CN105017254A - 4-(4-((9H-purine-6-base)sulphur)phenyl)thiazolyl-2-amine derivative and preparation method and application thereof - Google Patents
4-(4-((9H-purine-6-base)sulphur)phenyl)thiazolyl-2-amine derivative and preparation method and application thereof Download PDFInfo
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- CN105017254A CN105017254A CN201410175658.6A CN201410175658A CN105017254A CN 105017254 A CN105017254 A CN 105017254A CN 201410175658 A CN201410175658 A CN 201410175658A CN 105017254 A CN105017254 A CN 105017254A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/36—Sulfur atom
- C07D473/38—Sulfur atom attached in position 6
Abstract
The invention belongs to the field of chemical medicine and particularly relates to a 4-(4-((9H-purine-6-base)sulphur)phenyl)thiazolyl-2-amine derivative and a preparation method and application thereof. The structure of the 4-(4-((9H-purine-6-base)sulphur)phenyl)thiazolyl-2-amine derivative is shown in the formula I. The preparation method of the 4-(4-((9H-purine-6-base)sulphur)phenyl)thiazolyl-2-amine derivative and the application of the 4-(4-((9H-purine-6-base)sulphur)phenyl)thiazolyl-2-amine derivative in preparation of medicine for treating tumors are further provided. The synthetic route is short, reaction conditions are simple, the yield is high, and derivatization is easy. A series of compounds have good anti-tumor activity and low toxicity. A new choice is provided for preparation of the anti-tumor medicine. See the formula in the specification.
Description
Technical field
The invention belongs to chemical medicine, particularly 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives and its production and use.
Background technology
Worsen with global environment, malignant tumour becomes the primary arch-criminal threatening human health, and latest data shows, and China tumor incidence and mortality ratio are all acceleration mode development, brings huge pressure to society and family.Current main treatment means is operative treatment, radiotherapy and chemotherapy, and wherein, a large amount of clinical practices confirms the critical role of chemotherapeutics with research, so the chemotherapeutics of searching new texture, novel targets is called the task of top priority.
In antitumor drug, the medicine for cell cycle related proteins has illustrated good clinical efficacy and market outlook as taxol, vincristine(VCR) etc.The problems such as but this compounds exists, and toxicity is large, poor selectivity, easily generation resistance.Therefore, should study further such medicine, find potential associated protein target spot, for the treatment of tumour and drug-resistant tumor provides thinking.
The present invention, by computer ancillary drug means, for mitotic division check position associated protein, by using pharmacophore technology, screens relevant known compound storehouse, and from the beginning designs screening the compound obtained in conjunction with computer, finds novel cpd.By this compounds of design and synthesis, through the screening of tumor cell in vitro proliferation inhibition test, find that some of them compound has certain inhibit activities in various kinds of cell strain, and by acute toxicity test in body, its toxicity is evaluated.
Summary of the invention
First technical problem to be solved by this invention is to provide a class 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives, and structure is such as formula shown in I:
Wherein, R1 ~ R4 is independently H, C1 ~ C8 alkyl, C1 ~ C8 alkoxy or halogen;
R
5for
X1 ~ X5 is independently N or C;
R6 is H or C1 ~ C4 alkyl;
R7 ~ R25 be independently-H, halogen, C1 ~ C8 alkyl of halogen substiuted, C1 ~ C8 alkyl, C1 ~ C8 alkoxyl group, C3 ~ C8 cycloalkyl, 3 ~ 8 yuan of Heterocyclylalkyls,
c2 ~ C8 thiazolinyl, C2 ~ C8 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 8 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 8 yuan of described Heterocyclylalkyls or 3 ~ 8 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3.
Preferably, R1 ~ R4 is independently H, C1 ~ C4 alkyl, C1 ~ C4 alkoxy or halogen;
R
5for
X1 ~ X5 is independently N or C;
R6 is H or C1 ~ C4 alkyl;
R7 ~ R25 be independently-H, halogen, C1 ~ C4 alkyl of halogen substiuted, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 3 ~ 6 yuan of Heterocyclylalkyls,
c2 ~ C4 thiazolinyl, C2 ~ C4 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 6 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 6 yuan of described Heterocyclylalkyls or 3 ~ 6 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3.
It is preferred further,
R1 ~ R4 is independently H or C1 ~ C4 alkyl;
R
5for
X1 ~ X5 is independently N or C;
R6 is H or C1 ~ C4 alkyl;
R7 ~ R25 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 6 yuan of Heterocyclylalkyls,
-NO
2or-OCF
3; Heteroatoms in 6 yuan of described Heterocyclylalkyls is N, O or S, and heteroatomic number is 1 ~ 3.
It is most preferred,
R1 ~ R4 is independently H or methyl;
R
5for
X1 ~ X5 is independently N or C;
R6 is H;
R7 ~ R25 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, cyclopropyl,
-NO
2or-OCF
3; .
As preferred version of the present invention, in above-mentioned 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives, R5 is
structure is such as formula shown in II:
Wherein, R1 ~ R4 is independently H, C1 ~ C8 alkyl, C1 ~ C8 alkoxy or halogen;
X1 ~ X5 is independently N or C;
R6 is H or C1 ~ C4 alkyl;
R7 ~ R10 be independently-H, halogen, C1 ~ C8 alkyl of halogen substiuted, C1 ~ C8 alkyl, C1 ~ C8 alkoxyl group, C3 ~ C8 cycloalkyl, 3 ~ 8 yuan of Heterocyclylalkyls,
c2 ~ C8 thiazolinyl, C2 ~ C8 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 8 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 8 yuan of described Heterocyclylalkyls or 3 ~ 8 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3.
Preferably, R1 ~ R4 is independently H, C1 ~ C4 alkyl, C1 ~ C4 alkoxy or halogen;
X1 ~ X5 is independently N or C;
R6 is H or C1 ~ C4 alkyl;
R7 ~ R10 be independently-H, halogen, C1 ~ C4 alkyl of halogen substiuted, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 3 ~ 6 yuan of Heterocyclylalkyls,
c2 ~ C4 thiazolinyl, C2 ~ C4 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 6 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 6 yuan of described Heterocyclylalkyls or 3 ~ 6 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3.
It is preferred further,
R1 ~ R4 is independently H or C1 ~ C4 alkyl;
X1 ~ X5 is independently N or C;
R6 is H or C1 ~ C4 alkyl;
R7 ~ R10 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 6 yuan of Heterocyclylalkyls,
-NO
2or-OCF
3; Heteroatoms in 6 yuan of described Heterocyclylalkyls is N, O or S, and heteroatomic number is 1 ~ 3.
It is preferred further,
R1 ~ R4 is independently H or methyl;
X1 ~ X5 is independently N or C;
R6 is H;
R7 ~ R10 is independently-H ,-F ,-Cl or-Br.
As preferred version of the present invention, in above-mentioned 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives, R5 is
structural formula is such as formula shown in III:
Wherein, R1 ~ R4 is independently H, C1 ~ C8 alkyl, C1 ~ C8 alkoxy or halogen;
R6 is H or C1 ~ C4 alkyl;
R11 ~ R15 be independently-H, halogen, C1 ~ C8 alkyl of halogen substiuted, C1 ~ C8 alkyl, C1 ~ C8 alkoxyl group, C3 ~ C8 cycloalkyl, 3 ~ 8 yuan of Heterocyclylalkyls,
c2 ~ C8 thiazolinyl, C2 ~ C8 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 8 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 8 yuan of described Heterocyclylalkyls or 3 ~ 8 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3.
Preferably, R1 ~ R4 is independently H, C1 ~ C4 alkyl, C1 ~ C4 alkoxy or halogen;
R6 is H or C1 ~ C4 alkyl;
R11 ~ R15 be independently-H, halogen, C1 ~ C4 alkyl of halogen substiuted, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 3 ~ 6 yuan of Heterocyclylalkyls,
c2 ~ C4 thiazolinyl, C2 ~ C4 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 6 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 6 yuan of described Heterocyclylalkyls or 3 ~ 6 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3.
It is preferred further,
R1 ~ R4 is independently H or C1 ~ C4 alkyl;
R6 is H or C1 ~ C4 alkyl;
R11 ~ R15 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 6 yuan of Heterocyclylalkyls,
-NO
2or-OCF
3; Heteroatoms in 6 yuan of described Heterocyclylalkyls is N, O or S, and heteroatomic number is 1 ~ 3.
It is preferred further,
R1 ~ R4 is independently H or methyl;
R6 is H;
R11 ~ R15 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, cyclopropyl,
or-NO
2.
