CN101851218B - 4,5-disubstituted aryl isoselenazol derivative and application thereof - Google Patents

4,5-disubstituted aryl isoselenazol derivative and application thereof Download PDF

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Publication number
CN101851218B
CN101851218B CN201010156257.8A CN201010156257A CN101851218B CN 101851218 B CN101851218 B CN 101851218B CN 201010156257 A CN201010156257 A CN 201010156257A CN 101851218 B CN101851218 B CN 101851218B
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derivative
compound
isoselenazol
acid
disubstituted aryl
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CN101851218A (en
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张为革
卢汉翔
吴英良
倪佳
沈杞容
包凯
乔拂晓
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Shenyang Pharmaceutical University
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Abstract

The invention belongs to the technical flied of medicines and relates to a 4,5-disubstituted aryl isoselenazol derivative which has the following structure. The invention also provides pharmaceutically acceptable nonpoisonous salts and hydrates thereof formed from the derivative shown as the structural formula, and the pharmaceutically acceptable nonpoisonous salts comprises salts formed from the derivative and acid. Pharmacological activity test results indicate that the derivative has better antitumor activity and can be used as a tumor cell proliferation inhibitor on the aspect of preparing a medicament for tumor.

Description

4,5-disubstituted aryl isoselenazol derivative and uses thereof
Technical field
The invention belongs to medical technical field, relate to a kind of 4,5-disubstituted aryl isoselenazol derivative and uses thereof, exactly, relate to this compounds and as tumor cell proliferation inhibitor in the application of preparing aspect anti-tumor drug.
Background technology
Malignant tumour is the serious disease that threatens human health and life, in China, is the first lethal cause of disease.Find and find that treatment and the new drug of prophylaxis of tumours are the current key subjects that face.
Combretastatin A-4 (CA-4) is the separated cis-stilbene class natural product obtaining from the willow of South Africa, and its chemical name is (Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenol.CA-4 is tubulin polymerization inhibitor, presents very strong inhibition tumor cell proliferation activity, and its prodrug CA-4 phosphoric acid salt (CA-4P) has entered the clinical study stage three phases in the U.S..With CA-4, for lead compound designs, the existing a large amount of reports of the research of synthetic new active compound for anti tumor, but most CA-4 analogue exists or is active not high enough or toxicity is large or the shortcoming such as synthetic more complicated.Relevant report is referring to Pettit G.R., et al.Experientia, 1989,45,209; Nam N.H.Curr.Med.Chem., 2003,10,1697; Tron G.C., et al.J.Med.Chem., 2006,49,3033.
Summary of the invention
The object of the invention is to design, the synthetic analog with the CombretastatinA-4 of good anti-tumor activity, 4,5-disubstituted aryl isoselenazol derivative; In the anti-tumor activity test in vivo and in vitro of prepared compound, manifest good result.
Target product of the present invention can represent with following structural formula:
R 1～R 8be independently of one another-H ,-CN ,-NO 2,-X, R ,-OR ,-OC (O) R ,-C (O) OR ,-C (O) R ,-SO 2r ,-OP (O) are (OR) 2,-C (O) NRR ' ,-NRR ' ,-N (R) C (O) R ' ,-SR or two adjacent substituting groups are-OC (RR ') thus O-forms five-ring, thereby or two adjacent substituting groups be-CH=CH-CH=CH-,-CH=CH-CH=N-,-CH=CH-N=CH-form six-ring;
Wherein X is F, Br, Cl, I; R is H, C 1～C 6alkyl, aryl, arylalkyl, haloalkyl; R, R ' are H, C independently of one another 1～C 6alkyl, aryl, arylalkyl, haloalkyl;
Its precondition is:
Work as R 2for-F, and R 6for-SO 2during Me, R 1, R 3～R 5, R 7, R 8when different, be-H; Work as R 2for-Cl, and R 6during for-OMe, R 1, R 3～R 5, R 7, R 8when different, be-H; Work as R 2for-OMe, and R 6during for-Cl, R 1, R 3～R 5, R 7, R 8when different, be-H; Work as R 2for-Cl, and R 6during for-Cl, R 1, R 3～R 5, R 7, R 8when different, be-H; Work as R 2for-Me, and R 6during for-Cl, R 1, R 3～R 5, R 7, R 8when different, be-H; Work as R 2for-Cl, and R 6during for-Me, R 1, R 3～R 5, R 7, R 8when different, be-H; Work as R 2for-Me, and R 6during for-OMe, R 1, R 3～R 5, R 7, R 8when different, be-H; Work as R 2for-OMe, and R 6during for-OMe, R 1, R 3～R 5, R 7, R 8when different, be-H.
