CN106831724B - A kind of 1- Methyl-1H-indole-pyrazoline thiourea and its medicinal usage - Google Patents
A kind of 1- Methyl-1H-indole-pyrazoline thiourea and its medicinal usage Download PDFInfo
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Abstract
The invention discloses a kind of 1- Methyl-1H-indole-pyrazoline thiourea and pharmaceutically can at salt, have the following structure formula:Wherein, R1For H, Br or OCH3；R2For H, F, Cl, Br, OCH3、CH3Or 4-CF3.Compound of the present invention has good antitumor action, low to the toxicity of normal cell, has 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-indole-pyrazoline thiourea
And its medicinal usage.
Background technique
Tumour is body under the action of various tumorigenesis factors, the cell paraplasm of local organization and the new life that is formed
Object often shows as local lump.Tumour cell have the function of abnormal form, metabolism and.It grows vigorous and is often in duration
Growth.In recent years, tumour especially malignant tumour, which has become, seriously threatens one of disease of human health.In the whole world more than 50
Malignant tumour person is died of in hundred million populations every year on average up to 6,900,000 people, new cases are 8,700,000, and number is in continuous increase.
The methods of 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 drug of tumour, novel anti-tumor drug are being continuously updated the replacement, in the cure rate for improving tumor patient, extend
The survival of patients time delays disease etc. and has played huge effect.For many years, people constantly develop new antineoplastic
Object, and pass through structure of modification, it is intended to develop anti-tumor drug derivative new in a series.
The chemical structure transformation of drug is based on the original basic chemical structure of drug, to some of them functional group
It learns transformation or by two or more there is identical or different active chemical structure to be combined, obtain this kind of drug
New derivative.Original physicochemical property and pharmacological activity may be changed by structure, had in clinical application extremely heavy
The effect wanted.
Zhang Ya-Liang etc. devises a kind of with the inhibition active 1- Methyl-1H-indole-pyrazoline of microtubule polymerization
Class compound e1-e28 (Synthesis and Biological Evaluation of 1-Methyl-1H-indole-
Pyrazoline Hybrids as Potential Tubulin Polymerization Inhibitors.ChemMedChem
2016,11,1446-1458)。
Summary of the invention
The present invention has carried out structure of modification in prior art basis, to 1- Methyl-1H-indole-pyrazoline compounds,
Obtained it is a kind of activity improve 1- Methyl-1H-indole-pyrazoline thiourea and pharmaceutically can at salt, have such as
Flowering structure formula:
Wherein, R1For H, Br or OCH3；R2For H, F, Cl, Br, OCH3、CH3Or 4-CF3。
Above compound and pharmaceutically can at salt, preferably R2For 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:
R1For H, R2For H, 4-F, 4-Cl, 4-Br, 2-OCH3、3-OCH3、4-OCH3、3,4-OCH3、3,4,5-OCH3、4-CH3
Or 4-CF3；
Alternatively, R1For Br, R2For H, 4-F, 4-Cl, 4-Br, 3,4-OCH3Or 3,4,5-OCH3；
Alternatively, R1For OCH3, R2For H, 4-F, 4-Cl, 4-Br, 2-OCH3、3-OCH3、3,4-OCH3Or 3,4,5-OCH3。
It is more preferable:
R1For H, R2For H, 4-Br, 2-OCH3 or 3-OCH3；
Alternatively, R1For Br, R2For H, 4-F or 4-OCH3；
Alternatively, R1For OCH3, R2For H, 4-F or 4-Cl.
Compound of the present invention and pharmaceutically can at salt can be administered in the form of single medicine or can be with it
Its administered in combination.
The officinal salt of the compound of the present 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 sodium hydroxide, trishydroxymethylaminomethane and N- methyl-glucamine.
It is of the invention to additionally provide 1- Methyl-1H-indole-pyrazoline thiourea of the present invention and pharmaceutically
At salt application in preparation of anti-tumor drugs.The preferred breast cancer of the tumour, lung cancer, liver cancer etc..
