CN1333206A - Sulfuryl diphenyl indole compound and preparation process and use in medicine - Google Patents
Sulfuryl diphenyl indole compound and preparation process and use in medicine Download PDFInfo
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- CN1333206A CN1333206A CN 00120761 CN00120761A CN1333206A CN 1333206 A CN1333206 A CN 1333206A CN 00120761 CN00120761 CN 00120761 CN 00120761 A CN00120761 A CN 00120761A CN 1333206 A CN1333206 A CN 1333206A
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Abstract
The present invention relates to an indole compound containing sulfonyl diaryl, its preparation method, its medicine composite and its medical application for inhibiting and curing the disease related to cyclooxygenase, in particular, for curing various inflammations.
Description
The compound that contains the alkylsulfonyl diphenyl indole particularly relates to the new compound of general formula I, and preparation method thereof, contain one or more these compound compositions and this compound and suppress application in the medicine with cyclooxygenase 2 relative diseases in preparation.
NSAID (non-steroidal anti-inflammatory drug) has anti-inflammatory, pain relieving and refrigeration function, and these effects are owing to suppressed can conversion of arachidonic acid to generate the cyclooxygenase-2 activity of PGG and H.Known so far cyclooxygenase isozyme has two kinds of hypotypes: cyclooxygenase 1 and cyclooxygenase 2.Cyclooxygenase 1 is the structure-type enzyme, is present in the healthy tissues, and its physiological function is that conversion of arachidonic acid is oxidized to prostaglandin(PG), keeps gastrointestinal tract mucous defencive function and kidney normal function: cyclooxygenase 2 is the induction type enzyme.It is owing to for example irritation cells such as intracellular toxin, cytokine or hormone generate, and can cause inflammation by catalysis generation prostaglandin(PG).
At present, most nonsteroidal anti-inflammatory drugs know altogether all that to the effect of two kinds of above-mentioned enzymes they also suppress cyclooxygenase 1 when suppressing cyclooxygenase 2.When taking the treatment chronic inflammatory diseases for a long time, can cause gi tract and kidney injury.Therefore, the selective depressant of cyclooxygenase 2 should only have anti-inflammatory, pain relieving and refrigeration function, in addition, uterine contraction and potential antitumour activity that cyclooxygenase 2 inhibitor also can inhibitory hormone excite, but have elimination or reduce toxic action to gi tract and kidney.
So far, to cyclooxygenase 2 selective inhibiting medicines mostly is to contain amine sulphonyl aryl or methylsulfonyl aryl compound, for example contain sulfamic or methylsulfonyl aryl compound Niemi Shu Li (R.H.Brogden and A Ward.Drugs1998,36:732-753), NS-398 (Japan's special permission 292856,871119); Metro former times health (DE2756113, DE771216); Contain the tricyclic compound of pyrazoles such as Celecoxib (WO9641625, WO961227); The tricyclic compound JTE-522 (EP745598,961204) that contains the oxazole ring; Contain α, and the tricyclic compound of β-unsaturated-gamma lactone such as Rofecoxib (EP788476, WO9613483) etc.The indomethacin that contains indoles has stronger side effect owing to the restraining effect to cyclooxygenase 1 and 2 does not have selectivity as antiphlogiston.Be lead compound with the indomethacin, having more by force of developing suppresses active Benzazole compounds to cyclooxygenase 2, and L-7487780 and L-761066 (W.C.Black et al, Bioorg.Med.Chem.Lett, 1996,6:725-742 are for example arranged; WO9730030) do not contain alkylsulfonyl in the molecule.These compounds have in various degree selective inhibitory to cyclooxygenase 2, so be the anti-inflammatory drug of the less untoward reaction of a class.
In existing document, do not see the present invention's the report that contains alkylsulfonyl diaryl indoles so far as yet, and it is used to suppress the purposes of the anti-inflammatory compound of cyclooxygenase 2.
In order to overcome the deficiencies in the prior art, the object of the present invention is to provide a kind of novel cpd of alkylsulfonyl diaryl indoles;
Another object of the present invention is to provide a kind of preparation to contain alkylsulfonyl diaryl indole method;
A further object of the present invention is to provide a kind of pharmaceutical composition that contains one or more this compounds;
Another purpose of the present invention is to provide the purposes of a kind of this compound in the medicine of inhibition and cyclooxygenase 2 relative diseases.
In order to finish the present invention's purpose, the present invention takes following technical scheme:
The present invention relates to have the novel cpd of general formula I:
In the formula,
R
1Be selected from 4-methylsulfonyl, 4-sulfamyl, hydrogen, 4-halogen, 4-alkyl (C
1-C
3), 4-alkoxyl group (C
1-C
3), 4-acetamido, 3,4-dimethyl, 3,4-methylene-dioxy, 3,4-propylidene;
R
2Be selected from 4-methylsulfonyl, 4-sulfamyl, hydrogen, 4-halogen, 4-alkyl (C
1-C
3), 4-alkoxyl group (C
1-C
3), 4-acetamido, 3,4-dimethyl, 3,4-methylene radical dioxy base, 3,4-propylidene;
R
3Be selected from hydrogen.
Wherein: work as R
1During for methylsulfonyl or sulfamyl, R
2It is any one other group except that methylsulfonyl or sulfamyl; Work as R
2During for methylsulfonyl or sulfamyl, R
1It is any one other group except that methylsulfonyl or sulfamyl.
R among the present invention
1Be selected from described methylsulfonyl, sulfamyl, R
2Be selected from hydrogen, halogen is fluorine, chlorine, bromine, alkyl is a methyl, alkoxyl group is a methoxyl group.
Be the described compound of preparation general formula I of the present invention; the inventive method comprises; Fu-Ke reaction takes place in 2-(4-Methyl benzenesulfonyl amido)-phenylformic acid and substituted benzene; deprotection obtains the amino substituted diphenylamine ketone of 2-in strong acid again; get acid amides with acyl chloride reaction, reduction condensation is a target compound under the effect of zinc and titanium tetrachloride at last.
