CN106831724A - A kind of 1 methyl 1H indoles pyrazoline thioureas and its medicinal usage - Google Patents
A kind of 1 methyl 1H indoles pyrazoline thioureas and its medicinal usage Download PDFInfo
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Abstract
The invention discloses a kind of 1 methyl 1H indoles pyrazoline thioureas and pharmaceutically can into salt, with following structural formula：Wherein, R1It is H, Br or OCH3；R2It is H, F, Cl, Br, OCH3、CH3Or 4 CF3.Compound of the present invention has good antitumor action, and the toxicity to normal cell is low, with very big Development volue.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of 1- Methyl-1H-indoles-pyrazoline thiourea
And its medicinal usage.
Background technology
Tumour be body in the presence of various tumorigenesis factors, the cell paraplasm of local organization and the new life that is formed
Thing, often shows as local lump.Tumour cell has abnormal form, metabolism and function.It grows vigorous and is in often continuation
Growth.In recent years, especially malignant tumour has become one of disease of serious threat human health to tumour.In the whole world more than 50
Malignant tumour person up to 6,900,000 people is died from hundred million populations every year on average, new cases are 8,700,000, and numeral is in constantly increasing.
The methods such as chemotherapy, radiotherapy, operation, biological therapy and western medicines in treatment have become the most efficient method for the treatment of tumour.With
The development of the medicine of tumour, new antineoplastic is being continuously updated the replacement, is improving the cure rate of tumor patient, extension
The survival of patients time, the aspects such as disease are delayed to play huge effect.For many years, people constantly develop new antineoplastic
Thing, and by structure of modification, it is intended to develop antineoplastic derivative new in a series.
The chemical constitution transformation of medicine is based on the original basic chemical structure of medicine, to some of which functional group
Learn transformation or be combined two or more chemical constitutions with identical or different activity, obtain this kind of medicine
New derivative.Original physicochemical property and pharmacological activity may be changed by structure, had in clinical practice and extremely weighed
The effect wanted.
Zhang Ya-Liang etc. devise a class has the 1- Methyl-1H-indoles-pyrazoline for suppressing microtubule polymerization activity
Class compound e1-e28 (Synthesis and Biological Evaluation of 1-Methyl-1H-indole-
Pyrazoline Hybrids as Potential Tubulin Polymerization
Inhibitors.ChemMedChem2016,11,1446-1458)。
The content of the invention
The present invention has carried out structure of modification in prior art basis to 1- Methyl-1H-indoles-pyrazoline compounds,
Obtained a class activity improve 1- Methyl-1H-indoles-pyrazoline thiourea and pharmaceutically can into salt, with such as
Lower structural formula：
Wherein, R1It is H, Br or OCH3；R2It is H, F, Cl, Br, OCH3、CH3Or 4-CF3。
Above-claimed cpd and pharmaceutically can into salt, preferably R2It is H, 4-F, 4-Cl, 4-Br, 2-OCH3、3-OCH3、4-
OCH3、3,4-OCH3、3,4,5-OCH3、4-CH3Or 4-CF3。
Preferred compounds of the invention is as follows：
R1It is H, R2It is H, 4-F, 4-Cl, 4-Br, 2-OCH3、3-OCH3、4-OCH3、3,4-OCH3、3,4,5-OCH3、4-CH3Or
4-CF3；
Or, R1It is Br, R2It is H, 4-F, 4-Cl, 4-Br, 3,4-OCH3Or 3,4,5-OCH3；
Or, R1It is OCH3, R2It is H, 4-F, 4-Cl, 4-Br, 2-OCH3、3-OCH3、3,4-OCH3Or 3,4,5-OCH3。
More preferably：
R1It is H, R2It is H, 4-Br, 2-OCH3 or 3-OCH3；
Or, R1It is Br, R2It is H, 4-F or 4-OCH3；
Or, R1It is OCH3, R2It is H, 4-F or 4-Cl.
Compound of the present invention and pharmaceutically can into salt can be administered in the form of single medicine or can be with it
Its administered in combination.
The officinal salt of compound of the invention includes various inorganic or acylate such as hydrochloride, hydrobromate, phosphoric acid
Salt, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalates；It is various
Inorganic or organic alkali salt such as NaOH, trishydroxymethylaminomethane and N- methyl-glucamines.
It is of the invention to additionally provide 1- Methyl-1H-indoles-pyrazoline thiourea of the present invention and pharmaceutically
Into application of the salt in antineoplastic is prepared.The preferred breast cancer of tumour, lung cancer, liver cancer etc..
Present invention also offers a kind of antineoplastic pharmaceutical compositions, including 1- of the present invention Methyl-1H-indoles-pyrazoles
Quinoline thiourea and pharmaceutically can into salt and pharmaceutical carrier.The antineoplastic pharmaceutical compositions include as activity into
The compound or pharmaceutically acceptable salt thereof of the invention and pharmaceutical acceptable carrier for dividing.Preferably, pharmaceutical composition of the invention has 0.1-
The compound or pharmaceutically acceptable salt thereof of the invention as active component of 99.9% percentage by weight.
" pharmaceutical acceptable carrier " is included but is not limited to：Ion exchange material, aluminum oxide, aluminum stearate, lecithin, self-emulsifying medicine
Thing transmission system (SEDDS) such as d- TPGS 1000s, tween or other similar polymerisation medium medicines
Surfactant, the haemocyanin of preparation such as human serum albumins, buffer substance such as phosphate, amion acetic acid, sorbic acid, mountain
Potassium sorbate, the mixing of saturated vegetable fatty acid partial glyceride, water, salt, electrolyte such as sulfate protamine, disodium hydrogen phosphate, phosphorus
Potassium hydrogen phthalate, sodium chloride, zinc salt, silica gel, magnesium silicate etc..Polyvinyl pyrrolidone, cellulosic material, polyvinyl alcohol, carboxymethyl cellulose
Plain sodium, polyacrylate, ethene-polyoxyethylene-block polymer and lanolin, cyclodextrin such as α-, β-, gamma-cyclodextrin or its
The derivative such as hydroxyalkyl cyclodextrin such as 2- and 3- HP-β-CDs or other soluble derivatives etc. through chemical modification is equal
Can be used to promote the drug delivery of compound of the invention, its pharmaceutical salts or prodrug.
