CN104710355A - Preparation method and application of diphenyl thiourea compound containing niacinamide building blocks and salt of diphenyl thiourea compound - Google Patents
Preparation method and application of diphenyl thiourea compound containing niacinamide building blocks and salt of diphenyl thiourea compound Download PDFInfo
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- CN104710355A CN104710355A CN201510081559.6A CN201510081559A CN104710355A CN 104710355 A CN104710355 A CN 104710355A CN 201510081559 A CN201510081559 A CN 201510081559A CN 104710355 A CN104710355 A CN 104710355A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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Abstract
The invention relates to a diphenyl thiourea compound containing niacinamide building blocks and salt of the diphenyl thiourea compound. The chemical structure of the diphenyl thiourea compound is as shown in the description. The diphenyl thiourea compound and the salt, pharmaceutically acceptable, of the diphenyl thiourea compound have inhibiting effects on various tumour cell strains and can serve as effective components for preparing tumour treatment medicine.
Description
Technical field
The present invention relates to a class containing the diphenyl thiourea compounds of nicotinamide building block and the preparation method of salt thereof, and it is preparing the purposes in antitumor drug, belongs to thing chemical field.
Background technology
Cancer is one of principal disease of serious harm human health, and capturing cancer is current global research topic.According to the World Health Organization (WHO) report, whole world cancer patients increases by 1,000 ten thousand people every year, death about 7,000,000 people, and by 2020, cancer patients will increase 2,000 ten thousand people every year newly.At present, China is large about more than 1,600,000 people's cancer strickens every year, and 1,300,000 people die from cancer, and cancer is just becoming " second killer " of the serious harm human health being only second to cardiovascular disorder.Although over nearly 20 years, molecular biologically to develop rapidly, the understanding of people to cancer start by outer and in, by cell going deep into molecular level, and obtain many cancer therapy drugs by the method for chemosynthesis, but the anticarcinogen of these chemosynthesis great majority produce more serious toxic side effect to the normal cell of human body.How to avoid the toxic side effect of conventional anti-cancer medicines, thus obtain safer PTS thing, become the direction of medical personal's research.
Along with the development of the subject such as proteomics and genomics, people for medicine in vivo mechanism of action understanding gradually deeply, many selectively actings are also constantly found in the medicine of special target spot.The antitumor drug of single target spot is usually difficult to reach expection result for the treatment of and even there will be untoward reaction, and " Mutiple Targets " medicine single for several difference target drug coupling or choice for use being acted on multiple molecular target can demonstrate better curative effect and lower resistance in oncotherapy.
In recent years, FDA successively have approved the listing of multiple Mutiple Targets medicine, and Xarelto (sorafenib) can suppress the multiple kinases such as RAF, FLT3, VEGFR, PDGFR and KIT simultaneously, has obvious therapeutic action to advanced renal cell carcinoma and advanced liver cancer.In order to find the Mutiple Targets antitumor drug of better efficacy, Pharmaceutical Chemist has carried out a large amount of transformations to the structure of Xarelto, the overwhelming majority is Xarelto derivative (the C.R. Zhang based on diaryl urea structure, R.Q. Wang, G. Li, X.X. Xue, C.J. Sun, X.J. Qu and W.B. Li
bioorg. Med. Chem. Lett., 2013,
23, 1989-1992.; W.H. Zhan, Y.Y. Li, W.P. Huang, Y.J. Zhao, Z.G. YAO, S.Y. Yu, S.J. Yuan, F.L. Jiang, S. Yao and S.X. Li,
bioorg. Med. Chem, 2012,
20, 4323-4329. etc.).The Xarelto derivative (Figure 1B and 1C) of sulfur-bearing urea structure, to tumour cell HCT-116 and MDA-MB-231, there is good inhibit activities, some compounds can also suppress the phosphorylation of VEGFR and formation (the J.W. Yao of rat artery ring, Z.P. He, et al
chin. J. Chem, 2012,
30, 2423-2430; J.W. Yao, J. Chen et al,
bioorg. Med. Chem., 2012,
20, 2,923 2929; J.W. Yao, W.F. Xu,
bioorg. Med. Chem. Lett., 2012,
12, 6549-6553.).
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of diphenyl thiourea compounds and pharmacy acceptable salt thereof of nicotinamide, and it has higher target molecule associativity, water-soluble and druggability; Present invention also offers preparation method and its pharmaceutical composition prepared of the diphenyl thiourea compounds of described nicotinamide.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
One class, containing the diphenyl thiourea compounds of nicotinamide building block, is characterized in that it has the chemical structure of general formula as logical formula I:
（Ⅰ）
In formula I, R is selected from H, C
1-C
6alkyl, halogen ,-CF
3,-OCF
3,-NO
2,-CN, R
1o-, SO
2nH
2,-NHSO
2r
2,-NR
3r
4,-CONR
5r
6,-COOR
7, R
8cO-and their two replacement or trisubstituted combination, wherein R
1, R
2, R
3, R
4, R
5, R
6, R
7or R
8independently be selected from H or C
1-C
6alkyl;
X is selected from O or S.
Further, the R described in formula I is selected from H, C
1-C
4alkyl, F, Cl, Br ,-CF
3,-OCF
3,-CN, R
1o-,-NHSO
2r
2,-NR
3r
4,-CONR
5r
6, R
7cO-and their two replacement or trisubstituted combinations,
Wherein R
1, R
2, R
3, R
4, R
5, R
6or R
7independently be selected from H or C
1-C
4alkyl.
