CN106008394B - Mercaptobenzothiazoler amides compound and its preparation and the purposes as drug - Google Patents
Mercaptobenzothiazoler amides compound and its preparation and the purposes as drug Download PDFInfo
- Publication number
- CN106008394B CN106008394B CN201610344959.6A CN201610344959A CN106008394B CN 106008394 B CN106008394 B CN 106008394B CN 201610344959 A CN201610344959 A CN 201610344959A CN 106008394 B CN106008394 B CN 106008394B
- Authority
- CN
- China
- Prior art keywords
- benzo
- acetylamino
- thiazol
- sulfydryl
- benzamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to pharmaceutical technology fields, and in particular to a kind of mercaptobenzothiazoler amides compound and its preparation and the purposes as drug.Mercaptobenzothiazoler amides compound provided by the invention, including its pharmaceutical salts, shown in structure such as formula (I).The present invention also provides above-mentioned mercaptobenzothiazoler amides compounds, preparation method and application in preparation of anti-tumor drugs including its pharmaceutical salts.
Description
Technical field:
The present invention relates to pharmaceutical technology fields, specifically, be mercaptobenzothiazoler amides compound and its preparation with
As the purposes of drug, especially application in preparation of anti-tumor drugs.
Background technique:
Neddylation (neural precursor expression development is lowered, English abbreviation NEDD) access is intracellular very heavy
The non-lysosomal protein degradation approach wanted is that eukaryocyte maintains intracellular protein balance, adjusts the cell cycle, maintains cell survival
Important adjusting access.Neddylation access is similar with ubiquitination access, mainly by ubiquitin activating enzyme (E1, NAE), general
Plain desmoenzyme (E2) and ubiquitin ligase (E3) are catalyzed step by step, and ubiquitin or ubiquitin-like modifiers (NEDD8) are tagged on target protein,
To be modified or be degraded albumen.Important component of the Cullin-RING ligase (CRLs) as ubiquitin ligase,
It is the key signal albumen of Neddylation access and regulation, plays an important role in the degradation of control cell protein.Research
It was found that the phenomenon that leading to CRLs improper activation there are the overexpression of NEDD8 access in kinds of tumor cells (Soucy, T.A.,
et al.An inhibitor of NEDD8-activating enzyme as a new approach to treat
cancer.Clin Cancer Res,2009,15,3912-3916).Small molecule NAE (Chinese name ubiquitin kinase, full name in English
Ubiquitin Activating Enzyme) inhibitor can inhibit entire access from Neddylation circuit upstream, interfere CRL
The degradation of (full name in English Cullin-RING) target protein causes target protein in accumulation intracellular, lasting Neddylation access
Inhibit the DNA that can cause cell cycle dependant to replicate again, leads to cell cycling disorder, DNA synthesis imbalance, finally induction is thin
Born of the same parents' apoptosis (Soucy, T.A., et al.An inhibitor of NEDD8-activating enzyme as a new
approach to treat cancer.Nature,2009,458,732-736)。
Sulfamic acid ((1S, 2S, 4R) -4- (4- ((1S) -2,3- dihydro -1H- indenes -1- base amino) -7H- pyrrolo- [2,
3-d] pyrimidin-7-yl) -2- hydroxycyclopent base) and methyl esters (MLN4924) be first report small molecule NAE inhibitor, be sulfonamide
Class NAE inhibitor is currently in clinical I phase test, and has declared the (WO2006084281 such as PCT Patent, United States Patent (USP)
(A1), US20120330013 (A1)).Preclinical study shows that MLN4924 has intestinal cancer, osteosarcoma, liver cancer and breast cancer etc.
Excellent activity, and MLN4924 can significantly inhibit tumour growth, mediate tumor cell apoptosis.In recent years, research also found
NAE inhibitor MLN4924 has radiotherapy synergistic effect (Dongping, W., et al.Targeting NEDD8-activated
cullin-RING ligases for the treatment of cancer.Cancer Research,2012,72,282-
293)。
Chinese patent application CN104016987A discloses sulfamic acid ((1S, 2S, 4R) -4- { 4- [(1S) -2,3- bis-
Hydrogen -1H- indenes -1- base amino] -7H- pyrrolo- [2,3-D] pyrimidin-7-yl } -2- hydroxycyclopent base) methyl ester hydrochloride is as NAE
Inhibitor can be used for treating cell proliferative disorders, especially cancer and other illnesss related with E1 activity.
The small molecule NAE inhibitor reported at present is less, and in addition to MLN4924, majority of compounds activity is not high, it is necessary to
Research and develop the high-activity compound of new structure type.
Summary of the invention:
The purpose of the present invention is to provide a kind of new non-sulfonamides NAE inhibitor, specially mercaptobenzothiazoler acyl
Aminated compounds.Another object of the present invention is to provide the preparation method of mercaptobenzothiazoler amides compound.The present invention the
Three are designed to provide application of the mercaptobenzothiazoler amides compound as drug, and it is anti-swollen that the application is included in preparation
Purposes in tumor medicine, such compound can inhibit NAE activity to inhibit NEDD8 signal path, finally induce tumour cell
Apoptosis.
The present invention is transformed to obtain the little molecules in inhibiting of brand new by the virtual screening integrated structure to business database
Agent.And tested by Cytostatic to tumor cell experiment and WB, new non-sulfonamides NAE inhibitor is screened, it is of the invention
Compound can inhibit growth of tumour cell, mediate tumor cell apoptosis significantly.
The specific technical solution of the present invention is as follows:
As the first aspect of the present invention, a kind of mercaptobenzothiazoler amides compound, including its pharmaceutical salts, structure is such as
Formula (I)；
Wherein R1Be hydrogen, halogen, class halogen, low alkyl group, lower alkoxy, low-grade halogenated alkyl, naphthenic base, aryl,
Heteroaryl；
It is preferred that R1It is aryl, heteroaryl；
R2It is hydrogen, low alkyl group, lower alkoxy, low-grade halogenated alkyl, naphthenic base, aryl, heteroaryl；
It is preferred that R2It is low alkyl group, naphthenic base, aryl, heteroaryl；
X is-NHC (O)-,-C (O) NH- ,-C (O) O-；
Herein, term lower alkyl refers to the linear chain or branched chain saturated fat hydrocarbyl group containing 1 to 7 carbon atom, for example,
Methyl, ethyl, propyl, isopropyl, butyl, tert-butyl etc..Usual low alkyl group is preferably 1 to 4 carbon atom.