As preferred version of the present invention, in above-mentioned 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives, R5 is
structural formula is such as formula shown in IV:
Wherein, R1 ~ R4 is independently H, C1 ~ C8 alkyl, C1 ~ C8 alkoxy or halogen;
R6 is H or C1 ~ C4 alkyl;
R16 ~ R20 be independently-H, halogen, C1 ~ C8 alkyl of halogen substiuted, C1 ~ C8 alkyl, C1 ~ C8 alkoxyl group, C3 ~ C8 cycloalkyl, 3 ~ 8 yuan of Heterocyclylalkyls,
c2 ~ C8 thiazolinyl, C2 ~ C8 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 8 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 8 yuan of described Heterocyclylalkyls or 3 ~ 8 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3.
Preferably, R1 ~ R4 is independently H, C1 ~ C4 alkyl, C1 ~ C4 alkoxy or halogen;
R6 is H or C1 ~ C4 alkyl;
R16 ~ R20 be independently-H, halogen, C1 ~ C4 alkyl of halogen substiuted, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 3 ~ 6 yuan of Heterocyclylalkyls,
c2 ~ C4 thiazolinyl, C2 ~ C4 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 6 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 6 yuan of described Heterocyclylalkyls or 3 ~ 6 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3.
It is preferred further,
R1 ~ R4 is independently H or C1 ~ C4 alkyl;
R6 is H or C1 ~ C4 alkyl;
R16 ~ R20 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 6 yuan of Heterocyclylalkyls,
-NO
2or-OCF
3; Heteroatoms in 6 yuan of described Heterocyclylalkyls is N, O or S, and heteroatomic number is 1 ~ 3.
It is preferred further,
R1 ~ R4 is independently H or methyl;
R6 is H;
R11 ~ R15 is independently-H ,-F ,-Cl ,-Br ,-CF3, C1 ~ C4 alkyl or C1 ~ C4 alkoxyl group.
As preferred version of the present invention, in above-mentioned 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives, R5 is
structural formula is such as formula shown in V:
Wherein, R
1~ R
4be independently H, C1 ~ C8 alkyl, C1 ~ C8 alkoxy or halogen;
R
6for H or C1 ~ C4 alkyl;
R
21~ R
25be independently-H, halogen, C1 ~ C8 alkyl of halogen substiuted, C1 ~ C8 alkyl, C1 ~ C8 alkoxyl group, C3 ~ C8 cycloalkyl, 3 ~ 8 yuan of Heterocyclylalkyls,
c2 ~ C8 thiazolinyl, C2 ~ C8 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 8 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 8 yuan of described Heterocyclylalkyls or 3 ~ 8 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3.
Preferably, R
1~ R
4be independently H, C1 ~ C4 alkyl, C1 ~ C4 alkoxy or halogen;
R
6for H or C1 ~ C4 alkyl;
R
21~ R
25be independently-H, halogen, C1 ~ C4 alkyl of halogen substiuted, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 3 ~ 6 yuan of Heterocyclylalkyls,
c2 ~ C4 thiazolinyl, C2 ~ C4 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 6 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 6 yuan of described Heterocyclylalkyls or 3 ~ 6 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3.
It is preferred further,
R1 ~ R4 is independently H or C1 ~ C4 alkyl;
R6 is H or C1 ~ C4 alkyl;
R21 ~ R25 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 6 yuan of Heterocyclylalkyls,
-NO
2or-OCF
3; Heteroatoms in 6 yuan of described Heterocyclylalkyls is N, O or S, and heteroatomic number is 1 ~ 3.
It is preferred further,
R1 ~ R4 is independently H or methyl;
R6 is H;
R7 ~ R25 is independently-H ,-F ,-Cl ,-Br ,-CF
3, C1 ~ C4 alkyl or C1 ~ C4 alkoxyl group.
Most preferred, above-mentioned 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives, comprises following compound:
N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl) Isonicotinamide, N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-2-fluorine Isonicotinamide, N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-pyrazine-2-acid amides, N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-pyrimidine-5-acid amides, N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-pyridazine-4-acid amides, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(the chloro-3-of 4-(trifluoromethyl) phenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-methyl) phenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-methoxyl group) phenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(3-bromophenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(2-bromophenyl) thiocarbamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-oxyethyl group) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-tertiary butyl base) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-(trifluoromethyl) phenyl) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-(methoxyethoxy) phenyl) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-(cyclopropyl) phenyl) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-(morpholinyl) phenyl) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(the fluoro-phenyl of 3-) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(the fluoro-phenyl of 2-) cinnamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-phenylthiourea, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-(trifluoromethyl) phenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-(methoxyl group) phenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(2-bromophenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-fluorophenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(the chloro-3-of 4-(trifluoromethyl) phenyl) thiocarbamide.
The chemical structure that above-claimed cpd is corresponding is respectively:
Second technical problem to be solved by this invention is to provide the preparation method of above-mentioned 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives.The method comprises the following steps:
Wherein, R1 ~ R4 is independently H, C1 ~ C8 alkyl, C1 ~ C8 alkoxy or halogen;
X1 ~ X5 is independently N or C;
R
5for
R6 is H or C1 ~ C4 alkyl;
R7 ~ R25 be independently-H, halogen, C1 ~ C8 alkyl of halogen substiuted, C1 ~ C8 alkyl, C1 ~ C8 alkoxyl group, C3 ~ C8 cycloalkyl, 3 ~ 8 yuan of Heterocyclylalkyls,
c2 ~ C8 thiazolinyl, C2 ~ C8 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 8 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 8 yuan of described Heterocyclylalkyls or 3 ~ 8 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3;
Steps A: compound 1 and Acetyl Chloride 98Min. react in the basic conditions and prepare compound 2; Described alkali be in salt of wormwood, sodium carbonate, potassiumphosphate, cesium carbonate or potassium hydroxide any one;
Step B: compound 2 and Acetyl Chloride 98Min. acylation reaction occur under Catalyzed by Anhydrous Aluminium Chloride and prepare compound 3;
Step C: compound 3 in acid condition hydrolysis reaction prepares compound 4;
Step D: react in the concentrated hydrochloric acid that compound 4 and Sodium Nitrite are bathed at cryosel and form diazonium salt, then with KI, iodide reaction occurs and prepare compound 5;
Step e: compound 5 and bromide reagent generation bromo-reaction prepare compound 6; Described bromide reagent be in cuprous bromide, bromine or tetrabutyl tribromide ammonium any one;
Step F: compound 6 and thiocarbamide Hantsch occur and become thiazole to react to prepare compound 7; Temperature of reaction is 72 ~ 80 DEG C, and the time is 4h ~ 8h;
Step G: compound 7 and Ismipur react 6 ~ 8h at 125 ~ 150 DEG C in the basic conditions and prepare compound 8; Described alkalescence be in potassium hydroxide, salt of wormwood, potassium tert.-butoxide, cesium carbonate or potassiumphosphate any one;
Step H: compound 8 respectively with replacement γ-picolinic acid, substituted cinnamic acid condensation, or with replacement isocyanic ester, replace lsothiocyanates and become urea to prepare compound 9.
In above-mentioned preparation method's steps A, the solvent reacting used be in methylene dichloride, tetrahydrofuran (THF), chloroform or toluene any one, reaction times 0.5 ~ 3h.
In above-mentioned preparation method step B, temperature of reaction is 15 ~ 30 DEG C, and the reaction times is 1 ~ 3h, the solvent reacting used be in methylene dichloride, tetrahydrofuran (THF), chloroform or toluene any one.
In above-mentioned preparation method step C, described acidic conditions is under the condition of hydrochloric acid, and temperature of reaction is 80 ~ 100 DEG C, and hydrolysis time is 1 ~ 2h.
In above-mentioned preparation method step D, iodide reaction temperature is 15 ~ 30 DEG C, and the iodide reaction time is 6 ~ 7h.
In above-mentioned preparation method's step e, the temperature of reaction adopting cuprous bromide bromo is 70 DEG C; The temperature of reaction adopting bromine or tetrabutyl tribromide ammonium bromo is 15 ~ 30 DEG C; Reaction times is 7 ~ 9h.
3rd technical problem to be solved by this invention is to provide above-mentioned 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives and is preparing the purposes in antitumor drug.
Present invention also offers prodrug or the hydrate of above-mentioned 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives.Described prodrug is the derivative of above-claimed cpd, they self may have more weak activity or even not have activity, but (such as by metabolism, solvolysis or other mode) is converted to corresponding biologically active form upon administration, in physiological conditions.