Further, compound of the present invention is following compounds:
JYG01:6-{3-[3-(3,4-difluorophenyl) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG02:6-{3-[3-(4-chloro-phenyl-) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG03:6-{3-[3-(the fluoro-3-trifluoromethyl of 4-) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG04:6-{3-[3-(the chloro-3-trifluoromethyl of 4-) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG05:6-{3-[3-(the bromo-3-trifluoromethyl of 4-) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG06:6-{3-[3-(4-Trifluoromethoxyphen-l) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG07:6-{3-[3-(the chloro-4-fluorophenyl of 3-) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG08:6-{3-[3-(3-trifluoromethyl) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG09:6-{3-[3-(3,5-bis trifluoromethyl phenyl) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG10:6-{3-[3-(the bromo-3-trifluoromethyl of 4-) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG11:6-{3-[3-(the fluoro-3-trifluoromethyl of 4-) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG12:6-{3-[3-(the chloro-4-fluorophenyl of 3-) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG13:6-{3-[3-(3-trifluoromethyl) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG14:6-{3-[3-(3,5-bis trifluoromethyl phenyl) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG15:6-{3-[3-(4-chloro-phenyl-) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG16:6-{3-[3-(3,4-difluorophenyl) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG17:6-{3-[3-(3-trifluoromethyl-4-chlorophenyl) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG18:6-{3-[3-(4-Trifluoromethoxyphen-l) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG19:6-{3-[3-[2,4 dichloro benzene base] thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG20:6-{3-[3-[4-aminomethyl phenyl] thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG21:6-{3-[3-[4-fluorophenyl] thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG22:6-{3-[3-[3,4-3,5-dimethylphenyl] thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG23:6-{3-[3-[4-p-methoxy-phenyl] thioureido]-phenoxy group }-N-picoline-3-methane amide.
A synthetic method for the described diphenyl thiourea compounds containing nicotinamide building block, it comprises the steps:
The reactant aqueous solution of a:6-chlorine methyl niconate and methylamine or methylamine obtains compound N-methy 6-chlorine nicotinic acid amide;
B:N-methyl 6-chlorine nicotinic acid amide and Metha Amino Phenon or m-aminothiophenol condensation, obtain corresponding compound V;
C: compound ii obtains compound III with dithiocarbonic anhydride addition under triethylene diamine exists;
D: compound III, under the existence of solid phosgene, is sloughed hydrogen sulfide and obtained compounds Ⅳ;
E: compounds Ⅳ and compound V are obtained by reacting chemical compounds I in organic solvent, and described organic solvent is selected from dimethyl formamide, N,N-DIMETHYLACETAMIDE, methyl-sulphoxide or acetonitrile.
Further, described in synthetic method of the present invention, a is specially: 6-chlorine methyl niconate is dissolved in C
1-C
4fatty alcohol or chlorinated hydrocarbon solvent in, react with methylamine under-5 ~ 50 DEG C of conditions, aftertreatment obtains N-methyl 6-chlorine nicotinic acid amide; Wherein said solvent is methyl alcohol, ethanol, acetonitrile or methylene dichloride; The mol ratio of described 6-chlorine methyl niconate and methylamine is 1:1-10.
Further, described in synthetic method of the present invention, b is specially: get amino-phenol or m-aminothiophenol is dissolved in polar aprotic solvent, under basic catalyst or acid binding agent existent condition, with the condensation under 30-120 DEG C of condition of N-methyl-6-chlorine nicotinic acid amide, obtain compound V through aftertreatment; Wherein said solvent is dimethyl formamide, methyl-sulphoxide, chloroform or acetonitrile; Catalyzer or acid binding agent are potassium tert.-butoxide, sodium isopropylate, salt of wormwood, sodium carbonate or its mixture; The mol ratio of described Metha Amino Phenon or m-aminothiophenol and N-methyl 6-chlorine nicotinic acid amide is 2:1 ~ 1:2.
Further, described in synthetic method of the present invention, e is specially: compounds Ⅳ and compound V are obtained by reacting the compound with formula I in organic solvent, and wherein said solvent is dimethyl formamide, methyl-sulphoxide, chloroform, methylene dichloride or acetonitrile.
Containing a salt for the diphenyl thiourea compounds of nicotinamide building block, comprise the solvate of the diphenyl thiourea compounds inorganic acid salt of nicotinamide, organic acid salt or above-mentioned salt.
Further, inorganic acid salt of the present invention is hydrochloride, hydrobromate, hydrosulfate, vitriol or phosphoric acid salt; Be preferably hydrochloride, hydrosulfate or vitriol.
Further, organic acid salt of the present invention be mesylate, fluoroform sulphonate, benzene sulfonate, tosilate, 1-naphthalene sulfonic aicd salt, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, Citrate trianion, lactic acid salt, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate or mandelate; Be preferably mesylate, tosilate, benzene sulfonate, fumarate, maleate or malate.
Further, the solvate of salt of the present invention is the hydrate of salt.
A kind of anti-tumor drug, its activeconstituents comprises the diphenyl thiourea compounds containing nicotinamide building block of the present invention, or comprises the salt of the described diphenyl thiourea compounds containing nicotinamide building block.