Term lower alkoxy indicates to contain 1 to 7 carbon atom straight chain or branched alkoxy.
Term low-grade halogenated alkyl is the low alkyl group replaced containing 1 to 3 halogen atom.
Term aryl refers to substituted aryl, and the substitution refers to be replaced by following one or more groups: hydrogen, halogen
Element, hydroxyl, nitro, amino, cyano, carboxyl, low alkyl group, lower alkoxy, the aryl refer to monovalent monocyclic or bicyclic virtue
Race's carbocyclic hydrocarbon radicals, preferably 6-7 member aromatic ring system, preferred aryl include but is not limited to phenyl, naphthalene.
Term heteroaryl refers to substituted heteroaryl, and the substitution refers to be replaced by following one or more groups: hydrogen,
Halogen, hydroxyl, nitro, amino, cyano, carboxyl, low alkyl group, lower alkoxy, the heteroaryl refer to containing at most two
The aromatic heterocyclic ring systems of a ring.Preferred heteroaryl includes but is not limited to: thienyl, furyl, indyl, pyrrole radicals, pyridine
Base, pyrazinyl, oxazolyl, thiazolyl, quinolyl, pyrimidine radicals, imidazoles and tetrazole radical.
Term naphthenic base refers to the ring containing 3 to 7 carbon, for example, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.
Term halogen refers to chlorine, bromine, iodine or fluorine.
Term class halogen refers to cyano, trifluoromethyl, trifluoromethoxy.
Term hetero atom refers to the atom selected from nitrogen, oxygen and sulphur.
Formula (I) compound, preferably is selected from following compound:
N- (6- (2- ((3-hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) butyramide,
4- trifluoromethyl-N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzoyl
Amine,
N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -2- naphthalenecarboxamide,
The fluoro- N- of 4- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- methyl-N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
3,5- dimethyl-N-(6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzoyl
Amine,
The chloro- N- of 3,5- bis- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzoyl
Amine,
N- (6- (2- ((3-hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) thiophene-2-carboxamide derivatives,
N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) butyramide,
4- trifluoromethyl-N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzoyl
Amine,
N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -2- naphthalenecarboxamide,
The fluoro- N- of 4- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- methyl-N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -4- (fluoroform
Base) benzamide,
3,5- dimethyl-N-(6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -4- (trifluoro
Methyl) benzamide,
4- trifluoromethyl-N- (6- (2- ((2,4-xylyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzene first
Amide,
4- trifluoromethyl-N- (6- (2- (2- naphthalene sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- (2- pyrimidine sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- (2- imidazoles sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- (2- benzimidazole sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzoyl
Amine,
4- trifluoromethyl-N- (6- (2- (2- cyclohexyl sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- ((4- aminophenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzoyl
Amine,
4- trifluoromethyl-N- (6- (2- ((3- carboxyl pyridine) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzoyl
Amine.
Certain compounds of the invention can conventionally be prepared as the form of pharmaceutical salts.Including its acylate and nothing
Machine hydrochlorate: inorganic acid includes but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, diphosphonic acid, hydrobromic acid, nitric acid etc., organic acid include (but
It is not limited to) acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-methyl benzenesulfonic acid, salicylic acid, oxalic acid etc..
As a second aspect of the invention, the compound of the present invention can be used to lower section method be prepared:
The reaction stream formula of preparation method of the present invention is as follows:
Preparation method of the invention the following steps are included:
The conventional method of synthetic intermediate II: 2- amino-6-nitrobenzothiazole is dissolved in anhydrous organic solvent such as dichloro
Acid binding agent such as triethylamine, DMAP, pyridine etc. is added in methane, DMF, THF, toluene, benzene etc., be then added dropwise under ice bath be dissolved in it is identical
The substitution acyl chlorides of anhydrous organic solvent, room temperature reaction are reacted completely to raw material, obtain intermediate II through pillar layer separation.
The conventional method of synthetic intermediate III: intermediate II methanol, ethyl alcohol, ethyl acetate etc. are then slowly added into
5% palladium carbon is passed through hydrogen and reacts at room temperature to raw material and react completely, obtains intermediate III through pillar layer separation.
The conventional method of synthetic intermediate IV: by intermediate III be dissolved in anhydrous organic solvent for example methylene chloride, DMF, THF,
Acid binding agent such as triethylamine, DMAP, pyridine etc. is added in toluene, benzene etc., is then added dropwise under ice bath and is dissolved in identical anhydrous organic solvent
Chloracetyl chloride, room temperature reaction are reacted completely to raw material, obtain intermediate compound IV through pillar layer separation.
Synthesize target product I conventional method: by intermediate compound IV be dissolved in anhydrous organic solvent for example methylene chloride, DMF, THF,
Inorganic base such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate etc. is added in toluene, benzene etc., be then added dropwise under ice bath be dissolved in it is identical
The substitution thiophenol or mercaptan of anhydrous organic solvent, room temperature reaction are reacted completely to raw material, obtain target product through pillar layer separation
I。
As the third aspect of the present invention, the present invention provides above-mentioned mercaptobenzothiazoler amides compounds, including
Its pharmaceutical salts, the application as NAE inhibitor.
And the present invention provides above-mentioned mercaptobenzothiazoler amides compounds, including its pharmaceutical salts, it is anti-in preparation
Application in tumour medicine.
The compounds of this invention can be used in the drug that preparation inhibits NEDD8 signal path effect and NAE inhibitory activity.
It is studied through anti tumor activity in vitro, the compound of the present invention has good anti-tumor activity, they can be used for controlling
Treat tumour, including esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, endometrium, ovary, prostate,
The cancer that the positions such as testis, bladder, kidney, liver, pancreas, bone, connective tissue, skin, eye, brain and central nervous system occur, with
And thyroid cancer, leukaemia, suddenly king's evil, lymthoma and myeloma etc..
The compounds of this invention and its esters have good anti-tumor activity, and multiple Compound ira vitro anti-tumor activities reach
Nanomole grade, therefore the compounds of this invention and its esters can be used for preparing anti-tumor drug.
