CN106588716A - O-phenylsulfonyl-4-trifluoromethyl salicylamide compound and application thereof in preparing medicine against lung cancer - Google Patents
O-phenylsulfonyl-4-trifluoromethyl salicylamide compound and application thereof in preparing medicine against lung cancer Download PDFInfo
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- C07C309/63—Esters of sulfonic acids
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Abstract
The invention discloses an O-phenylsulfonyl-4-trifluoromethyl salicylamide compound shown in the formula (I), and discloses application of the O-phenylsulfonyl-4-trifluoromethyl salicylamide compound in preparing medicine against tumor, particularly against human lung cancer. The O-phenylsulfonyl-4-trifluoromethyl salicylamide compound has the advantages that a preparing method of the O-phenylsulfonyl-4-trifluoromethyl salicylamide compound is provided; a new medicine against human lung cancer with obvious antineoplastic activity is provided, thus a research basis is provided for new medicine screening, and the medicine against human lung cancer has a significant application prospect; the preparing process is simple, and industrialized production is benefited. The O-phenylsulfonyl-4-trifluoromethyl salicylamide compound is shown in the formula (I).
Description
(1) technical field
The present invention relates to a kind of O- benzene sulfonyls -4- trifluoromethyl salicylamide compounds and its prepare anti-human lung cancer drug
Application in thing.
(2) background technology
Pulmonary carcinoma is modal lung primary malignant tumor, is currently the first place of the whole world cancer cause of the death, most
Pulmonary carcinoma originates from bronchial mucosa epithelium, therefore also known as lung bronchogenic carcinoma.Nineteen ninety-five, the whole world had 600,000 people to die from pulmonary carcinoma, and often
, all rising, World Health Organization (WHO) (WHO) mortality rate announced in 2003 is 1,100,000/year for year number, sickness rate is 1,200,000/
Year.Over nearly more than 50 years, countries in the world are particularly industrially developed country, and the sickness rate and case fatality rate of pulmonary carcinoma rise rapidly, die from
In the male patient of carninomatosis, pulmonary carcinoma is ranked first, and the incidence rate that women suffers from pulmonary carcinoma especially has the trend of rising.Pulmonary carcinoma, into
For the serious big killer for threatening the people of the world's health and lives, its danger can not look down upon.
Chinese patent CN 102557983A《A kind of (4- substituted benzene formyls) fluorobenzene salicylamide compound and application》、
CN102603559A《A kind of phenylacetyl fluorobenzene salicylamide compound and application》Diflunisal is described respectively for salicylic acid
O- benzoyls, O- phenylacetyls fluorobenzene salicylamide compound and its application in antitumor drug prepared by parent.
Benzenesulfonyl compared with benzoyl, with bigger spatial volume, higher molecular polarity so as to thin to part
The particular space structure of born of the same parents has more preferable selectivity；Compared with phenylacetyl group, with more complete big π bonding electrons knot
Appropriateness is changed the pharmaceutical property of target molecule by structure.
In view of trifluoromethyl (CF3) it is same there is the strong characteristic such as electron-withdrawing, lipotropy and stable C-F keys, when
Acidity, dipole moment, polarity and the lipotropy of compound can effectively be changed after trifluoromethyl is introduced in drug effect molecule, while can
To strengthen the metabolic stability of biomolecule；And, trifluoromethyl salicylic acid is relatively cheap, be easy to get.
Human lung cancer is a kind of most commonly seen malignant tumor.Therefore, this patent is by tying to trifluoromethyl salicylic acid
Structure is modified, and prepares the fluorine-containing new drug with anti-human lung cancer activity, and tool has very great significance.
(3) content of the invention
It is an object of the present invention to provide a kind of O- benzene sulfonyls -4- trifluoromethyl salicylamide compounds, and its it is anti-preparing
Cancer drug, the application especially in anti-human lung-cancer medicament is prepared.