Compound of the present invention also comprises derivative shown in said structure formula formed pharmaceutically acceptable non-toxic salt and hydrate thereof, and these pharmaceutically acceptable non-toxic salt comprise this derivative and sour formed salt.Described acid can or be selected from the organic acid of acetic acid, citric acid, oxalic acid, tartrate, phenylformic acid, oxysuccinic acid for the mineral acid of hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid.The hydration number of described hydrate is any real number in 0～16.
The preferred part of compounds structure of the present invention is as follows:
Compound 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 6
Compound 7
Compound 8
Compound 9
Compound 10
Compound 11
Compound 12
Compound 13
Compound 14
Compound 15
Compound 16
Compound 17
The present invention also provides the preparation method of this compounds, of the present invention 4, and 5-disubstituted aryl isoselenazol derivative (I) can obtain according to following reaction scheme is synthetic:
3-is chloro-2, and 3-disubstituted aryl propenal analog derivative is dissolved in acetone, then adds Tetrabutyl amonium bromide successively, Potassium Selenocyanate, and ammonium chloride, stirs, heats up gradually, back flow reaction 9h.After completion of the reaction, be chilled to room temperature, topple over into saturated sodium bicarbonate aqueous solution, stir, be then extracted with ethyl acetate three times, organic layer washs with saturated sodium-chloride water solution, separates organic layer, and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying.Remove under reduced pressure after solvent, through column chromatography for separation, obtain product I, and yield 40-80% (ScholzM., et al.Eur.J.Med.Chem.2008,6,1152-9);
Wherein, R 1～R 6for 4 of amino, 5-disubstituted aryl isoselenazol derivative can be by corresponding R 1～R 6for the compound of nitro is prepared through reduction reaction, reductive agent be V-Brite B/tetrahydrofuran aqueous solution system (Baell J.B., et al.Tetrahedron.2006,62,7284-92);
Wherein, R 1～R 6for 4 of hydroxyl, 5-disubstituted aryl isoselenazol derivative can be by corresponding R 1～R 6for the compound of benzyloxy etc. is prepared through Deprotection reaction, the reagent that goes protecting group be titanium tetrachloride (Lin S.Y., et al.J.Org.Chem.2003,68,2968-71).
Provided by the present invention 4,5-disubstituted aryl isoselenazol derivative preparation method simple possible, yield is higher.
The present invention further provides the application of above-claimed cpd in the medicine of preparation treatment tumor disease.
4,5-disubstituted aryl isoselenazol derivative has the effect of good treatment tumor disease, has good development prospect in preparing antitumor drug.
Embodiment
By following example, will contribute to understand the present invention, but content of the present invention is not limited to example.
Agents useful for same of the present invention is commercially available, and nuclear magnetic resonance spectrum is measured by AVANCE-400, BrukerARX-300 fourier transform NMR spectrometer, and mass spectrum is measured by Brukee Esqure 2000, Shimadzu GCMS-QP5050A type mass spectrograph.
Embodiment 1:5-(4-p-methoxy-phenyl)-4-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 1)
By the chloro-3-of 3-(4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl) propenal (0.1g, 0.3mmol) be dissolved in acetone, the Tetrabutyl amonium bromide (0.009g, 0.03mmol) that adds successively again 0.1 equivalent, the Potassium Selenocyanate (0.12g of 3 equivalents, 0.9mmol), the ammonium chloride (0.04g, 0.9mmol) of 3 equivalents, stirs, heat up gradually, back flow reaction 9h.After completion of the reaction, be chilled to room temperature, topple over into saturated sodium bicarbonate aqueous solution, stir, be then extracted with ethyl acetate three times, organic layer washs with saturated sodium-chloride water solution, separates organic layer, and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying.Remove under reduced pressure after solvent, through column chromatography for separation, obtain product 1, yield 62.6%.The structural formula of compound 1, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 2:5-(2-fluorophenyl)-4-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 2)