The compounds of this invention acts synergistically with radiotherapy, can be used for radio therapy sensitization or the drug used with chemotherapy combined radiotherapy.Suppression
Other compounds of NEDD8 signal path effect processed inhibit other active compounds of NAE to join for radio therapy sensitization or with radiotherapy
The effect used is closed referring to document: Dongping, W., et al.Targeting NEDD8-activated cullin-RING
ligases for the treatment of cancer.Cancer Research,2012,72,282-293。
The present invention provides new thinking for oncotherapy.
Detailed description of the invention:
Fig. 1 is the western experimental result of part of compounds of the present invention.
Specific embodiment:
Below in conjunction with specific embodiments and the drawings, the invention will be further described.It should be understood that following embodiment is only used for
It illustrates rather than for limiting the scope of the invention.
In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, such as " molecular cloning: real
Test room handbook " condition or factory described in (New York:Cold Spring Harbor Laboratory Press, 1989)
The condition that quotient provides carries out.
Embodiment 1:N- (6- nitro benzo [d] thiazol-2-yl) butyramide
2- amino-6-nitrobenzothiazole 0.2g (1.0mmol) is dissolved in 20mL methylene chloride, triethylamine is slowly added dropwise
0.28mL.It measures butyric anhydride 0.12mL (1.0mmol) to be dissolved in 1mL methylene chloride and be slowly added dropwise into reaction system, room temperature
Under the conditions of, it is stirred to react 3h.Reaction solution is extracted twice with water and methylene chloride, merges organic phase, organic phase anhydrous slufuric acid
Sodium is dry, column chromatographic purifying, yellow solid, yield 90.4%.
1H NMR(300MHz,DMSO-d6) δ: 12.73 (s, 1H), 9.03 (d, J=2.3Hz, 1H), 8.26 (dd, J=
2.4,9.0Hz, 1H), 7.86 (d, J=8.9Hz, 1H), 2.49 (t, 2H), 1.59-1.71 (m, 2H), 0.91 (t, 3H)；ESI-
MS(m/z):264.22(M-H+).
Embodiment 2:N- (6- amino benzo [d] thiazol-2-yl) butyramide
N- (6- nitro benzo [d] thiazol-2-yl) butyramide 53mg (0.2mmol) is weighed to be placed in 20mL eggplant type bottle, it is molten
In anhydrous methanol 10mL, it is slowly added to 6mg palladium carbon, under the conditions of hydrogen shield, stirring at normal temperature 4h.Column chromatographic purifying, obtains Huang
Color solid, yield 98.7%.
1H NMR(300MHz,DMSO-d6) δ: 11.94 (s, 1H), 7.35 (d, J=8.5Hz, 1H), 6.95 (d, J=
2.0Hz, 1H), 6.65 (dd, J=2.1,8.5Hz, 1H), 5.12 (s, 2H), 2.37 (t, 2H), 1.51-1.66 (m, 2H), 0.87
(t,3H)；ESI-MS(m/z):236.25(M-H+),234.38(M+H+).
Embodiment 3:N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) butyramide
Intermediate N (6- amino benzo [d] thiazol-2-yl) butyramide 85mg (0.36mmol) is weighed, 50mL eggplant shape is placed in
In bottle, anhydrous methylene chloride 15mL, triethylamine 1mL is added.36 μ L of 2- chloracetyl chloride is measured, is diluted with 1mL anhydrous methylene chloride,
It is slowly added dropwise into reaction system, reaction 2.5h is stirred at room temperature.Reaction solution is quenched with water, and is extracted three times with methylene chloride and water,
Organic phase is washed twice with saturated salt solution, is merged concentration organic phase, is crossed column purification, obtain yellow solid, yield 73.6%.
1H NMR(300MHz,DMSO-d6) δ: 12.24 (s, 1H), 10.42 (s, 1H), 8.26 (s, 1H), 7.67 (d, J=
8.7Hz, 1H), 7.51 (d, J=8.7Hz, 1H), 4.26 (s, 2H), 2.45 (t, 2H), 1.59-1.67 (m, 2H), 0.91 (t,
3H)；ESI-MS(m/z):312.35(M+H+),310.21(M-H+).
Embodiment 4:N- (6- (2- ((3-hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) butyramide
Weigh intermediate N (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) butyramide 70mg (0.19mmol), carbon
Sour potassium 140mg, is placed in 25mL eggplant-shape bottle, and anhydrous DMF 10mL is added, 3- mercapto-phenol 28mg (0.22mmol) is slowly added dropwise
Into reaction system, reaction 3.5h is stirred at room temperature.It is extracted three times with ethyl acetate and water again, organic phase saturated common salt water washing
Twice, merge concentration organic phase, cross column purification, faint yellow solid, yield 69.1%.
1H NMR(300MHz,DMSO-d6)δ:12.26(s,1H),10.34(s,1H),9.58(s,1H),8.26(s,1H),
7.65 (d, J=8.7Hz, 1H), 7.48 (d, J=8.7Hz, 1H), 7.10 (t, 1H), 6.74-6.84 (m, 2H), 6.59 (d, J=
8.3Hz,1H),3.83(s,2H),2.44(t,2H),1.55-1.70(m,2H),0.90(t,3H)；ESI-MS(m/z):402.30
(M+H+),400.26(M-H+).
Embodiment 5:4- trifluoromethyl-N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazole -2-
Base) benzamide
Using method same as Example 4, with 4-trifluoromethyl-N- (6- (2- chloro acetylamino) benzo [d] thiazole-
2- yl) benzamide replace N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) butyramide, obtain faint yellow solid, receive
Rate 52.1%.
1H NMR(300MHz,DMSO-d6) δ: 13.08 (s, 1H), 10.28 (s, 1H), 9.75 (s, 1H), 8.30 (d, J=
8.3Hz, 2H), 7.94 (d, J=8.3Hz, 2H), 7.62 (dd, J=2.1,8.7Hz, 1H), 7.34 (t, 1H), 7.20 (t, 1H),
7.10-7.15(m,1H),6.90-6.94(m,1H),6.64-6.67(m,1H),4.74(s,2H)；ESI-MS(m/z):502.24
(M-H+).
