CN108689960A - 5- benzylidenes -2- phenyl thiazoles ketone compounds and its preparation and application - Google Patents
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
- C07D277/34—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The present invention relates to a kind of 5- benzylidenes -2- phenyl thiazoles ketone compounds and its preparations and application.Specifically, the compounds of this invention has general formula(I)Shown structure, wherein the definition of each group and substituent group is as noted in the discussion.Purposes the invention also discloses the preparation method of the compound and its in terms of prevention and/or treating cancer relevant disease.The compounds of this invention has the inhibitory activity of excellent protein-arginine methyltransferase 1 (PRMT1), protein-arginine methyltransferase 5 (PRMT5) and histone demethylase LSD1, and can induce apoptosis of tumor cells and tumour cell is arrested in the G1 phases, therefore can be used in preparing a series of treatments and arginine methyltransferase 1, the drug of arginine methyltransferase 5 and the abnormal relevant disease of histone demethylase LSD1 activity.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, more particularly to 5- benzylidenes -2- shown in a kind of Formulas I
The preparation and application of phenyl thiazole ketone compounds.
Background technology
Methylate on istone lysine and arginine is to study more deep one of posttranslational modification.Its shape that methylates
State is balanced by two major classes enzyme:Histone methyltransferase(histone methyltransferases, HMTs)And histone
Demethylase(Histone demethylases, HDMs).And its abnormality is related to many human diseases.
It is a kind of in nucleus and thin that the arginine that protein arginine transmethylase (PRMTs) family participates in, which methylates,
The posttranslational modification mode that cytoplasm is widely present, using S- Adenosyl-Methionines as methyl donor, methylate modification extract of protein ammonia
The nitrogen-atoms of sour side chain generates AdoHcy and methylarginine.The substrate of PRMTs is to be rich in glycine and essence
The protein of propylhomoserin structural domain.10 kinds of PRMTs are found altogether with mammal at present, wherein 8 kinds have biological activity.Root
According to the difference of methylate, I types and II type can be classified as:I type PRMT is catalyzed to form monomethyl arginine and asymmetric
Diethylarginine, II type PRMT is catalyzed to form MMA and symmetrical diethylarginine.PRMT1 and PRMT5 are belonging respectively to I
Type, II type PRMT.
The adjustment effect of istone lysine demethylase LSD1 is according to gene and organization decided, it participates in several
Tissue reaction, such as vertebrate animal development, cancer, inflammatory disease and neurodegenerative disease.Histone demethylase is in addition in base
Except the effect in adjusting, it also reported that they participate in supporting DNA replication dnas, cell cycle kinetics and fissional recently
Base molecule process.The mistake of these histone demethylases, which is adjusted, usually causes cell cycle arrest, and is also possible to lead
The unstability of genome in carcinogenic disease.
Sequence and structural conservation analysis shows, LSD1 belongs to the amine oxidase superfamily of FAD dependences, is widely present in
In the eucaryotes such as yeast, mammal.As monoamine oxidase(MAO)A member in family, LSD1 are unique using coenzyme F AD
Redox property, the monomethylation on specificity removal histone H 3 K4 and di-methylation modification.In addition to histone substrates
Outside, LSD1 also acts on a series of cell proliferations, apoptosis has the nonhistones substrate of important regulating and controlling effect, such as p53,
DNM/Ts and MYPT1 etc..Meanwhile LSD1 is present in a variety of transcription control complexes, regulates and controls the signal transduction of multiple keys
Access.In brief, LSD1 has highly important biological function, in embryonic development, cell Proliferation, chromosome separation, does
Key effect is played during cell regulation and control etc. are a series of.In addition, recently research have indicated that, activity exception and a variety of cancers of LSD1
Disease(Such as neuroblastoma, breast cancer, colon cancer)Generation, development have a close contact, and its be overexpressed it is horizontal with
The recurrence of prostate cancer has significant correlation.
The albumen that PRMT5 can methylate different participates in adjusting physiology course, such as PRMT5 can pass through the histone that methylates
With transcriptional elongation factor to influence gene transcription process;It can methylate Suppressor p53 change p53 state of activation.