The present invention also provides a kind of antineoplastic pharmaceutical compositions, including 1- of the present invention Methyl-1H-indole-pyrazoles
Quinoline thiourea and pharmaceutically can at salt and pharmaceutical carrier.The antineoplastic pharmaceutical compositions include as activity at
The compound of the present invention or its officinal salt and pharmaceutical acceptable carrier divided.Preferably, pharmaceutical composition of the invention has 0.1-
99.9% weight percent as the compound of the present invention of active constituent or its officinal salt.
" pharmaceutical acceptable carrier " includes but is not limited to: ion exchange material, aluminium oxide, aluminum stearate, lecithin, self-emulsifying medicine
Object transmission system (SEDDS) such as d- TPGS 1000, tween or other similar polymerisation medium drug
The surfactant of preparation, haemocyanin 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, ethylene-polyoxyethylene-block polymer and lanolin, cyclodextrin such as α-, β-, gamma-cyclodextrin or its
The hydroxyalkyl cyclodextrins such as the derivative through chemical modification such as 2- and 3- hydroxypropyl-β-cyclodextrin or other soluble derivatives etc. are equal
It can be used for promoting the drug delivery of the compound of the present 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), disintegrating agent (such as crosslinked carboxymethyl fecula sodium, croscarmellose sodium, low-substituted hydroxypropyl cellulose and friendship
Join PVP), lubricant (such as magnesium stearate), sorbefacient, flavouring agent, sweetener, diluent, excipient, wetting agent, solvent,
Solubilizer and colorant etc. can also be added in pharmaceutical composition of the invention.
The compound or pharmaceutically acceptable salt thereof and pharmaceutical composition of aforementioned present invention can pass through enteron aisle or parenteral route
Administration.Non-intestinal drug delivery agent includes injection, creme, ointment, patch, spray etc..Administration route includes subcutaneous, skin
In interior, intra-arterial, intravenous, intramuscular, intra-articular, synovia, breastbone is interior, intrathecal, intralesional, intracranial injection or infusion, alternatively, mouth
Clothes, part, rectum, intranasal, buccal, vagina, sublingual, intradermal, mucous membrane, tracheae, urethral administration, or pass through sucking aerosol or plant
Enter accumulation or needle thorn mode is administered.
The compound or pharmaceutically acceptable salt thereof of aforementioned present invention and the therapeutically effective amount of pharmaceutical composition are 0.001-
Between 100mg/kg/d, it can be used for single drug or the drug combination treatment of related disease, can be managed for those skilled in the art
The range of solution.
It is thin to human liver cancer in vitro that the present invention has investigated 1- Methyl-1H-indole-pyrazoline thiourea of the present invention
The inhibiting effect 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-indole-pyrazoline thiourea of the present invention has
Antitumor action, it is low to the toxicity of normal cell, have very big Development volue.
Specific embodiment
Illustrate specific steps of the invention by the following examples, but is not limited by the example.
Term as used in the present invention generally there are those of ordinary skill in the art usually to manage unless otherwise indicated
The meaning of solution.
The present invention is described in further detail combined with specific embodiments below and referring 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 invention in any way.
In the examples below, the various processes and method being not described in detail are conventional methods as known in the art.
The preparation of the 1- Methyl-1H-indole-pyrazoline thiourea of the present invention of embodiment 1
1- Methyl-1H-indole-pyrazoline thiourea of the present invention and pharmaceutically can at salt can be used it is as follows
Method is prepared.
Specifically the preparation method comprises the following steps: sequentially adding POCl into reaction vessel under condition of ice bath3(20mL) and DMF
(40mL), compound 1 (35mmol) react 2h, pour into ice water and adjust pH to 9.0 with NaOH, drying is extracted with ethyl acetate
Obtain compound 2.Under ice bath, compound 2 (25mmol) is added into reaction vessel, THF (15mL), NaH (62.5mmol) are stirred
15min is mixed, CH is added3I (33mmol) is reacted at room temperature for 24 hours.TLC tracking is sufficiently extracted with ethyl acetate after reaction dry
Compound 3.Compound 3 (2mmol) and acetophenone (2mmol), dehydrated alcohol (20mL) and KOH are added into reaction vessel
(6mmol), for 24 hours, ethyl alcohol and recrystallize with dichloromethane obtain compound 4 after filtering for room temperature reaction.Chemical combination is added into reaction vessel
Object 4 (1mmol), thiosemicarbazides (3mmol) and dehydrated alcohol (10mL) are added NaOH solution after stirring and dissolving, are heated to reflux
For 24 hours, it is sufficiently filtered after reaction, ethyl alcohol and recrystallize with dichloromethane obtain a series of 1- Methyl-1H-indole-pyrroles of the present invention
Oxazoline thiourea (compound 5), compound is as shown in table 1.