Present invention also offers such pharmaceutical composition, is add other pharmacy by above-mentioned 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives can accept complementary composition and be prepared.
4-of the present invention (4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives obtains on the basis of a large amount of screening, have anti-tumor activity, the development and application for antitumor drug provides new selection and thinking.
Embodiment
Embodiment 1 I A N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl) Isonicotinamide
Step 1
Take 3,5-xylidine (0.082mol) in 40mL methylene dichloride, add anhydrous K
2cO
3(0.164mol), ice bath cooling 30min, drips Acetyl Chloride 98Min. (0.164mol) with constant pressure funnel, drip off and naturally rise to room temperature reaction 2h afterwards, TLC (PE:EA=1:1) detection reaction, question response adds 20mL shrend completely and goes out, and dissolves with methylene dichloride, repeatedly wash organic phase with water 2 times, dilute hydrochloric acid washes 2 times, and collect organic phase, concentrate drying obtains N-(3,5-3,5-dimethylphenyl) ethanamide 13.30g is canescence tabular crystal product;
1H NMR:(DMSO-d6,400MHz): 2.01 (s, 3H), 2.22 (s, 6H), 6.66 (s, 1H), 7.19 (s, 2H), 9.74 (s, 1H) step 2
Take aluminum trichloride (anhydrous) (369.09mmol) with dry dichloromethane solution, Acetyl Chloride 98Min. (246.06 mmol) is dripped under ice-water bath, add N-(3 afterwards, 5-3,5-dimethylphenyl) ethanamide (82.02mmol), be warming up to room temperature, reaction 3h, TLC (PE:EA=1:1) detection reaction, question response terminates, reaction solution punching is analysed in 600mL water+20mL concentrated hydrochloric acid, then adds methylene dichloride dissolving, extraction, collect organic phase, concentrate drying directly throws next step;
1H NMR:(DMSO-d6，400MHz):2.03(s,3H),2.14(s,6H),2.42(s,3H),7.26(s,2H),9.88(s,1H)
Step 3
Add 60mL2N HCl and 60mL water by the solid obtained after concentrated, be heated to 80 ~ 100 DEG C of hydrolysis 2h, TLC (PE:EA=1:1) detection reaction terminals.Question response terminates, and adds saturated sodium bicarbonate cancellation, and modulation pH=8 ~ 9, have a large amount of solid precipitation to separate out, suction filtration solid, dried in vacuo overnight, obtain 13.04g pale yellow powder solid, is 1-(amino-2, the 6-3,5-dimethylphenyls of 4-) methyl phenyl ketone;
1H NMR:(DMSO-d6，400MHz):2.06(s,6H),2.34(s,3H),5.17(s,2H),6.21(s,2H)
Step 4
Take 1-(4-amino-2, 6-3,5-dimethylphenyl) methyl phenyl ketone (82.1mmol) is in 120mL concentrated hydrochloric acid and 40mL water, temperature <5 DEG C is cooled under cryosel bath, drip NaNO2 (98.52mmol) solution, dropping process keeps temperature lower than 5 DEG C, dropwise rear reaction 20min, drip KI (123.15mmol) solution afterwards, add and naturally rise to room temperature reaction 7h afterwards, TLC (PE:EA=4:1) detection reaction process, question response terminates, use saturated sodium bicarbonate cancellation, be extracted with ethyl acetate 4 times, merge organic phase, column chromatographic isolation and purification, obtain the 1-(4-iodo-2 of 14.35g brown oil liquid, 6-3,5-dimethylphenyl) methyl phenyl ketone.
1H NMR:(DMSO-d6，400MHz):2.14(s,6H),2.44(s,3H),7.48(s,2H)
Step 5
Take 1-(4-iodo-2,6-3,5-dimethylphenyl) methyl phenyl ketone (52.17mmol) is in ethyl acetate/chloroform (30mL:10mL) mixing solutions, add CuBr2 (102.98mmol), 65 ~ 70 DEG C of backflow 8h, TLC (PE:EA=30:1) detection reaction process, question response terminates, with saturated sodium bicarbonate and extraction into ethyl acetate, collect organic phase, obtain the bromo-1-of brown-red solid 18.6g2-(iodo-2, the 6-3,5-dimethylphenyls of 4-) ethyl ketone.Direct throwing next step.
Step 6
Take the bromo-1-of 2-(4-iodo-2,6-3,5-dimethylphenyl) ethyl ketone (52mmol) and thiocarbamide (52mmol) be in 80mL ethanol, stir at 72 ~ 80 DEG C and spend the night, produce a large amount of white opacity, reaction terminates suction filtration, use washing with alcohol filter cake, dry 22g white solid.
1H NMR:(DMSO-d6，400MHz):2.14(s,6H),6.46(s,1H),6.96(s,2H),7.32(s,2H).
Step 7
Take 4-(4-iodo-2,6-3,5-dimethylphenyl) thiazolyl-2-amine (0.515mmol), Ismipur (1.03mmol), Cu2O (0.026mmol) and KOH (1.03mmol) are in DMF (40mL) and water (10mL), and at 125 ~ 130 DEG C, reaction is spent the night.TLC monitors reaction, and question response terminates, and adds aqueous hydrochloric acid cancellation, repeatedly extracts with ethyl acetate and water, and collect organic phase, concentrate drying obtains yellow solid product.
1H NMR:(DMSO-d6，400MHz):2.15(s,6H),6.47(s,1H),6.95(s,2H),7.34(s,2H),8.49(s,1H),8.58(s,1H),13.57(s,1H)
Step 8
Take 4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyl) thiazolyl-2-amine (2.29mmol), γ-picolinic acid (2.29mmol), HATU (2.29mmol) and TEA (11.45mmol) be in THF, stirring at normal temperature is spent the night, question response terminates, repeatedly with ethyl acetate and water extraction, collect organic phase, column chromatography (PE:EA=4:1) obtains sterling, yellow solid, productive rate 65%.
1H NMR:(DMSO-d6，400MHz):2.15(s,6H),7.31(s,1H),7.42(s,2H),8.00(d,2H),8.52(s,1H),8.60(s,1H),8.82(d,2H),13.33(s,2H)
MS-ESI(m/z)：482.09(M+Na
+)
Embodiment 2 I B N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-2-fluorine Isonicotinamide
Method is with embodiment 1.
1H NMR:(DMSO-d6，400MHz):2.15(s,6H),7.28(s,1H),7.25(s,2H),7.75(d,1H),7.86(s,2H),8.60(s,1H),8.82(d,2H),8.62(d,1H),11.03(s,1H),13.13(s,1H)
MS-ESI(m/z)：477.09(M+H
+)
Embodiment 3 I C N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-pyrazine-2-acid amides
Method is with embodiment 1.
1H NMR:(DMSO-d6，400MHz):2.14(s,6H),7.25(s,2H),7.28(s,1H),8.53(s,1H),8.57(s,1H),8.89(d,1H),9.02(d,2H),9.96(s,1H),10.03(s,1H),13.43(s,1H)
MS-ESI(m/z)：460.20(M+H
+)
Embodiment 4 I D N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-pyrimidine-5-acid amides
Method is with embodiment 1.
1H NMR:(DMSO-d6，400MHz):2.15(s,6H),7.22(s,2H),7.26(s,1H),8.53(s,1H),8.57(s,1H),9.36(s,2H),9.51(s,1H),10.03(s,1H),12.03(s,1H)
MS-ESI(m/z)：460.20(M+H
+)
Embodiment 5 I E N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-pyridazine-4-acid amides
Method is with embodiment 1.