PRMT5 and its molecular chaperone protein MEP50 can form macromolecular complex with multiple protein, can be catalyzed Sm albumen,
Nucleolin, p53, histone H2A, H3 and H4, the methyl of a variety of substrate proteins in the cytoplasm such as SPT5 and MBD2 and nucleus
Change, therefore, PRMT5 plays key effect during RNA processing, chromatin remodeling and controlling gene expression etc..PRMT5 is logical
Hypermethylation RAF albumen regulates and controls MAPK/ERK signal paths, adjusts ribosomal life by methylating ribosome protein S 10
Object synthesizes, by regulating and controlling the expression of eIF4E and the translation of P53 to play an important role in cell survival.PRMT5 can inhibit
Apoptosis albumen 4(PDCD4)Tumor suppression function.The methyl transferase activity of PRMT5 can by MEP50 or
The phosphorylation of PRMT5 itself is regulated and controled.Thr5 on cyclin D1/CDK4 phosphorylations MEP50, has activated PRMT5's
Methyl transferase activity extends the life cycle of tumour cell.On the contrary, the tumorigenesis mutation on Jak2(V617F,K539L)Phosphoric acid
Change upper 297,304 and 306 tyrosine of PRMT5, the combination of PRMT5 and MEP50 can be destroyed, lowers to histone substrates
Methyl catalytic activity.
At present studies have found that in jacket cell lymph cancer and diffusivity large B cell lymphoid tumor there are PRMT1 and
The overexpression of PRMT5, PRMT and the proliferation of malignant tumour B cell have direct association with survival.Therefore PRMT be one have before
The cancer target of scape.There are one the micromolecular inhibitors of PRMT5 to enter clinical I phase conceptual phase.Have simultaneously multiple
The small molecule that antitumor activity is played using LSD1 as target enters clinical investigation phase.
In conclusion there is an urgent need in the art to develop novel arginine methyltransferase and histone demethylase suppression
Preparation.
Invention content
The purpose of the present invention is to provide a kind of general formulas(I)Shown compound and preparation method thereof and its preparation prevent and control
The application of composition in terms for the treatment of cancer-related diseases.
The first aspect of the present invention provides the compound of structure novel:.Wherein, R is-H
Or-CH3;R1, R2, R3And R4Can be separately or concurrently-H, C1-C3Alkyl, hydroxyl ,-O (C1-C3Alkyl) ,-N (C1-C3Alkyl)
(C1-C3Alkyl), benzyloxy, halogen ,-CO (O) (C1-C3Alkyl).
Wherein, general formula(I)Preferred structure is as follows:
Target product is prepared by following steps:The ethanol solution of the methyl benzonitrile of 0.05 ~ 2mol/L of configuration, thioacetic acid,
The ethanol solution of methyl benzonitrile is added in triethylamine and corresponding benzaldehyde derivative, is heated to reflux, removes solvent later, obtains
To target product.
Wherein, thioacetic acid, triethylamine and the molar ratio of corresponding benzaldehyde derivative and methyl benzonitrile are respectively 2
~2.4:1,0.2~0.5:1,0.5~0.8:1
Wherein, reflux temperature is 78 ~ 88 °C.
Wherein, it is 10-14h to be heated to reflux the time.
Wherein, the method for the removing solvent is vacuum rotary steam.
The general formula(I)And its pharmaceutical salts, prodrug, solvate, as active component, the pharmaceutical composition of preparation can
With prevention and/or the drug for the treatment of cancer or relevant disease.
The pharmaceutical compositions can be injection, wafer, tablet, pill, powder or granule.
Wherein, prevent and/or treat cancer be preferably leukaemia, lymthoma, breast cancer, lung cancer, carcinoma of urinary bladder, gastric cancer,
Cancer of pancreas, prostate cancer, colon cancer, Huppert's disease AML, liver cancer, melanoma, head and neck cancer, thyroid cancer, nephrocyte
Cancer, glioblast cancer and carcinoma of testis.
Wherein, relevant disease is arginine methyltransferase and the relevant disease of lysine demethylase enzymatic activity.
Compared with prior art, the present invention has following major advantage:
(1)The compound has stronger inhibitory activity to PRMT1, PRMT5 and LSD1;
(2)Preparation method is simple for the compound;
(3)The compound has stronger tumor cell proliferation inhibition activity, and is obtained in the cell to the targeting of PRMT5
Confirmation;
(4)Raw material is easy to get.
Description of the drawings:
Enzyme activity inhibitory activity of Fig. 1 compounds I-5 to PRMT1 and LSD1.
Fig. 2 compounds I-20 increases MV4-11, RCH-ACV, REH, Jeko, RS4.11, THP1, U937, NALM6 cell
The influence grown.