Other pharmaceutically acceptable auxiliaries such as filler (such as Lactis Anhydrous, starch, lactose bead and glucose), adhesive are (such as micro-
Crystalline cellulose), disintegrant (such as crosslinked carboxymethyl fecula sodium, Ac-Di-Sol, low-substituted hydroxypropyl cellulose and friendship
Connection PVP), lubricant (such as magnesium stearate), sorbefacient, flavouring agent, sweetener, diluent, excipient, wetting agent, solvent,
Solubilizer and colouring agent etc. can be also added in pharmaceutical composition of the invention.
The compound or pharmaceutically acceptable salt thereof and pharmaceutical composition of the invention described above can be by enteron aisle or parenteral routes
Administration.Non-intestinal drug delivery agent is including injection, creme, ointment, patch, spray etc..Method of administration includes subcutaneous, skin
Interior, intra-arterial, intravenous, intramuscular, in joint, in synovia, in breastbone, in intrathecal, focus, intracranial injection or infusion, or, mouth
Clothes, part, rectum, intranasal, buccal, vagina, sublingual, intracutaneous, mucous membrane, tracheae, urethral administration, or by sucking aerosol or plant
Enter accumulation or acupuncture mode is administered.
The compound or pharmaceutically acceptable salt thereof of the invention described above and the therapeutically effective amount of pharmaceutical composition are 0.001-
Between 100mg/kg/d, can be used for the single drug of relevant disease or drug combination treatment, be that those skilled in the art can manage
The scope of solution.
It is external thin to human liver cancer that the present invention has investigated 1- Methyl-1H-indoles-pyrazoline thiourea of the present invention
The inhibitory action of born of the same parents (HepG2), human breast cancer cell (MCF-7) and human lung adenocarcinoma cell (A549) and thin to people's kidney epithelium
It is good that the cytotoxicity result of born of the same parents (293T) shows that 1- Methyl-1H-indoles-pyrazoline thiourea of the present invention has
Antitumor action, the toxicity to normal cell is low, with very big Development volue.
Specific embodiment
Specific steps of the invention are illustrated by the following examples, but are not limited by the example.
The term for being used in the present invention, unless otherwise indicated, typically there are those of ordinary skill in the art generally to manage
The implication of solution.
The present invention is described in further detail with reference to specific embodiment and with reference to data.It should be understood that these embodiments are only
It is in order to demonstrate the invention, rather than to limit the scope of the present invention by any way.
In the examples below, the various processes and method not described in detail are conventional methods as known in the art.
The preparation of the 1- Methyl-1H-indoles-pyrazoline thiourea of the present invention of embodiment 1
1- Methyl-1H-indoles-pyrazoline thiourea of the present invention and pharmaceutically can into salt can adopt with the following method
It is prepared from.
Specifically preparation method is：Under condition of ice bath, to sequentially adding POCl in reaction vessel3(20mL) and DMF (40mL), changes
Compound 1 (35mmol), reacts 2h, pours into frozen water and adjusts pH to 9.0 with NaOH, is extracted with ethyl acetate dry compound 2.
Under ice bath, to addition compound 2 (25mmol) in reaction vessel, THF (15mL), NaH (62.5mmol) stir 15min, then
Add CH3I (33mmol) room temperature reactions 24h.TLC is tracked, and is fully extracted with ethyl acetate dry compound 3 after reaction.To
Compound 3 (2mmol) and acetophenone (2mmol), absolute ethyl alcohol (20mL) and KOH (6mmol), room temperature are added in reaction vessel
Reaction 24h, ethanol obtains compound 4 with recrystallize with dichloromethane after filtering.To addition compound 4 (1mmol), ammonia in reaction vessel
Base thiocarbamide (3mmol) and absolute ethyl alcohol (10mL), add NaOH solution after stirring and dissolving, be heated to reflux 24h, fully mistake after reaction
Filter, ethanol obtains a series of 1- Methyl-1H-indoles-pyrazoline thioureas of the present invention with recrystallize with dichloromethane
(compound 5), compound is as shown in table 1.
Table 1
Above-claimed cpd Structural Identification data are as follows：
5-(1-methyl-1H-indol-3-yl)-3-phenyl-4,5-dihydro-1H-pyrazole-1-
carbothioamide(z1)
Beige powder.Yield:66.0%.m.p.231-233 DEG C of1H NMR(400MHz,DMSO-d6)δ:8.01–7.88
(m, 3H), 7.83 (s, 1H), 7.53-7.43 (m, 3H), 7.39 (d, J=8.2Hz, 1H), 7.30 (d, J=7.9Hz, 1H),
7.19 (s, 1H), 7.12 (t, J=7.3Hz, 1H), 6.94 (t, J=7.3Hz, 1H), 6.18 (dd, J=11.4,3.3Hz, 1H),
(dd, J=17.9,3.4Hz, the 1H) of 3.97-3.81 (m, 1H), 3.73 (s, 3H), 3.2513C NMR(DMSO-d6,101MHz)δ:
176.40,155.78,137.38,131.57,131.00,129.25,128.31,127.56,125.15,121.57,119.29,
119.00,115.37,110.47,57.24,41.59,32.79.MS(ESI)m/z:335.13(C19H18N4S,[M+H]+)
.Anal.Calcd for C19H18N4S:C,68.23；H,5.42；N,16.75.Found:C,68.44；H,5.41；N,16.70.