Table 1
Above compound Structural Identification data are as follows:
5- (1- Methyl-1H-indole -3- base) -3- phenyl -4,5- dihydro-1 h-pyrazole -1- thioformamide (z1)
Beige powder, yield 66.0%, 231-233 DEG C of fusing point.1H 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),
3.97-3.81 (m, 1H), 3.73 (s, 3H), 3.25 (dd, J=17.9,3.4Hz, 1H)13C 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-indole -3- base) -4,5- dihydro-1 h-pyrazole -1- thioformamide
(z2)
Beige powder, yield 57.8%, 241-242 DEG C of fusing point.1H 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- chlorphenyl) -5- (1- Methyl-1H-indole -3- base) -4,5- dihydro-1 h-pyrazole -1- thioformamide
(z3)
Beige powder, yield 59.2%, 237-238 DEG C of fusing point.1H 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-indole -3- base) -4,5- dihydro-1 h-pyrazole -1- thioformamide
(z4)
Beige powder, yield 48.3%, 237-238 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:7.97(s,
1H), 7.88 (d, J=8.6Hz, 3H), 7.68 (d, J=8.6Hz, 2H), 7.39 (d, J=8.2Hz, 1H), 7.27 (d, J=
8.0Hz, 1H), 7.19 (s, 1H), 7.12 (t, J=7.6Hz, 1H), 6.94 (t, J=7.5Hz, 1H), 6.17 (dd, J=11.4,
3.3Hz, 1H), 3.96-3.79 (m, 1H), 3.73 (s, 3H), 3.24 (dd, J=18.0,3.4Hz, 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-indole -3- base) -3- (4- aminomethyl phenyl) -4,5- dihydro-1 h-pyrazole -1- thioformamide
(z5)
Beige powder, yield 70.2%, 254-255 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:7.88–7.77
(m, 4H), 7.39 (d, J=8.0Hz, 1H), 7.28 (d, J=8.0Hz, 3H), 7.19 (s, 1H), 7.14 (t, J=7.2Hz,
1H), 6.93 (t, J=7.2Hz, 1H), 6.15 (dd, J=11.2,3.2Hz, 1H), 3.90-3.83 (m, 1H), 3.73 (s, 3H),
3.23 (dd, J=18.0,3.2Hz, 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.
The thio first of 5- (1- Methyl-1H-indole -3- base) -3- (4- trifluoromethyl) -4,5- dihydro-1 h-pyrazole -1-
Amide (z6)
Beige crystals, yield 27.0%, 264-265 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ: 8.14 (d, J=
8.2Hz, 2H), 8.06 (s, 1H), 8.01 (s, 1H), 7.83 (d, J=8.3Hz, 2H), 7.40 (d, J=8.2Hz, 1H), 7.29
(d, J=7.9Hz, 1H), 7.21 (s, 1H), 7.13 (t, J=7.5Hz, 1H), 6.95 (t, J=7.4Hz, 1H), 6.22 (dd, J
=11.5,3.4Hz, 1H), 3.32-3.37 (m, 1H), 3.73 (s, 3H), 3.30 (dd, J=18.0,3.5Hz, 1H)13C NMR
(DMSO-d6,101MHz)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-indole -3- base) thio formyl of -4,5- dihydro-1 h-pyrazole -1-
Amine (z7)
Off-white powder, yield 90.1%, 228-229 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ: 8.14 (d, J=
6.4Hz, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.46 (t, J=7.1Hz, 1H), 7.41-7.31 (m, 2H), 7.17 (s,
1H), 7.12 (t, J=7.8Hz, 2H), 7.04 (t, J=7.5Hz, 1H), 6.95 (t, J=7.5Hz, 1H), 6.11 (dd, J=
11.4,3.3Hz, 1H), 4.01-3.86 (m, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 3.32 (dd, J=18.6,3.4Hz,