The technical solution used in the present invention is：
A kind of O- benzene sulfonyl -4- trifluoromethyl salicylamide compounds as shown in formula I：
In formula I, R1～R5H, methyl, fluorine, chlorine, nitro, methoxyl group, ethyoxyl are stood alone as each.
Further, during O- benzene sulfonyl -4- trifluoromethyl salicylamides compound of the structure as shown in formula I is table 1
One of compound：
Table 1：
The present invention also provides the preparation of the O- benzene sulfonyls -4- trifluoromethyl salicylamide compounds as shown in formula I
Method：4- trifluoromethyls salicylic acid as shown in formula II and the benzene sulfonyl chloride reaction shown in formula III, obtain shown in formula IV
O- benzene sulfonyl -4- trifluoromethyl salicylic acid；Then, with SOCl2Jing chlorides obtain the O- benzene sulfonyls -4- three shown in formula (V)
Methyl fluoride bigcatkin willow acyl chlorides；Finally, O- benzene as shown in (I) is obtained through amidation process with aminated compoundss shown in formula VI
Sulphonyl -4- trifluoromethyl salicylamide compounds.The equation of the reaction is shown below.
In formula I, R1～R5H, methyl, fluorine, chlorine, nitro, methoxyl group, ethyoxyl are stood alone as each.
Related synthetic method, can refer to Chinese patent CN102010366A, CN 102557983A, CN102603559A
And in Bioorg.Med.Chem.Lett.19 (2), the upper disclosures of 516-519.
Specifically, methods described recommends to carry out as follows：
(1) it is by the benzene sulfonyl chloride acetone solution shown in formula III, standby；By the 4- trifluoromethyl bigcatkin willows shown in formula II
Acid, acetone, sodium hydroxide are added in reaction bulb, stir 1.5h under room temperature.Benzene sulfonyl chloride-acetone is slowly added dropwise under ice bath molten
Liquid, stirring at normal temperature overnight, obtain reactant liquor A, and the reactant liquor A sucking filtration is obtained filtrate, in the filtrate add water, stirring
1h, sucking filtration, gained filter cake use ethanol-water solution (EtOH respectively:H2O=7:3), toluene washing, is dried, obtains shown in formula IV
O- benzene sulfonyl -4- trifluoromethyl bigcatkin willow acid crudes；
(2) will be O- benzene sulfonyls -4- trifluoromethyls bigcatkin willow acid crude (IV) obtained by step (1) shown in formula IV, dichloro sub-
In sulfone, toluene and DMF input reaction bulb, react 6 hours at 70 DEG C, obtain reactant liquor B, Jing evaporated under reduced pressure adds acetone molten
Solution, obtains the O- benzene sulfonyl -4- trifluoromethyl bigcatkin willow solution of acid chloride shown in formula (V), standby；
(3) under ice bath, aminated compoundss shown in formula VI and acetone are mixed to get into mixed liquor and are added to step (2) institute
State in the O- benzene sulfonyl -4- trifluoromethyl bigcatkin willow solution of acid chloride shown in formula (V), react 10h at normal temperatures, obtain reaction liquid C,
Reaction liquid C is filtered, in gained filtrate, adds water, agitated, crystallization to filter, washing with alcohol, butanone recrystallization obtain formula
(I) the O- benzene sulfonyl -4- trifluoromethyl salicylamide compounds shown in.
Present invention also offers the O- benzene sulfonyls -4- trifluoromethyl salicylamide compounds are preparing antitumor drug
In application, especially prepare the application in anti-human lung-cancer medicament.Jing is tested, O- benzene sulfonyls -4- trifluoromethyl bigcatkin willows of the present invention
Amides compound can substantially suppress the growth of human lung carcinoma cell under finite concentration, can be applied to people's lung as antitumor drug
The treatment of cancer.
Compared with prior art, the beneficial effects are mainly as follows：
(1) there is provided a kind of O- benzene sulfonyls -4- trifluoromethyl salicylamide compounds and preparation method thereof；
(2) there is provided a kind of new, anti-human lung-cancer medicament with obvious anti-tumor activity, research is provided for new medicament screen
Basis, with major application prospect；
(3) preparation flow of the compound is simple, beneficial to industrialization production.