Further, medicine of the present invention is by the described diphenyl thiourea compounds containing nicotinamide building block, or contain the salt of the diphenyl thiourea compounds of nicotinamide building block as activeconstituents, after in pharmacy, acceptable auxiliary material mixes, according to pharmaceutically acceptable pharmaceutical methods and processing requirement, be prepared as the solid oral forms preparation for the treatment of or prophylaxis of tumours, liquid oral type preparation or injection-type preparation;
Further, medicine of the present invention is by the diphenyl thiourea compounds containing nicotinamide building block, or contain the salt of the diphenyl thiourea compounds of nicotinamide building block as one of activeconstituents, after in other medicines and pharmacy, acceptable auxiliary material mixes, according to pharmaceutically acceptable pharmaceutical methods and processing requirement, be prepared as the solid oral forms preparation for the treatment of or prophylaxis of tumours, liquid oral type preparation or injection-type preparation.
The pharmaceutically acceptable salt with the compound of formula I structure of the present invention includes but not limited to following mineral acid and organic acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, 2-naphthene sulfonic acid, acetic acid, trifluoroacetic acid, oxysuccinic acid, tartrate, citric acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, the pharmaceutically acceptable salt that toluylic acid and tussol etc. generate.
Generalformulaⅰcompound of the present invention or its pharmaceutically acceptable salt, can with one or more pharmaceutically acceptable auxiliary materials, as carrier, weighting agent, tamanori, disintegrating agent, vehicle or thinner make pharmaceutical composition jointly.This pharmaceutical composition can make the formulations such as solid orally ingestible, liquid oral medicine or injection.Described solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule, oral solution, and described injection preparation comprises injection liquid drugs injection, injection powder pin, primary infusion and infusion solutions etc.
In the pharmacy of adding in medicine of the present invention or bromatology in acceptable auxiliary material, weighting agent comprises one or more composition of lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, calcium carbonate, Microcrystalline Cellulose; Tamanori comprises one or more composition of starch, polyvidone, Xylo-Mucine, Walocel MT 20.000PV, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more compositions of starch, polyvinylpolypyrrolidone, croscarmellose sodium, low replacement sodium cellulose glycolate, hydroxypropylcellulose, gas-producing disintegrant.
The beneficial effect that the present invention adopts technique scheme to produce is:
The present invention is by 1 on Xarelto C ring, 4-replacement changes 2 into, 5-replaces, change the binding pattern of target compound and target molecule, improve the water-soluble of target compound and druggability, majority of compounds of the present invention is to HCT116(human colon cancer cell), MDA-MB-231(human breast cancer cell), PC-3(Human Prostate Cancer Cells) and HepG2(human liver cancer cell) etc. various tumor cell strains there is significant restraining effect, containing the compound (JYG03 of electron withdrawing group on phenyl ring, JYG04, JYG09, JYG10, JYG14, JYG17) inhibit activities of tumour cell is better than to the compd B MCL9o (formula VI) of Xarelto and bibliographical information.
Generalformulaⅰcompound of the present invention or its pharmaceutically acceptable salt there is the restraining effect to various tumor cell strains, can be used as the medicine of effective constituent for the preparation of tumour aspect.The activity of generalformulaⅰcompound of the present invention is by extracorporeal anti-tumor modelling verification, tumor cell line selected by external activity test comprises: HepG2 cell lines, human prostate cancer cell line PC-3, human colon cancer cell strain HCT-116 and Breast cancer lines MDA-MB-231 etc., but is not limited to above-mentioned tumor cell line.
Generalformulaⅰcompound of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-1000mg/ people, is divided into once or administration for several times.The actual dosage taking generalformulaⅰcompound of the present invention can be determined according to interesting cases by doctor.These situations comprise: the physical state of patient, route of administration, the age, body weight, to the individual reaction of medicine, the severity etc. of symptom.
Accompanying drawing explanation
Fig. 1 is the Xarelto derivative of Xarelto and three kinds of sulfur-bearing urea structures;
Fig. 2 is the detected result that human umbilical vein endothelial cell (HUVECs) becomes tube chamber restraining effect to test;
Wherein Fig. 2 A is negative control;
Fig. 2 B is the experimental result of the Inhibition test of 0.05 μM of Xarelto;
Fig. 2 C is the experimental result of the Inhibition test of 0.1 μM of Xarelto;
Fig. 2 D is the experimental result of the Inhibition test of 0.05 μM of JYG17 of the present invention;
Fig. 2 E is the experimental result of the Inhibition test of 0.1 μM of JYG17 of the present invention.