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-indole -3- base) thio formyl of -4,5- dihydro-1 h-pyrazole -1-
Amine (z8)
Beige powder, yield 75.5%, 215-216 DEG C of fusing point.1H NMR(400MHz,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=8.0Hz, 1H), 7.19 (s, 1H), 7.12
(t, J=7.6Hz, 1H), 7.05 (d, J=7.6Hz, 1H), 6.95 (t, J=7.5Hz, 1H), 6.16 (dd, J=11.3,
3.1Hz, 1H), 3.91-3.82 (m, 1H), 3.82 (s, 3H), 3.73 (s, 3H), 3.26 (dd, J=18.0,3.2Hz, 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-indole -3- base) thio formyl of -4,5- dihydro-1 h-pyrazole -1-
Amine (z9)
Beige powder, yield 54.9%, 237-239 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ: 7.87 (d, J=
8.7Hz, 2H), 7.83 (s, 1H), 7.73 (s, 1H), 7.39 (d, J=8.2Hz, 1H), 7.29 (d, J=7.9Hz, 1H), 7.18
(s, 1H), 7.12 (t, J=7.5Hz, 1H), 7.02 (d, J=8.7Hz, 2H), 6.94 (t, J=7.5Hz, 1H), 6.14 (dd, J
=11.2,2.8Hz, 1H), 3.98-3.78 (m, 4H), 3.73 (s, 3H), 3.23 (dd, J=17.9,2.9Hz, 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-indole -3- base) -4,5- dihydro-1 h-pyrazole -1- is thio
Formamide (z10)
Beige powder, yield 26.5%, 217-219 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:7.88(s,
2H), 7.68 (d, J=1.7Hz, 1H), 7.39 (d, J=8.2Hz, 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=11.2,3.1Hz, 1H), 3.89-3.81 (m, 4H),
3.80 (s, 3H), 3.72 (s, 3H), 3.25 (dd, J=17.8,3.2Hz, 1H)13C NMR(DMSO-d6,101MHz)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-indole -3- base) -3- (3,4,5- trimethoxyphenyl) -4,5- dihydro-1 h-pyrazole -1- sulphur
For formamide (z11)
Beige powder, yield 34.7%, 188-189 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:7.93(s,
2H), 7.39 (d, J=8.2Hz, 1H), 7.34 (d, J=7.9Hz, 1H), 7.22 (s, 2H), 7.19-7.05 (m, 2H), 6.97
(t, J=7.4Hz, 1H), 6.17 (dd, J=11.2,2.9Hz, 1H), 3.88-3.77 (m, 7H), 3.73 (s, 3H), 3.70 (s,
3H),3.37–3.28(m,1H).13C NMR(DMSO-d6,101MHz)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- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- phenyl -4,5- dihydro-1 h-pyrazole -1- thioformamide
(z12)
Dark white powder, yield 56.9%, 249-251 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:7.97(s,
1H), 7.94 (d, J=5.1Hz, 2H), 7.87 (s, 1H), 7.52 (s, 1H), 7.49 (s, 3H), 7.39 (d, J=8.7Hz, 1H),
7.24 (d, J=7.2Hz, 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.
The thio formyl of 5- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- (4- fluorophenyl) -4,5- dihydro-1 h-pyrazole -1-
Amine (z13)
Beige crystals, yield 38.1%, 235-237 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:8.11–7.94
(m, 3H), 7.92 (s, 1H), 7.52 (s, 1H), 7.39 (d, J=8.7Hz, 1H), 7.33 (t, J=8.8Hz, 2H), 7.24 (d, J
=6.7Hz, 2H), 6.16 (dd, J=11.3,3.2Hz, 1H), 3.99-3.77 (m, 1H), 3.73 (s, 3H), 3.25 (dd, J=
18.0,3.2Hz,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.