Specifically, the method for the compound described in the preparation general formula I comprises the steps:
(A) toluene-obtains methyl thiobenzoxide through the methyl-sulfate alkylation;
(B) Tosyl chloride and ammoniacal liquor effect obtain para toluene sulfonamide;
(C) methyl thiobenzoxide (para toluene sulfonamide) is obtained first sulphur (ammonia sulphur) acyl group phenylformic acid under the oxidation of potassium permanganate;
(D) first sulphur (ammonia sulphur) acyl group phenylformic acid is refluxed in thionyl chloride obtain first sulphur (ammonia sulphur) acyl group Benzoyl chloride;
(E) anthranilic acid and Tosyl chloride are at alkali (K
2CO
3, Na
2CO
3) react in the solution, obtain 2-(4-Methyl benzenesulfonyl amido)-phenylformic acid through acidifying;
(F) 2-(4-Methyl benzenesulfonyl amido)-phenylformic acid is being selected from solvent C S with different substituted benzenes
2, benzene, toluene, o-Xylol, chlorobenzene, bromobenzene, methyl-phenoxide, Fu-Ke reaction takes place in temperature of reaction 50-150 ℃, 60-120 ℃ of decomposition of heating in strong acid again is with being selected from NaOH, KOH, K
2CO
3, Na
2CO
3, NH
3H
2The alkali neutralization of O obtains the amino substituted diphenylamine ketone of 2-;
(G) the amino substituted diphenylamine ketone of 2-with first sulphur (or ammonia sulphur) acyl group Benzoyl chloride is reacted in the presence of triethylamine obtain 2-[4-first sulphur (or ammonia sulphur) acyl group] benzoylamino-substituted diphenylamine ketone;
(H) in the presence of zinc and titanium tetrachloride, 2-[4-first sulphur (or ammonia sulphur) acyl group] to be reduced condensation be 2-[4-first sulphur (or ammonia sulphur) acyl group phenyl to benzoylamino-substituted diphenylamine ketone]-3-substituted-phenyl-indoles.
The invention still further relates to a kind of pharmaceutical composition that contains medicine effective dose as described compound of general formula I and pharmaceutically acceptable carrier.
Pharmaceutical research shows, compound of Formula I of the present invention has the activity that suppresses cyclooxygenase 2, has potent restraining effect for the generation of the cyclooxygenase 2 that causes because of inflammatory mediator; Because of the mouse swelling that carrageenin brings out, The compounds of this invention has obvious interception.The more important thing is, The compounds of this invention does not have or the low activity that suppresses cyclooxygenase 1 under the concentration that suppresses cyclooxygenase 2, therefore, the patient takes less untoward reaction, the particularly less toxic side effect that gi tract and kidney occur of occurring of The compounds of this invention meeting for a long time clinically.
The compounds of this invention is the NSAID (non-steroidal anti-inflammatory drug) that a class has selectively acting, also is a kind of cyclooxygenase 2 inhibitor, and it can be used for treating rheumatic arthritis, rheumatalgia, disease and symptoms such as various inflammation and heating.In addition, because cyclooxygenase 2 has high expression level and high-content in colon cancer tissue, cyclooxygenase 2 inhibitor can be used for treating particularly cancer such as the colorectal carcinoma and the rectum cancer.
Select for use pharmaceutical carrier well known to those skilled in the art can make the pharmaceutical composition of the The compounds of this invention that contains effective dosage.
The compounds of this invention or its composition can be with oral methods or the medications of parenteral road.Oral medication can be tablet, capsule, Drug coating, and non-have injection and suppository etc. through the intestines drug formulation.These preparations are according to the known method preparation of those skilled in the art.For making tablet, capsule, the used auxiliary material of Drug coating is the auxiliary agent of conventional usefulness, starch for example, gelatin, gum arabic, silica, polyoxyethylene glycol, the used solvent of liquid dosage form for example has water, ethanol, propylene glycol, plant oil such as Semen Maydis oil, peanut oil, olive wet goods.Containing in the preparation of The compounds of this invention also can have other auxiliary agents, tensio-active agent for example, lubricant, disintegrating agent, sanitas, correctives, pigment etc.
At tablet, capsule, Drug coating, the dosage that contains formula I compound of the present invention in injection or the suppository is to calculate with the compound amount that exists in the unit dosage form.The general content of formula I compound of the present invention is 10-50mg in unit dosage form, and preferred unit dosage form contains 20-100mg.
Be treatment rheumatic arthritis and other inflammation, heating, pain relieving, be 10-500mg The compounds of this invention every day that adult patient is taken, and is preferably 20-100mg, can once take or divide and take for 2-3 time; The dosage of children taking is preferably the 10-20mg/kg body weight according to every kg body weight 5-30mg.
Below with reference to embodiment invention is described further, but does not limit the scope of the invention.
Determining instrument used herein: the fusing point micro-fusing point instrument of Yanaco, NMR (Nuclear Magnetic Resonance) spectrum Vaariaan Mercury300 type nuclear magnetic resonance analyser.Preparation to 1 pair of methyl thiobenzoxide of preparation embodiment of methyl thiobenzoxide
KOH15.6g (0.28mol) is dissolved in the 100ml water, adds toluene-(Zhejiang Shou Er good fortune company limited, 99.3%) 17.6g (0.14mol), after the dissolving, the ice-water bath cooling drips methyl-sulfate 14.5ml (0.15mol), drips and finishes, stirring at room 5 hours, reheat backflow 30min.Cooling, and the extracted with diethyl ether organic phase (3 * 100ml), anhydrous magnesium sulfate drying, after steaming desolventized, cut 14.6 grams that underpressure distillation gets 104 ℃ (20mmHg) were to methyl thiobenzoxide, yield 74.5%.The preparation of preparation embodiment 2 para toluene sulfonamides of para toluene sulfonamide
25% strong aqua 100ml is splashed into Tosyl chloride (Shi Ying chemical plant, Changping, Beijing, purity＞97%) among the 38.1g (0.2mol), stirring at room 4 hours, placement is spent the night, suspension becomes starchiness, reflux 10min, cooling, filter collection solid, be washed to neutrality, the dry white powder 31.2g that gets is para toluene sulfonamide, yield 91.2%.