(4) specific embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This：
Embodiment 1：Prepare O- benzene sulfonyls -4- trifluoromethyl salicylic acid (IV)
It is by 35.3g (0.2mol) benzene sulfonyl chloride 30mL acetone solutions, standby；
20.6g (0.1mol) 4- trifluoromethyl salicylic acid, 200mL acetone, 8.0g (0.2mol) sodium hydroxide are added to
In reaction bulb, under room temperature, 1.5h is stirred.Benzene sulfonyl chloride-acetone soln is slowly added dropwise under ice bath, stirring at normal temperature is overnight.
Sucking filtration, adds 200mL water to filtrate, stirs 1h, separates out white solid, and sucking filtration, filter cake use ethanol-water solution respectively
(EtOH:H2O=7:3), toluene washing, is dried, obtains O- benzene sulfonyls -4- trifluoromethyls bigcatkin willow acid crude (IV), yield：
85.6%, fusing point：120-124 DEG C (correction).
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,DMSO,δppm):7.25 (s, 1H, 3-H), 7.69 (t, 2H, J=8.5Hz, 3 ', 5 '-H),
7.84 (dd, 2H, J=8.0Hz, 2 ', 6 '-H), 7.86 (d, 1H, J=8.5Hz, 5-H), 7.87 (m, 1H, J=8.5Hz, 4 '-
), H 8.03 (d, 1H, J=8.0Hz, 6-H), 13.69 (s, 1H ,-COOH).
Embodiment 2：Prepare N- phenyl-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -1)
Will be 5.2g (0.015mol) O- benzene sulfonyls -4- trifluoromethyls bigcatkin willow acid crude (IV), 3.6g (0.03mol) dichloro sub-
In sulfone, 40mL toluene and 4 drop DMF input reaction bulbs, react 6 hours under 70 DEG C (correction), evaporated under reduced pressure, obtain oily concentration
Liquid, adds 40mL acetone solutions, and O- benzene sulfonyl -4- trifluoromethyl bigcatkin willow acyl chlorides (V) solution is obtained, standby.
Under ice bath, the mixed liquor of 2.8g (0.03mol) aniline/10mL acetone in V solution for having prepared, is often added to
Temperature reaction 10h；Filter, add 100mL water, stirring, crystallization to filter to filtrate, washing with alcohol, butanone recrystallization obtain white N-
Phenyl-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -1), fusing point：128-131 DEG C (correction), yield：66.2%.
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,CDCl3,δppm):7.21 (t, 1H, J=7.5Hz, 4 "-H), 7.40 (t, 2H, J=8.0Hz,
3 ", 5 "-H), 7.45 (t, 2H, J=8.0Hz, 3 ', 5 '-H), 7.54 (s, 1H, 3-H), 7.59 (dd, 2H, J=8.0Hz, 2 ",
6 "-H), the 7.68 (- H of m, 1H, J=7.5Hz, 4 '), 7.69 (d, 1H, J=8.0Hz, 5-H), 7.77 (dd, 2H, J=8.0Hz,
2 ', 6 '-H), 8.05 (d, 1H, J=8.0Hz, 6-H), 8.38 (s, 1H ,-NH-).
Embodiment 3：Prepare N- (2- aminomethyl phenyls)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -2)
Aniline in embodiment 2 is replaced with 0.03mol 2-aminotoluenes, other operations obtain N- (2- first with embodiment 2
Base phenyl)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -2), fusing point：108-111 DEG C (correction), yield：53.8%.