The thio formyl of 5- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- (4- chlorphenyl) -4,5- dihydro-1 h-pyrazole -1-
Amine (z14)
Beige crystals, yield 31%, 250-251 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:8.02(s,1H),
7.95 (d, J=8.5Hz, 3H), 7.61-7.48 (m, 3H), 7.38 (d, J=8.7Hz, 1H), 7.24 (d, J=8.1Hz, 2H),
6.17 (dd, J=11.4,3.3Hz, 1H), 3.98-3.77 (m, 1H), 3.72 (s, 3H), 3.24 (dd, J=18.0,3.3Hz,
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.
The thio formyl of 5- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- (4- bromophenyl) -4,5- dihydro-1 h-pyrazole -1-
Amine (z15)
Beige powder, yield 26.5%, 255-257 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:8.02(s,
1H), 7.94 (s, 1H), 7.88 (d, J=8.6Hz, 2H), 7.68 (d, J=8.6Hz, 2H), 7.51 (s, 1H), 7.38 (d, J=
8.7Hz, 1H), 7.29-7.20 (m, 2H), 6.17 (dd, J=11.4,3.3Hz, 1H), 3.91-3.84 (m, 1H), 3.72 (s,
3H), 3.23 (dd, J=18.0,3.4Hz, 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- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- (4- methoxyphenyl) -4,5- dihydro-1 h-pyrazole -1- is thio
Formamide (z16)
White powder, yield 23.4%, 229-231 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ: 7.87 (d, J=
8.7Hz, 3H), 7.75 (s, 1H), 7.52 (s, 1H), 7.38 (d, J=8.7Hz, 1H), 7.23 (d, J=10.2Hz, 2H), 7.02
(d, J=8.7Hz, 2H), 6.13 (dd, J=11.2,3.0Hz, 1H), 3.96-3.78 (m, 4H), 3.73 (s, 3H), 3.21 (dd,
J=17.9,3.1Hz, 1H)13C NMR(DMSO-d6,101MHz)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- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- (3,4- Dimethoxyphenyl) -4,5- dihydro-1 h-pyrazole -1-
Thioformamide (z17)
Beige powder, yield 37.2%, 237-238 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ: 7.93 (d, J=
4.2Hz, 2H), 7.67 (d, J=1.7Hz, 1H), 7.55 (d, J=1.7Hz, 1H), 7.38 (d, J=8.7Hz, 1H), 7.32-
7.22 (m, 2H), 7.21 (s, 1H), 6.99 (d, J=8.5Hz, 1H), 6.14 (dd, J=11.2,3.1Hz, 1H), 3.88-3.81
(m, 4H), 3.80 (s, 3H), 3.72 (s, 3H), 3.22 (dd, J=17.8,3.2Hz, 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- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- (3,4,5- trimethoxyphenyl) -4,5- dihydro-1 h-pyrazole -
1- thioformamide (z18)
Dark white powder, yield 28.0%, 243-244 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:8.00(s,
2H), 7.59 (s, 1H), 7.39 (d, J=8.6Hz, 1H), 7.25 (d, J=13.7Hz, 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=18.8Hz, 1H)13C NMR
(DMSO-d6,101MHz)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- methoxyl group -1- Methyl-1H-indole -3- base) -3- phenyl -4,5- dihydro-1 h-pyrazole -1- thioformamide
(z19)
Yellow powder, yield 68.1%, 230-231 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ: 7.94 (d, J=
12.2Hz, 3H), 7.81 (s, 1H), 7.48 (s, 3H), 7.28 (d, J=9.0Hz, 1H), 7.17 (s, 1H), 6.75 (s, 2H),
6.15 (d, J=10.3Hz, 1H), 3.87 (dd, J=17.5,11.4Hz, 1H), 3.68 (s, 3H), 3.48 (s, 3H), 3.26 (d,
J=17.7Hz, 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- methoxyl group -1- Methyl-1H-indole -3- base) -4,5- dihydro-1 h-pyrazole -1- is thio
Formamide (z20)
Off-white powder, yield 40.1%, 238-239 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:8.02(dd,J
=8.7,5.6Hz, 2H), 7.87 (s, 1H), 7.81 (s, 1H), 7.41-7.24 (m, 3H), 7.16 (s, 1H), 6.75 (d, J=
8.4Hz, 2H), 6.15 (dd, J=11.2,2.8Hz, 1H), 3.94-3.78 (m, 1H), 3.69 (s, 3H), 3.51 (s, 3H),