Fusing point 137-138 ℃ of preparation to 3 pairs of methyl sulfonylbenzoic acids of the benzoic preparation embodiment of first sulphur (ammonia sulphur) acyl group
Will be (in (0.10mol), potassium permanganate 74.2g (0.40mol) and the 10% aqueous sodium hydroxide solution 7ml adding 700ml water to methyl thiobenzoxide 14.6g, after the reflux 4 hours, the ice-water bath cooling is carefully regulated pH=2 with the vitriol oil, keeps gradation adding NaH under the acidic conditions
SO
3The about 62g of powder a large amount of pale precipitations occur to reaction solution; leach precipitation,, filter with the dissolving of 2N sodium hydroxide solution; the filtrate decolouring; carefully be neutralized to a large amount of precipitations of appearance with the vitriol oil again, suction filtration, the washing solid is to neutrality; dry back solid Glacial acetic acid recrystallization; white plates crystallization 15.3g, for to methyl sulfonylbenzoic acid, yield 72.9%.
4 pairs of sulfamoylbenzoic acids of fusing point 268-270 ℃ embodiment
Get para toluene sulfonamide 17.1g (0.1mol); sodium hydroxide 20g (0.5mol); water 300ml mixed dissolution stirs gradation adding potassium permanganate 20g (0.13mol) down, after low-grade fever causes reaction; temperature rises to 70 ℃ naturally; when reacting liquid temperature began to descend, heat temperature raising to 90 ℃ added remaining potassium permanganate; continue reaction 2 hours; cooling is filtered, and filtrate is with the careful acidifying of concentrated hydrochloric acid; separate out precipitation; suction filtration, drying gets white powder 18.1g; for to sulfamoylbenzoic acid, yield 90%.
Fusing point 291-292 ℃ of preparation to 5 pairs of methylsulfonyl Benzoyl chlorides of preparation embodiment of first sulphur (ammonia sulphur) acyl group Benzoyl chloride
Get reflux 3 hours in the 30ml thionyl chloride to methyl sulfonylbenzoic acid 11.2g (0.056mol), until the reaction solution bleach, the evaporate to dryness thionyl chloride, white solid.The preparation of 6 pairs of sulfamyl Benzoyl chlorides of (standby) embodiment
Get reflux 8 hours in the 30ml thionyl chloride,, steam and remove thionyl chloride until the reaction solution bleach to sulfamoylbenzoic acid 11.3g (0.056mol), white solid.(standby) 2-(4-Methyl benzenesulfonyl amido)-benzoic preparation embodiment 7 2-(4-Methyl benzenesulfonyl amido)-benzoic preparation
Anhydrous sodium carbonate 26.0g heating is dissolved in the 150ml water, cold slightly, add anthranilic acid (sea, Beijing Nereid's refinement factory, purity＞99.5%) 13.7g (0.1mol) in batches, when temperature rises to 70 ℃, obtain settled solution, reacting liquid temperature is reduced to 60 ℃, and gradation adds p-toluenesulfonyl chloride (Shi Ying chemical plant, Changping, Beijing, purity＞97%) 23.0g (0.12mol), finish, kept 0.5 hour between 60-70 ℃, be warming up to 85 ℃, add the 1.0g gac, continue heating after 15 minutes, filtered while hot, filtrate is chilled to 50 ℃, be acid with the 6N hydrochloric acid conditioning solution, cooling, suction filtration, filter cake dilute hydrochloric acid, washing.Solid is with 95% ethyl alcohol recrystallization, crystallization 20.0g, be 2-(4-Methyl benzenesulfonyl amido)-phenylformic acid, yield 68.7%.
The preparation of the preparation embodiment 8 2-amino-benzophenone of fusing point 229-232 ℃ of 2-amino-substituted diphenylamine ketone
Get 2-(4-Methyl benzenesulfonyl amido)-phenylformic acid 14.6g (0.050mol) and mix with benzene 150ml, phosphorus pentachloride 11.9g (0.057mol), 50 ℃ were stirred 0.5 hour down, were chilled to 20-25 ℃, added 29.0g (0.218mol) aluminum trichloride (anhydrous) in batches.Finish, stirred 4 hours at 80-90 ℃.Be chilled to room temperature, pour in the cold 1N hydrochloric acid of 60ml, steam distillation is removed benzene, and filter collection residuum with dilute hydrochloric acid, water, 5% sodium carbonate solution washing, washes with water to neutrality respectively at last.
Solid is dissolved in the 160ml vitriol oil, is heated to 120 ℃ and stirred 15 minutes, pour into after the cooling in the trash ice, add small amount of activated, stirred 0.5 hour, filtration, filtrate neutralizes with strong aqua, gets yellow mercury oxide, the filter collection, washing is drained, and gets yellow powder.Recrystallization in the ethanol gets crystallization 6.63g, is 2-amino-benzophenone, yield 65.0%.
Fusing point 105-106 ℃ embodiment 9 2-amino-4 '-preparation of chloro benzophenone
Embodiment 8 identical methods are carried out, and difference is to get chlorobenzene 140ml and replaces benzene 150ml, and 150 ℃ are stirred 80 ℃ of stirrings of replacement in 6 hours 4 hours, and heating replaced 15min in 3 hours in the vitriol oil, obtained yellow solid.Recrystallization gets golden yellow needle crystal in the ethanol, is 2-amino-4 ＇-chloro benzophenone, yield 57.9%.
Fusing point 100.5-101.5 ℃ embodiment 10 2-amino-4 '-preparation of bromine benzophenone
Embodiment 8 identical methods are carried out, and difference is that bromobenzene 140ml replaces benzene 150ml, and 110 ℃ are stirred and replaced 80 ℃ in 6 hours and stirred 4 hours, and heating replaced 15min in 3 hours in the vitriol oil, obtained the glassy yellow solid, for 2-amino-4 '-the bromine benzophenone, yield 49.7%.