Embodiment 6:N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -2- naphthalene formyl
Amine
Using method same as Example 4, with N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) -2- naphthalene first
Amide replaces N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) butyramide, obtains faint yellow solid, yield 26.0%.
1H NMR(300MHz,DMSO-d6)δ:13.00(s,1H),10.40(s,1H),9.59(s,1H),8.84-8.87
(m, 1H), 8.36 (s, 1H), 8.18 (d, J=8.4Hz, 1H), 8.11 (t, 1H), 8.06 (d, J=8.3Hz, 1H), 7.71-
7.73 (m, 1H), 7.67-7.69 (m, 1H), 7.57 (dd, J=2.1,8.7Hz, 1H), 7.20 (t, 1H), 7.15 (t, 1H),
6.93-6.96(m,1H),6.83-6.86(m,1H),6.67-6.70(m,1H),6.61-6.64(m,1H),3.88(s,2H)；
ESI-MS(m/z):486.24(M+H+),970.89(2M+H+),484.27(M-H+).
The fluoro- N- of embodiment 7:4- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzene first
Amide
Using method same as Example 4, with the fluoro- N- of 4- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) benzene
Formamide replaces N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) butyramide, obtains faint yellow solid, yield
44.7%.
1H NMR(300MHz,DMSO-d6) δ: 12.88 (s, 1H), 10.39 (s, 1H), 9.59 (s, 1H), 8.35 (d, J=
1.6Hz, 1H), 8.21-8.26 (m, 2H), 7.75 (d, J=8.7Hz, 1H), 7.56 (dd, J=2.1,8.7Hz, 1H), 7.40-
7.46(m,2H),7.14(t,1H),6.83-6.87(m,2H),6.61-6.64(m,1H),3.88(s,2H)；ESI-MS(m/z):
454.23(M+H+),906.78(2M+H+),452.25(M-H+).
Embodiment 8:4- methyl-N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzene
Formamide
Using method same as Example 4, with 4- methyl-N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl)
Benzamide replaces N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) butyramide, obtains faint yellow solid 41mg, receives
Rate 46.1%.
1H NMR(300MHz,DMSO-d6) δ: 12.76 (s, 1H), 10.39 (s, 1H), 9.59 (s, 1H), 8.35 (d, J=
1.8Hz, 1H), 8.07 (d, J=8.1Hz, 2H), 7.75 (d, J=8.8Hz, 1H), 7.55 (dd, J=2.1,8.7Hz, 1H),
7.39 (d, J=8.1Hz, 2H), 7.14 (t, 1H), 6.81-6.86 (m, 2H), 6.61-6.64 (m, 1H), 3.88 (s, 2H),
2.42(s,3H)；ESI-MS(m/z):450.33(M+H+),898.93(2M+H+),448.27(M-H+).
Embodiment 9:3,5- dimethyl-N-(6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazole -2-
Base) benzamide
Using method same as Example 4, with 3,5-dimethyl-N -s (6- (2- chloro acetylamino) benzo [d] thiazole-
2- yl) benzamide replace N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) butyramide, obtain faint yellow solid, receive
Rate 49.6%.
1H NMR(300MHz,DMSO-d6) δ: 12.67 (s, 1H), 10.35 (s, 1H), 9.55 (s, 1H), 8.31 (d, J=
1.9Hz, 1H), 7.75 (s, 2H), 7.71 (d, J=8.6Hz, 1H), 7.53 (dd, J=2.1,8.7Hz, 1H), 7.28 (s, 1H),
7.11(t,1H),6.79-6.83(m,2H),6.58-6.61(m,1H),3.84(s,2H),2.35(s,6H)；ESI-MS(m/z):
464.40(M+H+926.96(2M+H+),462.26(M-H+).
The chloro- N- of embodiment 10:3,5- bis- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazole -2-
Base) benzamide
Using method same as Example 4, with 3,5-two chloro- N- (6- (2- chloro acetylamino) benzo [d] thiazole-2-
Base) benzamide replace N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) butyramide, obtain faint yellow solid, yield
48.0%.
1H NMR(300MHz,DMSO-d6)δ:10.38(s,1H),9.74(s,1H),9.55(s,1H),8.34(s,1H),
8.13 (d, J=1.8Hz, 1H), 7.92 (s, 1H), 7.53 (dd, J=2.1,8.7Hz, 1H), 7.16 (t, 1H), 7.10 (t,
1H),6.88-6.92(m,1H),6.78-6.82(m,1H),6.64-6.67(m,1H),6.57-6.61(m,1H),3.84(s,
2H)；ESI-MS(m/z):502.19(M-H+).
Embodiment 11:N- (6- (2- ((3-hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide
Using method same as Example 4, with N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) benzoyl
Amine replaces N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) butyramide, obtains faint yellow solid, yield 58.6%.
1H NMR(300MHz,DMSO-d6)δ:12.81(s,1H),10.35(s,1H),9.54(s,1H),8.32(s,1H),
8.12 (d, J=7.4Hz, 2H), 7.65 (t, 1H), 7.56 (t, 2H), 7.52 (dd, J=1.9,8.5Hz, 1H), 7.11 (t,
1H), 6.79-6.83 (m, 2H), 6.59 (dd, J=2.2,8.1Hz, 1H), 3.84 (s, 2H)；ESI-MS(m/z):436(M+H+),871.00(2M+H+),434.32(M-H+).
Embodiment 12:N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) thiophene -2-
Formamide
Using method same as Example 4, with N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) thiophene -2-
Formamide replaces N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) butyramide, obtains faint yellow solid, yield
67.4%.
1H NMR(300MHz,DMSO-d6)δ:12.94(s,1H),10.38(s,1H),9.58(s,1H),8.32(s,2H),
8.01 (d, J=4.3Hz, 1H), 7.72 (d, J=8.3Hz, 1H), 7.54 (dd, J=2.0,8.7Hz, 1H), 7.28 (t, 1H),
7.12(t,1H),6.79-6.85(m,2H),6.58-6.63(m,1H),3.86(s,2H)；ESI-MS(m/z):440.21(M-H+).
Embodiment 13:N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) butyramide
Using method same as Example 4,3- hydroxythiophenol is replaced with 4- chlorothio-phenol, obtains faint yellow solid,
Yield 60.1%.