3.27 (dd, J=17.9,3.0Hz, 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- chlorphenyl) -5- (5- methoxyl group -1- Methyl-1H-indole -3- base) -4,5- dihydro-1 h-pyrazole -1- is thio
Formamide (z21)
Dark white powder, yield 30.6%, 247-249 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ: 7.97 (d, J=
8.6Hz, 2H), 7.92 (s, 1H), 7.86 (s, 1H), 7.54 (d, J=8.6Hz, 2H), 7.28 (d, J=8.7Hz, 1H), 7.16
(s, 1H), 6.80-6.71 (m, 2H), 6.15 (dd, J=11.3,3.0Hz, 1H), 3.93-3.78 (m, 1H), 3.69 (s, 3H),
3.53 (s, 3H), 3.25 (dd, J=17.9,3.1Hz, 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- methoxyl group -1- Methyl-1H-indole -3- base) -4,5- dihydro-1 h-pyrazole -1- is thio
Formamide (z22)
Beige crystals, yield 31.7%, 240-242 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:7.95(s,
1H), 7.89 (d, J=8.6Hz, 3H), 7.68 (d, J=8.6Hz, 2H), 7.28 (d, J=8.8Hz, 1H), 7.16 (s, 1H),
6.80-6.71 (m, 2H), 6.15 (dd, J=11.3,2.9Hz, 1H), 3.89-3.81 (m, 1H), 3.68 (s, 3H), 3.53 (s,
3H), 3.24 (dd, J=17.9,3.0Hz, 1H)13C NMR(DMSO-d6,101MHz)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- methoxyl group -1- Methyl-1H-indole -3- base) -3- (2- methoxyphenyl) -4,5- dihydro-1 h-pyrazole -1-
Thioformamide (z23)
Brown ceramic powder, yield 26.4%, 208-209 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ: 8.19 (d, J=
7.8Hz, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.46 (t, J=7.8Hz, 1H), 7.28 (d, J=8.8Hz, 1H), 7.17
(s, 1H), 7.11 (d, J=8.4Hz, 1H), 7.04 (t, J=7.5Hz, 1H), 6.83-6.73 (m, 2H), 6.10 (dd, J=
11.3,2.8Hz, 1H), 3.96-3.89 (m, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 3.54 (s, 3H), 3.33 (dd, J=
18.6,2.9Hz,1H).13C NMR(DMSO-d6,101MHz)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- methoxyl group -1- Methyl-1H-indole -3- base) -3- (3- methoxyphenyl) -4,5- dihydro-1 h-pyrazole -1-
Thioformamide (z24)
Beige powder, yield 30.2%, 138-139 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:7.95(s,
1H), 7.91 (s, 1H), 7.61 (s, 1H), 7.45 (d, J=7.6Hz, 1H), 7.37 (t, J=7.9Hz, 1H), 7.28 (d, J=
9.6Hz, 1H), 7.17 (s, 1H), 7.05 (d, J=5.9Hz, 1H), 6.76 (d, J=6.7Hz, 2H), 6.15 (dd, J=11.2,
2.7Hz, 1H), 3.95-3.78 (m, 4H), 3.69 (s, 3H), 3.52 (s, 3H), 3.26 (dd, J=17.9,2.8Hz, 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- methoxyl group -1- Methyl-1H-indole -3- base) -4,5- dihydro -1H- pyrrole
Azoles -1- thioformamide (z25)
Light yellow crystal, yield 21.7%, 180-182 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:7.86(s,
2H), 7.70 (s, 1H), 7.32 (d, J=8.3,1H), 7.28 (d, J=8.8Hz, 1H), 7.15 (s, 1H), 6.99 (d, J=
8.4Hz, 1H), 6.82-6.72 (m, 2H), 6.12 (dd, J=11.1,2.6Hz, 1H), 3.88-3.76 (m, 7H), 3.69 (s,
3H), 3.53 (s, 3H), 3.25 (dd, J=17.7,2.7Hz, 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- methoxyl group -1- Methyl-1H-indole -3- base) -3- (3,4,5- trimethoxyphenyl) -4,5- dihydro -1H-
Pyrazoles -1- thioformamide (z26)
Pale yellow crystals, yield 14.8%, 196-198 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ:7.93(s,
2H), 7.31-7.24 (m, 3H), 7.13 (s, 1H), 6.81 (d, J=2.3Hz, 1H), 6.76 (dd, J=8.8,2.4Hz, 1H),
6.15 (dd, J=11.1,2.7Hz, 1H), 3.86-3.80 (m, 7H), 3.70 (d, J=3.9Hz, 6H), 3.56 (s, 3H), 3.32
(dd, J=17.9Hz, 2.9Hz, 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.