Fusing point 104-106 ℃ embodiment 11 2-amino-4 '-preparation of methyldiphenyl ketone
Embodiment 8 identical methods are carried out, and difference is that toluene 140ml replaces benzene 150ml, and 80-90 ℃ is stirred and replaced 80-90 ℃ in 3 hours and stirred 4 hours, obtains the glassy yellow solid, for 2-amino-4 '-methyldiphenyl ketone, yield 67.2%.
Fusing point 89-91 ℃ embodiment 12 2-amino-3 ', 4 '-preparation of dimethyl benzophenone
Embodiment 8 identical methods are carried out, and difference is that o-Xylol 80ml replaces benzene 150ml, and heating replaced 15min in 4 hours in the vitriol oil, obtained yellow solid, for 2-amino-3 ', 4 '-the dimethyl benzophenone, yield 35.5%.
Fusing point 77-78 ℃ embodiment 13 2-amino-4 '-preparation of methoxyl group benzophenone
Get 2-(4-Methyl benzenesulfonyl amido)-phenylformic acid 14.6g (0.050mol) and CS
250ml, phosphorus pentachloride 12g (0.058mol), reflux 1 hour.After reducing to room temperature, add the 10ml methyl-phenoxide, add aluminum trichloride (anhydrous) 15g (0.218mol) in batches, reaction solution keeps little boiling.Finish, backflow 45min, steaming desolventizes, and gained oily matter is transferred in the cold 1N hydrochloric acid of 60ml, stirs 1 hour, and filter collection residuum is washed with dilute hydrochloric acid, water, 5% sodium carbonate solution respectively, is washed to neutrality at last.
Solid is dissolved in the mixed solution of the 70ml vitriol oil and 70ml Glacial acetic acid,, pours in the trash ice after the cooling in 60 ℃ of stirrings 1 hour, add small amount of activated, stirred 0.5 hour, filter, filtrate neutralizes with strong aqua, gets yellow mercury oxide, suction filtration, washing is drained, and gets yellow powder, recrystallization in the ethanol, the block crystallization 6.5g of glassy yellow, for 2-amino-4 '-the methoxyl group benzophenone, yield 57.3%.
Fusing point 76-77 ℃ of 2-[4-first sulphur (ammonia sulphur) acyl group] preparation of preparation embodiment 14 2-(4-methylsulfonyl) benzoylamino-benzophenone of benzoylamino-substituted diphenylamine ketone
Get 2-amino-benzophenone 2.0g (0.010mol) and be dissolved in the 20ml anhydrous tetrahydro furan, add triethylamine 1.6ml (0.011mol), nitrogen protection; under the stirring at room, add tetrahydrofuran solution, stirred 2 hours methylsulfonyl Benzoyl chloride 2.0g (0.010mol); filter; concentrate column chromatography, developping agent: petrol ether/ethyl acetate (3/1); elutriant concentrates; get needle crystal, be 2-(4-methylsulfonyl) benzoylamino-benzophenone, yield 68.2%.
The preparation of fusing point 177-178 ℃ embodiment 15 2-(4-sulfamyl) benzoylamino-benzophenone
Get 2-amino-benzophenone 2.0g (0.010mol) and be dissolved in the 20ml tetrahydrofuran (THF), add triethylamine 1.6ml (0.011mol), nitrogen protection; under the stirring at room, add tetrahydrofuran solution, reacted 2 hours sulfamyl Benzoyl chloride 2.0g (0.010mol); filter; concentrate column chromatography, developping agent: petrol ether/ethyl acetate (1/1); elutriant concentrates; get needle crystal, be 2-(4-sulfamyl) benzoylamino-benzophenone, yield 59.5%.
Fusing point 216-218 ℃ embodiment 16 2-(4-methylsulfonyl) benzoylamino-4 '-preparation of chloro benzophenone
Embodiment 14 identical methods are carried out, difference be 2.3g2-amino-4 '-chloro benzophenone replaces 2.0g2-amino-benzophenone, obtains white solid, for 2-(4-methylsulfonyl) benzoylamino-4 '-chloro benzophenone, yield 75.7%.
Fusing point 186-188 ℃ embodiment 17 2-(4-sulfamyl) benzoylamino-4 '-preparation of chloro benzophenone
Embodiment 15 identical methods are carried out, difference be 2.3g2-amino-4 '-chloro benzophenone replaces 2.0g2-amino-benzophenone, obtains faint yellow solid, for 2-(4-sulfamyl) benzoylamino-4 '-chloro benzophenone, yield 53.6%.
Fusing point 198-200 ℃ embodiment 18 2-(4-methylsulfonyl) benzoylamino-4 '-preparation of bromine benzophenone
Embodiment 14 identical methods are carried out, difference be 2.8g2-amino-4 '-the bromine benzophenone replaces 2.0g2-amino-benzophenone, obtains faint yellow crystallization, for 2-(4-methylsulfonyl) benzoylamino-4 '-the bromine benzophenone, yield 67.5%.
Fusing point 176-178 ℃ embodiment 19 2-(4-sulfamyl) benzoylamino-4 '-preparation of bromine benzophenone
Embodiment 15 identical methods are carried out, difference be 2.8g2-amino-4 '-the bromine benzophenone replaces 2.0g2-amino-benzophenone, concentrates the oily matter that obtains and do not separated purification, directly carries out next step reaction.Embodiment 20 2-(4-methylsulfonyl) benzoylamino-4 '-preparation of methyldiphenyl ketone
Embodiment 14 identical methods are carried out, difference be 2.1g2-amino-4 '-methyldiphenyl ketone replaces 2.0g2-amino-benzophenone, obtains faint yellow crystallization, for 2-(4-methylsulfonyl) benzoylamino-4 '-methyldiphenyl ketone, yield 77.9%.
Fusing point 171-173 ℃ embodiment 21 2-(4-sulfamyl) benzoylamino-4 '-preparation of methyldiphenyl ketone
Embodiment 15 identical methods are carried out, difference be 2.1g2-amino-4 '-methyldiphenyl ketone replaces 2.0g2-amino-benzophenone, obtains white solid, for 2-(4-sulfamyl) benzoylamino-4 '-methyldiphenyl ketone, yield 12.0%.