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,CDCl3,δppm):2.35(s,3H,-CH3), 7.15 (t, 1H, J=7.0Hz, 4 "-H),
7.25 (d, 1H, J=7.0Hz, 6 "-H), 7.27 (t, 1H, J=7.5Hz, 5 "-H), 7.44 (t, 2H, J=8.0Hz, 3 ', 5 '-
H), 7.52 (s, 1H, 3-H), the 7.68 (- H of t, 1H, J=7.5Hz, 4 '), 7.69 (d, 1H, J=7.5Hz, 3 "-H), 7.72 (dd,
2H, J=8.5Hz, 2 ', 6 '-H), 7.99 (d, 1H, J=8.0Hz, 5-H), 8.06 (d, 1H, J=8.0Hz, 6-H), 8.19 (s,
1H,-NH-)。
Embodiment 4：Prepare N- (3- aminomethyl phenyls)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -3)
Aniline in embodiment 2 is replaced with 0.03mol 3- monomethylaniline .s, other operations obtain N- (3- first with embodiment 2
Base phenyl)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -3), fusing point：137-140 DEG C (correction), yield：72.3%.
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,CDCl3,δppm):2.40(s,3H,-CH3), 7.03 (d, 1H, J=7.5Hz, 4 "-H),
7.28 (t, 1H, J=8.0Hz, 5 "-H), 7.37 (d, 1H, J=8.0Hz, 6 "-H), 7.41 (s, 1H, 2 "-H), 7.47 (t, 2H, J
=8.0Hz, 3 ', 5 '-H), 7.54 (s, 1H, 3-H), 7.69 (d, 1H, J=8.0Hz, 5-H), 7.70 (t, 1H, J=9.0Hz,
4 '-H), 7.78 (dd, 2H, J=8.5Hz, 2 ', 6 '-H), 8.05 (d, 1H, J=8.0Hz, 6-H), 8.32 (s, 1H ,-NH-).
Embodiment 5：Prepare N- (4- aminomethyl phenyls)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -4)
Aniline in embodiment 2 is replaced with 0.03mol 4- monomethylaniline .s, other operations obtain N- (4- first with embodiment 2
Base phenyl)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -4), fusing point：195-197 DEG C (correction), yield：60.0%.
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,CDCl3,δppm):2.38(s,3H,-CH3), 7.20 (d, 2H, J=8.0Hz, 3 ", 5 "-H),
7.46 (t, 2H, J=7.0Hz, 3 ', 5 '-H), 7.47 (d, 2H, J=8.0Hz, 2 ", 6 "-H), 7.54 (s, 1H, 3-H), 7.68
(d, 1H, J=8.5Hz, 5-H), the 7.69 (- H of t, 1H, J=8.0Hz, 4 '), 7.77 (dd, 2H, J=8.5Hz, 2 ', 6 '-H),
8.05 (d, 1H, J=8.0Hz, 6-H), 8.32 (s, 1H ,-NH-).
Embodiment 6：Prepare N- (4- fluorophenyls)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -5)
Aniline in embodiment 2 is replaced with 0.03mol 4- fluoroanilines, other operations obtain N- (4- fluorobenzene with embodiment 2
Base)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -5), fusing point：150-153 DEG C (correction), yield：86.5%.
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,CDCl3,δppm):7.10 (t, 2H, J=9.0Hz, 3 ", 5 "-H), 7.46 (s, 1H, 3-H),
7.50 (t, 2H, J=8.0Hz, 3 ', 5 '-H), 7.58 (t, 2H, J=9.0Hz, 2 ", 6 "-H), 7.69 (d, 1H, J=9.0Hz, 5-
H), the 7.72 (- H of t, 1H, J=8.0Hz, 4 '), 7.79 (dd, 2H, J=8.5Hz, 2 ', 6 '-H), 8.07 (d, 1H, J=8.5Hz,
6-H),8.41(s,1H,-NH-)。
Embodiment 7：Prepare N- (2- chlorphenyls)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -6)
Aniline in embodiment 2 is replaced with 0.03mol 2- chloroanilines, other operations obtain N- (2- chlorobenzenes with embodiment 2
Base)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -6), fusing point：130-133 DEG C (correction), yield：74.6%.