Except using corresponding raw material, with the identical method of embodiment 1, prepare compound 2, yield is 55.4%; The structural formula of compound 2, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 3:5-(naphthalene-2-yl)-4-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 3)
Except using corresponding raw material, with the identical method of embodiment 1, prepare compound 3, yield is 75.6%; The structural formula of compound 3, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 4:5-(3-hydroxyl-4-p-methoxy-phenyl)-4-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 4)
Except using corresponding raw material, with the identical method of embodiment 1, prepare compound 5-(3-benzyloxy-4-p-methoxy-phenyl)-4-(3,4,5-trimethoxyphenyl)-1, the different selenazoles of 2-, be dissolved in again in methylene dichloride, add titanium tetrachloride, stirring at room 3h, slowly adds cold water, and be extracted with ethyl acetate, organic layer washs with saturated sodium-chloride water solution, separates organic layer and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, removes under reduced pressure after solvent, through column chromatography for separation, obtain compound 4, yield is 65.5%.; The structural formula of compound 4, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 5:5-(3-trifluoromethyl)-4-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 5)
Except using corresponding raw material, with the identical method of embodiment 1, prepare compound 5, yield is 43.0%; The structural formula of compound 5, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 6:5-(3-p-methoxy-phenyl)-4-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 6)
Except using corresponding raw material, with the identical method of embodiment 1, prepare compound 6, yield is 56.6%; The structural formula of compound 6, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 7:5-(3,4-Dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 7)
Except using corresponding raw material, with the identical method of embodiment 1, prepare compound 7, yield is 76.3%; The structural formula of compound 7, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 8:5-(4-hydroxy phenyl)-4-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 8)
Except using corresponding raw material, with the identical method of embodiment 4, prepare compound 8, yield is 43.0%; The structural formula of compound 8, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 9:5-(3-p-methoxy-phenyl)-4-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 9)
Except using corresponding raw material, with the identical method of embodiment 1, prepare compound 6, yield is 56.6%; The structural formula of compound 6, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 10:5-(4-Trifluoromethoxyphen-l)-4-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 10)
Except using corresponding raw material, with the identical method of embodiment 1, prepare compound 10, yield is 56.8%; The structural formula of compound 10, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 11:5-(3-methoxyl group-4-hydroxy phenyl)-4-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 11)
Except using corresponding raw material, with the identical method of embodiment 4, prepare compound 11, yield is 61.8%; The structural formula of compound 11, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 12:4-(3-nitro-4-p-methoxy-phenyl)-5-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 12)
Except using corresponding raw material, with the identical method of embodiment 1, prepare compound 12, yield is 53.6%; The structural formula of compound 12, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 13:4-(4-p-methoxy-phenyl)-5-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 13)
Except using corresponding raw material, with the identical method of embodiment 1, prepare compound 13, yield is 68.6%; The structural formula of compound 13, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 14:4-(3-hydroxyl-4-p-methoxy-phenyl)-5-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 14)