3-(4-fluorophenyl)-5-(1-methyl-1H-indol-3-yl)-4,5-dihydro-1H-
pyrazole-1-carbothioamide(z2)
Beige powder.Yield:57.8%.m.p.241-242 DEG C of1H NMR(400MHz,DMSO-d6)δ:8.00(dd,J
=8.7,5.6Hz, 2H), 7.94 (s, 1H), 7.87 (s, 1H), 7.39 (d, J=8.2Hz, 1H), 7.31 (dd, J=17.2,
8.4Hz, 3H), 7.19 (s, 1H), 7.12 (t, J=7.6Hz, 1H), 6.95 (t, J=7.5Hz, 1H), 6.17 (dd, J=11.4,
3.3Hz, 1H), 3.96-3.80 (m, 1H), 3.73 (s, 3H), 3.26 (dd, J=18.0,3.4Hz, 1H)13C NMR(DMSO-
d6,101MHz)δ:176.41,154.85,137.37,130.00,129.91,128.28,128.24,128.20,125.15,
121.57,119.30,118.99,116.44,116.23,115.34,110.46,57.35,41.68,32.79.MS(ESI)m/
z:353.12(C19H17FN4S,[M+H]+).Anal.Calcd for C19H17FN4S:C,64.75；H,4.86；N,
15.90.Found:C,64.65；H,4.87；N,15.89.
3-(4-chlorophenyl)-5-(1-methyl-1H-indol-3-yl)-4,5-dihydro-1H-
pyrazole-1-carbothioamide(z3)
Beige powder.Yield:59.2%.m.p.237-238 DEG C of1H NMR(400MHz,DMSO-d6)δ:7.95(d,J
=8.6Hz, 3H), 7.90 (s, 1H), 7.54 (d, J=8.6Hz, 2H), 7.39 (d, J=8.3Hz, 1H), 7.27 (d, J=
7.9Hz, 1H), 7.19 (s, 1H), 7.12 (t, J=7.2Hz, 1H), 6.95 (t, J=7.5Hz, 1H), 6.17 (dd, J=11.4,
3.3Hz, 1H), 3.95-3.80 (m, 1H), 3.73 (s, 3H), 3.25 (dd, J=18.0,3.4Hz, 1H) .MS (ESI) m/z:
369.09(C19H17ClN4S,[M+H]+).Anal.Calcd for C19H17ClN4S:C,61.86；H,4.65；N,
15.19.Found:C,61.98；H,4.64；N,15.19.
3-(4-bromophenyl)-5-(1-methyl-1H-indol-3-yl)-4,5-dihydro-1H-pyrazole-
1-carbothioamide(z4)
Beige powder.Yield:48.3%.m.p.237-238 DEG C of1H NMR(400 MHz,DMSO-d6)δ:7.97(s,
1H), 7.88 (d, J=8.6 Hz, 3H), 7.68 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.2 Hz, 1H), 7.27 (d, J=
8.0 Hz, 1H), 7.19 (s, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.94 (t, J=7.5 Hz, 1H), 6.17 (dd, J=
11.4,3.3 Hz, 1H), 3.96-3.79 (m, 1H), 3.73 (s, 3H), 3.24 (dd, J=18.0,3.4 Hz, 1H) .MS (ESI)
m/z:413.04(C19H17BrN4S,[M+H]+).Anal.Calcd for C19H17BrN4S:C,55.21；H,4.15；N,
13.55.Found:C,55.01；H,4.16；N,13.57.
5-(1-methyl-1H-indol-3-yl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazole-1-
carbothioamide(z5)
Beige powder.Yield:70.2%.m.p.254-255 DEG C of1H NMR(400 MHz,DMSO-d6)δ:7.88–
7.77 (m, 4H), 7.39 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 3H), 7.19 (s, 1H), 7.14 (t, J=7.2
Hz, 1H), 6.93 (t, J=7.2 Hz, 1H), 6.15 (dd, J=11.2,3.2 Hz, 1H), 3.90-3.83 (m, 1H), 3.73
(s, 3H), 3.23 (dd, J=18.0,3.2 Hz, 1H), 2.36 (s, 3H) .MS (ESI) m/z:349.14(C20H20N4S,[M+H
]+).Anal.Calcd for C20H20N4S:C,68.94；H,5.79；N,16.08.Found:C,68.84；H,5.81；N,
16.12。
5-(1-methyl-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-
1H-pyrazole-1-carbothioamide(z6)
Beige crystal.Yield:27.0%.m.p.264-265 DEG C of1H NMR(400 MHz,DMSO-d6)δ:8.14(d,
J=8.2Hz, 2H), 8.06 (s, 1H), 8.01 (s, 1H), 7.83 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.2 Hz, 1H),
7.29 (d, J=7.9 Hz, 1H), 7.21 (s, 1H), 7.13 (t, J=7.5 Hz, 1H), 6.95 (t, J=7.4 Hz, 1H),
6.22 (dd, J=11.5,3.4Hz, 1H), 3.32-3.37 (m, 1H), 3.73 (s, 3H), 3.30 (dd, J=18.0,3.5 Hz,
1H).13C NMR(DMSO-d6,101 MHz)δ:176.86,154.18,137.38,135.61,128.35,128.17,
126.12,126.08,125.89,125.14,121.59,119.34,118.95,115.27,110.48,57.60,41.44,
32.79.MS(ESI)m/z:403.11(C20H17F3N4S,[M+H]+).Anal.Calcd for C20H17F3N4S:C,59.69；H,
4.26；N,13.92.Found:C,59.66；H,4.25；N,13.94.