Influences of Fig. 3 compound I-5 and I-20 to the proliferation of MV4-11 cells.
Influences of Fig. 4 compound I-5 and I-19 on MV4-11 cells to the expressing quantity of SDMA.
Influences of Fig. 5 compounds I-5 to the MV4-11 cell cycles.
Influences of Fig. 6 compounds I-5 to MV4-11 Apoptosis.
Specific implementation mode
It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
1 general formula of embodiment(I)The preparation of compound
10 mL ethyl alcohol are dissolved to methyl benzonitrile(59 mg, 0.5 mmol), thioacetic acid(1 equivalent), triethylamine(1 equivalent)With
And corresponding benzaldehyde derivative(1 equivalent).Mixture is heated to reflux 12 hours, solvent is removed under reduced pressure later, residue is through column
Target compound is obtained after chromatographic isolation.
Obtain following product:
(Z) -5- benzylidenes -2- (pMethylbenzene) thiazole -4 (5H) -one(I-1), yellow solid (46 mg, 33%), fusing point
190-192 °C. 1H NMR (600 MHz, CDCl3) δ 8.12 (d, J = 7.8 Hz, 2H), 8.05 (s, 1H),
7.68 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H),
2.48 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 187.1, 183.4, 146.7, 138.1, 133.9,
131.0, 130.6, 130.0, 129.2, 129.2, 129.0, 126.6, 22.0. ESI-MS m/z: 280.0 [M+
H]+.
(Z) -5- (2- methoxybenzylidenes) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-2), yellow solid (57 mg,
37%), 166-168 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.51 (s, 1H), 8.11 (d, J = 8.4
Hz, 2H), 7.69 (dd, J = 7.8, 1.2 Hz, 1H), 7.46 – 7.42 (m, 1H), 7.35 (d, J =
8.4 Hz, 2H), 7.08 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 3.92 (s,
3H), 2.47 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 187.1, 183.5, 159.3, 146.5,
133.5, 132.8, 130.1, 129.5, 129.0, 126.5, 123.4, 121.0, 111.4, 55.8, 22.1.
ESI-MS m/z: 310.0 [M+H]+.
(Z) -5- (3- methoxybenzylidenes) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-3), yellow solid (66 mg,
43%), 158-160 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 8.01
(s, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 7.8
Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 7.8, 2.4 Hz, 1H), 3.89 (s,
3H), 2.48 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 187.1, 183.4 160.1 146.8 138.0
135.3 130.2 130.0, 129.2, 129.0, 126.9 123.2, 116.7, 115.6, 55.5 22.0. ESI-MSm/z: 310.0 [M+H]+.
(Z) -5- (4- methoxybenzylidenes) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-4), orange solids (53 mg,
34%), 221-223 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 7.8 Hz, 2H), 8.02
(s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 8.4
Hz, 2H), 3.89 (s, 3H), 2.48 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 186.4, 183.6,
162.0, 146.4, 138.2, 132.8, 13.0, 129.4, 128.8, 126.6, 123.8, 114.8, 55.6,
22.0. ESI-MS m/z: 310.0 [M+H]+.
(Z) -5- (3,4- dihydroxy benzenes methylene) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-5), red solid (34 mg,
22%), 256-258 °C of of fusing point1H NMR (600 MHz, MeOD) δ 8.11 (d, J = 8.4 Hz, 2H), 7.91
(s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 2.4 Hz, 1H), 7.18 (dd, J =
8.4, 2.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 2.48 (s, 3H). 13C NMR (150 MHz,
MeOD) δ 191.6, 187.1, 183.7, 146.8, 146.1, 139.8, 129.8, 129.1, 128.3, 125.5,
125.4, 121.6, 116.5, 115.7, 20.5. ESI-MS m/z: 312.0 [M+H]+.
(Z) -5- (4- hydroxy 3-methoxybenzenes methylene) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-6), Chinese red solid
(42 mg, 26%), 197-199 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz,
2H), 7.98 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.29 (dd, J = 8.4, 1.8 Hz, 1H),
7.15 (d, J = 1.8 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.00 (s, 3H), 2.48 (s,
3H). 13C NMR (150 MHz, CDCl3) δ 186.4, 183.7, 148.9, 147.1, 146.6, 138.7,
130.1, 129.5, 129.0, 126.6, 125.8, 123.8, 115.4, 112.8, 56.2, 22.1. ESI-MS m/ z: 326.0 [M+H]+.