1H NMR:(DMSO-d6，400MHz):2.16(s,6H),7.22(s,2H),7.26(s,1H),8.12(d,1H),8.53(s,1H),8.57(s,1H),9.51(d,1H),9.79(s,1H),10.03(s,1H),11.02(s,1H)
MS-ESI(m/z)：460.20(M+H
+)
Embodiment 6 I F1-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(the chloro-3-of 4-(trifluoromethyl) phenyl) thiocarbamide
Step 1
Take appropriate 3,5-xylidine (0.082mol) is in 40mLDCM, add anhydrous K 2CO3 (0.164mol), ice bath cooling 30min, Acetyl Chloride 98Min. (0.164mol) is dripped with constant pressure funnel, drip off and naturally rise to room temperature reaction 2h afterwards, TLC (PE:EA=2:1) detection reaction, question response adds 20mL shrend completely and goes out, and dissolves with DCM, repeatedly wash organic phase with water 2 times, dilute hydrochloric acid washes 2 times, and collect organic phase, concentrate drying obtains N-(3,5-3,5-dimethylphenyl) ethanamide 13.30g is canescence tabular crystal product;
1H NMR:(DMSO-d6，400MHz):2.01(s,3H),2.22(s,6H),6.66(s,1H),7.19(s,2H),9.74(s,1H)
Step 2
Take appropriate aluminum trichloride (anhydrous) (369.09mmol) with dry dichloromethane solution, Acetyl Chloride 98Min. (246.06mmol) is dripped under ice-water bath, add N-(3 afterwards, 5-3,5-dimethylphenyl) ethanamide (82.02mmol), be warming up to room temperature, reaction 3h, TLC (PE:EA=1:1) detection reaction, question response terminates, reaction solution punching is analysed in 600mL water+20mL concentrated hydrochloric acid, then adds DCM dissolving, extraction, collect organic phase, concentrate drying directly throws next step;
1H NMR:(DMSO-d6,400MHz): 2.03 (s, 3H), 2.14 (s, 6H), 2.42 (s, 3H), 7.26 (s, 2H), 9.88 (s, 1H) step 3
Add 60mL2N HCl and 60mL water by the solid obtained after concentrated, be heated to 80 ~ 100 DEG C of hydrolysis 2h, TLC (PE:EA=1:1) detection reaction terminals.Question response terminates, and adds saturated sodium bicarbonate cancellation, and modulation pH=8 ~ 9, have a large amount of solid precipitation to separate out, suction filtration solid, dried in vacuo overnight, obtain 13.04g pale yellow powder solid, is 1-(amino-2, the 6-3,5-dimethylphenyls of 4-) methyl phenyl ketone.
1H NMR:(DMSO-d6，400MHz):2.06(s,6H),2.34(s,3H),5.17(s,2H),6.21(s,2H)
Step 4
Take 1-(4-amino-2, 6-3,5-dimethylphenyl) methyl phenyl ketone (82.1mmol) is in 120mL concentrated hydrochloric acid and 40mL water, temperature <5 DEG C is cooled under cryosel bath, drip NaNO2 solution, dropping process keeps temperature lower than 5 DEG C, dropwise rear reaction 20min, drip KI solution afterwards, add and naturally rise to room temperature reaction 7h afterwards, TLC (PE:EA=4:1) detection reaction process, question response terminates, use saturated sodium bicarbonate cancellation, be extracted with ethyl acetate 4 times, merge organic phase, column chromatographic isolation and purification, obtain the 1-(4-iodo-2 of 14.35g brown oil liquid, 6-3,5-dimethylphenyl) methyl phenyl ketone.
1H NMR:(DMSO-d6，400MHz):2.14(s,6H),2.44(s,3H),7.48(s,2H)
Step 5
Take 1-(4-iodo-2,6-3,5-dimethylphenyl) methyl phenyl ketone (52.17mmol) is in ethyl acetate/chloroform (30mL:10mL) mixing solutions, add CuBr2 (102.98mmol), 65 ~ 70 DEG C of backflow 8h, TLC (PE:EA=30:1) detection reaction process, question response terminates, with saturated sodium bicarbonate and extraction into ethyl acetate, collect organic phase, obtain the bromo-1-of brown-red solid 18.6g2-(iodo-2, the 6-3,5-dimethylphenyls of 4-) ethyl ketone.Direct throwing next step.
Step 6
Take the bromo-1-of 2-(4-iodo-2,6-3,5-dimethylphenyl) ethyl ketone (52mmol) and thiocarbamide (52mmol) be in 80mL ethanol, stir at 72 ~ 80 DEG C and spend the night, produce a large amount of white opacity, reaction terminates suction filtration, use washing with alcohol filter cake, dry 22g white solid.
1H NMR:(DMSO-d6，400MHz):2.14(s,6H),6.46(s,1H),6.96(s,2H),7.32(s,2H).
Step 7
Take 4-(4-iodo-2,6-3,5-dimethylphenyl) thiazolyl-2-amine (0.515mmol), Ismipur (1.03mmol), Cu2O (0.026mmol) and KOH (1.03mmol) are in DMF (40mL) and water (10mL), and at 125 ~ 130 DEG C, reaction is spent the night.TLC monitors reaction, and question response terminates, and adds aqueous hydrochloric acid cancellation, repeatedly extracts with ethyl acetate and water, and collect organic phase, concentrate drying obtains yellow solid product.
1H NMR:(DMSO-d6，400MHz):2.15(s,6H),6.47(s,1H),6.95(s,2H),7.34(s,2H),8.49(s,1H),8.58(s,1H),13.57(s,1H)
Step 8
Take 4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyl) thiazolyl-2-amine (1.51mmol), the chloro-3-of 4-(trifluoromethyl)-isocyanic ester (3.02mmol), DIPEA (4.53mmol) is in DCM, stirring at normal temperature is spent the night, question response terminates, repeatedly with ethyl acetate and water extraction, collect organic phase, column chromatography (PE:EA=15:1) obtains sterling, white powder, productive rate 45%.
1H NMR:(DMSO-d6，400MHz):2.15(s,6H),7.12(s,1H),7.41(s,2H),7.67(d,1H),7.72(d,1H),8.13(s,1H),8.51(s,1H),8.60(s,1H),9.45(s,1H),10.83(s,1H),13.60(s,1H)
MS-ESI(m/z)：598.06(M+Na
+)
Embodiment 7 I G1-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(4-methyl) phenyl) thiocarbamide
Method is with embodiment 6.
1H NMR:(DMSO-d6，400MHz):2.15(s,6H),2.32(s,3H),7.12(s,1H),7.41(s,2H),7.67(d,2H),7.72(d,2H),8.51(s,1H),8.60(s,1H),9.02(s,1H),10.57(s,1H),13.71(s,1H)
MS-ESI(m/z)：510.60(M+Na
+)
Embodiment 8 I H1-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(4-methoxyl group) phenyl) thiocarbamide
Method is with embodiment 6.
1H NMR:(DMSO-d6，400MHz):2.14(s,6H),3.83(s,3H),6.92(d,2H),7.12(s,1H),7.39(s, 2H),7.57(d,2H),8.51(s,1H),8.60(s,1H),9.02(s,1H),10.57(s,1H),13.71(s,1H)
MS-ESI(m/z)：526.60(M+Na
+)
Embodiment 9 I I1-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(3-bromophenyl) thiocarbamide
Method is with embodiment 6.
1H NMR:(DMSO-d6，400MHz):2.12(s,6H),7.12(s,1H),7.17(t,1H),7.32～7.55(m,4H),7.86(s,1H),8.51(s,1H),8.60(s,1H),9.01(s,1H),10.55(s,1H),11.71(s,1H)
MS-ESI(m/z)：553.47(M+H
+)
Embodiment 10 I J1-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(2-bromophenyl) thiocarbamide
Method is with embodiment 6.
1H NMR:(DMSO-d6，400MHz):2.12(s,6H),7.08(s,1H),7.28～7.37(m,4H),7.78(d,1H),8.06(d,1H),8.51(s,1H),8.60(s,1H),8.82(s,1H),9.55(s,1H),12.71(s,1H)
MS-ESI(m/z)：553.50(M+H
+)
Embodiment 11 I K (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(4-oxyethyl group) cinnamide
Step 1
Take appropriate 3,5-xylidine (0.082mol) is in 40mLDCM, add anhydrous K 2CO3 (0.164mol), ice bath cooling 30min, Acetyl Chloride 98Min. (0.164mol) is dripped with constant pressure funnel, drip off and naturally rise to room temperature reaction 2h afterwards, TLC (PE:EA=2:1) detection reaction, question response adds 20mL shrend completely and goes out, and dissolves with DCM, repeatedly wash organic phase with water 2 times, dilute hydrochloric acid washes 2 times, and collect organic phase, concentrate drying obtains N-(3,5-3,5-dimethylphenyl) ethanamide 13.30g is canescence tabular crystal product;
1H NMR:(DMSO-d6,400MHz): 2.01 (s, 3H), 2.22 (s, 6H), 6.66 (s, 1H), 7.19 (s, 2H), 9.74 (s, 1H) step 2
Take appropriate aluminum trichloride (anhydrous) (369.09mmol) with dry dichloromethane solution, Acetyl Chloride 98Min. (246.06mmol) is dripped under ice-water bath, add N-(3 afterwards, 5-3,5-dimethylphenyl) ethanamide (82.02mmol), be warming up to room temperature, reaction 3h, TLC (PE:EA=1:1) detection reaction, question response terminates, reaction solution punching is analysed in 600mL water+20mL concentrated hydrochloric acid, then adds DCM dissolving, extraction, collect organic phase, concentrate drying directly throws next step;
1H NMR:(DMSO-d6,400MHz): 2.03 (s, 3H), 2.14 (s, 6H), 2.42 (s, 3H), 7.26 (s, 2H), 9.88 (s, 1H) step 3
Add 60mL2N HCl and 60mL water by the solid obtained after concentrated, be heated to 100 DEG C of hydrolysis 2h, TLC (PE:EA=1:1) detection reaction terminals.Question response terminates, and adds saturated sodium bicarbonate cancellation, and modulation pH=8 ~ 9, have a large amount of solid precipitation to separate out, suction filtration solid, dried in vacuo overnight, obtain 13.04g pale yellow powder solid, is 1-(amino-2, the 6-3,5-dimethylphenyls of 4-) methyl phenyl ketone.