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,CDCl3,δppm):7.13 (t, 1H, J=7.5Hz, 4 "-H), 7.31 (t, 1H, J=8.0Hz,
5 "-H), 7.36 (t, 2H, J=7.5Hz, 3 ', 5 '-H), 7.44 (d, 1H, J=8.0Hz, 3 "-H), 7.60 (t, 1H, J=
7.5Hz, 4 '-H), 7.66 (s, 1H, 3-H), 7.71 (d, 1H, J=7.5Hz, 5-H), 7.72 (dd, 2H, J=7.5Hz, 2 ', 6 '-
), H 8.04 (d, 1H, J=8.0Hz, 6-H), 8.36 (d, 1H, J=8.0Hz, 6 "-H), 8.69 (s, 1H ,-NH-).
Embodiment 8：Prepare N- (3- chlorphenyls)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -7)
Aniline in embodiment 2 is replaced with 0.03mol 3- chloroanilines, other operations obtain N- (3- chlorobenzenes with embodiment 2
Base)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -7), fusing point：167-170 DEG C (correction), yield：86.3%.
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,CDCl3,δppm):7.19 (d, 1H, J=8.5Hz, 4 "-H), 7.32 (t, 1H, J=8.5Hz,
5 "-H), 7.41 (d, 1H, J=8.5Hz, 6 "-H), 7.49 (s, 1H, 3-H), 7.50 (t, 2H, J=8.5Hz, 3 ', 5 '-H),
7.69 (s, 1H, 2 "-H), 7.70 (d, 1H, J=8.0Hz, 5-H), the 7.73 (- H of t, 1H, J=8.5Hz, 4 '), 7.79 (dd, 2H, J
=8.5Hz, 2 ', 6 '-H), 8.06 (d, 1H, J=8.5Hz, 6-H), 8.42 (s, 1H ,-NH-).
Embodiment 9：Prepare N- (4- chlorphenyls)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -8)
Aniline in embodiment 2 is replaced with 0.03mol 4- chloroanilines, other operations obtain N- (4- chlorobenzenes with embodiment 2
Base)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -8), fusing point：153-156 DEG C (correction), yield：83.3%.
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,CDCl3,δppm):7.37 (m, 2H, J=8.5Hz, 3 ", 5 "-H), 7.48 (s, 1H, 3-H),
7.49 (t, 2H, J=7.5Hz, 3 ', 5 '-H), 7.56 (t, 2H, J=9.0Hz, 2 ", 6 "-H), 7.70 (d, 1H, J=8.0Hz, 5-
H), the 7.73 (- H of t, 1H, J=8.0Hz, 4 '), 7.78 (dd, 2H, J=8.0Hz, 2 ', 6 '-H), 8.06 (d, 1H, J=8.0Hz,
6-H),8.45(s,1H,-NH)。
Embodiment 10：Prepare N- (2- nitrobenzophenones)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -9)
Aniline in embodiment 2 is replaced with 0.03mol 2- nitroanilines, other operations obtain N- (2- nitre with embodiment 2
Base phenyl)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -9), fusing point：160-163 DEG C (correction), yield：73.0%.
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,CDCl3,δppm):7.29 (t, 1H, J=8.0Hz, 4 "-H), 7.42 (t, 2H, J=8.0Hz,
3 ', 5 '-H), 7.47 (s, 1H, 3-H), the 7.61 (- H of t, 1H, J=7.5Hz, 4 '), 7.71 (d, 1H, J=8.5Hz, 5-H), 7.72
(t, 1H, J=8.0Hz, 5 "-H), 7.78 (dd, 2H, J=8.5Hz, 2 ', 6 '-H), 8.02 (d, 1H, J=8.0Hz, 6-H),
8.25 (d, 1H, J=8.0Hz, 3 "-H), 8.80 (d, 1H, J=9.0Hz, 6 "-H), 11.04 (s, 1H ,-NH-).
Embodiment 11：Prepare N- (2- methoxyphenyls)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -10)
Aniline in embodiment 2 is replaced with 0.03mol 2- aminoanisoles, other operations obtain N- (2- with embodiment 2
Methoxyphenyl)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -10), fusing point：131-133 DEG C (correction), yield：
73.9%.