Embodiment
For making above-mentioned purpose of the present invention, feature and advantage can become apparent more, are clearly and completely described, obviously below in conjunction with the embodiment of the present invention to technical scheme of the present invention, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
Embodiment 1 6-{3-[3-[the bromo-phenyl of 3-trifluoromethyl-4-] thioureido]-phenoxy group } synthesis of-N-picoline-3-methane amide (JYG10)
Step a:
nthe synthesis of-methyl-6-chloro-3-pyridyl methane amide
6-chlorine apellagrin methyl esters (10.0g, 58.3mmol) is dissolved in 10 mL methyl alcohol, under stirring, forms pale yellow solution, under 0-5 DEG C of condition, drip the aqueous methylamine solution (2.7g, 87.5mmol) of 40%, dropwise, room temperature reaction 4h.Then decompression and solvent recovery, resistates adds 100 mL ethyl acetate, and filter after stirring, filtrate uses saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, crystallization, filtration, drying, obtains Light yellow crystals 9.4g, yield 99.1%.Mp：140-142℃。
1H-NMR (DMSO-
d 6 , 400 MHz):
δ2.75 (d,
J = 4.5 Hz, 3H), 6.89 ( d,
J = 8.8 Hz, 1H), 8.16 (dd,
J = 8.7, 2.4 Hz, 1H), 8.46 (br d,
J = 4.4 Hz, 1H), 8.57 (d,
J = 2.3 Hz, 1H). ESI-MS
m/z171.1 [M+H]
+。
The synthesis of step b:6-(3-amino-benzene oxygen)-N-methyl-nicotinamide (V-1)
By Metha Amino Phenon (2.7g, 24.9mmol) add in dimethyl formamide (DMF) (50mL), then potassium tert.-butoxide (2.8g is added, 24.9mmol), N-methyl-6-chloro-3-pyridyl methane amide (4.0g, 23.5mmol) and salt of wormwood (1.4g, 16.5mmol), be warming up to 80-85 DEG C, insulation 12h.Reaction solution is down to room temperature, add the saturated aqueous common salt of 200mL ethyl acetate and 200 mL, aqueous phase ethyl acetate 200mL extracts twice, merges organic phase, with saturated common salt water washing 3 times, anhydrous sodium sulfate drying, is evaporated to dry, vacuum-drying, obtain light yellow solid 6-(3-amino-benzene oxygen)-N-methyl-nicotinamide (V-1) 2.40g, yield: 42.1 %, m.p:144 ~ 146 DEG C, purity: 99.6 %(HPLC).
1H-NMR (400 MHz, DMSO-d6) δ 2.79 (d, J = 4.48 Hz, 3H), 5.33 (s, 2H), 6.95 (m, 1H), 7.11 (d, J = 8.56 Hz, 1H), 7.41 (m, 2H), 7.46 (t, J = 1.84 Hz, 1H), 8.23 (dd, J = 2.4, 8.6 Hz, 1H), 8.52 (q, J = 4.48 Hz, 1H), 8.59 (d, J = 2.28 Hz, 1H); ESI-MS m/z 244.2 [M+H]+。
Compound (V-1) be have general formula for (V) compound in one, other replace nicotinamide (V) the same embodiment of synthetic method.As the synthesis of 6-(3-aminobenzene-thio)-N-methyl-nicotinamide (V-2).
M-aminothiophenol (2.7g, 24.9mmol) is added DMF(50mL) in, then add potassium tert.-butoxide (3.8g, 33.2mmol), N-methyl-6-chloro-3-pyridyl methane amide (4.0g, 23.5mmol) and salt of wormwood (1.4g, 16.5mmol), be warming up to 80-85 DEG C, insulation 10h.Reaction solution is down to room temperature, add the saturated aqueous common salt of 200mL ethyl acetate and 200 mL, aqueous phase ethyl acetate 200mL extracts twice, merges organic phase, with saturated common salt water washing 3 times, anhydrous sodium sulfate drying, is evaporated to dry, vacuum-drying, obtain brown solid 6-(3-aminobenzene-thio)-N-methyl-nicotinamide (V-2) 4.6g, yield: 77.1 %, m.p:169 ~ 170 DEG C, purity: 99.6 %(HPLC).
1H-NMR (400 MHz, DMSO-
d 6 )
δ2.95 (d,
J = 5.12 Hz, 3H), 4.10 (br s, 2H), 6.35-6.39 (m, 2H), 6.56 (dd,
J = 7.8, 1.5 Hz, 1H), 6.94 (dd,
J = 5.5, 2.5 Hz, 1H), 7.14 (t,
J= 7.8 Hz, 1H), 7.69 (d,
J= 2.5 Hz, 1H), 8.11 (q,
J= 4.8 Hz, 1H), 8.35 (d,
J= 5.2 Hz, 1H); ESI-MS
m/z260.2 [M+H]
+。
The synthesis of step c, d:3-trifluoromethyl-4-chlorobenzene lsothiocyanates (IV-1)
In 250 mL there-necked flasks, add 3-trifluoromethyl-4-chloroaniline (25.8 g, 132.3 mmol), triethylene diamine (44.46 g, 396.9 mmol) and 135 mL toluene, stirring at room temperature is dissolved.Then dithiocarbonic anhydride (30.06 g, 396.9 mmol) is dripped in 2.0 h, in 15-25 DEG C of insulation reaction 8-10 h after dripping off, reaction terminate after, suction filtration, filter cake with 20 mL toluene drip washing once, dry, obtain pale yellow powder shape 3-trifluoromethyl-4-chloroaniline dithio formate.3-trifluoromethyl-4-chloroaniline the dithio formate of gained is suspended in 200 mL chloroforms, starts stirring and be chilled to-5-0 DEG C.Slowly drip the 60 mL chloroforms being dissolved with solid phosgene [two (trichloromethyl) carbonic ether, BTC] (12.43 g, 42.0 mmol), after dripping off, ice bath reacts 1 h, then room temperature reaction 1 h, is finally heated to backflow, insulation 1.5-2 h.After reaction terminates, be cooled to room temperature, suction filtration removing insolubles, filtrate decompression is distilled, and obtains 3-trifluoromethyl-4-chlorobenzene lsothiocyanates crude product.Through column chromatography, (concentrating under reduced pressure obtains pale yellow oily liquid body 23.5 g, purity for silica gel G, pure sherwood oil wash-out: 99.6 % (GC), bp:248-251 DEG C, yield: 80.5 %.
Compound (IV-1) be have general formula for (IV) compound in one, the available similar synthetic method of other substituted benzene lsothiocyanates (IV) obtain, be specially:
3,4-difluorobenzene lsothiocyanates (IV-2): light yellow transparent liquid, productive rate 74.5 %, bp:170-172 DEG C, purity: 99.1 % (GC).