1H NMR:(DMSO-d6，400MHz):2.06(s,6H),2.34(s,3H),5.17(s,2H),6.21(s,2H)
Step 4
Take 1-(4-amino-2, 6-3,5-dimethylphenyl) methyl phenyl ketone (82.1mmol) is in 120mL concentrated hydrochloric acid and 40mL water, temperature <5 DEG C is cooled under cryosel bath, drip NaNO2 solution, dropping process keeps temperature lower than 5 DEG C, dropwise rear reaction 20min, drip KI solution afterwards, add and naturally rise to room temperature reaction 7h afterwards, TLC (PE:EA=4:1) detection reaction process, question response terminates, use saturated sodium bicarbonate cancellation, be extracted with ethyl acetate 4 times, merge organic phase, column chromatographic isolation and purification, obtain the 1-(4-iodo-2 of 14.35g brown oil liquid, 6-3,5-dimethylphenyl) methyl phenyl ketone.
1H NMR:(DMSO-d6，400MHz):2.14(s,6H),2.44(s,3H),7.48(s,2H)
Step 5
Take 1-(4-iodo-2,6-3,5-dimethylphenyl) methyl phenyl ketone (52.17mmol) is in ethyl acetate/chloroform (30mL:10mL) mixing solutions, add CuBr2 (102.98mmol), 65 ~ 70 DEG C of backflow 8h, TLC (PE:EA=30:1) detection reaction process, question response terminates, with saturated sodium bicarbonate and extraction into ethyl acetate, collect organic phase, the bromo-1-of brown-red solid 18.6g2-(iodo-2, the 6-3,5-dimethylphenyls of 4-) ethyl ketone.Direct throwing next step.
Take the bromo-1-of 2-(iodo-2, the 6-3,5-dimethylphenyls of 4-) ethyl ketone (52mmol) and thiocarbamide (52mmol) in 80mL ethanol, stir at 80 DEG C and spend the night, produce a large amount of white opacity, reaction terminates suction filtration, uses washing with alcohol filter cake, dry 22g white solid.
1H NMR:(DMSO-d6，400MHz):2.14(s,6H),6.46(s,1H),6.96(s,2H),7.32(s,2H).
Step 6
Take 4-(4-iodo-2,6-3,5-dimethylphenyl) thiazolyl-2-amine (0.515mmol), Ismipur (1.03mmol), Cu2O (0.026mmol) and KOH (1.03mmol) are in DMF (40mL) and water (10mL), and at 125 ~ 130 DEG C, reaction is spent the night.TLC monitors reaction, and question response terminates, and adds aqueous hydrochloric acid cancellation, repeatedly extracts with ethyl acetate and water, and collect organic phase, concentrate drying obtains yellow solid product.
1H NMR:(DMSO-d6，400MHz):2.15(s,6H),6.47(s,1H),6.95(s,2H),7.34(s,2H),8.49(s,1H),8.58(s,1H),13.57(s,1H)
Step 7
Take 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-amine (2.29mmol), 4-ethoxy-cinnamic acid (2.29mmol), HATU (2.29mmol) and TEA (11.45mmol) in THF, stirring at normal temperature is spent the night, question response terminates, repeatedly with ethyl acetate and water extraction, collect organic phase, column chromatography (DCM:MeOH=10:1) obtains sterling, off-white color solid, productive rate 50%.
1H NMR:(DMSO-d6，400MHz):1.34(t,2H),2.12(s,6H),4.08(q,3H),6.79(d,1H),7.01(d,2H),7.16(s,1H),7.37(s,2H),7.60(d,2H),7.69(s,1H),8.32(s,1H),8.48(S,1H),12.39(s,1H),13.52(s,1H)
MS-ESI(m/z)：551.14(M+Na
+)
Embodiment 12 I L (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(4-tertiary butyl base) cinnamide
Method is with embodiment 11.
1H NMR:(DMSO-d6，400MHz):1.30(s,9H),2.15(s,6H),6.92(d,1H),7.22(s,1H),7.41(s,2H),7.50(d,2H),7.58(d,2H),7.74(d,1H),8.53(S,1H),8.62(s,1H),12.41(s,1H),13.62(s,1H)
MS-ESI(m/z)：563.18(M+Na
+)
Embodiment 13 I M (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(4-(trifluoromethyl) phenyl) cinnamide
Method is with embodiment 11.
1H NMR:(DMSO-d6，400MHz):2.15(s,6H),7.08(d,1H),7.25(s,1H),7.41(s,2H),7.82～7.89(m,5H),8.51(s,1H),8.61(s,1H),12.53(s,1H),13.59(s,1H)
MS-ESI(m/z)：575.10(M+Na
+)
Embodiment 14 I N (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(4-(nitro) phenyl) cinnamide
Method is with embodiment 11.
1H NMR:(DMSO-d6，400MHz):2.14(s,6H),7.12(d,1H),7.26(s,1H),7.41(s,2H),7.87(d,1H),7.92(d,2H),8.32(d,2H),8.52(s,1H),8.61(s,1H),12.58(s,1H),13.59(s,1H)
MS-ESI(m/z)：552.1(M+Na
+)
Embodiment 15 I O (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(4-(methoxyethoxy) phenyl) cinnamide
Method is with embodiment 11.
1H NMR:(DMSO-d6，400MHz):2.15(s,6H),3.31(s,3H),3.80(t,2H),4.30(t,3H),6.89(d,1H),7.32(s,1H),7.41(s,2H),7.51(d,2H),7.58(d,2H),7.37(d,1H),8.53(s,1H),8.62(s,1H),12.39(s,1H),13.60(s,1H)
MS-ESI(m/z)：559.67(M+H
+)
Embodiment 16 I P (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(4-(cyclopropyl) phenyl) cinnamide
Method is with embodiment 11.
MS-ESI(m/z)：547.67(M+Na+)
Embodiment 17 I Q (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(4-(morpholinyl) phenyl) cinnamide
Method is with embodiment 11.
MS-ESI(m/z)：570.70(M+H
+)
Embodiment 18 I R (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(the fluoro-phenyl of 3-) cinnamide
Method is with embodiment 11.
MS-ESI(m/z)：525.60(M+H
+)
Embodiment 19 I S (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(the fluoro-phenyl of 2-) cinnamide
Method is with embodiment 11.
MS-ESI(m/z)：525.60(M+H
+)
Embodiment 20 I T1-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-phenylthiourea
Step 1
Take appropriate 3,5-xylidine (0.082mol) is in 40mLDCM, add anhydrous K 2CO3 (0.164mol), ice bath cooling 30min, Acetyl Chloride 98Min. (0.164mol) is dripped with constant pressure funnel, drip off and naturally rise to room temperature reaction 2h afterwards, TLC (PE:EA=2:1) detection reaction, question response adds 20mL shrend completely and goes out, and dissolves with DCM, repeatedly wash organic phase with water 2 times, dilute hydrochloric acid washes 2 times, and collect organic phase, concentrate drying obtains N-(3,5-3,5-dimethylphenyl) ethanamide 13.30g is canescence tabular crystal product;
1H NMR:(DMSO-d6，400MHz):2.01(s,3H),2.22(s,6H),6.66(s,1H),7.19(s,2H),9.74(s,1H)
Step 2
Take appropriate aluminum trichloride (anhydrous) (369.09mmol) with dry dichloromethane solution, Acetyl Chloride 98Min. (246.06mmol) is dripped under ice-water bath, add N-(3 afterwards, 5-3,5-dimethylphenyl) ethanamide (82.02mmol), be warming up to room temperature, reaction 3h, TLC (PE:EA=1:1) detection reaction, question response terminates, reaction solution punching is analysed in 600mL water+20mL concentrated hydrochloric acid, then adds DCM dissolving, extraction, collect organic phase, concentrate drying directly throws next step;
1H NMR:(DMSO-d6，400MHz):2.03(s,3H),2.14(s,6H),2.42(s,3H),7.26(s,2H),9.88(s,1H)
Step 3
Add 60mL2N HCl and 60mL water by the solid obtained after concentrated, be heated to 95 ~ 100 DEG C of hydrolysis 2h, TLC (PE:EA=1:1) detection reaction terminals.Question response terminates, and adds saturated sodium bicarbonate cancellation, and modulation pH=8 ~ 9, have a large amount of solid precipitation to separate out, suction filtration solid, dried in vacuo overnight, obtain 13.04g pale yellow powder solid, is 1-(amino-2, the 6-3,5-dimethylphenyls of 4-) methyl phenyl ketone.