(Z) -5- (4- methoxyl group -3- hydroxy-benzylidenes) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-7), red solid
(62 mg, 38%), 206-208 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz,
2H), 7.95 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 1.8 Hz, 1H), 7.21
(dd, J = 8.4, 1.8 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H), 2.47 (s,
3H). 13C NMR (150 MHz, CDCl3) δ 186.8, 183.8, 149.3, 146.6, 146.3, 138.4,
130.1, 129.4, 129.0, 127.6, 125.5, 124.5, 115.6, 111.0, 56.3, 22.1. ESI-MS m/ z: 326.0 [M+H]+.
(Z) -5- (3,5- dimethoxybenzylidens) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-8), yellow solid (64
Mg, 38%), 184-186 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz, 2H),
7.94 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 2.4 Hz, 2H), 6.56 (t, J
= 2.4 Hz, 1H), 3.86 (s, 6H), 2.47 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 187.3,
183.4, 161.3, 146.9, 138.2, 135.8, 130.1, 129.3, 129.1, 127.2, 108.6, 103.2,
55.7, 22.1. ESI-MS m/z: 340.0 [M+H]+.
(Z) -5- (3,4- dimethoxybenzylidens) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-9), yellow-orange solid (44
Mg, 26%), 187-189 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 2H),
8.00 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.32 (dd, J = 8.4, 1.8 Hz, 1H), 7.18
(d, J = 1.8 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H),
2.48 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 186.4, 183.7, 150.9, 149.6, 146.6,
138.6, 130.1, 129.5, 129.0, 127.0, 125.6, 124.1, 112.9, 111.6, 56.3, 56.2,
22.2. ESI-MS m/z: 340.0 [M+H]+.
(Z) -5- (3- hydroxyl -4,5- dimethoxybenzylidens) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-11), orange
Solid (59 mg, 33%), 179-181 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 8.4
Hz, 2H), 7.91 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 1.8 Hz, 1H),
6.77 (d, J = 1.8 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 2.48 (s, 3H). 13C NMR
(150 MHz, CDCl3) δ 187.0, 183.6, 152.6, 149.8, 146.8, 138.2, 138.1, 130.1,
129.8, 129.4, 129.1, 126.0, 110.1, 107.8, 61.3, 56.2, 22.1. ESI-MS m/z: 356.0
[M+H]+.
(Z) -5- (4- hydroxyl -3,5- dimethoxybenzylidens) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-12), orange red
Color solid (50 mg, 28%), 227-229 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 8.4
Hz, 2H), 7.96 (s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 6.93 (s, 2H), 3.99 (s, 6H),
2.48 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 186.3, 183.6, 147.6, 146.6, 138.9,
138.2, 130.1, 129.4, 129.0, 125.6, 124.1, 108.1, 56.6, 22.2. ESI-MS m/z:
356.0 [M+H]+.
(Z) -5- (4- cumenes methylene) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-24), yellow solid (59 mg,
37%), 146-148 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 2H), 8.04
(s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.37 (m, 4H), 2.98 (dt, J = 13.8, 6.6 Hz,
1H), 2.48 (s, 3H), 1.29 (s, 3H) , 1.28 (s, 3H). 13C NMR (150 MHz, CDCl3) δ
187.0, 183.7, 152.8, 146.7, 138.4, 131.6, 131.1, 130.1, 129.4, 129.0, 127.6,
125.6, 34.4, 23.8, 22.1. ESI-MS m/z: 322.1 [M+H]+.
(Z) -5- (4- (dimethylamino) benzylidene) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-25), violet solid
(63 mg, 36%), 161-163 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.08 (d, J = 8.4 Hz,
2H), 7.97 (s, 1H), 7.55 (d, J = 9.0 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 6.72
(d, J = 9.0 Hz, 2H), 3.44 (q, J = 7.2 Hz, 4H), 2.45 (s, 3H), 1.22 (t, J = 7.2
Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 184.9, 184.1, 150.1, 145.6, 139.7, 133.7,
129.9, 129.9, 129.6, 120.8, 119.4, 111.7, 44.8, 22.0, 12.7. ESI-MS m/z: 351.1
[M+H]+.