Except using corresponding raw material, with the identical method of embodiment 4, prepare compound 14, yield is 70.6%; The structural formula of compound 14, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 15:4-(3-amino-4-methoxyl phenyl)-5-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 15)
Compound 12 (0.05g, 0.1mmol) is dissolved in tetrahydrofuran (THF), and stirring at room 0.5h adds V-Brite B (0.09g, 0.5mmol), adds water, and-5 ℃ are stirred 4h.After completion of the reaction, be extracted with ethyl acetate, organic layer washs with saturated sodium-chloride water solution, separates organic layer and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, removes under reduced pressure after solvent, through column chromatography for separation, obtains compound 15, and yield is 34.3%; The structural formula of compound 15, 1h-NMR and MS data are listed in the table below in-1.
Embodiment 16:5-(3-nitro-4-p-methoxy-phenyl)-4-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 16)
Except using corresponding raw material, with the identical method of embodiment 1, prepare compound 16, yield is %; The structural formula of compound 16, 1h-NMR and MS data are listed in the table below in-1
Embodiment 17:5-(3-amino-4-methoxyl phenyl)-4-(3,4,5-trimethoxyphenyl)-1, the preparation of the different selenazoles of 2-(compound 17)
Except using corresponding raw material, with the identical method of embodiment 15, prepare compound 17, yield is 36.5%; The structural formula of compound 17, 1h-NMR and MS data are listed in the table below in-1
Embodiment 18: the anti tumor activity in vitro test of compound of the present invention
External activity testing method and result are as follows: wherein, and the positive control experiment group of clinical conventional antitumor drug cis-platinum.
Anti-tumor activity body outer screening test-1
Screening method: tetrazolium (micoculture tetrozolium, MTT) reduction method
Cell strain: human colon cancer cell strain Lo Vo cell line
Action time: 72h
Half-inhibition concentration (the IC of each compound to tumor growth 50, μ M) and in Table-2.Anti-tumor activity body outer screening test-2
Screening method: tetrazolium (micoculture tetrozolium, MTT) reduction method
Cell strain: enter Adenocarcinoma of lung cell line A549 cell line
Action time: 72h
Half-inhibition concentration (the IC of each compound to tumor growth 50, μ M) and in Table-2.
Anti-tumor activity body outer screening test 3
Screening method: tetrazolium (micoculture tetrozolium, MTT) reduction method
Cell strain: human T lymphocyte's leukemia cell line Jurkat T cell line
Action time: 72h
Half-inhibition concentration (the IC of each compound to tumor growth 50, μ M) and in Table-2.
Embodiment 19: anti-tumor activity test in the animal body of compound of the present invention
Select the good compound 4 of external activity and compound 15 to carry out anti-tumor activity test in animal body, model used is little s-180 sarcoma model, and positive control medicine is clinical conventional antitumor drug 5 FU 5 fluorouracil.
Experimental technique: select the S-180 knurl kind of 18-22 gram of female kunming mice and well-grown 7-11 days, tumor tissue is made to cell suspension, be seeded to right side of mice armpit subcutaneous, about 1.0-2.0 * 10 6cell/only, inoculate random minute cage after 24 hours, continuous 7 days of intraperitoneal injection.Within after drug withdrawal 24 hours, put to death animal, weigh, knurl weight, calculate and respectively organize average knurl weight, by following formula, obtain tumor control rate and carry out t check.
Tumor control rate=[(the average knurl weight of the average knurl weight-treatment group of blank group)/(the average knurl weight of blank group)] * 100%
Experimental result is in Table-3.
Embodiment 20: in the animal body of compound of the present invention, acute toxicity is tentatively tested
Select the interior good compound 4 of anti-tumor activity of animal body and compound 15 to carry out acute toxic test in animal body.
Select each 10 of 18-22 gram of female kunming mices, after intraperitoneal injection compound 4, compound 15 each 500mg/kg, occur that autonomic movement suppresses respectively, writhing, and the inhibition to body weight gain, food ration, water uptake, but have no dead mouse.After the drug withdrawal a few days, it is normal that surviving animals is recovered, the LD of intraperitoneal administration 50value is greater than 500mg/kg.
Table-1
Table-2
Table-3