2 in vitro antitumor activity assay of embodiment
IC50: half inhibiting rate kills cancer cell ability for compound.
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 measured using MTT [3- (4,5)-bis- methyl -2- thiazole-(2,5)-phenyl bromination tetrazole is blue] method
The compound being prepared 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 when inhibiting 293T cell survival rate to 50%
Concentration C C50To indicate.
(1) preparation of culture solution: DMEM (basal medium) 89%, fetal calf serum 10%, Penicillin Streptomycin Solution
(10000IU/mL, 10000 μ g/mL) 1%.
The culture of (2) four kinds of adherent cancer cells: using above-mentioned culture solution, (nutrient solution volume is about the 1/ of culture bottle capacity
10), at 37 DEG C, 5%CO2It is cultivated in incubator, judges the generation time according to the growth conditions of cancer cell.
(3) preparation of various concentration drug: stock solution is prepared using DMEM (a small amount of DMSO hydrotropy), 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；Stock 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 spare in -20 DEG C of refrigerators.
(4) cell incubation: logarithmic growth phase tumour cell, tune concentration of cell suspension are 1-1.5 × 105/ mL, after mixing
(100 hole μ L/) is added in 96 well culture plates, at 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator.
(5) dosing: the drug of the various concentration gradient 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 (culture solution, cell, drug), control group (culture solution and cell)
With blank group (only culture solution).
(6) survivaling cell detects: in having cultivated 96 orifice plates after 48h, adding 10 hole μ L/ MTT (5mg/mL)；It is put at 37 DEG C
After setting 4h, supernatant is removed, adds 150 hole μ L/ DMSO, oscillation to first a ceremonial jade-ladle, used in libation crystallizes all dissolutions；Existed using automatic microplate reader
The optical density (OD value) in each hole is detected at 570nm wavelength.
The calculating of inhibiting rate:
Growth inhibition ratio=(1- survival rate) × 100%=[1- (OD experiment-OD blank)/(OD control-OD is empty
It is white)] × 100% (average optical density of OD experiment expression experimental group, the average optical density of OD control expression control group, OD blank
Indicate the average optical density of blank group).
According to drug concentration-inhibitory rate of cell growth standard curve, its IC is sought50, unit μM.
The results are shown in Table 2.
Table 2
| Compound | MCF-7/IC50 | A549/IC50 | HepG2/IC50 | 293T/CC50 |
| 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 |
The above result shows that 1- Methyl-1H-indole-pyrazoline thiourea of the present invention has good resist
Function of tumor is low to the toxicity of normal cell.
Claims (3)
1. a kind of 1- Methyl-1H-indole-pyrazoline thiourea and pharmaceutically can at salt, have the following structure formula:
R1For H, R2For 2-OCH3Or 3-OCH3；Or R1For Br, R2For H or R1For OCH3, R2For 2-OCH3。
2. the Methyl-1H-indole of 1- described in claim 1-pyrazoline thiourea and drug can at salt it is anti-swollen in preparation
Application in tumor medicine.
3. a kind of antineoplastic pharmaceutical compositions, it is characterised in that including the Methyl-1H-indole of 1- described in claim 1-pyrazoline sulphur
Carbamide compounds and drug can at salt and pharmaceutically acceptable carrier.
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