(Z) -5- (4- (diethylamino) benzylidene) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-26), violet solid
(43 mg, 27%), 222-224 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz,
2H), 8.00 (s, 1H), 7.59 (d, J = 9.0 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 6.75
(d, J = 9.0 Hz, 2H), 3.10 (s, 6H), 2.46 (s, 3H). 13C NMR (150 MHz, CDCl3) δ
185.2, 184.1, 152.2, 145.8, 139.7, 133.4, 123.0, 129.8, 128.7, 121.6, 120.1,
112.1, 40.2, 22.0. ESI-MS m/z: 323.0 [M+H]+.
(Z) -5- (3,4- dimethylbenzylidenes) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-27), yellow solid (38
Mg, 25%), 200-202 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H),
8.01 (s, 1H), 7.43 (d, J = 6.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 2.48 (s,
3H), 2.35 (s, 3H), 2.34 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 187.0, 183f.7,
146.6, 140.9, 138.8, 137.8, 132.1, 131.7, 130.0, 130.1, 129.5, 129.0, 128.5,
125.3, 22.2, 20.2, 20.0. ESI-MS m/z: 308.1 [M+H]+.
(Z) -5- (4- methyl benzylidenes) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-28), yellow solid (35 mg,
24%), 230-232 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 2H), 8.03
(s, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.8
Hz, 2H), 2.48 (s, 3H), 2.43 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 187.0, 183.7,
146.7, 142.0, 138.4, 131.3, 130.9, 130.2, 130.1, 129.4, 129.0, 125.5, 22.1,
21.8. ESI-MS m/z: 294.0 [M+H]+.
(Z) -5- (the fluoro- 4- methyl benzylidenes of 3-) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-29), orange/yellow solid (70
Mg, 45%), 230-232 °C of 1H NMR (600 MHz, CDCl3) δ 8.12 (d, J=8.4 Hz, 2H) of fusing point,
7.97 (s, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.33 (m, 3H), 2.49 (s, 3H), 2.35 (d,
J = 1.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 187.0, 183.5, 147.0, 136.9, 133.6,
133.6, 132.4, 132.4, 130.2, 129.3, 129.2, 126.9, 126.8, 22.8, 15.0. ESI-MS m/ z: 312.1 [M+H]+.
(Z) -5- (the fluoro- 3- methyl benzylidenes of 4-) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-30), yellow solid (59
Mg, 38%), 209-211 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 7.8 Hz, 2H),
7.97 (s, 1H), 7.50 (d, J = 6.6 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.13 (dd, J
= 11.4, 6.6 Hz, 1H), 2.48 (s, 3H), 2.36 (s, 3H). 13C NMR (150 MHz, CDCl3) δ
187.0, 183.5, 163.7, 162.0, 146.9, 137.3, 134.2, 134.2, 130.3, 130.1, 129.3,
129.1, 126.5, 126.0, 116.4, 22.2, 14.8. ESI-MS m/z: 312.0 [M+H]+.
(Z) -5- (3- trifluoromethyls benzylidene) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-31), orange solids (59
Mg, 34%), 196-198 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.13 (d, J = 8.4 Hz, 2H),
8.03 (s, 1H), 7.90 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz,
1H), 7.64 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 2.49 (s, 3H). 13C NMR
(150 MHz, CDCl3) δ 187.2, 183.1, 147.3, 135.81, 134.9, 133.6, 132.1, 131.9,
130.2, 130.0, 129.3, 129.1, 128.7, 124.7, 122.9, 22.2. ESI-MS m/z: 348.0 [M+
H]+.
(Z) -5- (4- chlorobenzenes methylene) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-32), brown solid (47 mg,
30%), 187-189 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 7.8 Hz, 2H), 7.98
(s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.8
Hz, 2H), 2.48 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 186.8, 183.2, 146.9, 137.0,
136.4, 132.4, 131.7, 130.1, 129.6, 129.1, 129.0, 127.1, 22.0. ESI-MS m/z:
313.9 [M+H]+.
(Z) -5- (4- bromobenzenes methylene) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-33), brown solid (64 mg,
36%), 240-242 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 2H), 7.96
(s, 1H), 7.64 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.8
Hz, 2H), 2.48 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 187.0, 183.4, 147.1, 136.6,
132.9, 132.7, 132.0, 130.2, 129.2, 127.4, 125.6, 22.2. ESI-MS m/z: 357.9 [M+
H]+.