3-(2-methoxyphenyl)-5-(1-methyl-1H-indol-3-yl)-4,5-dihydro-1H-
pyrazole-1-carbothioamide(z7)Milk-white powder.Yield:90.1%.m.p.228-229 DEG C of1H
NMR(400 MHz,DMSO-d6)δ:8.14 (d, J=6.4 Hz, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.46 (t, J=
7.1 Hz, 1H), 7.41-7.31 (m, 2H), 7.17 (s, 1H), 7.12 (t, J=7.8 Hz, 2H), 7.04 (t, J=7.5 Hz,
1H), 6.95 (t, J=7.5 Hz, 1H), 6.11 (dd, J=11.4,3.3 Hz, 1H), 4.01-3.86 (m, 1H), 3.76 (s,
3H), 3.73 (s, 3H), 3.32 (dd, J=18.6,3.4 Hz, 1H) .MS (ESI) m/z:365.14(C20H20N4OS,[M+H]+)
.Anal.Calcd for C20H20N4OS:C,65.91；H,5.53；N,15.37.Found:C,65.89；H,5.53；N,15.33.
3-(3-methoxyphenyl)-5-(1-methyl-1H-indol-3-yl)-4,5-dihydro-1H-
pyrazole-1-carbothioamide(z8)Beige powder.Yield:75.5%.m.p.215-216 DEG C of1H NMR
(400 MHz,DMSO-d6)δ:7.95(s,1H),7.91(s,1H),7.58(s,1H),7.45–7.33(m,3H),7.29(d,J
=8.0 Hz, 1H), 7.19 (s, 1H), 7.12 (t, J=7.6 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.95 (t, J=
7.5 Hz, 1H), 6.16 (dd, J=11.3,3.1 Hz, 1H), 3.91-3.82 (m, 1H), 3.82 (s, 3H), 3.73 (s, 3H),
3.26 (dd, J=18.0,3.2 Hz, 1H) .MS (ESI) m/z:365.14(C20H20N4OS,[M+H]+).Anal.Calcd for
C20H20N4OS:C,65.91；H,5.53；N,15.37.Found:C,66.04；H,5.51；N,15.39.
3-(4-methoxyphenyl)-5-(1-methyl-1H-indol-3-yl)-4,5-dihydro-1H-
pyrazole-1-carbothioamide(z9)Beige powder.Yield:54.9%.m.p.237-239 DEG C of1H NMR
(400 MHz,DMSO-d6)δ:7.87 (d, J=8.7Hz, 2H), 7.83 (s, 1H), 7.73 (s, 1H), 7.39 (d, J=8.2
Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.18 (s, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.02 (d, J=8.7 Hz,
2H), 6.94 (t, J=7.5 Hz, 1H), 6.14 (dd, J=11.2,2.8 Hz, 1H), 3.98-3.78 (m, 4H), 3.73 (s,
3H), 3.23 (dd, J=17.9,2.9 Hz, 1H)13C NMR(DMSO-d6,101MHz)δ:175.96,161.63,155.75,
137.38,129.30,128.33,125.15,123.99,121.55,119.25,119.03,115.38,114.70,110.44,
57.08,55.85,41.66,32.79.MS(ESI)m/z:365.14(C20H20N4OS,[M+H]+).Anal.Calcd for
C20H20N4OS:C,65.91；H,5.53；N,15.37.Found:C,65.88；H,5.54；N,15.40.
3-(3,4-dimethoxyphenyl)-5-(1-methyl-1H-indol-3-yl)-4,5-dihydro-1H-
pyrazole-1-carbothioamide(z10)
Beige powder.Yield:26.5%.m.p.217-219 DEG C of1H NMR(400 MHz,DMSO-d6)δ:7.88(s,
2H), 7.68 (d, J=1.7 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.34-7.25 (m, 2H), 7.17 (s, 1H), 7.12
(t, J=7.6Hz, 1H), 7.01-6.92 (m, 2H), 6.15 (dd, J=11.2,3.1 Hz, 1H), 3.89-3.81 (m, 4H),
3.80 (s, 3H), 3.72 (s, 3H), 3.25 (dd, J=17.8,3.2 Hz, 1H)13C NMR(DMSO-d6,101 MHz)δ:
175.95,155.81,151.51,149.37,137.38,128.22,125.19,124.13,121.57,121.52,119.27,
119.09,115.44,111.69,110.42,109.82,57.16,56.12,56.05,41.62,32.78.MS(ESI)m/z:
395.15(C21H22N4O2S,[M+H]+).Anal.Calcd for C21H22N4O2S:C,63.94；H,5.62；N,
14.20.Found:C,63.89；H,5.64；N,14.21.
5-(1-methyl-1H-indol-3-yl)-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-
pyrazole-1-carbothioamide(z11)
Beige powder.Yield:34.7%.m.p.188-189 DEG C of1H NMR(400 MHz,DMSO-d6)δ:7.93(s,
2H), 7.39 (d, J=8.2 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.22 (s, 2H), 7.19-7.05 (m, 2H), 6.97
(t, J=7.4Hz, 1H), 6.17 (dd, J=11.2,2.9 Hz, 1H), 3.88-3.77 (m, 7H), 3.73 (s, 3H), 3.70 (s,
3H),3.37–3.28(m,1H).13C NMR(DMSO-d6,101 MHz)δ:176.18,155.69,153.51,139.95,
137.39,127.89,127.04,125.22,121.59,119.28,119.14,115.59,110.39,105.05,60.60,
57.33,56.55,41.76,32.78.MS(ESI)m/z:425.16(C22H24N4O3S,[M+H]+).Anal.Calcd for
C22H24N4O3S:C,62.24；H,5.70；N,13.20.Found:C,62.21；H,5.71；N,13.19.