1H NMR:(DMSO-d6，400MHz):2.06(s,6H),2.34(s,3H),5.17(s,2H),6.21(s,2H)
Step 4
Take 1-(4-amino-2, 6-3,5-dimethylphenyl) methyl phenyl ketone (82.1mmol) is in 120mL concentrated hydrochloric acid and 40mL water, temperature <5 DEG C is cooled under cryosel bath, drip NaNO2 solution, dropping process keeps temperature lower than 5 DEG C, dropwise rear reaction 20min, drip KI solution afterwards, add and naturally rise to room temperature reaction 7h afterwards, TLC (PE:EA=4:1) detection reaction process, question response terminates, use saturated sodium bicarbonate cancellation, be extracted with ethyl acetate 4 times, merge organic phase, column chromatographic isolation and purification, obtain the 1-(4-iodo-2 of 14.35g brown oil liquid, 6-3,5-dimethylphenyl) methyl phenyl ketone.
1H NMR:(DMSO-d6，400MHz):2.14(s,6H),2.44(s,3H),7.48(s,2H)
Step 5
Take 1-(4-iodo-2,6-3,5-dimethylphenyl) methyl phenyl ketone (52.17mmol) is in ethyl acetate/chloroform (30mL:10mL) mixing solutions, add CuBr2 (102.98mmol), 65 ~ 70 DEG C of backflow 8h, TLC (PE:EA=30:1) detection reaction process, question response terminates, with saturated sodium bicarbonate and extraction into ethyl acetate, collect organic phase, obtain the bromo-1-of brown-red solid 18.6g2-(iodo-2, the 6-3,5-dimethylphenyls of 4-) ethyl ketone.Direct throwing next step.
Step 6
Take the bromo-1-of 2-(4-iodo-2,6-3,5-dimethylphenyl) ethyl ketone (52mmol) and thiocarbamide (52mmol) be in 80mL ethanol, stir at 72 ~ 80 DEG C and spend the night, produce a large amount of white opacity, reaction terminates suction filtration, use washing with alcohol filter cake, dry 22g white solid.
1H NMR:(DMSO-d6，400MHz):2.14(s,6H),6.46(s,1H),6.96(s,2H),7.32(s,2H).
Step 7
Take 4-(4-iodo-2,6-3,5-dimethylphenyl) thiazolyl-2-amine (0.515mmol), Ismipur (1.03mmol), Cu2O (0.026mmol) and KOH (1.03mmol) are in DMF (40mL) and water (10mL), and at 125 ~ 130 DEG C, reaction is spent the night.TLC monitors reaction, and question response terminates, and adds aqueous hydrochloric acid cancellation, repeatedly extracts with ethyl acetate and water, and collect organic phase, concentrate drying obtains yellow solid product.
1H NMR:(DMSO-d6，400MHz):2.15(s,6H),6.47(s,1H),6.95(s,2H),7.34(s,2H),8.49(s,1H),8.58(s,1H),13.57(s,1H)
Step 8
Take 4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyl) thiazolyl-2-amine (2mmol), PITC (2mmol) is in pyridine (20ml), 100 ~ 110 DEG C of stirrings are spent the night, question response terminates, repeatedly with ethyl acetate and water extraction, collect organic phase, column chromatography (DCM:MeOH=20:1) obtains sterling, yellow solid, productive rate 62%.
1H NMR:(DMSO-d6，400MHz):2.19(s,6H),7.15～7.90(m,8H),8.51(s,1H),8.59(s,1H),10.39(s,1H),11.81(s,1H),13.60(s,1H)
MS-ESI(m/z)：512.1(M+Na
+)
Embodiment 21 I U1-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(4-(trifluoromethyl) phenyl) thiocarbamide
Method is with embodiment 20.
1H NMR:(DMSO-d6，400MHz):2.21(s,6H),6.97(s,1H),7.50(s,2H),7.56(d,2H),7.96(d,2H),8.52(s,1H),8.59(s,1H),10.37(s,1H),13.43(s,1H),13.62(s,1H)
MS-ESI(m/z)：580.64(M+Na
+)
Embodiment 22 I V1-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(4-(methoxyl group) phenyl) thiocarbamide
Method is with embodiment 20.
1H NMR:(DMSO-d6，400MHz):2.18(s,6H),3.74(s,3H),6.98(d,3H),7.28(d,2H),7.37(s,2H),8.49(s,1H),8.57(s,1H),9.60(s,1H),13.563(s,1H),13.623(s,1H)
MS-ESI(m/z)：542.10(M+Na
+)
Embodiment 23 I W1-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(2-bromophenyl) thiocarbamide
Method is with embodiment 20.
1H NMR:(DMSO-d6，400MHz):2.17(s,6H),7.19(m,2H),7.42(s,3H),7.69(d,1H),7.83(d,1H),8.50(s,1H),8.59(s,1H),12,14(s,1H),13.11(s,1H),13.59(s,1H)
MS-ESI(m/z)：591.53(M+Na
+)
Embodiment 24 I X1-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(4-fluorophenyl) thiocarbamide
Method is with embodiment 20.
1H NMR:(DMSO-d6，400MHz):2.17(s,6H),6.97(s,1H),7.17(t,4H),7.40(t,4H),8.51(s,1H),8.59(s,1H),9.84(s,2H),13.54(s,1H)
MS-ESI(m/z)：530.63(M+Na
+)
Embodiment 25 I Y1-(4-(4-((9H-purine-6-base) sulphur)-2,6-3,5-dimethylphenyls) thiazol-2-yl)-3-(the chloro-3-of 4-(trifluoromethyl) phenyl) thiocarbamide
Method is with embodiment 20.
1H NMR:(DMSO-d6，400MHz):2.20(s,6H),6.98(s,1H),7.49(s,2H),7.54(s,1H),8.14(s,1H),8.3(s,1H),8.52(s,1H),8.58(s,1H),10.4(s,1H),13.34(s,1H),13.61(s,1H)
MS-ESI(m/z)：615.08(M+Na
+)
Pharmacodynamic experiment part
One, cell growth inhibition assay
1, experiment reagent
Methyl thiazoly tetrazolium assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylte trazoliumb romide, MTT), dimethyl sulfoxide (DMSO) (DMSO), EL purchased from American Sigma company (St.Louis, MO).DMEM, RPMI-1640, foetal calf serum and pancreatin are from buying in Gibco company (Auckland, N.Z).The new compound related in the present invention synthesizes gained voluntarily by my laboratory, to be mixed with the storing solution of 90mmol/L in vitro in experiment with DMSO, and lucifuge to be stored in ﹣ 20 DEG C of refrigerators for subsequent use, when experiment uses, be diluted to desired concn with perfect medium.
Clone and cultivation thereof: the Breast cancer lines (MDA-MB-231 and MDA-MB-468) that this laboratory uses, human cervical carcinoma cell lines (Hela) and human chronic myeloblastic leukemia cell strain (K562) are all bought in American Type Culture Collection center (ATCC).
Breast cancer lines (MDA-MB-231 and MDA-MB-468), human cervical carcinoma cell lines (Hela) use the foetal calf serum and microbiotic (the penicillin 100U/mL that contain 10%, Streptomycin sulphate 100U/mL) DMEM perfect medium cultivate, and be placed in 37 DEG C, 5%CO
2, incubator under saturated humidity condition.
Human chronic myeloblastic leukemia cell strain (K562) uses to be cultivated containing the foetal calf serum of 10% and the RPMI-1640 perfect medium of microbiotic (penicillin 100U/mL, Streptomycin sulphate 100U/mL), and is placed in 37 DEG C, 5%CO
2, incubator under saturated humidity condition.