(Z) -5- (2- fluorobenzylidenes) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-34), yellow solid (45 mg,
30%), 192-194 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.29 (s, 1H), 8.11 (d, J = 7.8
Hz, 2H), 7.74 (t, J = 7.2 Hz, 1H), 7.49 – 7.43 (m, 1H), 7.37 (d, J = 7.8 Hz,
2H), 7.30 (t, J = 7.2 Hz, 1H), 7.21 – 7.16 (m, 1H), 2.48 (s, 3H). 13C NMR (150
MHz, CDCl3) δ 187.0, 182.9, 146.9, 132.7, 132.7, 130.0, 129.5, 129.5, 129.2,
129.1, 129.0, 124.7, 116.4, 116.2, 22.0. ESI-MS m/z: 298.0 [M+H]+.
(Z) -5- (4- fluorobenzylidenes) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-35), yellow solid (42 mg,
28%), 226-228 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 2H), 8.01
(s, 1H), 7.70 – 7.67 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 8.4 Hz,
2H), 2.48 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 186.9, 183.3, 146.8, 136.7 132.8
132.7, 130.0, 129.1, 129.0, 126.3 116.7, 22.0. ESI-MS m/z: 298.0 [M+H]+.
(Z) -5- (2,4 difluorobenzene methylene) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-36), yellow solid (55 mg,
35%), 196-198 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.20 (s, 1H), 8.10 (d, J = 7.8
Hz, 2H), 7.73 (td, J = 8.4, 6.0 Hz, 1H), 7.37 (d, J = 7.8 Hz, 2H), 7.05 (td,
J = 8.4, 2.4 Hz, 1H), 6.94 (ddd, J = 10.8, 8.4, 2.4 Hz, 1H), 2.48 (s, 3H). 13C
NMR (150 MHz, CDCl3) δ 186.9, 183.0, 147.2, 130.6, 130.6, 130.2, 129.2,
129.2, 128.5, 128.4, 128.2, 112.7, 112.5, 105.1, 22.2. ESI-MS m/z: 316.0 [M+
H]+.
(Z) -5- (4- benzyloxies benzylidene) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-37), orange solids (66 mg,
34%), 182-184 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 2H), 8.01
(s, 1H), 7.64 (d, J =8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 7.8
Hz, 2H), 7.37 – 7.35 (m, 3H), 7.09 (d, J = 8.4 Hz, 2H), 5.15 (s, 2H), 2.47
(s, 3H). 13C NMR (150 MHz, CDCl3) δ 186.4, 183.6, 161.1, 146.4, 138.1, 136.1,
132.8, 130.0, 129.3, 128.8, 128.8, 128.3, 127.5, 126.8, 123.9, 115.7, 70.2,
22.0. ESI-MS m/z: 386.0 [M+H]+.
(Z) -5- (4- methoxycarbonyl groups benzylidene) -2- (pMethylbenzene) thiazole -4 (5H) -one(I-38), orange/yellow solid (49
Mg, 29%), 212-214 °C of of fusing point1H NMR (600 MHz, CDCl3) δ 8.14 (d, J = 8.4 Hz, 2H),
8.11 (d, J = 8.4 Hz, 2H), 8.02 (s, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.37 (d, J
= 8.4 Hz, 2H), 3.95 (s, 3H), 2.48 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 187.3,
183.2, 166.3, 147.3, 138.1, 136.3, 131.7, 130.4, 130.4, 130.2, 129.2, 129.1,
129.0, 52.6, 22.2. ESI-MS m/z: 337.9 [M+H]+。
Embodiment 2 tests the enzyme activity inhibitory activity of compound using radioisotopic method.
1. preparing 1x test buffers(Improved Tris-HCl buffer solutions);2. diluted compounds are needed in 96 orifice plates
Concentration;3. preparing protein solution, 1x test buffers are also used;4. substrate is added in 1x test buffers, to prepare substrate molten
Liquid;5. by [3H]- SAM is added to Zhi Bei [ in 1x test buffers;3H]- SAM solution;6. SAM is added to 1x test buffers
It is middle to prepare cold SAM solution;7. pipetting in 10 μ L protein solutions to containing compound 96 orifice plate;8. incubation at room temperature 15 minutes;
9. 10 μ L substrate solutions are added into each hole;10. 10 μ L [ are added into each hole;3H]- SAM solution initiation reactions;11.
Incubation at room temperature 240 minutes.12. the cold SAM solution of 10 μ L is added into each hole terminates reaction;13. 40 μ L reaction mixing of transfer
On solution to GF/B plates, with tri-distilled water vacuum cleaning 3 times;14. reading number on MicroBeta liquid scintillations/luminescence counter
According to;Inhibit 15. being calculated according to formula %Inh=(peak signal-compound signal)/(peak signal-minimum signal) × 100
Rate, peak signal are obtained from enzyme and substrate reactions, and minimum signal is obtained from substrate.GraphPad is used after data processing
Prism 5.0 maps.Positive control is done using SAH.