1H NMR(300MHz,DMSO-d6) δ: 12.24 (s, 1H), 10.34 (s, 1H), 8.23 (d, J=2.0Hz, 1H),
7.64 (d, J=8.7Hz, 1H), 7.45 (dd, J=2.1,8.8Hz, 1H), 7.40-7.44 (m, 2H), 7.36-7.39 (m, 2H),
3.88(s,2H),2.43(t,2H),1.59-1.64(m,2H),0.89(t,3H)；ESI-MS(m/z):420.22(M+H+),
418.21(M-H+).
Embodiment 14:4- trifluoromethyl-N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazole -2-
Base) benzamide
Using method same as Example 4,3- hydroxythiophenol is replaced with 4- chlorothio-phenol, obtains faint yellow solid,
Yield 58.7%.
1H NMR(300MHz,DMSO-d6) δ: 13.06 (s, 1H), 10.38 (s, 1H), 8.31 (s, 1H), 8.28 (d, J=
8.1Hz, 2H), 7.93 (d, J=8.3Hz, 2H), 7.70-7.74 (m, 1H), 7.51 (dd, J=2.0,8.7Hz, 1H), 7.42-
7.46(m,2H),7.37-7.40(m,2H),3.89(s,2H)；ESI-MS(m/z):522.40(M+H+),520.26(M-H+).
Embodiment 15:N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -2- naphthalene formyl
Amine
Using method same as Example 4,3- hydroxythiophenol is replaced with 4- chlorothio-phenol, with N- (6- (2- chloracetyl
Amino) benzo [d] thiazol-2-yl) -2- naphthalenecarboxamide replace N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) butyryl
Amine obtains faint yellow solid, yield 65.3%.
1H NMR(300MHz,DMSO-d6)δ:12.67(s,1H),10.39(s,1H),8.81(s,1H),8.31(s,1H),
8.13 (d, J=8.6Hz, 1H), 8.07 (t, 2H), 8.02 (d, J=8.0Hz, 1H), 7.73 (d, J=8.2Hz, 1H), 7.68
(t, 1H), 7.64 (t, 1H), 7.52 (dd, J=2.0,8.7Hz, 1H), 7.44 (d, J=8.6Hz, 2H), 7.39 (d, J=
8.6Hz,2H),3.91(s,2H)；ESI-MS(m/z):504.11(M+H+),502.29(M-H+).
The fluoro- N- of embodiment 16:4- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzene first
Amide
Using method same as Example 4,3- hydroxythiophenol is replaced with 4- chlorothio-phenol, with the fluoro- N- of 4- (6- (2-
Chloro acetylamino) benzo [d] thiazol-2-yl) benzamide replace N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl)
Butyramide obtains faint yellow solid, yield 25%.
1H NMR(300MHz,DMSO-d6)δ:13.69(s,1H),11.23(s,1H),9.13(s,1H),9.02(q,2H),
8.55 (d, J=8.6Hz, 1H), 8.33 (dd, J=2.0,8.7Hz, 1H), 8.25-8.29 (m, 2H), 8.19-8.24 (m, 4H),
4.72(s,2H)；ESI-MS(m/z):470.24(M-H+).
Embodiment 17:4- methyl-N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -4-
(trifluoromethyl) benzamide
3- hydroxythiophenol is replaced with 4- chlorothio-phenol using method same as Example 4, with 4- methyl-N- (6- (2-
Chloro acetylamino) benzo [d] thiazol-2-yl) benzamide replace N- (6- (2- chloro acetylamino) benzo [d] thiazol-2-yl)
Butyramide obtains faint yellow solid, yield 63.8%.
1H NMR(300MHz,DMSO-d6) δ: 12.74 (s, 1H), 10.39 (s, 1H), 8.31 (s, 1H), 8.05 (d, J=
8.1Hz, 2H), 7.73 (d, J=8.6Hz, 1H), 7.52 (dd, J=1.8,8.7Hz, 1H), 7.44-7.49 (m, 2H), 7.39-
7.43(m,2H),7.35-7.39(m,2H),3.91(s,2H),2.41(s,3H)；ESI-MS(m/z):468.35(M+H+),
466.26(M-H+).
Embodiment 18:3,5- dimethyl-N-(6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazole -2-
Base) -4- (trifluoromethyl) benzamide
Using method same as Example 4,3- hydroxythiophenol is replaced with 4- chlorothio-phenol, with 3,5-dimethyl-N -s
(6- (2- chloro acetylamino) benzo [d] thiazol-2-yl) benzamide replaces N- (6- (2- chloro acetylamino) benzo [d] thiazole-
2- yl) butyramide, obtain faint yellow solid, yield 70.6%.
1H NMR(300MHz,DMSO-d6) δ: 12.69 (s, 1H), 10.40 (s, 1H), 8.31 (d, J=1.8Hz, 1H),
7.76 (s, 2H), 7.72 (d, J=8.7Hz, 1H), 7.53 (dd, J=1.9,8.7Hz, 1H), 7.46 (d, J=8.7Hz, 2H),
7.40 (d, J=8.7Hz, 2H), 7.28 (s, 1H), 3.91 (s, 2H), 2.36 (s, 6H)；ESI-MS(m/z):480.26(M+H+).
Embodiment 19:4- trifluoromethyl-N- (6- (2- ((2,4-xylyl) sulfydryl) acetylamino) benzo [d] thiazole-
2- yl) benzamide
Using method same as Example 4,3- hydroxythiophenol is replaced with 2,4-thioxylenols, obtains pale yellow colored solid
Body 96mg, yield 73.3%.
1H NMR(300MHz,DMSO-d6)δ:13.09(s,1H),10.35(s,1H),8.32(s,2H),8.30(s,1H),
7.95 (d, J=8.3Hz, 2H), 7.74 (d, J=8.7Hz, 1H), 7.53 (dd, J=2.0,8.8Hz, 1H), 7.33 (d, J=
7.9Hz, 1H), 7.05 (s, 1H), 7.01 (d, J=8.1Hz, 1H), 3.79 (s, 2H), 2.32 (s, 3H), 2.24 (s, 3H)；
ESI-MS(m/z):514.31(M-H+).
Embodiment 20:4- trifluoromethyl-N- (6- (2- (2- naphthalene sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzene first
Amide
Using method same as Example 4,3- hydroxythiophenol is replaced with beta naphthal, obtains faint yellow solid, yield
63.0%.