Claims (6)

1.4,5-disubstituted aryl isoselenazol derivative, is characterized in that, its structural formula is as follows:
R 1, R 2, R 3be OR simultaneously; R 4, R 8for hydrogen; R 6for OH or OR;
R 5, R 7be independently of one another-H ,-CN ,-NO 2, R ,-OH ,-OR ,-OC (O) R ,-OC (O) H ,-C (O) OR ,-C (O) OH ,-C (O) R ,-C (O) H ,-SO 2r ,-OP (O) are (OR) 2,-C (O) NHR ' ,-C (O) NRR ' ,-NHR ' ,-NRR ' ,-NHC (O) R ' ,-NRC (O) R ' ,-SR;
R is C 1～C 6alkyl, R ' are H or C 1～C 6alkyl;
Or
R 5, R 6, R 7be OR simultaneously; R 4, R 8for hydrogen; R 2for OH or OR;
R 1, R 3be independently of one another-H ,-CN ,-NO 2, R ,-OH ,-OR ,-OC (O) R ,-OC (O) H ,-C (O) OR ,-C (O) OH ,-C (O) R ,-C (O) H ,-SO 2r ,-OP (O) are (OR) 2,-C (O) NHR ' ,-C (O) NRR ' ,-NHR ' ,-NRR ' ,-NHC (O) R ' ,-NRC (O) R ' ,-SR;
R is C 1～C 6alkyl, R ' are H or C 1～C 6alkyl.
2. pharmaceutically acceptable non-toxic salt claimed in claim 14,5-disubstituted aryl isoselenazol derivative forms.
3. according to claim 24, the formed pharmaceutically acceptable non-toxic salt of 5-disubstituted aryl isoselenazol derivative, is characterized in that, described non-toxic salt is this derivative and sour formed salt.
4. according to claim 34, the formed pharmaceutically acceptable non-toxic salt of 5-disubstituted aryl isoselenazol derivative, is characterized in that: described acid is selected from the mineral acid of hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid or is selected from the organic acid of acetic acid, citric acid, oxalic acid, tartrate, phenylformic acid, oxysuccinic acid.
One kind as claimed in claim 14, the preparation method of 5-disubstituted aryl isoselenazol derivative, is characterized in that:
4,5-disubstituted aryl isoselenazol derivative (I) can obtain according to following reaction scheme is synthetic:
By 3-chloro-2,3-disubstituted aryl propenal analog derivative is dissolved in acetone, add successively again Tetrabutyl amonium bromide, Potassium Selenocyanate, ammonium chloride, stir, heat up gradually, back flow reaction 9 h, after completion of the reaction, be chilled to room temperature, topple over into saturated sodium bicarbonate aqueous solution, stir, be then extracted with ethyl acetate three times, organic layer washs with saturated sodium-chloride water solution, separate organic layer, and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, remove under reduced pressure after solvent, through column chromatography for separation, obtain product I, yield 40-80%; Wherein, R 1, R 3, R 5for 4 of amino, 5-disubstituted aryl isoselenazol derivative is by corresponding R 1, R 3, R 5for the compound of nitro is prepared through reduction reaction, reductive agent is V-Brite B/tetrahydrofuran aqueous solution system; Wherein, R 1, R 2, R 3, R 5, R 6for 4 of hydroxyl, 5-disubstituted aryl isoselenazol derivative is by corresponding R 1, R 2, R 3, R 5, R 6for the compound of benzyloxy, through Deprotection reaction, prepare, the reagent that goes protecting group is titanium tetrachloride.
6. claimed in claim 14,5-disubstituted aryl isoselenazol derivative or the application of non-toxic salt claimed in claim 2 in preparing antitumor drug.
CN201010156257.8A 2010-04-27 2010-04-27 4,5-disubstituted aryl isoselenazol derivative and application thereof Expired - Fee Related CN101851218B (en)

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Investigations concerning the COX/5-LOX inhibiting and hydroxyl radical scavenging potencies of novel 4,5-diaryl isoselenazoles;Michael Scholz et al.;《European Journal of Medicinal Chemistry》;20070922;第43卷;1152-1159 *
MichaelScholzetal..InvestigationsconcerningtheCOX/5-LOXinhibitingandhydroxylradicalscavengingpotenciesofnovel4 5-diaryl isoselenazoles.《European Journal of Medicinal Chemistry》.2007

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