2. experimental result
2. compound of table is to PRMT5 enzyme activity inhibitory activity
In the present invention, the meaning of " NT " is NOT Tested, i.e., the meaning that do not test.
3 compound of table is to PRMT1 enzyme activity inhibitory activity
In the present invention, the meaning of " NT " is NOT Tested, i.e., the meaning that do not test.
4 compound of table is to LSD1 enzyme activity inhibitory activity
In the present invention, the meaning of " NT " is NOT Tested, i.e., the meaning that do not test.
Choose enzyme activity inhibitory activity of the preferred compound I-5 to PRMT1 and LSD1:
The influence of 3 compound on intracellular of embodiment proliferation
1. test method
(1)Cell culture
Culture solution used in MV4-11, Jeko, KOPN8, RCH-ACV, REH, RS4.11, THP1, U937, NALM6 cell culture
It is the fetal calf serum of RPMI 1640+10%, while germ contamination in order to prevent, culture solution add 100 U/mL penicillin
With 100 μ g/mL streptomysins.It is cultivated under the conditions of 37 DEG C, 5% CO2 saturated humidities, the cell of experiment is in logarithmic growth
Phase.
(2)Cell-proliferation activity detects
It is 1 × 10 to adjust cell concentration5/ mL is simultaneously inoculated in 24 well culture plates, per pore volume 1mL, sets up control group and reality
Group is tested, control group adds DMSO, experimental group that PRMT5 active small moleculars inhibitor is added and ultimate density is made to reach 0-100 μM.It is right
MV4-11 cells are provided with 3 detection time points, are 4,8 and 12 days respectively;To RCH-ACV, REH, RS4.11, THP1, U937,
NALM6 cells are provided with 6 days detection time points.Cell is placed in 37 DEG C and 5% CO2 incubators culture to Each point in time
When, detect amount of viable cell with CellTiter-Glo reagents.
2. experimental result
Experimental result is as shown in Fig. 2, compound I-20 is thin to MV4-11, RCH-ACV, REH, RS4.11, THP1, U937, NALM6
The proliferation of born of the same parents has certain inhibiting effect, wherein the proliferation inhibition activity to MV4-11 is most strong, shows stronger selection
Property, the results are shown in Figure 3 within 12 days, IC50It is 3.30 μM.
The influence of SDMA in 4 compound on intracellular of embodiment
1. experimental method
Western Blot detection SDMA expression
It is 5 × 10 to adjust MV4-11 cell concentrations5/ ml is simultaneously inoculated in 6 well culture plates, per 2 ml of pore volume, sets up control
Group and experimental group, control group only add DMSO, experimental group that I-5, I-20 is added so that final concentration of 0-5 μM.Cell be placed in 37 DEG C,
It is collected after 5% CO2 incubator cultures 96h, obtains total protein of cell.2 × SDS is proportionally added into protein sample, after mixing
98 DEG C of denaturation 10min, and detached in 4-12% SDS PAGE.Albumen electricity is transferred to nitrocellulose membrane, 5% skim milk room is used in combination
Temperature closing 0.5h.The 4 DEG C of closings of SDMA and GADPH antibody are overnight.It is washed 3 times, every time 5 minutes with 1 × TBST;Horseradish mistake after dilution
The secondary antibody of oxide enzyme label, is incubated at room temperature 1h.1 × TBST is washed 3 times, every time 5 minutes.It is shone using ECL Western Blot
Detection reagent and analysis system develop the color.
2. experimental result
The expressing quantity that SDMA is detected by Western blot western blot hybrid experiments probes into compound pair with this
The arginic influence of intracellular symmetric dimethylization.Studies have shown that SmD3 albumen is the substrate of PRMT5, can be methylated by PRMT5
Modification, thus SmD3 can be used for track administration after PRMT5 intracellular variation.Experimental result(Fig. 4)It has been shown that, intracellular
SmD3me2s is obviously inhibited, it is possible to speculate that the suppressing cell reproduction effect of the series compound is repressed by PRMT5
Direct result, this also illustrates, our this kind of compounds are not missed the target in intracellular.As shown in figure 4,0-15 μM of compound I-5 or
It, can be with the intracellular SmD3me2s signals of the inhibition of concentration dependent after I-19 acts on 96 h of MV4-11 cells.