3-trifluoromethyl PhNCS (IV-3): weak yellow liquid, productive rate 74.3 %, bp:206-208 DEG C, purity: 98.8 % (GC, S.Q. Jiang, Z.Y. Wang, Z.J. Jiang, W.Y. Chen, J.H. Li,
journal of Sichuan Normal University (Nature Science), 2011,
34, 388-391.)
3,5-bis trifluoromethyl PhNCS (IV-4): light yellow transparent liquid, productive rate 69.0 %, bp:63 DEG C (2.5 mmHg), purity: 99.0 % (GC).
3-trifluoromethyl-4-bromobenzene lsothiocyanates (IV-5): off-white color solid, productive rate 76.8 %, mp:34-36 DEG C, purity 98.8 %(GC, B. Xie, G.G. Zhou,
chemical Industry Times, 2006,
20, 71-75.).
3-chloro-4-fluorobenzene lsothiocyanates (IV-6): pale yellowish oil liquid, productive rate 85.2 %, bp:228-230 DEG C, purity: 99.5 % (GC, S.Q. Jiang, Z.Y. Wang, Z.J. Jiang, W.Y. Chen, J.H. Li,
journal of Sichuan Normal University (Nature Science), 2011,
34, 388-391.)
3-trifluoromethyl-4-fluorobenzene lsothiocyanates (IV-7): pale yellowish oil liquid, productive rate 79.6 %, boiling point 243-246 DEG C, purity 98.7 %(GC).
4-trifluoromethoxy PhNCS (IV-8): light yellow clear liquid, productive rate 78.4 %, bp. 230-231 DEG C, purity 99.3 %(GC).
4-chlorobenzene lsothiocyanates (IV-9): light yellow solid, productive rate 84.6 %, fusing point 43-45 DEG C, purity: 99.1 % (GC, P. Zhu, J.Y. Feng,
journal of Nanyang Teachers ' College, 2005,
4, 57-60.)
2,4 dichloro benzene lsothiocyanates (IV-10): off-white color solid, productive rate 68.5 %, fusing point 37-42 DEG C, purity: 98.8 % (GC.)
4-methylbenzene lsothiocyanates (IV-11): white solid, productive rate 78.4 %, fusing point 25-27 DEG C, purity: 99.3 % (GC, P. Zhu, J.Y. Feng,
journal of Nanyang Teachers ' College, 2005,
4, 57-60.)
3,4-dimethyl benzene lsothiocyanates (IV-12): white solid, productive rate 74.2 %, fusing point 74-77 DEG C, purity: 98.3 % (GC, B. Xie, G.G. Zhou,
chemical Industry Times, 2006,
20, 71-75.)
4-fluorobenzene lsothiocyanates (IV-13): light yellow solid, productive rate 67.6 %, fusing point 25-26 DEG C, purity: 99.4 % (GC, P. Zhu, J.Y. Feng,
journal of Nanyang Teachers ' College, 2005,
4, 57-60.)
4-anisole lsothiocyanates (IV-14): off-white color solid, productive rate 59.6 %, fusing point 19-21 DEG C, purity: 99.6% (GC)
Step e: the synthesis of target compound
By 6-(3-amino-benzene oxygen)-N-methyl-nicotinamide (V-1) (1.5 g, 6.2 mmol) add in 100 mL, tri-mouthfuls of reaction flasks, add DMF 10 mL stirring and dissolving, ice bath is cooled to 0 ~ 5 DEG C, slow dropping 3-trifluoromethyl-4-chlorophenyl lsothiocyanates (IV-1) (1.5 g, 6.2 mmol) DMF solution 10 mL, about about 2 h are reacted under 0 ~ 5 DEG C of condition, remove room temperature reaction about 12 h after ice bath, the saturated aqueous common salt of 200 mL ethyl acetate and 200 mL is added to reaction solution, aqueous phase ethyl acetate 200 mL extracts twice, merge organic phase, with saturated common salt water washing 3 times, anhydrous sodium sulfate drying, be evaporated to dry, vacuum-drying, obtain off-white color solid (JYG17), yield: 56.8 %, m.p:154-156 DEG C.
JYG17 be have general formula for (I) compound in an example, other have the same embodiment of synthetic method of the compound of formula I, and experimental result is as shown in table 1 below.
Table 1 compound JYG 01 to JYG 23
Continued 1
In upper table, the structural characterization data of compound JYG 01 to JYG 23 are as shown in table 2-1 to 2-8.
Table 2-1
Table 2-2
Table 2-3
Table 2-4
Table 2-5
Table 2-6
Table 2-7
Table 2-8
Embodiment 2
100, tablet
JYG01 10.0g
Lactose 12.0g
Pregelatinized Starch 2.5g
Microcrystalline Cellulose 2.5g
Xylo-Mucine 0.8g
10% povidone solution QS
Magnesium Stearate QS
Talcum powder QS
Preparation technology: activeconstituents and auxiliary material are pulverized rear mistake 100 mesh sieve in advance, takes main ingredient JYG01 and adds auxiliary material lactose, pregelatinized Starch, Xylo-Mucine and Microcrystalline Cellulose and fully mix, and crosses 60 mesh sieve three times, add 10% povidone solution, mixing, softwood processed, crosses 20 mesh sieves, obtained wet grain, after 50-60 DEG C of drying, add Magnesium Stearate and talcum powder sieves in advance, fully mix, detect, compressing tablet.