5-(5-bromo-1-methyl-1H-indol-3-yl)-3-phenyl-4,5-dihydro-1H-pyrazole-
1-carbothioamide(z12)Dark white powder.Yield:56.9%.m.p.249-251 DEG C of1H NMR(400
MHz,DMSO-d6)δ:7.97 (s, 1H), 7.94 (d, J=5.1 Hz, 2H), 7.87 (s, 1H), 7.52 (s, 1H), 7.49 (s,
3H), 7.39 (d, J=8.7 Hz, 1H), 7.24 (d, J=7.2 Hz, 2H), 6.23-6.10 (m, 1H), 3.98-3.80 (m,
1H),3.73(s,3H),3.29–3.18(m,1H).MS(ESI)m/z:413.04(C19H17BrN4S,[M+H]+).Anal.Calcd
for C19H17BrN4S:C,55.21；H,4.15；N,13.55.Found:C,55.31；H,4.14；N,13.53.
5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(4-fluorophenyl)-4,5-dihydro-1H-
pyrazole-1-carbothioamide(z13)
Beige crystal.Yield:38.1%.m.p.235-237 DEG C of1H NMR(400 MHz,DMSO-d6)δ:8.11–
7.94 (m, 3H), 7.92 (s, 1H), 7.52 (s, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.33 (t, J=8.8 Hz, 2H),
7.24 (d, J=6.7 Hz, 2H), 6.16 (dd, J=11.3,3.2 Hz, 1H), 3.99-3.77 (m, 1H), 3.73 (s, 3H),
3.25 (dd, J=18.0,3.2 Hz, 1H) .MS (ESI) m/z:431.03(C19H16BrFN4S,[M+H]+).Anal.Calcd
for C19H16BrFN4S:C,52.91；H,3.74；N,12.99.Found:C,52.87；H,3.73；N,13.02.
5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-
pyrazole-1-carbothioamide(z14)
Beige crystal.Yield:31%.m.p.250-251 DEG C of1H NMR(400 MHz,DMSO-d6)δ:8.02(s,
1H), 7.95 (d, J=8.5 Hz, 3H), 7.61-7.48 (m, 3H), 7.38 (d, J=8.7 Hz, 1H), 7.24 (d, J=8.1
Hz, 2H), 6.17 (dd, J=11.4,3.3 Hz, 1H), 3.98-3.77 (m, 1H), 3.72 (s, 3H), 3.24 (dd, J=18.0,
3.3 Hz,1H).MS(ESI)m/z:447.00(C19H16BrClN4S,[M+H]+).Anal.Calcd for C19H16BrClN4S:
C,50.96；H,3.60；N,12.51.Found:C,50.84；H,3.61；N,12.47.
5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(4-bromophenyl)-4,5-dihydro-1H-
pyrazole-1-carbothioamide(z15)
Beige powder.Yield:26.5%.m.p.255-257 DEG C of1H NMR(400 MHz,DMSO-d6)δ:8.02(s,
1H), 7.94 (s, 1H), 7.88 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.51 (s, 1H), 7.38 (d, J
=8.7 Hz, 1H), 7.29-7.20 (m, 2H), 6.17 (dd, J=11.4,3.3 Hz, 1H), 3.91-3.84 (m, 1H), 3.72
(s, 3H), 3.23 (dd, J=18.0,3.4 Hz, 1H) .MS (ESI) m/z:490.95(C19H16Br2N4S,[M+H]+)
.Anal.Calcd for C19H16Br2N4S:C,46.36；H,3.28；N,11.38.Found:C,46.50；H,3.28；N,
11.39。
5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(4-methoxyphenyl)-4,5-dihydro-
1H-pyrazole-1-carbothioamide(z16)
White powder.Yield:23.4%.m.p.229-231 DEG C of1H NMR(400 MHz,DMSO-d6)δ:7.87(d,J
=8.7Hz, 3H), 7.75 (s, 1H), 7.52 (s, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.23 (d, J=10.2 Hz, 2H),
7.02 (d, J=8.7 Hz, 2H), 6.13 (dd, J=11.2,3.0 Hz, 1H), 3.96-3.78 (m, 4H), 3.73 (s, 3H),
3.21 (dd, J=17.9,3.1 Hz, 1H)13C NMR(DMSO-d6,101 MHz)δ:175.95,161.66,155.89,
136.02,129.49,129.35,126.96,123.96,123.89,121.46,115.51,114.67,112.58,112.08,
56.76,55.85,41.85,33.00.MS(ESI)m/z:443.05(C20H19BrN4OS,[M+H]+).Anal.Calcd for
C20H19BrN4OS:C,54.18；H,4.32；N,12.64.Found:C,53.98；H,4.33；N,12.60.
5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3,4-dimethoxyphenyl)-4,5-
dihydro-1H-pyrazole-1-carbothioamide(z17)
Beige powder.Yield:37.2%.m.p.237-238 DEG C of1H NMR(400 MHz,DMSO-d6)δ:7.93(d,J
=4.2Hz, 2H), 7.67 (d, J=1.7 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H),
7.32-7.22 (m, 2H), 7.21 (s, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.14 (dd, J=11.2,3.1 Hz, 1H),
3.88-3.81 (m, 4H), 3.80 (s, 3H), 3.72 (s, 3H), 3.22 (dd, J=17.8,3.2 Hz, 1H) .MS (ESI) m/z:
473.06(C21H21BrN4O2S,[M+H]+).Anal.Calcd for C21H21BrN4O2S:C,53.28；H,4.47；N,
11.84.Found:C,53.31；H,4.46；N,11.81.
5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3,4,5-trimethoxyphenyl)-4,5-
dihydro-1H-pyrazole-1-carbothioamide(z18)
Dark white powder.Yield:28.0%.m.p.243-244 DEG C of1H NMR(400 MHz,DMSO-d6)δ:
8.00 (s, 2H), 7.59 (s, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.25 (d, J=13.7 Hz, 3H), 7.18 (s, 1H),
6.16 (d, J=10.9Hz, 1H), 3.92-3.76 (m, 7H), 3.73 (s, 3H), 3.70 (s, 3H), 3.28 (d, J=18.8 Hz,
1H).13C NMR(DMSO-d6,101 MHz)δ:176.15,155.90,153.49,139.98,136.02,129.00,
127.03,126.97,124.01,121.56,115.67,112.54,112.08,105.13,60.61,57.01,56.57,
41.96,33.00.MS(ESI)m/z:503.07(C22H23BrN4O3S,[M+H]+).Anal.Calcd for C22H23BrN4O3S:
C,52.49；H,4.61；N,11.13.Found:C,52.44；H,4.62；N,11.14.