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,CDCl3,δppm):3.97(s,3H,-CH3-), 6.96 (d, 1H, J=8.0Hz, 3 "-H),
7.00 (t, 1H, J=8.0Hz, 5 "-H), 7.14 (t, 1H, J=8.0Hz, 4 "-H), 7.31 (t, 2H, J=8.0Hz, 3 ', 5 '-
H), the 7.57 (- H of t, 1H, J=8.0Hz, 4 '), 7.64 (dd, 2H, J=8.0Hz, 2 ', 6 '-H), 7.67 (d, 1H, J=8.0Hz,
5-H), 7.72 (s, 1H, 3-H), 8.04 (d, 1H, J=8.0Hz, 6-H), 8.28 (dd, 1H, J=8.0Hz, 6 "-H), 8.96 (s,
1H,-NH-)。
Embodiment 12：Prepare N- (4- methoxyphenyls)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -11)
Aniline in embodiment 2 is replaced with 0.03mol 4- aminoanisoles, other operations obtain N- (4- with embodiment 2
Methoxyphenyl)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -1), fusing point：166-168 DEG C (correction), yield：
79.8%.
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,CDCl3,δppm):3.86(s,3H,-CH3), 6.93 (d, 2H, J=9.0Hz, 3 ", 5 "-H),
7.48 (t, 2H, J=8.0Hz, 3 ', 5 '-H), 7.50 (d, 2H, J=9.0Hz, 2 ", 6 "-H), 7.51 (s, 1H, 3-H), 7.68
(d, 1H, J=8.0Hz, 5-H), the 7.70 (- H of t, 1H, J=7.5Hz, 4 '), 7.78 (dd, 2H, J=8.5Hz, 2 ', 6 '-H),
8.06 (d, 1H, J=8.0Hz, 6-H), 8.30 (s, 1H ,-NH-).
Embodiment 13：Prepare N- (2- ethoxyl phenenyls)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -12)
Aniline in embodiment 2 is replaced with 0.03mol 2- phenetidines, other operations obtain N- (2- with embodiment 2
Ethoxyl phenenyl)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -12), fusing point：92-95 DEG C (correction), yield：
64.5%.
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,CDCl3,δppm):1.54 (t, 3H, J=7.0Hz ,-CH3), 4.18 (q, 2H, J=
7.0Hz,-CH2-), 6.94 (d, 1H, J=7.5Hz, 3 "-H), 6.97 (t, 1H, J=8.0Hz, 5 "-H), 7.11 (t, 1H, J=
8.0Hz, 4 " and-H), 7.27 (t, 2H, J=8.0Hz, 3 ', 5 '-H), the 7.55 (- H of t, 1H, J=8.0Hz, 4 '), 7.61 (dd, 2H, J
=8.0Hz, 2 ', 6 '-H), 7.68 (d, 1H, J=8.5Hz, 5-H), 7.73 (s, 1H, 3-H), 8.03 (d, 1H, J=8.0Hz, 6-
H), 8.29 (d, 1H, J=9.0Hz, 6 "-H), 8.96 (s, 1H ,-NH-).
Embodiment 14：Prepare N- (2,4 difluorobenzene base)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -13)
With 0.03mol 2,4 difluorobenzenes amine replace embodiment 2 in aniline, other operation with embodiment 2, obtain N- (2,
4- difluorophenyls)-O- benzene sulfonyls -4- trifluoromethyl salicylamides (I -13), fusing point：119-122 DEG C (correction), yield：
80.2%.
1H nuclear magnetic resonance maps are analyzed as follows：
1H NMR(500MHz,CDCl3,δppm):6.93 (m, 1H, J=9.0Hz, 3 "-H), 6.95 (t, 1H, J=8.5Hz,
5 "-H), 7.46 (t, 2H, J=8.0Hz, 3 ', 5 '-H), 7.53 (s, 1H, 3-H), the 7.68 (- H of t, 1H, J=7.5Hz, 4 '),
7.70 (d, 1H, J=8.0Hz, 5-H), 7.78 (dd, 2H, J=8.0Hz, 2 ', 6 '-H), 8.07 (d, 1H, J=8.0Hz, 6-H),
8.26 (q, 1H, J=9.0Hz, 6 "-H), 8.39 (s, 1H ,-NH-).