Embodiment 3
Capsule 100
JYG05 15.0g
Silica 1 .8g
Magnesium Stearate QS
Preparation technology: by activeconstituents JYG05 and auxiliary material silicon-dioxide, Magnesium Stearate, crosses 100 mesh sieves after pulverizing respectively in advance, fully mixes, and detects, filling with No. 4 capsules.
Embodiment 4
Orally disintegrating tablet 100
JYG07 5.0g
N.F,USP MANNITOL 18.0g
Microcrystalline Cellulose 18.0g
Xylo-Mucine 1.0g
Magnesium Stearate QS
Silicon-dioxide QS
Preparation technology: activeconstituents JYG07 and auxiliary material are pulverized rear mistake 100 mesh sieve in advance, fully mixes, adopts roll squeezer cake of press, then crosses 18 mesh sieves with pelletizing machine, finally add Magnesium Stearate, fully mix, and detects, compressing tablet.
Embodiment 5
Granule 100 bags
JYG10 30.0g
Lactose 55.0g
N.F,USP MANNITOL 14.0g
Aspartame 0.05g
Essence 0.05g
Hydroxypropylcellulose QS
Preparation technology: activeconstituents JYG10 and auxiliary material are pulverized rear mistake 100 mesh sieve in advance, fully mixes, then add tamanori and obtain softwood, 14 mesh sieves are granulated, 55 DEG C of dryings, the whole grain of 12 mesh sieve, detect, packaging.
Embodiment 6
Freeze-dried
JYG12 5.0g
Poloxamer 2.0g
Sodium hydroxide 0.3g
Citric Acid QS
N.F,USP MANNITOL 40.0g
Lactose 30.0g
Water for injection 150.0ml
Preparation technology: get water for injection 100.0ml, adds main ingredient JYG12, N.F,USP MANNITOL, lactose, poloxamer stirring and dissolving.Adjust pH to be 7.0-9.0 with the Citric Acid of 1mol/L, mend and add water to 150ml.Add the gac of 0.5g, stir 30min at 30 DEG C, de-charcoal.Employing filtering with microporous membrane is degerming, and filtrate is by often propping up 1ml packing, and after pre-freeze 2h, freezing lower drying under reduced pressure 12h, dry 5h again after to sample temperature to room temperature, obtained white loose block, seals and get final product.
Embodiment 7
Primary infusion
JYD17 25.0mg
Tutofusin tris 20.0g
Low molecular dextran 500.0g
EDTA-2Na 15.0g
Sodium bicarbonate QS
Water for injection 5000.0ml
Take water for injection 2000.0 ml, add main ingredient JYD17, Tutofusin tris, low molecular dextran, EDTA-2Na stirring and dissolving.Adjust pH to be 7.0-9.0 with sodium bicarbonate, add 10 g gacs at 20-50 DEG C of whip attachment 30 min, carbon removal, mend and add water to 5000.0 ml.Essence filter, embedding every bottle 50 ml, sterilizing and get final product.
Embodiment 8 tumor cell in vitro inhibit activities is tested
Experiment material
HepG2 cell lines, human prostate cancer cell line PC-3, human colon cancer cell strain HCT-116 and Breast cancer lines MDA-MB-231 are provided by Weifang biotechnology medicine garden by cell strain source, adopt cellar culture, experimentation all adopts logarithmic phase cell.MTT and DMSO is Sigma Products, and 96 orifice plates provide by Jinan Bioisystech Co., Ltd of going away for some great undertakings.
Instrument: CO
2incubator (Forma 3110, USA), Bechtop (BCN-1360, east, Harbin connection), microplate reader (BioRad550, USA), inverted microscope (Nikon), Tissue Culture Flask (Costar, USA), 96 porocyte culture plates (Costar, USA).
Software: Microsoft Excel statistical analysis software
Experimental technique
Respectively by HCT-116 cell strain, MDA-MB-231 cell strain, PC-3 cell strain and HepG2 cell strain suspension inoculation in 96 orifice plates (100 μ L/ hole), namely 5 × 10
3individual cells/well, after cell breeds and spends the night, adds the substratum of 100 μ L containing different concns compound in every hole, each concentration establishes three multiple holes, do blank when not adding the hole reading of cell, add the hole that cell do not add compound and make compound blank well, Xarelto makes positive control.In 37 DEG C, 5% CO
2in hatch 48 h, every hole adds the MTT staining fluid of 10 μ L 0.5%, after continuing to hatch 4 h, centrifugal 3 min under 2500 rpm conditions, then throw plate abandon substratum in hole, add DMSO, 100 μ L/ holes.Abundant vibration mixing, in 570 nm(absorbing wavelength in microplate reader), 630 nm(assist wavelength) place measures the absorbancy OD value in every hole, with OD
570-OD
630difference calculate.The control drug arranged is respectively: Xarelto (sorafenib) or BMCL9o.
Inhibitory rate of cell growth is calculated as follows, and (namely the OD value in formula is OD
570-OD
630difference).
The inhibiting rate Microsoft Excel statistical analysis software corresponding according to drug level does straight-line regression, obtains straight-line equation, and the drug level calculating inhibiting rate corresponding 50% time is the 503nhibiting concentration (IC of testing sample to tumour cell
50).The IC of every strain cell is measured under above-mentioned similarity condition
50, every strain cell experiment continuously in triplicate, is averaged.
Experimental result is in table 3.