Fusing point 216-218 ℃ embodiment 22 2-(4-methylsulfonyl) benzoylamino-3 ', 4 '-preparation of dimethyl benzophenone
Embodiment 14 identical methods are carried out; difference be 2.3g2-amino-3 ', 4 '-the dimethyl benzophenone replaces 2.0g2-amino-benzophenone, the oily matter after concentrating is without column chromatography; adding small amount of thermal ethanol shakes up; precipitation is separated out in placement, suction filtration, the own ester washing of small amount of acetic acid; get faint yellow solid; for 2-(4-methylsulfonyl) benzoylamino-3 ', 4 '-the dimethyl benzophenone, yield 41.3%.
Fusing point 206-207 ℃ embodiment 23 2-(4-sulfamyl) benzoylamino-3 ', 4 '-preparation of dimethyl benzophenone
Embodiment 15 identical methods are carried out, difference be 2.3g2-amino-3 ', 4 '-the dimethyl benzophenone replaces 2.0g2-amino-benzophenone; obtain faint yellow solid; for 2-(4-sulfamyl) benzoylamino-3 ', 4 '-the dimethyl benzophenone, yield 49.6%.
Fusing point 251-253 ℃ embodiment 24 2-(4-methylsulfonyl) benzoylamino-4 '-preparation of methoxyl group benzophenone
Embodiment 14 identical methods are carried out; difference be 2.3g2-amino-4 '-the methoxyl group benzophenone replaces 2.0g2-amino-benzophenone; obtain faint yellow solid; ethanol-hexyl acetate recrystallization gets faint yellow column crystallization; for 2-(4-methylsulfonyl) benzoylamino-4 '-the methoxyl group benzophenone, yield 32.4%.
Fusing point 160-161 ℃ embodiment 25 2-(4-sulfamyl) benzoylamino-4 '-preparation of methoxyl group benzophenone
Embodiment 15 identical methods are carried out, difference be 2.3g2-amino-4 '-the methoxyl group benzophenone replaces 2.0g2-amino-benzophenone, obtains white solid, for 2-(4-sulfamyl) benzoylamino-4 '-the methoxyl group benzophenone, yield 55.3%.
Fusing point 173-174 ℃ of 2-[4-first sulphur (ammonia sulphur) acyl group phenyl]-preparation of preparation embodiment 26 2-(4-methylsulfonyl the phenyl)-3-phenyl-indole of 3-substituted-phenyl-indoles
Get 2-(4-methylsulfonyl) benzoylamino-benzophenone 1.14g (3mmol) and put into the exsiccant there-necked flask; nitrogen protection adds zinc powder (90%) 0.87g (12mmol) and 20ml anhydrous tetrahydro furan, drips anhydrous titanium tetrachloride 0.7ml (6.2mmol); drip and finish; reflux 1.5 hours, cooling is after steaming desolventizes; add the water-soluble inorganic salt (if still having the black insolubles to add a small amount of dilute hydrochloric acid) that go; suction filtration, washing is drained.Wash the lixiviation cake with acetone, steam to remove acetone again, the gained solid is through the decompression column chromatography, developping agent: petrol ether/ethyl acetate (3/1), elutriant concentrate white crystals, be 2-(4-methylsulfonyl phenyl)-3-phenyl-indole, yield 56.2%.
Fusing point 221-222 ℃; M
+: 361.1098, C
22H
19NO
2S;
1HNMR (CD
3COCD
3) δ: 3.1 (s, 3H, SO
2CH
3), 7.0-7.9 (m, 13H, Ar-H), 8.4 (b, 1H, N-H).The preparation of embodiment 27 2-(4-sulfamyl phenyl)-3-phenyl-indole
Get 2-(4-sulfamyl) benzoylamino-benzophenone 1.14g (3mmol) in the exsiccant there-necked flask; nitrogen protection; add zinc powder (90%) 0.87g (12mmol) and 20ml anhydrous tetrahydro furan, drip anhydrous titanium tetrachloride 0.7ml (6.2mmol), drip and finish; reflux 1.5 hours; cooling after steaming desolventizes, adds the water-soluble inorganic salt (if still having the black insolubles to add a small amount of dilute hydrochloric acid) that go; suction filtration is drained.Wash the lixiviation cake with acetone, steam to remove acetone again, the gained solid is through the decompression column chromatography, developping agent: petrol ether/ethyl acetate (2/1), elutriant concentrate white crystals, be 2-(4-sulfamyl phenyl)-3-phenyl-indole, yield 433.9%.
Fusing point 231-232 ℃; M
+: 348, C
22H
18N
2O
2S;
1HNMR (300MHz, CD
3COCD
3) δ: 3.9 (s, 2H, SO
2NH
2), 7.0-7.9 (m, 13H, Ar-H), 10.8 (s, 1H, N-H).The preparation of embodiment 28 2-(4-methylsulfonyl phenyl)-3-(4-chloro-phenyl-)-indoles
Embodiment 26 identical methods are carried out; difference be 1.24g 2-(4-methylsulfonyl) benzoylamino-4 '-chloro benzophenone replaces 1.14g 2-(4-methylsulfonyl) benzoylamino-benzophenone; obtain white powder; be 2-(4-methylsulfonyl phenyl)-3-(4-chloro-phenyl-)-indoles, yield 65.5%.
Fusing point 198.5-200.5 ℃;
1HNMR (300MHz, CDCl
3) δ: 3.09 (s, 3H, SO
2CH
3), 7.16-7.85 (m, 12H, Ar-H), 8.65 (s, 1H, N-H); Ultimate analysis: C
21H
16NO
2SCl, calculated value %:C66.05, H4.22, N3.67; Measured value %:C65.98, H4.50, N3.56.The preparation of embodiment 29 2-(4-sulfamyl phenyl)-3-(4-chloro-phenyl-)-indoles
Operate according to embodiment 27 identical methods; different is with 1.24g 2-(4-sulfamyl) benzoylamino-4 '-chloro benzophenone replaces 1.14g 2-(4-sulfamyl) benzoylamino-benzophenone; obtain white powder; be 2-(4-sulfamyl phenyl)-3-(4-chloro-phenyl-)-indoles, yield 73.9%.
