CN108484615A - A kind of compound, synthetic method and its purposes in the preparation of antitumor drugs - Google Patents
A kind of compound, synthetic method and its purposes in the preparation of antitumor drugs Download PDFInfo
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- CN108484615A CN108484615A CN201810510066.3A CN201810510066A CN108484615A CN 108484615 A CN108484615 A CN 108484615A CN 201810510066 A CN201810510066 A CN 201810510066A CN 108484615 A CN108484615 A CN 108484615A
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- alk
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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 for containing cyano containing cyano（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
Technical field
The invention belongs to chemical medicine, it is related to a kind of compound, synthetic method and its in the preparation of antitumor drugs
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 invention further relates to the tricyclic antidepressants containing cyano
Formula（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 fire-bar adds, 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 the external inhibitory activity to NCI-H2228 cells,
Wherein the external inhibitory activity of ALK-Q03, ALK-Q04, ALK-Q05, ALK-Q10 is better than Alectinib, and experiment measures
ICs of the Alectinib to NCI-H2228 cells50For 50nM.
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- (naphthalene -2- bases) phenyl) -5,6,7,8- tetrahydrochysene -4H- benzos
[4,5] synthesis of 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 is added into the solution for the compound 3 (14.26g, 59.85mmol) being dissolved in ethyl alcohol (100mL)
(20mL) after mixture is stirred at room temperature 5 hours, is concentrated to give crude product, then MeOH (30mL) is used to be beaten, obtains ash
White solid 5- amino -3- (3- methyl benzofuran -2- bases) -1H- pyrazoles -4- formonitrile HCNs (compound 4), 9.81g, yield are
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] miaow
The synthesis of azoles simultaneously [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- (naphthalene -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).Naphthalene -2- boric acid (40.00mmol) and potassium carbonate (5.53g, 40.00mmol) are added in the mixture.So
PdNPs catalyst (0.4mmol%Pd) is added afterwards, and mixture is vigorously stirred 30 minutes in a nitrogen atmosphere in 60 DEG C.It will be anti-
Mixture is answered to be added in 0.2mol/L sodium hydroxide solutions (100mL) and extracted with ethyl acetate (100mL).It will be organic laminated
And and in air naturally volatilization crystallization, obtain off-white powder product 2- (3- methyl benzofuran -2- bases) -7- (2- (naphthalenes -
2- yls) phenyl) -5,6,7,8- tetrahydrochysene -4H- benzos [4,5] imidazo [1,2-b] pyrazoles -3- nitriles, 17.24g, yield is
89.7%。1H-NMR (400 MHz, CDCl3) δ: 2.02(s, 4H), 2.36(m, 1H), 2.40(m, 2H), 2.80
(m, 1H), 3.02(m, 1H), 3.17(m, 1H), 5.88(s, 1H), 7.22(t, 1H), 7.28(t, 1H),
7.37-7.42(m, 3H), 7.50(d, 1H), 7.55-7.60(m, 4H), 7.63(t, 1H), 7.77(m, 1H),
7.99(d, 1H), 8.06(d, 1H), 8.09(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,
121.98, 122.84, 124.59, 125.41, 125.52, 126.64, 127.21, 127.55, 127.59,
128.47, 128.51, 129.14, 129.27, 129.46, 130.11, 134.11, 134.27, 134.44,
136.38, 139.03, 141.97, 142.03, 151.06, 151.19. LC-MS(ESI, pos, ion) m/z: 519
[M+H]。
2 2- of embodiment (3- methyl benzofuran -2- bases) -7- (2- (the fluoro- naphthalene -2- bases of 7-) 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).Fluoro- naphthalene -2- the boric acid (40.00mmol) of 7- and potassium carbonate (5.53g, 40.00mmol) are added to the mixture
In.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- naphthalene -2- bases of 7-) phenyl) -5,6,7,8- tetrahydrochysene -4H- benzos [4,5] imidazo [1,2-b] pyrazoles -3- nitriles,
17.48g, yield 88%.LC-MS(ESI, pos, ion) m/z: 537[M+H].
3 2- of embodiment (3- methyl benzofuran -2- bases) -7- (2- (7- methyl-naphthalene -2- bases) 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).7- methyl-naphthalene -2- boric acid (40.00mmol) 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- (7- methyl-naphthalene -2- bases) phenyl) -5,6,7,8- tetrahydrochysene -4H- benzos [4,5] imidazo [1,2-b] pyrazoles -3- nitriles,
16.56g, yield 84%.LC-MS(ESI, pos, ion) m/z: 533[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-Q01 | 2.8 |
| ALK-Q02 | 1.7 |
| ALK-Q03 | 1.2 |
| ALK-Q04 | 1.3 |
| ALK-Q05 | 1.2 |
| ALK-Q06 | 2.8 |
| ALK-Q07 | 3.0 |
| ALK-Q08 | 4.1 |
| ALK-Q09 | It does not determine |
| ALK-Q10 | 2.2 |
| 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 containing cyano（Ⅰ）, structure is
,
Wherein：R1、R2、R3、R4It is independently selected from H, F or CH3。
2. containing the tricyclic compounds formula of cyano containing cyano as described in claim 1（Ⅰ）Pharmaceutically acceptable salt
Or solvate.
3. containing the tricyclic compounds formula of cyano containing cyano as described in claim 1（Ⅰ）, characterized in that 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.
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|---|---|---|---|---|
| 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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Application publication date: 20180904 |