5-(5-methoxy-1-methyl-1H-indol-3-yl)-3-phenyl-4,5-dihydro-1H-
pyrazole-1-carbothioamide(z19)Yellow powder.Yield:68.1%.m.p.230-231 DEG C of1H NMR
(400 MHz,DMSO-d6)δ:7.94 (d, J=12.2 Hz, 3H), 7.81 (s, 1H), 7.48 (s, 3H), 7.28 (d, J=9.0
Hz, 1H), 7.17 (s, 1H), 6.75 (s, 2H), 6.15 (d, J=10.3 Hz, 1H), 3.87 (dd, J=17.5,11.4 Hz,
1H), 3.68 (s, 3H), 3.48 (s, 3H), 3.26 (d, J=17.7 Hz, 1H) .MS (ESI) m/z:365.14(C20H20N4OS,[M
+H]+).Anal.Calcd for C20H20N4OS:C,65.91；H,5.53；N,15.37.Found:C,65.79；H,5.51；N,
15.34。
3-(4-fluorophenyl)-5-(5-methoxy-1-methyl-1H-indol-3-yl)-4,5-dihydro-
1H-pyrazole-1-carbothioamide(z20)
Milk-white powder.Yield:40.1%.m.p.238-239 DEG C of1H NMR(400 MHz,DMSO-d6)δ:
8.02 (dd, J=8.7,5.6 Hz, 2H), 7.87 (s, 1H), 7.81 (s, 1H), 7.41-7.24 (m, 3H), 7.16 (s, 1H),
6.75 (d, J=8.4 Hz, 2H), 6.15 (dd, J=11.2,2.8 Hz, 1H), 3.94-3.78 (m, 1H), 3.69 (s, 3H),
3.51 (s, 3H), 3.27 (dd, J=17.9,3.0 Hz, 1H) .MS (ESI) m/z:383.13(C20H19FN4OS,[M+H]+)
.Anal.Calcd for C20H19FN4OS:C,62.81；H,5.01；N,14.65.Found:C,63.01；H,5.00；N,
14.69。
3-(4-chlorophenyl)-5-(5-methoxy-1-methyl-1H-indol-3-yl)-4,5-dihydro-
1H-pyrazole-1-carbothioamide(z21)
Dark white powder.Yield:30.6%.m.p.247-249 DEG C of1H NMR(400 MHz,DMSO-d6)δ:
7.97 (d, J=8.6 Hz, 2H), 7.92 (s, 1H), 7.86 (s, 1H), 7.54 (d, J=8.6 Hz, 2H), 7.28 (d, J=8.7
Hz, 1H), 7.16 (s, 1H), 6.80-6.71 (m, 2H), 6.15 (dd, J=11.3,3.0 Hz, 1H), 3.93-3.78 (m, 1H),
3.69 (s, 3H), 3.53 (s, 3H), 3.25 (dd, J=17.9,3.1 Hz, 1H) .MS (ESI) m/z:399.10
(C20H19ClN4OS,[M+H]+).Anal.Calcd for C20H19ClN4OS:C,60.22；H,4.80；N,14.05.Found:C,
60.13；H,4.78；N,14.09.
3-(4-bromophenyl)-5-(5-methoxy-1-methyl-1H-indol-3-yl)-4,5-dihydro-
1H-pyrazole-1-carbothioamide(z22)
Beige crystal.Yield:31.7%.m.p.240-242 DEG C of1H NMR(400 MHz,DMSO-d6)δ:7.95(s,
1H), 7.89 (d, J=8.6 Hz, 3H), 7.68 (d, J=8.6 Hz, 2H), 7.28 (d, J=8.8 Hz, 1H), 7.16 (s,
1H), 6.80-6.71 (m, 2H), 6.15 (dd, J=11.3,2.9 Hz, 1H), 3.89-3.81 (m, 1H), 3.68 (s, 3H),
3.53 (s, 3H), 3.24 (dd, J=17.9,3.0 Hz, 1H)13C NMR(DMSO-d6,101 MHz)δ:176.37,154.91,
153.64,132.69,132.23,130.90,129.45,129.16,125.35,124.41,114.59,111.25,111.22,
101.34,57.49,55.40,40.99,32.94.MS(ESI)m/z:443.05(C20H19BrN4OS,[M+H]+)
.Anal.Calcd for C20H19BrN4OS:C,54.18；H,4.32；N,12.64.Found:C,54.06；H,4.32；N,
12.67。
5-(5-methoxy-1-methyl-1H-indol-3-yl)-3-(2-methoxyphenyl)-4,5-dihydro-
1H-pyrazole-1-carbothioamide(z23)
Brown powder.Yield:26.4%.m.p.208-209 DEG C of1H NMR(400 MHz,DMSO-d6)δ:8.19(d,J
=7.8Hz, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H),
7.17 (s, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.83-6.73 (m, 2H), 6.10 (dd,
J=11.3,2.8 Hz, 1H), 3.96-3.89 (m, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 3.54 (s, 3H), 3.33 (dd, J
=18.6,2.9 Hz, 1H)13C NMR(DMSO-d6,101 MHz)δ:176.13,158.79,155.31,153.65,
132.70,132.56,129.62,129.20,125.40,121.09,120.15,114.90,112.93,111.32,111.17,
101.39,57.09,56.16,55.47,44.62,32.93.MS(ESI)m/z:395.15(C21H22N4O2S,[M+H]+)
.Anal.Calcd for C21H22N4O2S:C,63.94；H,5.62；N,14.20.Found:C,63.79；H,5.64；N,
14.16。
5-(5-methoxy-1-methyl-1H-indol-3-yl)-3-(3-methoxyphenyl)-4,5-dihydro-
1H-pyrazole-1-carbothioamide(z24)
Beige powder.Yield:30.2%.m.p.138-139 DEG C of1H NMR(400 MHz,DMSO-d6)δ:7.95(s,
1H), 7.91 (s, 1H), 7.61 (s, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.28 (d, J
=9.6 Hz, 1H), 7.17 (s, 1H), 7.05 (d, J=5.9 Hz, 1H), 6.76 (d, J=6.7 Hz, 2H), 6.15 (dd, J=
11.2,2.7 Hz, 1H), 3.95-3.78 (m, 4H), 3.69 (s, 3H), 3.52 (s, 3H), 3.26 (dd, J=17.9,2.8 Hz,
1H).MS(ESI)m/z:395.15(C21H22N4O2S,[M+H]+).Anal.Calcd for C21H22N4O2S:C,63.94；H,
5.62；N,14.20.Found:C,64.04；H,5.61；N,14.19.