Fusing point 298-300 ℃;
1HNMR (300MHz, DMSO) δ: 3.29 (s, 2H, SO
2NH
2), 7.05-7.81 (m, 12H, Ar-H), 11.75 (s, 1H, N-H).The preparation of embodiment 30 2-(4-methylsulfonyl phenyl)-3-(4-bromophenyl)-indoles
Operate according to embodiment 26 identical methods; different is with 1.40g 2-(4-methylsulfonyl) benzoylamino-4 '-the bromine benzophenone replaces 1.14g 2-(4-methylsulfonyl) benzoylamino-benzophenone; without column chromatography; steam except that the ethanol-acetone recrystallization of the solid behind the acetone; get faint yellow prism-shaped crystallization; be 2-(4-methylsulfonyl phenyl)-3-(4-bromophenyl)-indoles, yield 75.2%.
Fusing point 225-226 ℃;
1HNMR (300MHz, DMSO) δ: 3.09 (s, 3H, SO
2CH
3), 7.16-7.84 (m, 12H, Ar-H), 8.69 (s, 1H, N-H); Ultimate analysis: C
21H
16NO
2SBr, calculated value %:C59.16, H3.78, N3.29; Measured value %:C59.32, H3.88, N3.39.The preparation of embodiment 31 2-(4-sulfamyl phenyl)-3-(4-bromophenyl)-indoles
Operate with embodiment 27 identical methods; different is with product replacement 1.14g 2-(4-sulfamyl) benzoylamino-benzophenone of purifying not separating of embodiment 19; obtain pale yellow powder; be 2-(4-sulfamyl phenyl)-3-(4-bromophenyl)-indoles, two step yields 11.7%.
Fusing point 277-279;
1HNMR (300MHz, CDCl
3) δ: 3.23 (s, 2H, SO
2NH
2), 7.04-7.80 (m, 12H, Ar-H), 11.70 (s, 1H, N-H).The preparation of embodiment 32 2-(4-methylsulfonyl phenyl)-3-(4-aminomethyl phenyl)-indoles
Operate according to embodiment 26 identical methods; different is with 1.18g2-(4-methylsulfonyl) benzoylamino-4 '-methyldiphenyl ketone replaces 1.14g 2-(4-methylsulfonyl) benzoylamino-benzophenone; steam except that the solid ethyl alcohol recrystallization behind the acetone; get faint yellow crystallization; be 2-(4-methylsulfonyl phenyl)-3-(4-aminomethyl phenyl)-indoles, yield 77.4%.
Fusing point 197-198 ℃;
1HNMR (300MHz, DMSO) δ: 2.35 (s, 3H, CH
3), 3.21 (s, 3H, SO
2CH
3), 7.01-7.88 (m, 12H, Ar-H), 11.64 (s, 1H, N-H); Ultimate analysis: C
22H
19NO
2S, calculated value %:C73.10, H5.02, N3.88; Measured value %:C72.86, H5.44, N3.75.The preparation of embodiment 33 2-(4-sulfamyl phenyl)-3-(4-aminomethyl phenyl)-indoles
Operate according to embodiment 27 identical methods; different is with 1.18g 2-(4-sulfamyl) benzoylamino-4 '-methyldiphenyl ketone replaces 1.14g 2-(4-methylsulfonyl) benzoylamino-benzophenone; without column chromatography; steam except that the solid acetone-water recrystallization behind the acetone; get faint yellow crystallization; be 2-(4-sulfamyl phenyl)-3-(4-aminomethyl phenyl)-indoles, yield 55.3%.
Fusing point 293-295 ℃;
1HNMR (300MHz, DMSO) δ: 2.34 (s, 3H, CH
3), 3.43 (s, 2H, SO
2NH
2), 7.01-7.77 (m, 12H, Ar-H), 11.59 (s, 1H, N-H); Ultimate analysis: C
22H
18N
2O
2S, calculated value %:C69.60, H5.01, N7.73; Measured value %:C69.39, H5.20, N7.48.The preparation of embodiment 34 2-(4-methylsulfonyl phenyl)-3-(3, the 4-3,5-dimethylphenyl)-indoles
Carry out according to embodiment 26 identical methods; different is with 1.22g 2-(4-methylsulfonyl) benzoylamino-3 '; 4 '-dimethyl benzophenone replacement 1.14g 2-(4-methylsulfonyl) benzoylamino-benzophenone; the solid that steaming removes behind the acetone gets needle crystal with acetone-ethyl alcohol recrystallization; be 2-(4-methylsulfonyl phenyl)-3-(3; the 4-3,5-dimethylphenyl)-and indoles, yield 67.0%.
Fusing point 206-207 ℃;
1HNMR (300MHz, DMSO) δ: 2.23 (s, 3H, CH
3), 2.26 (s, 3H, CH
3), 3.21 (s, 3H, SO
2CH
3), 6.99-7.88 (m, 12H, Ar-H), 11.62 (s, 1H, N-H); Ultimate analysis: C
23H
21NO
2S, calculated value %:C73.57, H5.64, N3.73; Measured value %:C73.30, H5.73, N3.59.The preparation of embodiment 35 2-(4-sulfamyl phenyl)-3-(3, the 4-3,5-dimethylphenyl)-indoles
Carry out according to embodiment 27 identical methods; different is with 1.20g 2-(4-sulfamyl) benzoylamino-3 '; 4 '-dimethyl benzophenone replacement 1.14g 2-(4-sulfamyl) benzoylamino-benzophenone; obtain pale yellow powder; be 2-(4-sulfamyl phenyl)-3-(3; the 4-3,5-dimethylphenyl)-and indoles, yield 49.6%.