The influence of 5 compound on intracellular period of embodiment and apoptosis
1. experimental method
It is 2 × 10 to adjust MV4-11 cell concentrations5/ ml is simultaneously inoculated in 12 well culture plates, per pore volume 1 mL, sets up pair
According to group and experimental group, control group adds DMSO to do negative control, and experimental group is separately added into compound 1 so that final concentration of 0-15 μM.
48h treated cells centrifugation (1000rpm centrifuges 5 min) is collected, and wash cell 2 times with PBS, (1000rpm centrifuges 5
Min), abandon supernatant and collect cell, fixed overnight with 70% ethyl alcohol, cell is washed again with precooling PBS, with cell cycle reagent weight
It is outstanding to be incubated 10min.In apoptosis experiment, 72h treated cells centrifugation (1000rpm centrifuges 5 min) is collected, and is washed with PBS
It washs cell 2 times (1000rpm centrifuges 5 min), abandons supernatant and collect cell, the binding buffer that 500 μ L are added suspend carefully
Born of the same parents.It is protected from light in 5 μ L Annexin V-FITC of addition and 55 μ L PI, mixing, room temperature, reacts 10 min.Cell cycle and apoptosis
Detection and analysis carry out on BD flow cytometers.
2. experimental result
As shown in figure 5, the compound I-5 of various concentration has apparent retardation to the cell cycle of MV4-11 cells, it will be thin
Born of the same parents are arrested in the G1 phases.
The compound I-5 of various concentration plays the role of MV4-11 cells apoptosis-induced, such as Fig. 6, in 0-15 μM of concentration
For drug effect after 96 h of MV4-11 cells, compound can be with the inducing cell apoptosis rate of concentration dependent.Therefore, compound
I-5 has very strong apoptosis-induced effect to MV4-11 cells.
Claims (9)
1. a kind of 5- benzylidenes -2- phenyl thiazole ketone compounds, including general formula(I)And its it is geometric isomer, pharmaceutical salts, preceding
Medicine, solvate, which is characterized in that structure is general formula(I):, wherein R be-H or-
CH3;R1, R2, R3And R4Can be separately or concurrently-H, C1-C3Alkyl, hydroxyl ,-O (C1-C3Alkyl) ,-N (C1-C3Alkyl) (C1-C3
Alkyl), benzyloxy, halogen ,-CO (O) (C1-C3Alkyl).
2. compound according to claim 1, which is characterized in that the general formula(I)For following compounds:
。
3. a kind of preparation method of compound described in claim 1, which is characterized in that prepare target production by following steps
Object:The ethanol solution of the methyl benzonitrile of 0.05 ~ 2.0mol/L is configured, thioacetic acid, triethylamine and corresponding benzaldehyde spread out
The ethanol solution of methyl benzonitrile is added in biology, is heated to reflux, removes solvent later, obtains target product.
4. according to the method described in claim 3, it is characterized in that, the thioacetic acid, triethylamine and corresponding benzene first
The molar ratio of aldehyde derivatives and methyl benzonitrile is respectively 2 ~ 2.4:1,0.2~0.5:1,0.5~0.8:1.
5. according to the method described in claim 3, it is characterized in that, the reflux temperature is 78 ~ 88 °C, return time is
10-14h。
6. a kind of compound described in claim 1 prepares the application of Pharmaceutical composition, characterized in that the compound, and
As active component, medicament forms can be injection, wafer, tablet, ball for its isomers, pharmaceutical salts, prodrug, solvate
Agent, powder or granule.
7. the Pharmaceutical composition described in a kind of compound described in claim 1 or claim 6 prevents and/or controls preparing
Treat the application of the drug of cancer or relevant disease.
8. application according to claim 7, which is characterized in that the prevention and/or treating cancer be preferably leukaemia,
It is lymthoma, breast cancer, lung cancer, carcinoma of urinary bladder, gastric cancer, cancer of pancreas, prostate cancer, colon cancer, Huppert's disease AML, liver cancer, black
Melanoma, head and neck cancer, thyroid cancer, clear-cell carcinoma, glioblast cancer and carcinoma of testis.
9. application according to claim 7, which is characterized in that the relevant disease is arginine methyltransferase and relies
The relevant disease of propylhomoserin demethylase enzymatic activity.
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