2, mtt assay
Collect the cell of logarithmic phase, and adjust concentration of cell suspension according to the speed of Growth of Cells, be inoculated into 96 orifice plates with the density of 2500 ~ 4000 cells/well, every pore volume 100 μ L; 96 orifice plates are placed in 37 DEG C, overnight incubation in 5%CO2 cell cultures incubator; Diluted chemical compound is become corresponding concentration in the mode of 3 times of dilutions by next day, and use I a ~ I l of different concns (final concentration is respectively 90,30,10,3,1,0.3 μm of ol/L) to process cell respectively, each concentration gradient establishes 3 ~ 5 multiple holes, and isopyknic solvent control group is set, the content of the DMSO in every hole all requires below 0.1% (the DMSO on cell proliferation of 0.1% does not have a significant effect); Put 37 DEG C, cultivate 96 hours in 5%CO2 cell cultures incubator, drug treating group and the every hole of control group add 20 μ L MTT solution (5mg/mL), continue in incubator, hatch 2 ~ 4 hours, stop cultivating after first a ceremonial jade-ladle, used in libation is formed, incline supernatant liquor, and every hole adds 150 μ L DMSO (for suspension cell, after termination is cultivated, every hole adds the 20%SDS solution of 50 μ L, and overnight incubation treats that first a ceremonial jade-ladle, used in libation is entirely molten); Shaking table shakes 15-20 minute, in microplate reader (λ=570nm) upper mensuration each hole absorbance value (OD570), gets its mean value record result.Cell proliferation inhibition rate=(control group OD570-experimental group OD570)/control group OD570 × 100%.Experiment at least repeats 3 times, asks calculate IC according to the inhibiting rate GraphPad Prism software of different concns
50.
3, experimental result
In I A ~ I W, the extracorporeal anti-tumor proliferation function of part of compounds on four different tumor cell lines is in table 1.
Table 1
The compound of the present invention to preparation has carried out the body outer cell proliferation Inhibition test research of Breast cancer lines (MDA-MB-231, MDA-MB-468), human cervical carcinoma cell lines (Hela) and human chronic myeloblastic leukemia cell strain (K562), result represents that prepared compound all has good restraining effect to above-mentioned cell, and partial data sees the above table 1.
Claims (11)
1.4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives, its structure is such as formula shown in I:
Wherein, R1 ~ R4 is independently H, C1 ~ C8 alkyl, C1 ~ C8 alkoxy or halogen;
R
5for
X1 ~ X5 is independently N or C;
R6 is H or C1 ~ C4 alkyl;
R7 ~ R25 be independently-H, halogen, C1 ~ C8 alkyl of halogen substiuted, C1 ~ C8 alkyl, C1 ~ C8 alkoxyl group, C3 ~ C8 cycloalkyl, 3 ~ 8 yuan of Heterocyclylalkyls,
c2 ~ C8 thiazolinyl, C2 ~ C8 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 8 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 8 yuan of described Heterocyclylalkyls or 3 ~ 8 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3.
2. 4-according to claim 1 (4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives, is characterized in that:
R1 ~ R4 is independently H, C1 ~ C4 alkyl, C1 ~ C4 alkoxy or halogen;
X1 ~ X5 is independently N or C;
R6 is H or C1 ~ C4 alkyl;
R7 ~ R25 be independently-H, halogen, C1 ~ C4 alkyl of halogen substiuted, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 3 ~ 6 yuan of Heterocyclylalkyls,
c2 ~ C4 thiazolinyl, C2 ~ C4 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 6 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 6 yuan of described Heterocyclylalkyls or 3 ~ 6 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3;
It is preferred further,
R1 ~ R4 is independently H or C1 ~ C4 alkyl;
X1 ~ X5 is independently N or C;
R6 is H or C1 ~ C4 alkyl;
R7 ~ R25 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 6 yuan of Heterocyclylalkyls,
-NO
2or-OCF
3; Heteroatoms in 6 yuan of described Heterocyclylalkyls is N, O or S, and heteroatomic number is 1 ~ 3;
It is most preferred,
R1 ~ R4 is independently H or methyl;
X1 ~ X5 is independently N or C;
R6 is H;
R7 ~ R25 is independently-H ,-F ,-Cl ,-Br ,-CF
3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, cyclopropyl,
-NO
2or-OCF
3.
3. 4-according to claim 1 (4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives, is characterized in that: R5 is
structure is such as formula shown in II:
Wherein, R1 ~ R4 is independently H, C1 ~ C8 alkyl, C1 ~ C8 alkoxy or halogen;
X1 ~ X5 is independently N or C;
R6 is H or C1 ~ C4 alkyl;
R7 ~ R10 be independently-H, halogen, C1 ~ C8 alkyl of halogen substiuted, C1 ~ C8 alkyl, C1 ~ C8 alkoxyl group, C3 ~ C8 cycloalkyl, 3 ~ 8 yuan of Heterocyclylalkyls,
c2 ~ C8 thiazolinyl, C2 ~ C8 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 8 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 8 yuan of described Heterocyclylalkyls or 3 ~ 8 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3;
Preferably,
R1 ~ R4 is independently H, C1 ~ C4 alkyl, C1 ~ C4 alkoxy or halogen;
X1 ~ X5 is independently N or C;
R6 is H or C1 ~ C4 alkyl;
R7 ~ R10 be independently-H, halogen, C1 ~ C4 alkyl of halogen substiuted, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 3 ~ 6 yuan of Heterocyclylalkyls,
c2 ~ C4 thiazolinyl, C2 ~ C4 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 6 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 6 yuan of described Heterocyclylalkyls or 3 ~ 6 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3;
It is preferred further,
R1 ~ R4 is independently H or C1 ~ C4 alkyl;
X1 ~ X5 is independently N or C;
R6 is H or C1 ~ C4 alkyl;
R7 ~ R10 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 6 yuan of Heterocyclylalkyls,
-NO
2or-OCF
3; Heteroatoms in 6 yuan of described Heterocyclylalkyls is N, O or S, and heteroatomic number is 1 ~ 3;
It is preferred further,
R1 ~ R4 is independently H or methyl;
X1 ~ X5 is independently N or C;
R6 is H;
R7 ~ R10 is independently-H ,-F ,-Cl or-Br.
4. 4-according to claim 1 (4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives, is characterized in that: R5 is
structural formula is such as formula shown in III:
Wherein, R1 ~ R4 is independently H, C1 ~ C8 alkyl, C1 ~ C8 alkoxy or halogen;
R6 is H or C1 ~ C4 alkyl;
R11 ~ R15 be independently-H, halogen, C1 ~ C8 alkyl of halogen substiuted, C1 ~ C8 alkyl, C1 ~ C8 alkoxyl group, C3 ~ C8 cycloalkyl, 3 ~ 8 yuan of Heterocyclylalkyls,
c2 ~ C8 thiazolinyl, C2 ~ C8 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 8 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 8 yuan of described Heterocyclylalkyls or 3 ~ 8 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3;
Preferably, R1 ~ R4 is independently H, C1 ~ C4 alkyl, C1 ~ C4 alkoxy or halogen;
R6 is H or C1 ~ C4 alkyl;
R11 ~ R15 be independently-H, halogen, C1 ~ C4 alkyl of halogen substiuted, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 3 ~ 6 yuan of Heterocyclylalkyls,
c2 ~ C4 thiazolinyl, C2 ~ C4 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 6 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 6 yuan of described Heterocyclylalkyls or 3 ~ 6 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3;
It is preferred further,
R1 ~ R4 is independently H or C1 ~ C4 alkyl;
R6 is H or C1 ~ C4 alkyl;
R11 ~ R15 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 6 yuan of Heterocyclylalkyls,
-NO
2or-OCF
3; Heteroatoms in 6 yuan of described Heterocyclylalkyls is N, O or S, and heteroatomic number is 1 ~ 3;
It is preferred further,
R1 ~ R4 is independently H or methyl;
R6 is H;
R11 ~ R15 is independently-H ,-F ,-Cl ,-Br ,-CF
3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, cyclopropyl,
or-NO
2.