1H NMR(300MHz,DMSO-d6)δ:13.09(s,1H),10.48(s,1H),8.35(s,1H),8.32(s,1H),
8.30 (s, 1H), 7.91-7.80 (m, 3H), 7.88 (d, J=8.2Hz, 2H), 7.83 (d, J=7.9Hz, 1H), 7.74 (d, J=
8.3Hz, 1H), 7.56 (d, J=8.1Hz, 2H), 7.50-7.53 (m, 1H), 7.45-7.50 (m, 1H), 4.03 (s, 2H)；ESI-
MS(m/z):538.40(M+H+),1074.92(2M+H+),536.27(M-H+).
Embodiment 21:4- trifluoromethyl-N- (6- (2- (2- pyrimidine sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzene
Formamide
Using method same as Example 4,3- hydroxythiophenol is replaced with 2- mercaptopyrimidine, obtains faint yellow solid,
Yield 76.2%.
1H NMR(300MHz,DMSO-d6) δ: 13.09 (s, 1H), 10.47 (s, 1H), 8.66 (d, J=4.9Hz, 2H),
8.35 (s, 1H), 8.31 (d, J=8.2Hz, 2H), 7.95 (d, J=8.2Hz, 2H), 7.75 (d, J=9.0Hz, 1H), 7.59
(dd, J=1.8,8.8Hz, 1H), 7.24 (t, 1H), 4.15 (s, 2H)；ESI-MS(m/z):490.30(M+H+),978.80(2M
+H+),488.28(M-H+).
Embodiment 22:4- trifluoromethyl-N- (6- (2- (2- imidazoles sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzene
Formamide
Using method same as Example 4,3- hydroxythiophenol is replaced with 2- mercaptoimidazole, obtains faint yellow solid,
Yield 66.1%.
1H NMR(300MHz,DMSO-d6) δ: 13.11 (s, 1H), 12.36 (s, 1H), 10.64 (s, 1H), 8.34 (d, J=
1.7Hz, 1H), 8.31 (d, J=8.3Hz, 2H), 7.96 (d, J=8.3Hz, 2H), 7.75 (d, J=8.6Hz, 1H), 7.55
(dd, J=1.8,8.8Hz, 1H), 7.09 (s, 2H), 3.94 (s, 2H)；ESI-MS(m/z):478.20(M+H+),476.17(M-
H+).
Embodiment 23:4- trifluoromethyl-N- (6- (2- (2- benzimidazole sulfydryl) acetylamino) benzo [d] thiazole -2-
Base) benzamide
Using method same as Example 4,3- hydroxythiophenol is replaced with 2-mercaptobenzimidazole, obtains pale yellow colored solid
Body, yield 45.7%.
1H NMR(300MHz,DMSO-d6) δ: 13.12 (s, 1H), 12.68 (s, 1H), 10.72 (s, 1H), 8.37 (d, J=
1.7Hz, 1H), 8.31 (d, J=8.2Hz, 2H), 7.95 (d, J=8.4Hz, 2H), 7.75 (d, J=8.7Hz, 1H), 7.58
(dd, J=2.0,8.8Hz, 1H), 7.53 (s, 1H), 7.39 (d, J=4.5Hz, 1H), 7.10-7.17 (m, 2H), 4.32 (s,
2H)；ESI-MS(m/z):528.20(M+H+),526.15(M-H+).
Embodiment 24:4- trifluoromethyl-N- (6- (2- (2- cyclohexyl sulfydryl) acetylamino) benzo [d] thiazol-2-yl)
Benzamide
Using method same as Example 4,3- hydroxythiophenol is replaced with sulfydryl hexamethylene, obtains yellow solid, received
Rate 34%.
1H NMR(300MHz,DMSO-d6) δ: 13.10 (s, 1H), 10.25 (s, 1H), 8.37 (d, J=1.5Hz, 1H),
8.31 (d, J=8.1Hz, 2H), 7.95 (d, J=8.2Hz, 2H), 7.74 (d, J=8.7Hz, 1H), 7.55 (dd, J=2.0,
8.7Hz,1H),3.36(s,2H),2.54-2.92(m,1H),1.94-2.03(m,2H),1.66-1.73(m,2H),1.54-
1.59(m,1H),1.20-1.31(m,5H)；ESI-MS(m/z):494.51(M+H+),492.35(M-H+).
Embodiment 25:4- trifluoromethyl-N- (6- (2- ((4- aminophenyl) sulfydryl) acetylamino) benzo [d] thiazole -2-
Base) benzamide
Using method same as Example 4,3- hydroxythiophenol is replaced with 4- aminothiophenol, obtains pale yellow colored solid
Body, yield 70.4%.
1H NMR(300MHz,DMSO-d6)δ:13.09(s,1H),10.17(s,1H),8.33(s,2H),8.30(s,1H),
7.95 (d, J=8.4Hz, 2H), 7.73 (d, J=8.7Hz, 1H), 7.52 (dd, J=1.9,8.7Hz, 1H), 7.17 (d, J=
8.4Hz, 2H), 6.51 (d, J=8.4Hz, 2H), 5.32 (s, 2H), 3.57 (s, 2H)；ESI-MS(m/z):503.50(M+H+),
1004.82(2M+H+),501.27(M-H+).
Embodiment 26:4- trifluoromethyl-N- (6- (2- ((3- carboxyl pyridine) sulfydryl) acetylamino) benzo [d] thiazole -2-
Base) benzamide
Using method same as Example 4,3- hydroxythiophenol is replaced with 2- mercaptonicotinic acid, obtains violet solid, received
Rate 64.9%.
1H NMR(300MHz,DMSO-d6) δ: 10.33 (s, 1H), 8.45 (dd, J=2.0,4.8Hz, 1H), 8.31 (d, J
=8.0Hz, 2H), 8.26 (d, J=1.5Hz, 1H), 8.12 (dd, J=1.7,7.4Hz, 1H), 7.90 (d, J=8.1Hz, 2H),
7.64 (d, J=8.6Hz, 1H), 7.52 (dd, J=1.7,78.2Hz, 1H), 7.13 (q, 1H), 3.90 (s, 2H)；ESI-MS(m/
z):531(M-H+).