Embodiment 15～27：Anti-tumor activity is tested
Anti tumor activity in vitro test (note：This method of testing, referred to as mtt assay, are the method for a maturation.)
A. principle：It is insoluble that succinate dehydrogenase in living cells mitochondria can make exogenous Thiazolyl blue (MTT) be reduced to water
Property bluish violet crystallization first a ceremonial jade-ladle, used in libation (Formazan) be deposited in cell, and dead cell is without this function.Dimethyl sulfoxide (DMSO)
The first a ceremonial jade-ladle, used in libation in cell can be dissolved, first a ceremonial jade-ladle, used in libation light absorption value is determined with enzyme-linked immunosorbent assay instrument at 490nm wavelength, cell can be reflected indirectly
Proliferative conditions and number change.In the range of certain cell number, MTT is crystallized the amount to be formed and is directly proportional to cell number.
B. cell：
Human lung carcinoma cell line (H446, purchased from Shanghai Inst. of Life Science, CAS)
C. experimental procedure
1) preparation of sample：Compound I-1～I-13 prepared by Example 2～14, per 1mg samples with 20 μ L
DMSO dissolves, then takes 2 μ L, 1000 μ L culture fluid (seeing below the preparation of culture fluid in the cultivation of step (2) cell) dilutions, matches somebody with somebody
Into the sample liquid of 100 μ g/mL, then with culture fluid serial dilution to concentration 10 μ g/mL and 1 μ g/mL.
The preparation of 5mg/mLMTT：MTT solution is configured with normal saline, concentration is 5mg/mL.
2) culture of cell
The preparation of culture fluid：Contain 800,000 units of Penicillin, 1.0g chains in per 1000mL DMEM culture fluid (Gibco companies)
Mycin, 10% inactivation calf serum.
The culture of cell：Tumor cell H446 is inoculated in culture fluid, 37 DEG C of (correction), 5%CO are put2In incubator
Culture, 3～5d are passed on.
3) inhibitory action of the determination sample to growth of tumour cell
By cell ethylenediaminetetraacetic acid (EDTA)-pancreatin Digestive system (0.25% pancreatin, 0.02%EDTA, with Hank ' s
Buffer is configured) digestion, and cell concentration is diluted to for 1 × 10 with culture fluid6/ mL, is added in 96 porocyte culture plates, per hole
100 μ L, put 37 DEG C of (correction), 5%CO2After 24h is cultivated in incubator, incline culture fluid, the sample that addition is diluted with culture fluid
Product, per 200 μ L of hole, each concentration adds 3 holes, puts 37 DEG C of (correction), 5%CO2Cultivate in incubator, in cell culture after 72h
The MTT of 5mg/mL is added in hole, per 10 μ L of hole, 37 DEG C (correction) incubation 3h is put, is added DMSO, per 150 μ L of hole, use agitator
(Haimen kylin Medical Instruments factory, QL-9001) vibrates, and is completely dissolved first a ceremonial jade-ladle, used in libation, with enzyme-linked immunosorbent assay instrument (U.S. BIO-RAD
Company, 680 types) light absorption value is detected at 490nm wavelength.With control sample containing cisplatin under similarity condition and same concentration DMSO
The cell of culture fluid culture calculates suppression ratio of the sample to growth of tumour cell according to formula (1) as blank, and respectively
The suppression ratio of compounds on cell growth under individual concentration, calculates the half of each sample with SPSS softwares (being purchased from SPSS Inc. of the U.S.)