Table 3 test compounds sample is to the half-inhibition concentration IC of tumor cell in vitro
50
Experiment conclusion: as can be seen from above-mentioned Vitro Experimental Results, the diphenyl thiourea compounds containing nicotinamide of logical formula I of the present invention is to human prostate cell strain PC-3, Breast cancer lines MDA-MB-231, human colon cancer cell strain HCT-116 and HepG2 cell lines have certain restraining effect, wherein phenyl ring contains the compound JYG03 of two electron withdrawing group, JYG04, JYG09, JYG10, JYG14 and JYG17 is all stronger to the inhibit activities of four kinds of tumour cells, the inhibit activities of JYG04 and JYG17 to four strain tumour cells is all better than the analog BMCL9o of positive control medicine Xarelto and bibliographical information.
The restraining effect of embodiment 9 In Vitro Anti angiogenic action-human umbilical vein endothelial cell (HUVECs) is become tube chamber
Experimental principle: by Human umbilical vein endothelial cells (human umbilical vein endothelial cells, HUVECs) cultivate on Matrigel, by the impact of various angiogenesis factor, HUVECs can breed, extend, move and be interconnected into tubular structure, and the synthesized diphenyl thiourea compounds (as JYG17) containing nicotinamide can suppress the generation of new vessel, by comparing the activity suppressing the degree of new vessel to carry out assessing compound.
Experimental technique:
In an aseptic environment, the Matrigel 50 μ L diluted by the substratum 1:1 by M199 model is laid in 96 orifice plates, and poke small bubbles with rifle head, plate is put in 37 ° of C, 5% CO
2100 μ L compounds of the different concns set are added after cultivating at least 30 min in incubator.Carry out digestion HUVECs with pancreas enzyme-EDTA, and carry out cell counting, make containing 20000 cell/50 μ L in every hole, using the Xarelto of comparable sodium as positive control, in 37 ° of C, 5% CO
2after cultivating 6 h in incubator, take pictures under microscope.
Experimental result as shown in Figure 2.After cultivating 6 h without the HUVECs of any drug treating in Matrigel, increasing connection can be formed, become tube chamber shape (Fig. 2 A).Positive control Xarelto (Fig. 2 C) when 0.1 μM of concentration can greatly reduce the connection between HUVECs, and when 0.05 μM of concentration, (Fig. 2 B) is to being connected with certain restraining effect between HUVECs, becomes a small amount of tube chamber shape; JYG17 is when 0.05 μM of concentration (Fig. 2 D) and 0.1 μM of (Fig. 2 E) concentration to being connected with significant restraining effect between HUVECs, and its inhibition is better than positive control medicine sorafenib.
Above-described embodiment is only be described the preferred embodiment of the present invention; not scope of the present invention is limited; under not departing from the present invention and designing the prerequisite of spirit; the common engineering technical personnel in this area, to the improvement of the various distortion that technical scheme of the present invention is made, all should fall in protection domain that claims of the present invention determine.
Claims (10)
1. a class is containing the diphenyl thiourea compounds of nicotinamide building block, it is characterized in that it has the chemical structure of general formula as logical formula I:
In formula I, R is selected from H, C
1-C
6alkyl, halogen ,-CF
3,-OCF
3,-NO
2,-CN, R
1o-, SO
2nH
2,-NHSO
2r
2,-NR
3r
4,-CONR
5r
6,-COOR
7, R
8cO-and their two replacement or trisubstituted combination, wherein R
1, R
2, R
3, R
4, R
5, R
6, R
7or R
8independently be selected from H or C
1-C
6alkyl;
X is selected from O or S.
2. the diphenyl thiourea compounds containing nicotinamide building block according to claim 1, is characterized in that the R described in formula I is selected from H, C
1-C
4alkyl, F, Cl, Br ,-CF
3,-OCF
3,-CN, R
1o-,-NHSO
2r
2,-NR
3r
4,-CONR
5r
6, R
7cO-and their two replacement or trisubstituted combinations,
Wherein R
1, R
2, R
3, R
4, R
5, R
6or R
7independently be selected from H or C
1-C
4alkyl.
3. the diphenyl thiourea compounds containing nicotinamide building block according to claim 1, is characterized in that described compound is following compounds:
JYG01:6-{3-[3-(3,4-difluorophenyl) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG02:6-{3-[3-(4-chloro-phenyl-) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG03:6-{3-[3-(the fluoro-3-trifluoromethyl of 4-) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG04:6-{3-[3-(the chloro-3-trifluoromethyl of 4-) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG05:6-{3-[3-(the bromo-3-trifluoromethyl of 4-) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG06:6-{3-[3-(4-Trifluoromethoxyphen-l) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG07:6-{3-[3-(the chloro-4-fluorophenyl of 3-) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG08:6-{3-[3-(3-trifluoromethyl) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG09:6-{3-[3-(3,5-bis trifluoromethyl phenyl) thioureido]-thiophenyl }-N-picoline-3-methane amide;
JYG10:6-{3-[3-(the bromo-3-trifluoromethyl of 4-) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG11:6-{3-[3-(the fluoro-3-trifluoromethyl of 4-) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG12:6-{3-[3-(the chloro-4-fluorophenyl of 3-) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG13:6-{3-[3-(3-trifluoromethyl) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG14:6-{3-[3-(3,5-bis trifluoromethyl phenyl) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG15:6-{3-[3-(4-chloro-phenyl-) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG16:6-{3-[3-(3,4-difluorophenyl) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG17:6-{3-[3-(3-trifluoromethyl-4-chlorophenyl) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG18:6-{3-[3-(4-Trifluoromethoxyphen-l) thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG19:6-{3-[3-[2,4 dichloro benzene base] thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG20:6-{3-[3-[4-aminomethyl phenyl] thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG21:6-{3-[3-[4-fluorophenyl] thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG22:6-{3-[3-[3,4-3,5-dimethylphenyl] thioureido]-phenoxy group }-N-picoline-3-methane amide;
JYG23:6-{3-[3-[4-p-methoxy-phenyl] thioureido]-phenoxy group }-N-picoline-3-methane amide.