Fusing point 251-253 ℃;
1HNMR (300MHz, DMSO) δ: 2.24 (s, 3H, CH
3), 2.26 (s, 3H, CH
3), 3.43 (s, 2H, SO
2NH
2), 7.00-7.78 (m, 12H, Ar-H), 11.64 (s, 1H, N-H); Ultimate analysis: C
22H
20N
2O
2S, calculated value %:C70.19, H5.35, N7.44; Measured value %:C70.17, H5.39.N7.38.The preparation of embodiment 36 2-(4-methylsulfonyl phenyl)-3-(4-p-methoxy-phenyl)-indoles
Operate according to embodiment 26 identical methods; different is with 1.23g 2-(4-methylsulfonyl) benzoylamino-4 '-the methoxyl group benzophenone replaces 1.14g 2-(4-methylsulfonyl) benzoylamino-benzophenone; obtain faint yellow chip solid; be 2-(4-methylsulfonyl phenyl)-3-(4-p-methoxy-phenyl)-indoles, yield 74.7%.
Fusing point 218.5-220.5 ℃;
1HNMR (300MHz, CDCl
3) δ: 3.08 (s, 3H, SO
2CH
3), 3.87 (s, 3H, OCH
3), 6.95-7.86 (m, 12H, Ar-H), 8.41 (s, 1H, N-H).The preparation of embodiment 37 2-(4-sulfamyl phenyl)-3-(4-p-methoxy-phenyl)-indoles
Operate according to embodiment 27 identical methods; different is with 1.23g 2-(4-sulfamyl) benzoylamino-4 '-the methoxyl group benzophenone replaces 1.14g 2-(4-sulfamyl) benzoylamino-benzophenone; obtain pale yellow powder; be 2-(4-sulfamyl phenyl)-3-(4-p-methoxy-phenyl)-indoles, yield 73.9%.
Fusing point 280-282 ℃;
1HNMR (300MHz, DMSO) δ: 3.28 (s, 2H, SO
2NH
2), 3.79 (s, 3H, OCH
3), 6.97-7.78 (m, 12H, Ar-H), 11.59 (s, 1H, N-H); Ultimate analysis: C
21H
18N
2O
3S, calculated value %:C66.65, H4.79, N7.40; Measured value %:C66.46, H5.05, N6.89.The 2 vitro inhibition activity tests of experimental example 1 cyclooxygenase
This experiment adopts method well known to those skilled in the art to carry out.After getting peritoneal macrophage and suitable dilution, be seeded on the 24 porocyte culture plates.5% carbonic acid gas is cultivated this cell down, and is made its adherent 2 hours for 37 degrees centigrade.With RPMI1640 flushing not adherent cell is removed, added random the choosing respectively, add stimulant LPS then in the solution of the certain density compound that obtains through embodiment 28,29 to attached cell.At 5% carbonic acid gas, 37 degrees centigrade stimulated 2 hours down, added the substrate arachidonic acid, and 37 degrees centigrade of temperature were incubated 20 minutes, collected supernatant, and with the content of radioimmunoassay mensuration supernatant terminal prostaglandin E2, it the results are shown in Table 1.The 2 vitro inhibition activity tests of experimental example 2 cyclooxygenase
Experiment adopts method well known to those skilled in the art to carry out.After the bovine aortic endothelial cells digestion of cultivating, through suitably being seeded on the 48 porocyte culture plates after the dilution.Changed liquid once, and made cytogamy in 2-3 days.The compound that adding obtains through embodiment 28,29, in 5% carbonic acid gas, 37 degrees centigrade of temperature were incubated 20 minutes, collected supernatant, measured supernatant terminal 6-ketone prostaglandin F with radioimmunoassay
1aContent, it the results are shown in Table 1.
Embodiment COX-2 IC50, mol/L COX-1,10
-6The M inhibiting rate
28 6.0×10
-10 36
29 9.1×10
-11 56
Know through above-mentioned test-results those skilled in the art, compound of the present invention has anti-inflammatory action to Mammals.And the present invention comprises in the application of people's anti-inflammatory drug having good prospect the preparation Mammals.
Claims (18)
1, as the benzazolyl compounds that contains the alkylsulfonyl diaryl of general formula I:
In the formula,
R
1Be selected from 4-methylsulfonyl, 4-sulfamyl, hydrogen, 4-halogen, 4-alkyl (C
1-C
3), 4-alkoxyl group (C
1-C
3), 4-acetamido, 3,4-dimethyl, 3,4-methylene radical dioxy base, 3,4-propylidene;
R
2Be selected from 4-methylsulfonyl, 4-sulfamyl, hydrogen, 4-halogen, 4-alkyl (C
1-C
3), 4-alkoxyl group (C
1-C
3), 4-acetamido, 3,4-dimethyl, 3,4-methylene radical dioxy base, 3,4-propylidene;
R
3Be selected from hydrogen.
Wherein: work as R
1During for methylsulfonyl or sulfamyl, R
2It is any one other group except that methylsulfonyl or sulfamyl; Work as R
2During for methylsulfonyl or sulfamyl, R
1It is any one other group except that methylsulfonyl or sulfamyl.
2, compound as claimed in claim 1 is characterized in that R in the described compound
1The halogen that is selected from is fluorine chlorine, bromine, and alkyl is a methyl, and alkoxyl group is a methoxyl group, R
2Be selected from methylsulfonyl, sulfamyl.
3,, it is characterized in that compound is 2-(4-methylsulfonyl phenyl)-3-phenyl-indole as claim 1 or 2 described compounds.
4,, it is characterized in that compound is 2-(4-sulfamyl phenyl)-3-phenyl-indole as claim 1 or 2 described compounds.
5,, it is characterized in that compound is 2-(4-methylsulfonyl phenyl)-3-(4-chloro-phenyl-)-indoles as claim 1 or 2 described compounds.
6,, it is characterized in that compound is 2-(4-sulfamyl phenyl)-3-(4-chloro-phenyl-)-indoles as claim 1 or 2 described compounds.
7,, it is characterized in that compound is 2-(4-methylsulfonyl phenyl)-3-(4-bromophenyl)-indoles as claim 1 or 2 described compounds.
8,, it is characterized in that compound is 2-(4-sulfamyl phenyl)-3-(4-bromophenyl)-indoles as claim 1 or 2 described compounds.