Inhibition concentration (IC50), as a result as shown in table 1：
Computing formula：Suppression ratio (%)=(ODIt is blank-ODSample)/ODIt is blank× 100% formula (1)
Table 2：IC of each compound to H44650(mg/L)
| Embodiment | Compound | IC50mg/L | Evaluate |
| 15 | Ⅰ-1 | 76.94 | Minor effect |
| 16 | Ⅰ-2 | 14.94 | Weak effect |
| 17 | Ⅰ-3 | 17.65 | Weak effect |
| 18 | Ⅰ-4 | 96.54 | Minor effect |
| 19 | Ⅰ-5 | 7.44 | Effectively |
| 20 | Ⅰ-6 | 19.55 | Weak effect |
| 21 | Ⅰ-7 | 37.22 | Weak effect |
| 22 | Ⅰ-8 | 4.14 | Effectively |
| 23 | Ⅰ-9 | >100 | It is invalid |
| 24 | Ⅰ-10 | 46.07 | Weak effect |
| 25 | Ⅰ-11 | >100 | It is invalid |
| 26 | Ⅰ-12 | 43.48 | Weak effect |
| 27 | Ⅰ-13 | 11.35 | Weak effect |
As it can be seen from table 1 according to the evaluation criterion of active anticancer, the compound shown in formula I -5 and I -8 has preferable
Anti- H446 human lung carcinoma cells activity.
Claims (5)
1. a kind of O- benzene sulfonyl -4- trifluoromethyl salicylamide compounds as shown in formula I：
In formula I, R1～R5H, methyl, fluorine, chlorine, methoxy or ethoxy are stood alone as each.
2. O- benzene sulfonyls -4- trifluoromethyl salicylamide compounds as claimed in claim 1, it is characterised in that the O- benzene
Sulphonyl -4- trifluoromethyl salicylamides compound is one of 1 compound of table：
Table 1：
3. O- benzene sulfonyls -4- trifluoromethyl salicylamide compounds as claimed in claim 1 or 2 are preparing antitumor drug
In application.
4. it is as claimed in claim 3 to apply, it is characterised in that the tumor is human lung cancer.
5. it is as claimed in claim 3 to apply, it is characterised in that the O- benzene sulfonyls -4- trifluoromethyl salicylamide compounds
Compound shown in formula I -5 or I -8.
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Citations (4)
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|---|---|---|---|---|
| US3055928A (en) * | 1960-03-28 | 1962-09-25 | Smith Kline French Lab | Esters of 2-carbamoylbenzenesulfonic acids |
| CN1658855A (en) * | 2002-06-06 | 2005-08-24 | 株式会社医药分子设计研究所 | O-substituted hydroxyaryl derivatives |
| CN101502523A (en) * | 2009-03-06 | 2009-08-12 | 浙江工业大学 | Application of benzoyl fluorobenzene salicylamide compound in preparing anti-tumor medicament |
| CN102614198A (en) * | 2012-03-05 | 2012-08-01 | 浙江工业大学 | Application of (4-substituted benzene formyl) fluorobenzene salicylamide compound in preparation of anti-lung-cancer medicines |
-
2016
- 2016-11-18 CN CN201611028238.0A patent/CN106588716B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3055928A (en) * | 1960-03-28 | 1962-09-25 | Smith Kline French Lab | Esters of 2-carbamoylbenzenesulfonic acids |
| CN1658855A (en) * | 2002-06-06 | 2005-08-24 | 株式会社医药分子设计研究所 | O-substituted hydroxyaryl derivatives |
| CN101502523A (en) * | 2009-03-06 | 2009-08-12 | 浙江工业大学 | Application of benzoyl fluorobenzene salicylamide compound in preparing anti-tumor medicament |
| CN102614198A (en) * | 2012-03-05 | 2012-08-01 | 浙江工业大学 | Application of (4-substituted benzene formyl) fluorobenzene salicylamide compound in preparation of anti-lung-cancer medicines |
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| MARTIN KRÁTKÝ等: "Antimycobacterial Activity of Salicylanilide Benzenesulfonates", 《MOLECULES》 * |
| STEPHEN L. GWALTNEY等: "Novel Sulfonate Derivatives: Potent Antimitotic Agents", 《BIOORG. MED. CHEM. LETT.》 * |
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