3-(3,4-dimethoxyphenyl)-5-(5-methoxy-1-methyl-1H-indol-3-yl)-4,5-
dihydro-1H-pyrazole-1-carbothioamide(z25)
Light yellow crystal.Yield:21.7%.m.p.180-182 DEG C of1H NMR(400 MHz,DMSO-d6)δ:
7.86 (s, 2H), 7.70 (s, 1H), 7.32 (d, J=8.3,1H), 7.28 (d, J=8.8 Hz, 1H), 7.15 (s, 1H), 6.99
(d, J=8.4 Hz, 1H), 6.82-6.72 (m, 2H), 6.12 (dd, J=11.1,2.6 Hz, 1H), 3.88-3.76 (m, 7H),
3.69 (s, 3H), 3.53 (s, 3H), 3.25 (dd, J=17.7,2.7 Hz, 1H) .MS (ESI) m/z:425.16(C22H24N4O3S,
[M+H]+).Anal.Calcd for C22H24N4O3S:C,62.24；H,5.70；N,13.20.Found:C,62.31；H,5.71；
N,13.24。
5-(5-methoxy-1-methyl-1H-indol-3-yl)-3-(3,4,5-trimethoxyphenyl)-4,5-
dihydro-1H-pyrazole-1-carbothioamide(z26)
Light yellow crystal.Yield:14.8%.m.p.196-198 DEG C of1H NMR(400 MHz,DMSO-d6)δ:
7.93 (s, 2H), 7.31-7.24 (m, 3H), 7.13 (s, 1H), 6.81 (d, J=2.3 Hz, 1H), 6.76 (dd, J=8.8,2.4
Hz, 1H), 6.15 (dd, J=11.1,2.7 Hz, 1H), 3.86-3.80 (m, 7H), 3.70 (d, J=3.9 Hz, 6H), 3.56
(s, 3H), 3.32 (dd, J=17.9 Hz, 2.9 Hz, 1H) .MS (ESI) m/z:455.17(C23H26N4O4S,[M+H]+)
.Anal.Calcd for C23H26N4O4S:C,60.77；H,5.77；N,12.33.Found:C,60.98；H,5.76；N,
12.35。
The anti tumor activity in vitro of embodiment 2 is determined
IC50：Half inhibiting rate, is that compound kills cancer cell ability.
Human liver cancer cell (HepG2), human breast cancer cell (MCF-7), human lung adenocarcinoma cell (A549).
CC50：Half toxic concentration, toxicity of the compound to normal cell.
People's renal epithelial cell (293T).
Embodiment 1 is determined using MTT [3- (4,5)-bis- methyl -2- thiazoles-(2,5)-phenyl bromination tetrazole is blue] methods
The compound for preparing is to human liver cancer cell (HepG2), human breast cancer cell (MCF-7) and human lung adenocarcinoma cell (A549)
Drug concentration (half maximal inhibitory concentration, IC of the inhibiting rate when reaching 50%50).And
To the cytotoxicity of people's renal epithelial cell (293T), the toxicity of each compound is with suppressing 293T cell survival rates to when 50%
Concentration C C50To represent.
(1) preparation of nutrient solution：DMEM (basal medium) 89%, hyclone 10%, Penicillin Streptomycin Solution
(10000IU/mL, 10000 μ g/mL) 1%.
(2) four kinds of cultures of adherent cancer cell：Using above-mentioned nutrient solution, (nutrient solution volume is about the 1/ of blake bottle capacity
10), in 37 DEG C, 5%CO2Cultivated in incubator, the growth conditions according to cancer cell judge the generation time.
(3) preparation of various concentrations medicine：Storing solution is prepared using DMEM (a small amount of DMSO hydrotropies), the every hole after dosing is thin
The final concentration of DMSO is usually no more than 0.05%-0.1% in born of the same parents' suspension；Storing solution is diluted to six concentration gradients with DMEM
(100 μM, 50 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM)；It is stored in standby in -20 DEG C of refrigerators.
(4) cell incubation：Take the logarithm growth period tumour cell, tune concentration of cell suspension is 1-1.5 × 105/ mL, after mixing
Add in 96 well culture plates (100 μ L/ holes), in 37 DEG C, 5%CO224h is cultivated in incubator.
(5) dosing：The medicine of the various concentrations gradient that will have been diluted is added separately in 96 well culture plates, each concentration ladder
Degree sets 3 multiple holes, continues to cultivate 48h.Experiment is divided into experimental group (nutrient solution, cell, medicine), control group (nutrient solution and cell)
With blank group (only nutrient solution).
(6) survivaling cell detection：In 96 orifice plates after having cultivated 48h, plus the μ L/ holes of MTT (5mg/mL) 10；Put at 37 DEG C
After putting 4h, supernatant, plus the μ L/ holes of DMSO 150, vibration to first a ceremonial jade-ladle, used in libation crystallization all dissolvings are removed；Existed using automatic ELIASA
The optical density (OD values) in each hole is detected at 570nm wavelength.