4. as described in claim 1 ~ 3 any one, contain a synthetic method for the diphenyl thiourea compounds of nicotinamide building block, it is characterized in that it comprises the steps:
The reactant aqueous solution of a:6-chlorine methyl niconate and methylamine or methylamine obtains compound N-methy 6-chlorine nicotinic acid amide;
B:N-methyl 6-chlorine nicotinic acid amide and Metha Amino Phenon or m-aminothiophenol condensation, obtain corresponding compound V;
C: compound ii obtains compound III with dithiocarbonic anhydride addition under triethylene diamine exists;
D: compound III, under the existence of solid phosgene, is sloughed hydrogen sulfide and obtained compounds Ⅳ;
E: compounds Ⅳ and compound V are obtained by reacting chemical compounds I in organic solvent, and described organic solvent is selected from dimethyl formamide, N,N-DIMETHYLACETAMIDE, methyl-sulphoxide or acetonitrile.
5. the synthetic method of the diphenyl thiourea compounds containing nicotinamide building block according to claim 4, is characterized in that:
Described a is specially: 6-chlorine methyl niconate is dissolved in C
1-C
4fatty alcohol or chlorinated hydrocarbon solvent in, react with methylamine under-5 ~ 50 DEG C of conditions, aftertreatment obtains N-methyl 6-chlorine nicotinic acid amide; Wherein said solvent is methyl alcohol, ethanol, acetonitrile or methylene dichloride; The mol ratio of described 6-chlorine methyl niconate and methylamine is 1:1-10;
Described b is specially: get amino-phenol or m-aminothiophenol is dissolved in polar aprotic solvent, under basic catalyst or acid binding agent existent condition, with the condensation under 30-120 DEG C of condition of N-methyl-6-chlorine nicotinic acid amide, obtains compound V through aftertreatment; Wherein said solvent is dimethyl formamide, methyl-sulphoxide, chloroform or acetonitrile; Catalyzer or acid binding agent are potassium tert.-butoxide, sodium isopropylate, salt of wormwood, sodium carbonate or its mixture; The mol ratio of described Metha Amino Phenon or m-aminothiophenol and N-methyl 6-chlorine nicotinic acid amide is 2:1 ~ 1:2;
Described e is specially: compounds Ⅳ and compound V are obtained by reacting the compound with formula I in organic solvent, and wherein said solvent is dimethyl formamide, methyl-sulphoxide, chloroform, methylene dichloride or acetonitrile.
6. as described in claim 1 ~ 3 any one containing the salt of diphenyl thiourea compounds for nicotinamide building block, it is characterized in that described salt comprises the solvate of the diphenyl thiourea compounds inorganic acid salt of nicotinamide, organic acid salt or above-mentioned salt.
7., according to claim 6 containing the salt of the diphenyl thiourea compounds of nicotinamide building block, it is characterized in that described inorganic acid salt is hydrochloride, hydrobromate, hydrosulfate, vitriol or phosphoric acid salt; Be preferably hydrochloride, hydrosulfate or vitriol;
Described organic acid salt be mesylate, fluoroform sulphonate, benzene sulfonate, tosilate, 1-naphthalene sulfonic aicd salt, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, Citrate trianion, lactic acid salt, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate or mandelate; Be preferably mesylate, tosilate, benzene sulfonate, fumarate, maleate or malate.
8. according to claim 6 or 7, contain the salt of the diphenyl thiourea compounds of nicotinamide building block, it is characterized in that the solvate of described salt is the hydrate of salt.
9. an anti-tumor drug, it is characterized in that its activeconstituents comprises the diphenyl thiourea compounds containing nicotinamide building block as described in claim 1 ~ 3 any one, or comprise the salt of the diphenyl thiourea compounds containing nicotinamide building block as claimed in claim 6.
10. anti-tumor drug as claimed in claim 9, is characterized in that:
By the diphenyl thiourea compounds containing nicotinamide building block as described in claim 1 ~ 3 any one, or the salt of the diphenyl thiourea compounds containing nicotinamide building block as claimed in claim 6 is as activeconstituents, after in pharmacy, acceptable auxiliary material mixes, according to pharmaceutically acceptable pharmaceutical methods and processing requirement, be prepared as the solid oral forms preparation for the treatment of or prophylaxis of tumours, liquid oral type preparation or injection-type preparation;
Or: by the diphenyl thiourea compounds containing nicotinamide building block as described in claim 1 ~ 3 any one, or the salt of the diphenyl thiourea compounds containing nicotinamide building block as claimed in claim 6 is as one of activeconstituents, after in other medicines and pharmacy, acceptable auxiliary material mixes, according to pharmaceutically acceptable pharmaceutical methods and processing requirement, be prepared as the solid oral forms preparation for the treatment of or prophylaxis of tumours, liquid oral type preparation or injection-type preparation.
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