-NMR (400 MHz, CDCl3) δ: 2.02(s, 3H), 7.22(t, 1H), 7.28(t, 1H), 7.50(d, 1H), 7.59(d, 1H). 13C-NMR (125 MHz, CDCl3) δ: 8.77, 70.27, 110.70, 114.73, 115.12, 120.25, 121.98, 122.84, 125.52, 133.14, 142.27, 151.19, 159.35. LC-MS(ESI, pos, ion) m/z: 239[M+H].
1.4 7- (2- chlorphenyls) -2- (3- methyl benzofuran -2- bases) -5,6,7,8- tetrahydrochysene -4H- benzos [4,5] imidazo The synthesis of [1,2-b] pyrazoles -3- nitriles：
The additionization into the bromo- 4- of 2- (2- chlorphenyls) hexamethylene -1- ketone (11.84g, the 41.18mmol) solution being dissolved in HOAC Object 4 (9.81g, 41.18mmol) is closed, obtained mixture is stirred 8 hours at 108 DEG C, then concentrates reaction mixture, It adds ethyl acetate (100mL) and brine (100mL) stirring is layered later, washed with brine (2*100mL) after detaching organic layer It washs, after sodium sulphate drying, concentration obtains colorless oil 7- (2- chlorphenyls) -2- (3- methyl benzofuran -2- bases) -5,6, 7,8- tetrahydrochysene -4H- benzos [4,5] imidazo [1,2-b] pyrazoles -3- nitriles (compound 5), 15.82g, yield 90%.1H-NMR (400 MHz, CDCl3) δ: 2.00(m, 1H), 2.02(s, 3H), 2.37(m, 1H), 2.54(t, 2H), 2.64 (m, 1H), 3.30(m, 1H), 3.65(m, 1H), 5.98(s, 1H), 7.14-7.19(m, 2H), 7.22(t, 1H), 7.28(t, 1H), 7.32(m, 1H), 7.50(d, 1H), 7.59(d, 1H), 7.65(m, 1H). 13C-NMR (125 MHz, CDCl3) δ: 8.77, 22.19, 24.76, 25.97, 39.32, 66.94, 106.59, 110.70, 114.66, 116.33, 120.25, 121.98, 122.84, 125.52, 127.02, 127.51, 130.08, 130.11, 130.14, 133.99, 134.27, 139.03, 142.92, 151.06, 151.19. LC-MS(ESI, pos, ion) m/z: 427[M+H].
1.5 2- (3- methyl benzofuran -2- bases) -7- (2- (pyridine -2- bases) phenyl) -5,6,7,8- tetrahydrochysene -4H- benzos [4, 5] synthesis of imidazo [1,2-b] pyrazoles -3- nitriles：
Compound 5 (15.82g, 37.06mmol) is dissolved in the H of 100mL2O:EtOH(1:1) three-necked bottle is placed in mixture In (500mL).It is mixed that pyridine -2- ylboronic acids (4.92g, 40.00mmol) and potassium carbonate (5.53g, 40.00mmol) are added to this It closes in object.Then PdNPs catalyst (0.4mmol%Pd) is added, and mixture is vigorously stirred 30 in 60 DEG C in a nitrogen atmosphere Minute.Reaction mixture is added in 0.2mol/L sodium hydroxide solutions (100mL) and is extracted with ethyl acetate (100mL). Organic layer is merged, and volatilization crystallization naturally in air, obtains off-white powder product 2- (3- methyl benzofurans -2- Base) -7- (2- (pyridine -2- bases) phenyl) -5,6,7,8- tetrahydrochysene -4H- benzos [4,5] imidazo [1,2-b] pyrazoles -3- nitriles, 15.66g, yield 90%.1H-NMR (400 MHz, CDCl3) δ: 2.02(s, 4H), 2.43(m, 1H), 2.50(t, 2H), 2.71(m, 1H), 3.04(m, 2H), 5.95(s, 1H), 6.90(t, 1H), 7.14(d, 1H), 7.22(t, 1H), 7.28(m, 2H), 7.38(m, 2H), 7.50(d, 1H), 7.58(m, 2H), 8.02(d, 1H), 8.37(d, 1H). 13C-NMR (125 MHz, CDCl3) δ: 8.77, 22.19, 24.76, 25.97, 40.26, 66.94, 106.59, 110.70, 114.66, 116.33, 120.25, 121.44, 121.98, 122.84, 124.18, 125.14, 125.52, 127.31, 127.42, 128.92, 130.11, 134.27, 137.33, 139.03, 144.06, 145.73, 149.10, 151.06, 151.19, 159.19. LC-MS(ESI, pos, ion) m/z: 470 [M+H].
2 2- of embodiment (3- methyl benzofuran -2- bases) -7- (2- (the fluoro- pyridine -2- bases of 3-) phenyl) -5,6,7,8- tetrahydrochysenes - The synthesis of 4H- benzos [4,5] imidazo [1,2-b] pyrazoles -3- nitriles：
Compound 5 (15.82g, 37.06mmol) is dissolved in the H of 100mL2O:EtOH(1:1) three-necked bottle is placed in mixture In (500mL).Fluoro- pyridine -2- the boric acid (40.00mmol) of 3- and potassium carbonate (5.53g, 40.00mmol) are added to the mixing In object.Then PdNPs catalyst (0.4mmol%Pd) is added, and mixture is vigorously stirred 30 points in 60 DEG C in a nitrogen atmosphere Clock.Reaction mixture is added in 0.2mol/L sodium hydroxide solutions (100mL) and is extracted with ethyl acetate (100mL).It will Organic layer merges, and volatilization crystallization naturally in air, obtains off-white powder product 2- (3- methyl benzofuran -2- bases) - 7- (2- (the fluoro- pyridine -2- bases of 3-) phenyl) -5,6,7,8- tetrahydrochysene -4H- benzos [4,5] imidazo [1,2-b] pyrazoles -3- nitriles (are changed Close object 6), 15.50g, yield 86%.LC-MS(ESI, pos, ion) m/z: 488[M+H].
3 2- of embodiment (3- methyl benzofuran -2- bases) -7- (2- (3- methvl-pyridinium -2- bases) phenyl) -5,6,7,8- four The synthesis of hydrogen -4H- benzos [4,5] imidazo [1,2-b] pyrazoles -3- nitriles：
Compound 5 (15.82g, 37.06mmol) is dissolved in the H of 100mL2O:EtOH(1:1) three-necked bottle is placed in mixture In (500mL).It is mixed that 3- methvl-pyridinium -2- boric acid (40.00mmol) and potassium carbonate (5.53g, 40.00mmol) are added to this It closes in object.Then PdNPs catalyst (0.4mmol%Pd) is added, and mixture is vigorously stirred 30 in 60 DEG C in a nitrogen atmosphere Minute.Reaction mixture is added in 0.2mol/L sodium hydroxide solutions (100mL) and is extracted with ethyl acetate (100mL). Organic layer is merged, and volatilization crystallization naturally in air, obtains off-white powder product 2- (3- methyl benzofurans -2- Base) -7- (2- (3- methvl-pyridinium -2- bases) phenyl) -5,6,7,8- tetrahydrochysene -4H- benzos [4,5] imidazo [1,2-b] pyrazoles - 3- nitriles (compound 6), 15.04g, yield 84%.LC-MS(ESI, pos, ion) m/z: 484[M+H].
Test example：Inhibitory activity of the compounds of this invention to ALK kinases
The inhibitory activity that the compounds of this invention carries out wild type ALK kinases measures, and uses the HTRF of Cisbio companies KinEASETM-TK Assay kits detection compounds are to Wildtype ALK kinases（Wild type ALK kinases, hat section of Sino-U.S.） Inhibitory activity.
One, test method：
By compound（DMSO final concentration of 1%）Respectively with reaction substrate（Final concentration of 1 μM）, ATP（Final concentration of 20 μM）, with And Wildtype ALK kinases（Final concentration of 1ng/ μ l）It is mixed in the reaction system that final volume is 10 μ l（MgCl containing 5mM2, 1X Kinase buffer and 1mM DTT）.Concussion is reacted 35 minutes after 30 seconds in 30 DEG C.Add 5 μ l per hole after completion of the reaction Sa-XL665 solution and 5 μ l TK Antibody-Eu（K）, after mixing in 30 DEG C of avoid light places 60 minutes with reaction was completed. In read plate on PerkinElmer EnVision plate readers（615nM, 665nM）, 665/615 ratio is calculated, and analyze data.
Inhibiting rate (%)=[1- (R compounds-Rmin)/(Rmax-Rmin)] × 100
665/615 ratio minimum value（Rmin, for 665/615 ratio in the case of 10.4 μM of positive control drug LDK-378 is added）, 665/615 ratio maximum value（Rmax, to be added without 665/615 ratio in the case of compound）, 665/615 ratio test value（Rization Object is closed, for 665/615 ratio under given compound concentration）.
The IC50 of compound is calculated by using XLfit programs in Excel.
Two, experimental result and conclusion：
The external ALK kinase inhibiting activities of 1 the compounds of this invention of table
Number IC50（nM）
ALK-N01 0.6
ALK-N02 0.3
ALK-N03 0.3
ALK-N04 0.2
ALK-N06 0.6
ALK-N07 1.0
ALK-N10 0.7
Alectinib 1.6
As seen from the above table, the compounds of this invention has good ALK kinase inhibiting activities, antitumor drug can be used as to carry out more Deepen into research and development.