The calculating of inhibiting rate：
Growth inhibition ratio=(1- survival rates) × 100%=[1- (OD experiment-OD blank)/(OD control-OD blank)] ×
100% (OD experiments represent the AO of experimental group, and OD controls represent the AO of control group, and OD blank represents empty
The AO of white group).
According to the standard curve of drug concentration-inhibitory rate of cell growth, its IC is sought50, unit μM.
Result is as shown in table 2.
Table 2
| Compound | ||||
| z1 | 3.68±0.09 | 6.7±0.24 | 1.71±0.002 | 278.22±8.01 |
| z2 | 10.56±0.11 | 9.74±0.04 | 2.48±0.01 | 321.85±6.60 |
| z3 | 7.93±0.18 | 5.63±0.16 | 2.49±0.11 | 291.28±0.12 |
| z4 | 5.45±0.21 | 11.51±0.34 | 3.48±0.04 | 301.49±10.08 |
| z5 | 4.87±0.11 | 2.12±0.01 | 1.57±0.03 | 68.93±0.05 |
| z6 | 6.51±0.07 | 9.71±0.32 | 2.8±0.10 | 298.53±0.75 |
| z7 | 0.98±0.03 | 4.89±0.14 | 0.75±0.01 | 197.2±1.58 |
| z8 | 2.39±0.05 | 2.36±0.03 | 0.47±0.02 | 347.12±13.32 |
| z9 | 8.85±0.3 | 12.86±0.26 | 3.87±0.10 | 283.33±3.85 |
| z10 | 9.56±0.24 | 18.2±0.45 | 4.02±0.03 | 320.19±1.81 |
| z11 | 14.15±0.17 | 7.55±0.06 | 3.58±0.04 | 416.28±10.46 |
| z12 | 1.51±0.02 | 2.09±0.05 | 0.19±0.01 | 304.55±3.58 |
| z13 | 0.89±0.03 | 0.87±0.02 | 0.57±0.002 | 521.4±17.91 |
| z14 | 3±0.06 | 4.6±0.13 | 1.96±0.03 | 278.15±7.06 |
| z15 | 5.69±0.17 | 7.2±0.11 | 1.31±0.001 | 238.79±8.22 |
| z16 | 5.49±0.23 | 30.41±1.12 | 4.07±0.13 | 156.21±5.76 |
| z17 | 9.41±0.04 | 20.45±0.51 | 4.08±0.03 | 430.69±9.44 |
| z18 | 8.52±0.26 | 14.68±0.14 | 2.25±0.004 | 401.91±15.07 |
| z19 | 7.78±0.24 | 21.08±0.67 | 6.89±0.15 | 421.06±11.75 |
| z20 | 4.73±0.14 | 14.36±0.51 | 5.09±0.17 | 299.81±10.21 |
| z21 | 4.72±0.17 | 23.49±0.14 | 1.28±0.02 | 107.93±2.54 |
| z22 | 7.43±0.22 | 8.66±0.17 | 4.99±0.17 | 300.41±0.52 |
| z23 | 6.18±0.06 | 3.44±0.14 | 0.2±0.002 | 284.35±10.41 |
| z24 | 8.52±0.21 | 13.74±0.16 | 4.06±0.12 | 612.34±17.82 |
| z25 | 7.11±0.02 | 12.32±0.22 | 3.33±0.14 | 500.02±12.68 |
| z26 | 4.63±0.03 | 9.51±0.25 | 2.43±0.07 | 215.33±6.65 |
Result above shows, 1- Methyl-1H-indoles-pyrazoline thiourea of the present invention has good antitumor
Effect, the toxicity to normal cell is low.
Claims (6)
1. a kind of 1- Methyl-1H-indoles-pyrazoline thiourea and pharmaceutically can into salt, with following structural formula：
Wherein, R1It is H, Br or OCH3；R2It is H, F, Cl, Br, OCH3、CH3Or 4-CF3。
2. compound as claimed in claim 1 and medicine can into salt, it is characterised in that R2It is H, 4-F, 4-Cl, 4-Br, 2-
OCH3、3-OCH3、4-OCH3、3,4-OCH3、3,4,5-OCH3、4-CH3Or 4-CF3。
3. compound as claimed in claim 2 and medicine can into salt, it is characterised in that：
R1It is H, R2It is H, 4-F, 4-Cl, 4-Br, 2-OCH3、3-OCH3、4-OCH3、3,4-OCH3、3,4,5-OCH3、4-CH3Or 4-
CF3；
Or, R1It is Br, R2It is H, 4-F, 4-Cl, 4-Br, 3,4-OCH3Or 3,4,5-OCH3；
Or, R1It is OCH3, R2It is H, 4-F, 4-Cl, 4-Br, 2-OCH3、3-OCH3、3,4-OCH3Or 3,4,5-OCH3。
4. compound as claimed in claim 3 and medicine can into salt, it is characterised in that：
R1It is H, R2It is H, 4-Br, 2-OCH3Or 3-OCH3；
Or, R1It is Br, R2It is H, 4-F or 4-OCH3；
Or, R1It is OCH3, R2It is H, 4-F or 4-Cl.
5. 1- Methyl-1H-indoles-pyrazoline thiourea described in any one of claim 1-4 and medicine can into salt exist
Prepare the application in antineoplastic.
6. a kind of antineoplastic pharmaceutical compositions, it is characterised in that including 1- Methyl-1H-indoles described in claim any one of 1-4-
Pyrazoline thiourea and medicine can into salt and pharmaceutically acceptable carrier.
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| CN105541804A (en) * | 2016-03-04 | 2016-05-04 | 南京大学 | Preparation method and application of indole formylamino-pyrazole derivatives |
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