5. 4-according to claim 1 (4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives, is characterized in that: R5 is
structural formula is such as formula shown in IV:
Wherein, R1 ~ R4 is independently H, C1 ~ C8 alkyl, C1 ~ C8 alkoxy or halogen;
R6 is H or C1 ~ C4 alkyl;
R16 ~ R20 be independently-H, halogen, C1 ~ C8 alkyl of halogen substiuted, C1 ~ C8 alkyl, C1 ~ C8 alkoxyl group, C3 ~ C8 cycloalkyl, 3 ~ 8 yuan of Heterocyclylalkyls,
c2 ~ C8 thiazolinyl, C2 ~ C8 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 8 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 8 yuan of described Heterocyclylalkyls or 3 ~ 8 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3;
Preferably,
R1 ~ R4 is independently H, C1 ~ C4 alkyl, C1 ~ C4 alkoxy or halogen;
R6 is H or C1 ~ C4 alkyl;
R16 ~ R20 be independently-H, halogen, C1 ~ C4 alkyl of halogen substiuted, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 3 ~ 6 yuan of Heterocyclylalkyls,
c2 ~ C4 thiazolinyl, C2 ~ C4 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 6 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 6 yuan of described Heterocyclylalkyls or 3 ~ 6 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3;
It is preferred further,
R1 ~ R4 is independently H or C1 ~ C4 alkyl;
R6 is H or C1 ~ C4 alkyl;
R16 ~ R20 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 6 yuan of Heterocyclylalkyls,
-NO
2or-OCF
3; Heteroatoms in 6 yuan of described Heterocyclylalkyls is N, O or S, and heteroatomic number is 1 ~ 3;
It is preferred further,
R1 ~ R4 is independently H or methyl;
R6 is H;
R11 ~ R15 is independently-H ,-F ,-Cl ,-Br ,-CF
3, C1 ~ C4 alkyl or C1 ~ C4 alkoxyl group.
6. 4-according to claim 1 (4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives, is characterized in that: R5 is
structural formula is such as formula shown in V:
Wherein, R
1~ R
4be independently H, C1 ~ C8 alkyl, C1 ~ C8 alkoxy or halogen;
R
6for H or C1 ~ C4 alkyl;
R
21~ R
25be independently-H, halogen, C1 ~ C8 alkyl of halogen substiuted, C1 ~ C8 alkyl, C1 ~ C8 alkoxyl group, C3 ~ C8 cycloalkyl, 3 ~ 8 yuan of Heterocyclylalkyls,
c2 ~ C8 thiazolinyl, C2 ~ C8 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 8 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 8 yuan of described Heterocyclylalkyls or 3 ~ 8 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3;
Preferably, R
1~ R
4be independently H, C1 ~ C4 alkyl, C1 ~ C4 alkoxy or halogen;
R
6for H or C1 ~ C4 alkyl;
R
21~ R
25be independently-H, halogen, C1 ~ C4 alkyl of halogen substiuted, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 3 ~ 6 yuan of Heterocyclylalkyls,
c2 ~ C4 thiazolinyl, C2 ~ C4 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 6 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 6 yuan of described Heterocyclylalkyls or 3 ~ 6 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3;
It is preferred further,
R1 ~ R4 is independently H or C1 ~ C4 alkyl;
R6 is H or C1 ~ C4 alkyl;
R21 ~ R25 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, C3 ~ C6 cycloalkyl, 6 yuan of Heterocyclylalkyls,
-NO
2or-OCF
3; Heteroatoms in 6 yuan of described Heterocyclylalkyls is N, O or S, and heteroatomic number is 1 ~ 3;
It is preferred further,
R1 ~ R4 is independently H or methyl;
R6 is H;
R7 ~ R25 is independently-H ,-F ,-Cl ,-Br ,-CF
3, C1 ~ C4 alkyl or C1 ~ C4 alkoxyl group.
7. 4-according to claim 1 and 2 (4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives, is characterized in that: comprise following compound:
N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl) Isonicotinamide, N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-2-fluorine Isonicotinamide, N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-pyrazine-2-acid amides, N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-pyrimidine-5-acid amides, N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-pyridazine-4-acid amides, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(the chloro-3-of 4-(trifluoromethyl) phenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-methyl) phenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-methoxyl group) phenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(3-bromophenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(2-bromophenyl) thiocarbamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-oxyethyl group) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-tertiary butyl base) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-(trifluoromethyl) phenyl) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-(methoxyethoxy) phenyl) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-(cyclopropyl) phenyl) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-(morpholinyl) phenyl) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(the fluoro-phenyl of 3-) cinnamide, (E)-N-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(the fluoro-phenyl of 2-) cinnamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-phenylthiourea, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-(trifluoromethyl) phenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-(methoxyl group) phenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(2-bromophenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(4-fluorophenyl) thiocarbamide, 1-(4-(4-((9H-purine-6-base) sulphur)-2, 6-3,5-dimethylphenyl) thiazol-2-yl)-3-(the chloro-3-of 4-(trifluoromethyl) phenyl) thiocarbamide.
8. the preparation method of 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives described in claim 1 ~ 7, is characterized in that: comprise the following steps:
R1 ~ R4 is independently H, C1 ~ C8 alkyl, C1 ~ C8 alkoxy or halogen;
X1 ~ X5 is independently N or C;
R
5for
R6 is H or C1 ~ C4 alkyl;
R7 ~ R25 be independently-H, halogen, C1 ~ C8 alkyl of halogen substiuted, C1 ~ C8 alkyl, C1 ~ C8 alkoxyl group, C3 ~ C8 cycloalkyl, 3 ~ 8 yuan of Heterocyclylalkyls,
c2 ~ C8 thiazolinyl, C2 ~ C8 alkynyl ,-CN ,-OH, C3 ~ C8 cycloalkenyl group, 3 ~ 8 yuan of heterocycloalkenyl ,-NO
2or-OCF
3; Heteroatoms in 3 ~ 8 yuan of described Heterocyclylalkyls or 3 ~ 8 yuan of heterocycloalkenyl is N, O or S, and heteroatomic number is 1 ~ 3;
Steps A: compound 1 and Acetyl Chloride 98Min. react in the basic conditions and prepare compound 2; Described alkali be in salt of wormwood, sodium carbonate, potassiumphosphate, cesium carbonate or potassium hydroxide any one;
Step B: compound 2 and Acetyl Chloride 98Min. acylation reaction occur under Catalyzed by Anhydrous Aluminium Chloride and prepare compound 3;
Step C: compound 3 in acid condition hydrolysis reaction prepares compound 4;
Step D: react in the concentrated hydrochloric acid that compound 4 and Sodium Nitrite are bathed at cryosel and form diazonium salt, then with KI, iodide reaction occurs and prepare compound 5;
Step e: compound 5 and bromide reagent generation bromo-reaction prepare compound 6; Described bromide reagent be in cuprous bromide, bromine or tetrabutyl tribromide ammonium any one;
Step F: compound 6 and thiocarbamide Hantsch occur and become thiazole to react to prepare compound 7; Temperature of reaction is 72 ~ 80 DEG C, and the time is 4h ~ 8h;
Step G: compound 7 and Ismipur react 6 ~ 8h at 125 ~ 150 DEG C in the basic conditions and prepare compound 8; Described alkali be in potassium hydroxide, salt of wormwood, potassium tert.-butoxide, cesium carbonate or potassiumphosphate any one;
Step H: compound 8 respectively with replacement γ-picolinic acid, substituted cinnamic acid condensation, or with replacement isocyanic ester, replace lsothiocyanates and become urea to prepare compound 9.
9. the purposes of 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives described in any one of claim 1 ~ 7 in preparation tumor.
10. the prodrug of 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives described in any one of claim 1 ~ 7 or hydrate.
11. pharmaceutical compositions are added the complementary composition of pharmaceutically acceptable be prepared from by 4-(4-((9H-purine-6-base) sulphur) phenyl) thiazolyl-2-sulfonamide derivatives described in any one of claim 1 ~ 7.
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| CN110903289A (en) * | 2018-09-14 | 2020-03-24 | 四川大学 | Purine-aminomethyl-pyridone derivative, preparation method and application thereof |
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| CN102232071A (en) * | 2008-09-26 | 2011-11-02 | 财团法人卫生研究院 | Fused multicyclic compounds as protein kinase inhibitors |
| CN102558147A (en) * | 2010-12-23 | 2012-07-11 | 江苏先声药物研究有限公司 | Compound, and preparation method and application thereof |
| US20140107109A1 (en) * | 2012-10-12 | 2014-04-17 | Amgen Inc. | Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use |
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| CN102232071A (en) * | 2008-09-26 | 2011-11-02 | 财团法人卫生研究院 | Fused multicyclic compounds as protein kinase inhibitors |
| CN102558147A (en) * | 2010-12-23 | 2012-07-11 | 江苏先声药物研究有限公司 | Compound, and preparation method and application thereof |
| US20140107109A1 (en) * | 2012-10-12 | 2014-04-17 | Amgen Inc. | Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110903289A (en) * | 2018-09-14 | 2020-03-24 | 四川大学 | Purine-aminomethyl-pyridone derivative, preparation method and application thereof |
| CN110903289B (en) * | 2018-09-14 | 2023-02-03 | 四川大学 | Purine-aminomethyl-pyridone derivative, preparation method and application thereof |
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