Claims (6)

1. a kind of tricyclic compounds formula containing cyano（Ⅰ）, structure is
, wherein：R1、R2、R3、R4It is independently selected from H, F or CH3。
2. the tricyclic compounds formula containing cyano as described in claim 1（Ⅰ）Pharmaceutically acceptable salt or solvation Object.
3. the tricyclic compounds formula containing cyano as described in claim 1（Ⅰ）, characterized in that it is selected from following compound：
。
4. the tricyclic compounds formula containing cyano as described in claim 1（Ⅰ）Synthetic route be：
。
5. the tricyclic compounds formula containing cyano as claimed in claim 1 or 2（Ⅰ）Inhibit as anaplastic lymphoma kinase The application of agent.
6. the tricyclic compounds formula containing cyano as claimed in claim 1 or 2（Ⅰ）Application as antitumor drug.
CN201810510067.8A 2018-05-25 2018-05-25 A kind of tricyclic compounds containing cyano and its purposes in antitumor drug Withdrawn CN108467397A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104884458A (en) * 2013-04-25 2015-09-02 百济神州有限公司 Fused heterocyclic compounds as protein kinase inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104884458A (en) * 2013-04-25 2015-09-02 百济神州有限公司 Fused heterocyclic compounds as protein kinase inhibitors

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