9,, it is characterized in that compound is 2-(4-methylsulfonyl phenyl)-3-(4-aminomethyl phenyl)-indoles as claim 1 or 2 described compounds.
10,, it is characterized in that compound is 2-(4-sulfamyl phenyl)-3-(4-aminomethyl phenyl)-indoles as claim 1 or 2 described compounds.
11,, it is characterized in that compound is 2-(4-methylsulfonyl phenyl)-3-(3, the 4-3,5-dimethylphenyl)-indoles as claim 1 or 2 described compounds.
12,, it is characterized in that compound is 2-(4-sulfamyl phenyl)-3-(3, the 4-3,5-dimethylphenyl)-indoles as claim 1 or 2 described compounds.
13,, it is characterized in that compound is 2-(4-methylsulfonyl phenyl)-3-(4-p-methoxy-phenyl)-indoles as claim 1 or 2 described compounds.
14,, it is characterized in that compound is 2-(4-sulfamyl phenyl)-3-(4-p-methoxy-phenyl)-indoles as claim 1 or 2 described compounds.
15, a kind of method for preparing the compound described in claim 1 or 2, its feature comprises the steps:
(A) toluene-obtains methyl thiobenzoxide through the methyl-sulfate alkylation;
(B) Tosyl chloride and ammoniacal liquor effect obtain para toluene sulfonamide;
(C) methyl thiobenzoxide (para toluene sulfonamide) is obtained first sulphur (ammonia sulphur) acyl group phenylformic acid under the oxidation of potassium permanganate;
(D) first sulphur (ammonia sulphur) acyl group phenylformic acid is refluxed in thionyl chloride obtain first sulphur (ammonia sulphur) acyl group Benzoyl chloride;
(E) anthranilic acid and Tosyl chloride are at K
2CO
3Perhaps Na
2CO
3React in the solution, obtain 2-(4-Methyl benzenesulfonyl amido)-phenylformic acid through acidifying;
(F) with 2-(4-Methyl benzenesulfonyl amido)-phenylformic acid and different substituted benzenes, be selected from CS
2, in benzene, toluene, o-Xylol, chlorobenzene, bromobenzene or the methyl-phenoxide solvent, at 50-150 ℃ Fu-Ke reaction takes place down, 60-120 ℃ of decomposition of heating in strong acid again is with being selected from NaOH, KOH, K
2CO
3, Na
2CO
3, NH
3H
2The alkali neutralization of O obtains the amino substituted diphenylamine ketone of 2-;
(G) the amino substituted diphenylamine ketone of 2-with first sulphur (or ammonia sulphur) acyl group Benzoyl chloride is reacted in the presence of triethylamine obtain 2-[4-first sulphur (or ammonia sulphur) acyl group] benzoylamino-substituted diphenylamine ketone;
(H) in the presence of zinc and titanium tetrachloride, 2-[4-first sulphur (or ammonia sulphur) acyl group] to be reduced condensation be 2-[4-first sulphur (or ammonia sulphur) acyl group phenyl to benzoylamino-substituted diphenylamine ketone]-3-substituted-phenyl-indoles.
16, use in the medicine of preparation inhibition cyclooxygenase 2 as claim 1 or 2 described compounds.
17, the application in the medicine of preparation treatment inflammation in mammals as claim 1 or 2 described compounds.
18, a kind of pharmaceutical composition that contains medicine effective dose as compound as claimed in claim 1 or 2 and pharmaceutically acceptable carrier.
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|---|---|---|---|
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7645881B2 (en) | 2004-07-22 | 2010-01-12 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| US7772271B2 (en) | 2004-07-14 | 2010-08-10 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| US7781478B2 (en) | 2004-07-14 | 2010-08-24 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| US7868037B2 (en) | 2004-07-14 | 2011-01-11 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| CN104447434A (en) * | 2014-12-04 | 2015-03-25 | 中国矿业大学 | Method for synthesis of p-carboxybenzene sulfonamide through catalytic oxidation |
| WO2017197870A1 (en) * | 2016-05-16 | 2017-11-23 | 中国矿业大学 | Method for oxidatively synthesizing p-carboxybenzene sulfonamide by means of oxygen |
| CN109678788A (en) * | 2019-01-19 | 2019-04-26 | 湘潭大学 | A kind of 1,2- diaryl indoles, derivative and its synthetic method |
| CN109824530A (en) * | 2019-04-04 | 2019-05-31 | 南京大学 | A method of adjacent amino aromatic ketone is synthesized by aromatic carboxylic acids |
-
2000
- 2000-07-11 CN CN 00120761 patent/CN1127482C/en not_active Expired - Fee Related
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7772271B2 (en) | 2004-07-14 | 2010-08-10 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| US7781478B2 (en) | 2004-07-14 | 2010-08-24 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| US7868037B2 (en) | 2004-07-14 | 2011-01-11 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| US7973069B2 (en) | 2004-07-14 | 2011-07-05 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| US7645881B2 (en) | 2004-07-22 | 2010-01-12 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| CN104447434A (en) * | 2014-12-04 | 2015-03-25 | 中国矿业大学 | Method for synthesis of p-carboxybenzene sulfonamide through catalytic oxidation |
| WO2017197870A1 (en) * | 2016-05-16 | 2017-11-23 | 中国矿业大学 | Method for oxidatively synthesizing p-carboxybenzene sulfonamide by means of oxygen |
| CN109678788A (en) * | 2019-01-19 | 2019-04-26 | 湘潭大学 | A kind of 1,2- diaryl indoles, derivative and its synthetic method |
| CN109678788B (en) * | 2019-01-19 | 2021-05-04 | 湘潭大学 | 1, 2-diaryl indole, derivative and synthetic method thereof |
| CN109824530A (en) * | 2019-04-04 | 2019-05-31 | 南京大学 | A method of adjacent amino aromatic ketone is synthesized by aromatic carboxylic acids |
| CN109824530B (en) * | 2019-04-04 | 2021-09-28 | 南京大学 | Method for synthesizing o-amino aromatic ketone from aromatic carboxylic acid |
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|---|---|
| CN1127482C (en) | 2003-11-12 |
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