Embodiment 27: Cytostatic to tumor cell experiment
Cytostatic to tumor cell experiment is carried out to the compound of the present invention, experimental method uses conventional mtt assay (such as
Lv Qiujun edits " developmental pharmacology research method ", Chemical Industry Press, 2007:242-243).
Cell strain selects HCT116 (people's colon-cancer cell) U2OS (human osteosarcoma cell) to carry out control experiment, by Shanghai medicine
Industrial research institute pharmacological evaluation room freezes and passes on.Culture solution is that DMEM+10%FBS+ is dual anti-.
MTT solution is prepared: being weighed 0.5 gram of MTT, is dissolved in the phosphate buffer (PBS) of 100mL or without phenol red culture medium
In, with 0.22 μm of membrane filtration to remove the bacterium in solution, puts 4 DEG C and be kept in dark place.
Sample preparation: after DMSO (Merck) dissolution, the solution or uniform mixed that PBS (-) is made into 1000 μ g/mL is added
Suspension, then with PBS (-) dilution containing DMSO.
The compound MLN4924 of high activity is made into positive reference substance solution with same condition.
Mtt assay: it is 5-6 × 10 that concentration, which is added, in the every hole of 96 orifice plates4The 100 μ L of cell suspension of a/mL, sets 37 DEG C, 5%CO2Training
It supports in case.After 24 hours, addition sample liquid, 10 holes μ L/, if duplicate hole, 37 DEG C, 5%CO2Effect 72 hours.Every hole is added
Lysate is added after 4 hours in the 20 μ L of MTT solution of 5mg/mL, effect, and 100 holes μ L/ are set in incubator, complete with MK-2 after dissolution
Automatic microplate reader surveys 570nm OD value.Calculation of half inhibitory concentration IC50。
Experimental result is shown in Table 1, wherein sample refers to the mercaptobenzothiazoler amides compound prepared in corresponding embodiment
(example: embodiment 4:N- (6- (2- ((3-hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) butyramide).
The half-inhibitory concentration IC of the test compound on tumor cell of table 150(unit: μM)
The experimental results showed that, most compounds of the invention have good anti-tumor activity, especially embodiment above
7,8,9,12,13,15,16,17,19,20,23,25 noval chemical compound, the compounds of this invention can be used as good antitumor agent.
Embodiment 28:WB experiment
Show the compound of embodiment 9,20,25 and the effect machine of positive control drug MLN4924 by western experiment
Make identical, gray analysis shows that three compounds can effectively inhibit circuit upstream albumen NEDD8 and other albumen phase interactions
With downstream albumen UBC12 has obvious accumulation phenomena in cell, and shows preferable concentration dependent, as shown in Figure 1.
Therefore, mercaptobenzothiazoler amides compound of the present invention can be used for preparing NAE micromolecular inhibitor.
The basic principles, main features and advantages of the present invention have been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, various changes and improvements may be made to the invention without departing from the spirit and scope of the present invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent defines.
Claims (2)
1. the preparation method of a kind of mercaptobenzothiazoler amides compound or its pharmaceutical salts, which is characterized in that preparation method
Reaction stream formula is as follows:
Preparation method the following steps are included:
A, synthetic intermediate (II): 2- amino-6-nitrobenzothiazole is dissolved in anhydrous organic solvent, acid binding agent is added, then
The substitution acyl chlorides for being dissolved in identical anhydrous organic solvent is added dropwise under ice bath, room temperature reaction is reacted completely to raw material, through pillar layer separation
Obtain intermediate (II)；
B, synthetic intermediate (III): intermediate (II) is dissolved in organic solvent, 5% palladium carbon is then slowly added into, is passed through hydrogen chamber
Temperature reaction is reacted completely to raw material, obtains intermediate (III) through pillar layer separation；
C, synthetic intermediate (IV): intermediate (III) is dissolved in anhydrous organic solvent, acid binding agent is added, is then added dropwise under ice bath
It is dissolved in the chloracetyl chloride of identical anhydrous organic solvent, room temperature reaction is reacted completely to raw material, obtains intermediate through pillar layer separation
(IV)；
D, it synthesizes target product (I): intermediate (IV) being dissolved in anhydrous organic solvent, inorganic base is added, is then added dropwise under ice bath
It is dissolved in the substitution thiophenol or mercaptan of identical anhydrous organic solvent, room temperature reaction is reacted completely to raw material, obtained through pillar layer separation
Target product (I)；
The mercaptobenzothiazoler amides compound is selected from following any:
N- (6- (2- ((3-hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) butyramide,
4- trifluoromethyl-N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -2- naphthalenecarboxamide,
The fluoro- N- of 4- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- methyl-N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
3,5- dimethyl-N-(6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
The chloro- N- of 3,5- bis- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
N- (6- (2- ((3-hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) thiophene-2-carboxamide derivatives,
N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) butyramide,
4- trifluoromethyl-N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -2- naphthalenecarboxamide,
The fluoro- N- of 4- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- methyl-N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -4- (trifluoromethyl) benzene
Formamide,
3,5- dimethyl-N-(6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -4- (fluoroform
Base) benzamide,
4- trifluoromethyl-N- (6- (2- ((2,4-xylyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzoyl
Amine,
4- trifluoromethyl-N- (6- (2- (2- naphthalene sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- (2- pyrimidine sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- (2- imidazoles sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- (2- benzimidazole sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- (2- cyclohexyl sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- ((4- aminophenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
Or
4- trifluoromethyl-N- (6- (2- ((3- carboxyl pyridine) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide.
2. a kind of mercaptobenzothiazoler amides compound or its pharmaceutical salts are in preparation NEDD8 signal pathway inhibitor or NAE suppression
Application in preparation, the mercaptobenzothiazoler amides compound are selected from following any:
N- (6- (2- ((3-hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) butyramide,
4- trifluoromethyl-N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -2- naphthalenecarboxamide,
The fluoro- N- of 4- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- methyl-N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
3,5- dimethyl-N-(6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
The chloro- N- of 3,5- bis- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
N- (6- (2- ((3-hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) thiophene-2-carboxamide derivatives,
N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) butyramide,
4- trifluoromethyl-N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -2- naphthalenecarboxamide,
The fluoro- N- of 4- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- methyl-N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -4- (trifluoromethyl) benzene
Formamide,
3,5- dimethyl-N-(6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -4- (fluoroform
Base) benzamide,
4- trifluoromethyl-N- (6- (2- ((2,4-xylyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzoyl
Amine,
4- trifluoromethyl-N- (6- (2- (2- naphthalene sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- (2- pyrimidine sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- (2- imidazoles sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- (2- benzimidazole sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- (2- cyclohexyl sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
4- trifluoromethyl-N- (6- (2- ((4- aminophenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,
Or
4- trifluoromethyl-N- (6- (2- ((3- carboxyl pyridine) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610344959.6A CN106008394B (en) | 2016-05-23 | 2016-05-23 | Mercaptobenzothiazoler amides compound and its preparation and the purposes as drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610344959.6A CN106008394B (en) | 2016-05-23 | 2016-05-23 | Mercaptobenzothiazoler amides compound and its preparation and the purposes as drug |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106008394A CN106008394A (en) | 2016-10-12 |
| CN106008394B true CN106008394B (en) | 2018-12-04 |
Family
ID=57096196
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610344959.6A Expired - Fee Related CN106008394B (en) | 2016-05-23 | 2016-05-23 | Mercaptobenzothiazoler amides compound and its preparation and the purposes as drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106008394B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107021937B (en) * | 2017-03-27 | 2019-06-21 | 沈阳药科大学 | Benzothiazole Carbox amide and its application |
| CN115594671B (en) * | 2021-07-08 | 2024-03-15 | 沈阳药科大学 | Benzothiazole derivative, preparation method and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7951810B2 (en) * | 2005-02-04 | 2011-05-31 | Millennium Pharmaceuticals, Inc. | Substituted pyrrolo[2,3-d]pyrimidines as inhibitors of E1 activating enzymes |
| NZ570084A (en) * | 2006-02-02 | 2011-07-29 | Millennium Pharm Inc | Inhibitors of E1 activating enzymes |
| EP2430026A1 (en) * | 2009-05-14 | 2012-03-21 | Millennium Pharmaceuticals, Inc. | Hydrochloride salt of ((1s,2s,4r)-4-{4-[(1s)-2,3-dihydro-1h-inden-1-ylamino]-7h-pyrrolo [2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate |
-
2016
- 2016-05-23 CN CN201610344959.6A patent/CN106008394B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN106008394A (en) | 2016-10-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Machado et al. | Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-aryl-3-[(thieno [3, 2-b] pyridin-7-ylthio) phenyl] ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors | |
| Di Fruscia et al. | The Discovery of a Highly Selective 5, 6, 7, 8‐Tetrahydrobenzo [4, 5] thieno [2, 3‐d] pyrimidin‐4 (3H)‐one SIRT2 Inhibitor that is Neuroprotective in an in vitro Parkinson’s Disease Model | |
| Liu et al. | Design, synthesis and biological evaluation of novel thieno [3, 2-d] pyrimidine derivatives possessing diaryl semicarbazone scaffolds as potent antitumor agents | |
| Zhang et al. | Discovery and evaluation of triple inhibitors of VEGFR-2, TIE-2 and EphB4 as anti-angiogenic and anti-cancer agents | |
| CN106916101A (en) | Double target spot inhibitor of NAMPT/HDAC and preparation method thereof | |
| El‐Adl et al. | 5‐(4‐Methoxybenzylidene) thiazolidine‐2, 4‐dione‐derived VEGFR‐2 inhibitors: design, synthesis, molecular docking, and anticancer evaluations | |
| Sahner et al. | Combining in silico and biophysical methods for the development of Pseudomonas aeruginosa quorum sensing inhibitors: an alternative approach for structure-based drug design | |
| Liu et al. | Design and synthesis of sulfonamide-substituted diphenylpyrimidines (SFA-DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors with improved activity toward B-cell lymphoblastic leukemia | |
| Zhan et al. | Design, synthesis and antitumor activities of novel bis-aryl ureas derivatives as Raf kinase inhibitors | |
| Sun et al. | Discovery of novel anti-angiogenesis agents. Part 8: Diaryl thiourea bearing 1H-indazole-3-amine as multi-target RTKs inhibitors | |
| Türe et al. | Synthesis, anticancer activity, toxicity evaluation and molecular docking studies of novel phenylaminopyrimidine—(thio) urea hybrids as potential kinase inhibitors | |
| CN106699785A (en) | 2-(N-oxide pyridine-2-ylamino)-pyrido[2,3-d]pyrimidin-7-one compound as CDK4/6 inhibitor | |
| CN106008394B (en) | Mercaptobenzothiazoler amides compound and its preparation and the purposes as drug | |
| Zhao et al. | Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors | |
| Wang et al. | Discovery of multi-target receptor tyrosine kinase inhibitors as novel anti-angiogenesis agents | |
| Liu et al. | Phosphamide-containing diphenylpyrimidine analogues (PA-DPPYs) as potent focal adhesion kinase (FAK) inhibitors with enhanced activity against pancreatic cancer cell lines | |
| Pillaiyar et al. | Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27 | |
| Routholla et al. | Design, synthesis and binding mode of interaction of novel small molecule o-hydroxy benzamides as HDAC3-selective inhibitors with promising antitumor effects in 4T1-Luc breast cancer xenograft model | |
| Wang et al. | Design, synthesis and biological evaluation of novel 4-phenoxypyridine based 3-oxo-3, 4-dihydroquinoxaline-2-carboxamide derivatives as potential c-Met kinase inhibitors | |
| Casalvieri et al. | Substituted pteridinones as p90 ribosomal S6 protein kinase (RSK) inhibitors: A structure-activity study | |
| Ballesteros-Casallas et al. | Synthesis of 2, 7-diarylpyrazolo [1, 5-a] pyrimidine derivatives with antitumor activity. Theoretical identification of targets | |
| CN108530464A (en) | A kind of multiple target point kinase inhibitor | |
| Zhou et al. | Design, synthesis and evaluation of anti-proliferative activity of 2-aryl-4-aminoquinazoline derivatives as EGFR inhibitors | |
| CN109824640A (en) | A kind of coumarin kind compound and its pharmaceutical composition, preparation method and application | |
| CN101896460B (en) | Proteinase inhibitors useful for treating cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181204 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |