CN105315180A - Novel sulfonylaniline compound and its preparation method and medical use - Google Patents
Novel sulfonylaniline compound and its preparation method and medical use Download PDFInfo
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- CN105315180A CN105315180A CN201410245432.9A CN201410245432A CN105315180A CN 105315180 A CN105315180 A CN 105315180A CN 201410245432 A CN201410245432 A CN 201410245432A CN 105315180 A CN105315180 A CN 105315180A
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Abstract
The invention discloses a novel sulfonylaniline compound and its preparation method and medical use. The novel compound and its pharmaceutical composition have strong effects of diminishing inflammation, easing pain and resisting tumors, have no obvious toxic or side effect, and provide a novel drug choice for clinical treatment on various inflammations, pain and tumors. The invention also provides the preparation method of the novel sulfonylaniline compound. The preparation method has simple processes and a low cost and easily realizes industrial large-scale production.
Description
Technical field
The present invention relates to class I non-steroid relieving inflammation and relaxing pain compound, be specifically related to new sulfonanilide compound, and the preparation method of this compounds, and using composition application in biomedicine field as anti-inflammation analgesis medicament and antitumor drug that this compounds or derivatives thereof or its salt are main component.
Technical background
NSAID (non-steroidal anti-inflammatory drug) (NonsteroidalAntiinflammatoryDrugs, NSAIDs) be the antiphlogiston of a class not containing steroidal structure, such medicine has anti-inflammatory, rheumatism, pain relieving, bring down a fever and the effect such as anticoagulation, is widely used in the alleviation of osteoarthritis, rheumatoid arthritis, multiple heating and various pain symptom clinically.NSAIDs chemical structure is different, but all by suppressing the activity blocks arachidonic acid of cyclooxygenase (Cyclo-oxygenase, COX) to be converted into prostaglandin(PG), prostacyclin and thromboxane A
2(TXA
2) and play pharmacological action.Discovered in recent years COX has two kinds of isomer C OX
1and COX
2.COX
1the prostaglandin(PG) that induction produces mainly plays physiology and defencive function, as maintain gastrointestinal tract mucosa integrity, regulate renal blood flow and platelet function; COX
2be then a kind of cytokine induction, it is only present in the tissue of damaged.Mainly express in scavenger cell, fibroblast, cartilage, endothelium and epidermic cell, COX
2the prostaglandin(PG) catalyzed and synthesized causes inflammatory, has very strong to cause inflammation, induced pain effect.COX thus
2suppression be crucial to the treatment of inflammation, pains and other diseases.
First kind NSAIDs medicine is non-selective COX inhibitor, at suppression COX
2while also inhibits COX
1, there is serious gastrointestinal side effect and liver renal toxicity thus.The NSAIDs medicine of Equations of The Second Kind is COX
2selective depressant, reduces because COX
1suppressed and the gi tract toxic side effect that produces, simultaneously effectively improves relieving inflammation and relaxing pain effect.Current COX
2selective depressant be the main flow direction of NSAIDs medicine, sulfonanilide compound nimesulide is exactly COX
2the representative medicine of Selective depression.Widely apply with Be very effective.But discovered in recent years nimesulide has certain hepatotoxicity.Therefore, researcher begins one's study new sulfonanilide compound, less to obtaining side effect, the anti-inflammation analgesis medicament that curative effect is higher.
Along with deeply carrying out of research, having report to point out is that the sulfonanilide compound of representative has certain antitumor action with nimesulide, for this compounds provides a new medicinal direction.
Summary of the invention
In order to solve problems of the prior art, the present invention is intended to searching one class sulfonanilide compound, while it has good anti-inflammatory, analgesia, antitumous effect, toxic side effect is lower, for the various inflammation of clinical treatment or pain or tumour provide a kind of new medication to select.
Containing benzene ring structure in marketed products nimesulide chemical structural formula, in its building-up process, need the synthesis material introducing sweat phenyl, improve the risk of toxic side effects, and clinical practice for many years demonstrates nimesulide has certain toxicity to liver kidney.
The applicant finds unexpectedly, and chemicals of the present invention not only have than the better anti-inflammatory of nimesulide, analgesic effect, but also have antitumor action, and without obvious toxic-side effects.
For achieving the above object, the present invention is to provide the compound or derivatives thereof or its salt with following general formula (I) structure by the following technical solutions:
Wherein R is C
1-C
8alkyl.
Above-mentioned C
1-C
8alkyl refer to the straight or branched alkyl with 1 ~ 8 carbon atom, such as methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group etc.
Preferably, R is C
1-C
4alkyl, more preferably, R is methyl, namely formula (I) compound is 4-nitro-2-(4 '-methoxyl group--cyclohexyl)-methanesulfonanilide, it has cis and trans two kinds of steric isomers, in a specific examples, sulfonanilide compound of the present invention can be independent 4-nitro-2-[(cis) 4 '-methoxycyclohexyl oxygen base] methanesulfonanilide (formula II compound), also can be 4-nitro-2-[(trans) 4 '-methoxycyclohexyl oxygen base] methanesulfonanilide (formula III compound), can also be the cis of 4-nitro-2-(4 '-methoxycyclohexyl oxygen base) methanesulfonanilide and trans mixture.
The present invention also provides a kind of preparation method of compound 4-nitro-2-(4 '-methoxycyclohexyl oxygen base) methanesulfonanilide, and its synthetic route refers to Fig. 1.
The present invention provides the preparation method of formula (II) and formula (III) compound respectively.
The method of preparation formula (II) described compound, it comprises the steps:
1) o-fluoronitrobenzene with to methoxycyclohexanol condensation in the basic conditions, obtain the mixture of the cis-trans-isomer of 2-(4-methoxycyclohexyl oxygen base) oil of mirbane;
2) mixture of the cis-trans-isomer of 2-(4-methoxycyclohexyl oxygen base) oil of mirbane obtains 2-[(cis)-4-methoxycyclohexyl oxygen base] oil of mirbane and 2-[(trans)-4-methoxycyclohexyl oxygen base] oil of mirbane after pillar layer separation;
3) 2-[(cis)-4-methoxycyclohexyl oxygen base] oil of mirbane is through reduction; Mesylation; nitration reaction, obtains 4-nitro-2-[(cis)-4 '-methoxyl group--cyclohexyl oxygen base] methanesulfonanilide (formula II).
Preferably, above-mentioned steps 1) described under alkaline condition condensation refer to and to carry out in the DMF solution of sodium hydride.
Preferably, above-mentioned steps 2) described in pillar layer separation refer to that silica gel column chromatography is separated, the eluent of employing be selected from sherwood oil, normal hexane, hexanaphthene, ethyl acetate one or more.
Preferably, above-mentioned steps 3) described in reduction be carry out pass into hydrogen atmosphere in palladium carbon ethanolic soln under; Described Mesylation refers to that in methylene dichloride and triethylamine solution, add p-dimethylamino-azo-benzene acyl chlorides carries out; Described nitration reaction refer in glacial acetic acid solution with nitric acid reaction.
In a specific examples, formula (II) compound prepares as follows:
1) o-fluoronitrobenzene with at DMF solution, alkali is added to methoxycyclohexanol, such as sodium hydride, carry out condensation reaction, obtain the mixture of the cis-trans-isomer of 2-(4-methoxycyclohexyl oxygen base) oil of mirbane;
2) mixture of the cis-trans-isomer of 2-(4-methoxycyclohexyl oxygen base) oil of mirbane is through pillar layer separation, such as silicagel column, be preferably 200-300 order silica gel column chromatography to be separated, eluent can be selected from sherwood oil, normal hexane, hexanaphthene, ethyl acetate one or more, in a specific examples, eluent is the mixed solution of sherwood oil and ethyl acetate, collect elutriant, obtain 2-[(cis)-4-methoxycyclohexyl oxygen base] oil of mirbane and 2-[(trans)-4-methoxycyclohexyl oxygen base] oil of mirbane;
3) 2-[(cis)-4-methoxycyclohexyl oxygen base] oil of mirbane makees catalyzer with 10% palladium carbon in autoclave; hydrogenating reduction nitro obtains aminocompound; aminocompound obtains target compound, 4-nitro-2-[(cis)-4 '-methoxyl group--cyclohexyl oxygen base] methanesulfonanilide (formula II) with concentrated nitric acid is nitrated in glacial acetic acid again in pyridine solution and after methylsulfonyl chloride reaction protection amino.
The method of preparation formula (III) described compound, it comprises the steps:
1) o-fluoronitrobenzene with to methoxycyclohexanol condensation in the basic conditions, obtain the mixture of the cis-trans-isomer of 2-(4-methoxycyclohexyl oxygen base) oil of mirbane;
2) mixture of the cis-trans-isomer of 2-(4-methoxycyclohexyl oxygen base) oil of mirbane obtains 2-[(cis)-4-methoxycyclohexyl oxygen base] oil of mirbane and 2-[(trans)-4-methoxycyclohexyl oxygen base] oil of mirbane after pillar layer separation;
3) 2-[(trans)-4-methoxycyclohexyl oxygen base] oil of mirbane is through reduction; Mesylation; nitration reaction, obtains 4-nitro-2-[(trans)-4 '-methoxyl group--cyclohexyl oxygen base] methanesulfonanilide (formula III).
Preferably, above-mentioned steps 1) described under alkaline condition condensation refer to and to carry out in the DMF solution of sodium hydride.
Preferably, above-mentioned steps 2) described in pillar layer separation refer to that silica gel column chromatography is separated, the eluent of employing be selected from sherwood oil, normal hexane, hexanaphthene, ethyl acetate one or more.
Preferably, above-mentioned steps 3) described in reduction be carry out pass into hydrogen atmosphere in palladium carbon ethanolic soln under; Described Mesylation refers to that in methylene dichloride and triethylamine solution, add p-dimethylamino-azo-benzene acyl chlorides carries out; Described nitration reaction refer in glacial acetic acid solution with nitric acid reaction.
In a specific examples, formula (III) compound prepares as follows:
1) o-fluoronitrobenzene be that alkali carries out condensation reaction with sodium hydride in DMF solution to methoxycyclohexanol, obtain the mixture of the cis-trans-isomer of 2-(4-methoxycyclohexyl oxygen base) oil of mirbane;
2) mixture of the cis-trans-isomer of 2-(4-methoxycyclohexyl oxygen base) oil of mirbane is separated through 200-300 order silica gel column chromatography, elutriant is the mixed solution of sherwood oil and ethyl acetate, collect elutriant, obtain 2-[(cis)-4-methoxycyclohexyl oxygen base] oil of mirbane and 2-[(trans)-4-methoxycyclohexyl oxygen base] oil of mirbane;
3) 2-[(trans)-4-methoxycyclohexyl oxygen base] oil of mirbane makees catalyzer with 10% palladium carbon in autoclave; hydrogenating reduction nitro obtains aminocompound; aminocompound obtains target compound, 4-nitro-2-[(trans)-4 '-methoxyl group--cyclohexyl oxygen base] methanesulfonanilide (formula III) with concentrated nitric acid is nitrated in glacial acetic acid again in pyridine solution and after methylsulfonyl chloride reaction protection amino
Compound 4-nitro-2-(4 '-methoxycyclohexyl oxygen base) methanesulfonanilide of the present invention can obtain by above-mentioned chemical reactive synthesis, wherein, the raw materials such as o-fluoronitrobenzene, 4-methoxycyclohexanol, ethanol, Methanesulfonyl chloride, palladium carbon and reagent can be buy from commercial channel to obtain, and do not impose any restrictions for its source or acquiring way the present invention.
Further, the product that above-mentioned chemical reaction obtains can also be further purified.The purification process that can be exemplified by the present invention; also can be by those skilled in the art's other conventional separation purification method thinkable; such as crystallization, column chromatography, high performance liquid chromatography etc. obtain, as long as can realize the object of the invention, all within scope.The present invention is to this chemical reaction product whether purifying or adopt which kind of means of purification not to be restricted.
The present invention also provides formula I or derivatives thereof or its salt preparing the application in anti-inflammatory analgesic or antitumor drug.Described formula I is preferably 4-nitro-2-(4 '-methoxycyclohexyl oxygen base) methanesulfonanilide, is more preferably 4-nitro-2-[(trans)-4 '-methoxycyclohexyl oxygen base] methanesulfonanilide.
The present invention also provides a kind of pharmaceutical composition, its with formula I or its salt or derivatives thereof for activeconstituents.Described formula I is preferably 4-nitro-2-(4 '-methoxycyclohexyl oxygen base) methanesulfonanilide, is more preferably 4-nitro-2-[(trans) 4 '-methoxycyclohexyl oxygen base] methanesulfonanilide.
The contained I of described pharmaceutical composition or its salt or derivatives thereof and pharmaceutically acceptable carrier, it can be used for prevention or treats various inflammation, pain, the diseases such as cancer.
Described pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, such as: thinner, vehicle are as water etc.; Weighting agent is as starch, sucrose etc.; Tackiness agent is as derivatived cellulose, gelatin etc.; Disintegrating agent is as agar, calcium carbonate etc.; Tensio-active agent is as cetyl alcohol etc.; Lubricant is as talcum powder, calcium stearate etc.; Perfume compound, sweeting agent etc. can be added in addition.Above-mentioned pharmaceutically acceptable carrier can be used alone, also can conbined usage.As long as persons of ordinary skill in the art may appreciate that and can realize object of the present invention, any pharmaceutically acceptable auxiliary material or vehicle all can be used for preparing pharmaceutical composition of the present invention.
Acceptable salt in the pharmacopedics that the salt of formula I of the present invention refers to formula I, according to substituent kind, sometimes formed acid salt or with salt formed by alkali.Specifically can exemplify: with the acid salt of the mineral acids such as hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid; Or, with organic acid acid salt such as formic acid, acetic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, amygdalic acid, tartrate, dibenzoyl tartaric acid, ditoluoyltartaric, citric acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, aspartic acid, L-glutamic acid; With salt formed by the mineral alkalis such as sodium, potassium, magnesium, calcium, aluminium; Or, with salt formed by the organic basess such as methylamine, ethamine, thanomin, Methionin, ornithine; With salt or ammonium salt etc. formed by each seed amino acids such as ethanoyl leucine and amino acid derivative.
According to the present invention, pharmaceutical composition of the present invention can be prepared by means known in the art, such as, combined with other medicines by formula (I) compound or mix with pharmaceutical carrier.
The beneficial effect that this aspect can obtain at least comprises:
1. provide the sulfonanilide compound that a class is new, it has anti-inflammatory, the analgesic effect stronger than marketed products nimesulide, and has antitumor action, for the various inflammation of clinical treatment or pain or tumour provide a kind of new medication to select;
2. the preparation method of formula I of the present invention is simple, and synthesis material is easy to get, and is easy to industrialization and produces;
3. compound of the present invention not only has higher curative effect, and toxicity test proves that it is without obvious toxicity simultaneously, illustrates that the more existing sulfonanilide medicine of its security improves a lot.
Accompanying drawing explanation
The synthetic route chart of Fig. 1: 4-nitro-2-(4 '-methoxycyclohexyl oxygen base) methanesulfonanilide.
The proton nmr spectra of Fig. 2: Compound C 344U.
The proton nmr spectra of Fig. 3: Compound C 344D.
The carbon-13 nmr spectra of Fig. 4: Compound C 344U.
The carbon-13 nmr spectra of Fig. 5: Compound C 344D.
Single-crystal x-the diffractogram of Fig. 6: Compound C 344U.
Single-crystal x-the diffractogram of Fig. 7: Compound C 344D.
Embodiment
For making the present invention easier to understand, describe the present invention in detail below in conjunction with embodiment, these embodiments only play illustrative effect, are not limited to range of application of the present invention, NM specific experiment method in the following example, conveniently experimental technique carries out usually.
Not specified part, " % " represents weight percent.
The chemical reagent used in the present invention or reaction raw materials are all conventional chemical raw material or reagent, can be obtained from commercially available channel by purchase.
General formula (I) compound can synthesize with the following example, purifying, crystallization, but following embodiment is only exemplary exemplifying, and not does any type of restriction to the present invention.
The preparation of embodiment 12-(4-methoxycyclohexyl oxygen base) oil of mirbane (compound 2)
Sodium hydride (80g, 2mol) by 60% is dissolved in 1000mlN, in dinethylformamide (DMF), under agitation drips 130g (1mol) 4-methoxycyclohexanol.Dropwise, stirring at room temperature 1hr, drip 2-fluoronitrobenzene 141g (1mol), dropwise to reaction solution, reaction solution stirs and spends the night.Pressure reducing and steaming solvent, residual oil liquid, with chloroform extraction twice after thin up, merges organic phase, washing organic phase, anhydrous sodium sulfate drying.Siccative is gone out in filtration, and concentrating under reduced pressure organic phase, obtains yellow oil 2-(4-methoxycyclohexyl oxygen base) oil of mirbane 243g, yield 97%.
The separation of suitable, the anti-2-of embodiment 2 (4-methoxycyclohexyl oxygen base) oil of mirbane
Sample is mixed by after the oily matter 50 grams of compound 2 and 50 grams of 200-300 object silica gel acetic acid ethyl dissolutions, room temperature is dried, with mixed solvent (n-hexane/ethyl acetate=100: 1 to 20: 1) to compound 2 carry out gradient column chromatography be separated, respectively the collection component containing different compound of normal hexane with ethyl acetate.Wherein, the compound that Rf value is large is trans-compound, the compound that Rf value is little is cis-compound, concentrating under reduced pressure is almost solvent-free, obtains the trans 2-of 15g (4-methoxycyclohexyl oxygen base) oil of mirbane (compound 3) and 17g cis 2-(4-methoxycyclohexyl oxygen base) oil of mirbane.(compound 4)
The preparation of the trans 2-of embodiment 3 (4-methoxycyclohexyl oxygen base) aniline (compound 5)
By previous step gained compound 3 (7g, 0.028mol) be dissolved in 100ml methyl alcohol, add the palladium carbon of 1g10%, middle pressure hydrogenation (4-5atm) reacts 10 hours, cross and filter siccative, concentrating under reduced pressure obtains the trans 2-of light yellow solid (4-methoxycyclohexyl oxygen base) aniline, 5.8g, yield 95%.
The preparation of embodiment 4 cis 2-(4-methoxycyclohexyl oxygen base) aniline (compound 6):
By previous step gained compound 4 (7g, 0.028mol) be dissolved in 100ml methyl alcohol, add the palladium carbon of 1g10%, middle pressure hydrogenation (4-5atm) reacts 10 hours, cross and filter siccative, concentrating under reduced pressure obtains light yellow solid cis 2-(4-methoxycyclohexyl oxygen base) aniline, 5.7g, yield 92%.
The preparation of embodiment 52-[(trans)-4-methoxycyclohexyl oxygen base] methanesulfonanilide (compound 7)
Be dissolved in by previous step gained compound 5 (5.8g, 0.026mol) in 20ml pyridine, drip Methanesulfonyl chloride 3.5g (0.031mol), dropwise in ice bath downhill reaction liquid, reaction solution continues at stirring at room temperature reaction 2hr.Reaction solution is poured in frozen water, and drips hydrochloric acid to pH=1 ~ 2, separate out white crystal.Filter, washing, vacuum-drying, obtains 2-[(trans)-4-methoxycyclohexyl oxygen base] methanesulfonanilide, 6.6g, yield 85%.
Embodiment 62-[(cis)-4-methoxycyclohexyl oxygen base] methanesulfonanilide (compound 8)
Be dissolved in 20ml pyridine by previous step gained compound 6 (5.0,0.023mol), drip Methanesulfonyl chloride 3.0g (0.028mol), dropwise in ice bath downhill reaction liquid, reaction solution continues at stirring at room temperature reaction 2hr.Reaction solution is poured in frozen water, and drips hydrochloric acid to pH=1 ~ 2, separate out white crystal.Filter, washing, vacuum-drying, 2-[(cis)-4-methoxycyclohexyl oxygen base] methanesulfonanilide, 5.9g yield 86%.
The preparation of embodiment 74-nitro-2-[(trans)-4 '-methoxycyclohexyl oxygen base] methanesulfonanilide (hereinafter referred to as C344U)
Compound 7 (8g, 0.027mol) is dissolved in 20ml acetic acid, at room temperature in reaction solution, drips nitric acid (60%, 3.4g, 0.032mol), dropwise, reaction solution reflux 1hr.Reaction solution is poured in frozen water, and dripping sodium hydroxide is 9 ~ 10 to pH, separates out yellow crystal.Filter, washing, vacuum-drying, obtain crude product 9g, crude product Virahol/hexanaphthene recrystallization, obtains crude product 8.4g, yield 90%.
C344U hydrogen nuclear magnetic resonance modal data is as follows: (Fig. 2 is shown in by collection of illustrative plates)
1H-NMRBrukerAVANCEIII400INCDCl3：87.97(dd，J＝2.4，8.8Hz，1H)，7.84(d，J＝2.4Hz，1H)，7.72(d，J＝8.8Hz，1H)，7.34(s，1H)，4.58(m，1H)，3.45(s，3H)，3.39(m，1H)，3.18(s，3H)，2.11-2.26(m，4H)，1.54-1.73(m，4H).
C344U carbon-13 nmr spectra data are as follows: (Fig. 4 is shown in by collection of illustrative plates)
13C-NMRBrukerAVANCEIII400INCD3COCD3：δ147.1，144.0，134.4，118.6，116.6，108.1，77.0，76.5，55.0，39.6，27.9，27.8.
C344U is the compound represented by formula III, belongs to transconfiguration (Fig. 6 is shown in by C344U single X-ray diffractometer collection of illustrative plates).
The preparation of embodiment 84-nitro-2-[(cis)-4 '-methoxycyclohexyl oxygen base] methanesulfonanilide [compound 10 (hereinafter referred to as C344D)]
Upper step gained compound 8 (5g, 0.017mol) is dissolved in 20ml acetic acid, at room temperature in reaction solution, drips nitric acid (60%, 3.0g, 0.028mol), dropwise, reaction solution reflux 1h.Reaction solution is poured in frozen water, and dripping sodium hydroxide to pH value is 9 ~ 10, separates out white crystals.Filter, washing, vacuum-drying, obtain crude product 4g, crude product Virahol/hexanaphthene recrystallization, obtains crude product 5.4g, yield 93%.
C344D hydrogen nuclear magnetic resonance modal data is as follows: (Fig. 3 is shown in by collection of illustrative plates)
1H-NMRBrukerAVANCEIII400INCDCl3：87.94(dd，J＝2.4，8.8Hz，1H)，7.83(d，J＝2.4Hz，1H)，7.71(d，J＝8.8Hz，1H)，7.32(s，1H)，4.57(m，1H)，3.47(m，1H)，3.41(s，3H)，3.15(s，3H)，1.93-2.04(m，6H)，1.69-1.77(m，2H).
C344D carbon-13 nmr spectra data are as follows: (Fig. 5 is shown in by collection of illustrative plates)
13C-NMRBrukerAVANCEIII400INCDCl3：δ145.7，143.8，133.5，117.3，116.9，107.9，76.4，74.6，55.7，40.2，27.3，26.6.
C344D is the compound represented by formula II, belongs to cis-structure.(Fig. 7 is shown in by the single X-ray diffractometer collection of illustrative plates of C344D)
The anti-inflammatory and analgesic effect of embodiment 9 Compound C 344U and Compound C 344D
Take nimesulide as positive control drug, the mouse acetic acid twisting analgesic effect of Compound C 344U and C344D and the drug effect effect of rat assist agent arthritis are evaluated, result display Compound C 344U and C344D anti-inflammatory and analgesic effect clear and definite, and effect is all obviously better than positive drug nimesulide, the results are shown in Table 1-2.
The analgesic activity of table 1. gavage Compound C 344U, C344D Dichlorodiphenyl Acetate writhing mouse
* P < 0.05, * * P < 0.01, * * * P < 0.001 is compared with model control group
Table 2 Compound C 344U, C344D are to the effect of rat assist agent arthritis novo lesions
* P < 0.05, * * P < 0.01, * * * P < 0.001 is compared with model control group
The antitumor action of embodiment 10 Compound C 344U, C344D.
Taking human cervical carcinoma Hela cell as subject cell, is the restraining effect of Experimental agents detection compound 9 and compound 10 pairs of tumor cell proliferations respectively with the compound 9 of 5 gradient concentrations and compound 10.
Experimental technique: the Hela cell in vegetative period of taking the logarithm, 96 well culture plates are inoculated in the cell density of 4 × 104/mL, every hole 100 μ L, often organize and 6 multiple holes are set, inhale after cultivating 24h and abandon original fluid, add the compound 9 containing different concns (0,25,50,100,200 μm of ol/L) and compound 10200 μ L respectively.Respectively at 24,48 and 72h, the MTT solution 20 μ L that mass concentration is 5g/L is added in every hole, after continuing to cultivate 4h, whole supernatant liquor is abandoned in careful suction, then in every hole, 150 μ L dimethyl sulfoxide (DMSO) (DMSO) are added, concussion 10min all dissolves to crystallization, and in microplate reader, absorbancy OD value is measured at 490nm wavelength place.Experiment repetition 3 times, with 0 concentration in contrast, calculates cell proliferation inhibition rate: inhibiting rate (%)=(1-OD experiment/OD contrasts) × 100% as follows.Data are in table 3.
Table 3: Compound C 344U, C344D are to the restraining effect of Hela cell proliferation
The propagation of result: Compound C 344U and Compound C 344D to Hela cell has obvious restraining effect, and m-dose-dependence when being.
The acute toxicity test in mice of embodiment 11 Compound C 344U, C344D
Maximum dosage method is adopted to carry out studies on acute toxicity to ICR mouse, with maximum administration volume (0.5ml/10gBW), maximum administration concentration (0.3g/ml) is after single oral gavage gives Compound C 344U and Compound C 344D (15000g/kgBW) respectively, within continuous 14 days, observe its general clinical symptom, outward appearance, crawler behavior, position attitude, breathing state, excretion, toxic reaction and death condition etc.And within the 14th day, each treated animal body weight is weighed after the 7th day and administration before administration, after administration, administration group and negative control group compare.Result shows: after the administration of tested material group mouse, within 14 day observation period, animal all survives; Mouse outward appearance, crawler behavior, position attitude, breathing state and excretion are showed no obvious abnormalities; Each group of Mouse Weight increases and negative control group mouse comparing difference unknown significance meaning.Do not find that internal organs have obvious pathological change through dissecting surviving animals.As can be seen here: ICR mouse stomach gives Compound C 344U and Compound C 344D maximal dose is showed no overt toxicity reaction.
Above-mentioned experiment shows, preferred compound C344U and C344D of the present invention has clear and definite anti-inflammatory, analgesia and antitumor action, and compared with marketed drug nimesulide, its anti-inflammatory pain-stopping effect is obviously better than the other side, more significantly, the compounds of this invention C344U, C344D is without obvious toxic-side effects.
The above is only the preferred embodiments of the present invention, not any pro forma restriction is done to the present invention, although the present invention discloses as above with preferred embodiment, but and be not used to limit the present invention, any those skilled in the art, not departing from the scope of technical solution of the present invention, make a little change when the technology contents of above-mentioned announcement can be utilized or be modified to the Equivalent embodiments of equivalent variations, in every case be the content not departing from technical solution of the present invention, according to any simple modification that technical spirit of the present invention is done above embodiment, equivalent variations and modification, all still belong in the scope of technical solution of the present invention.
Claims (11)
1. there is compound or derivatives thereof or its salt of following formula (I) structure:
Wherein R represents the alkyl of C1-C8.
2. compound or derivatives thereof or its salt as claimed in claim 1, it is characterized in that, R is methyl.
3. compound or derivatives thereof as claimed in claim 2 or its salt, it is characterized in that, described compound is cis or trans geometric structure, and its chemical structural formula is respectively:
4. prepare a method for described formula (II) compound, it comprises the steps:
1) o-fluoronitrobenzene with to methoxycyclohexanol condensation in the basic conditions, obtain the mixture of the cis-trans-isomer of 2-(4-methoxycyclohexyl oxygen base) oil of mirbane;
2) mixture of the cis-trans-isomer of 2-(4-methoxycyclohexyl oxygen base) oil of mirbane obtains 2-[(cis)-4-methoxycyclohexyl oxygen base] oil of mirbane and 2-[(trans)-4-methoxycyclohexyl oxygen base] oil of mirbane after pillar layer separation;
3) 2-[(cis)-4-methoxycyclohexyl oxygen base] oil of mirbane is through reduction; Mesylation; nitration reaction, obtains 4-nitro-2-[(cis)-4 '-methoxyl group--cyclohexyl oxygen base] methanesulfonanilide (formula II).
5. prepare a method for described formula (III) compound, it comprises the steps:
1) o-fluoronitrobenzene with to methoxycyclohexanol condensation in the basic conditions, obtain the mixture of the cis-trans-isomer of 2-(4-methoxycyclohexyl oxygen base) oil of mirbane;
2) mixture of the cis-trans-isomer of 2-(4-methoxycyclohexyl oxygen base) oil of mirbane obtains 2-[(cis)-4-methoxycyclohexyl oxygen base] oil of mirbane and 2-[(trans)-4-methoxycyclohexyl oxygen base] oil of mirbane after pillar layer separation;
3) 2-[(trans)-4-methoxycyclohexyl oxygen base] oil of mirbane is through reduction; Mesylation; nitration reaction, obtains 4-nitro-2-[(trans)-4 '-methoxyl group--cyclohexyl oxygen base] methanesulfonanilide (formula III).
6. the method as described in claim 4 or 5, wherein step 1) described under alkaline condition condensation refer to and to carry out in the DMF solution of sodium hydride.
7. the method as described in claim 4 or 5, wherein step 2) described in pillar layer separation refer to that silica gel column chromatography is separated, the eluent of employing be selected from sherwood oil, normal hexane, hexanaphthene, ethyl acetate one or more.
8. the method as described in claim 4 or 5, wherein step 3) described in reduction be carry out pass into hydrogen atmosphere in palladium carbon ethanolic soln under; Described Mesylation refers to that in methylene dichloride and triethylamine solution, add p-dimethylamino-azo-benzene acyl chlorides carries out; Described nitration reaction refer in glacial acetic acid solution with nitric acid reaction.
9. the application in anti-inflammatory, analgesia or antitumor drug prepared by compound or derivatives thereof according to any one of claims 1 to 3 or its salt.
10. a pharmaceutical composition, its with compound or its salt or derivatives thereof according to any one of claims 1 to 3 for sole active agent.
Pharmaceutical composition described in 11. claims 10 is preparing the application in anti-inflammatory, analgesia or antitumor drug.
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| US5374764A (en) * | 1991-08-08 | 1994-12-20 | Taisho Pharmaceutical Co., Ltd. | 5-aminosulfonanilide compounds |
| CN1247529A (en) * | 1996-12-18 | 2000-03-15 | 小野药品工业株式会社 | Sulfonamide and carboxamide derivatives and drugs containing same as active ingredient |
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| US4885367A (en) * | 1987-11-19 | 1989-12-05 | Taisho Pharmaceutical Co., Ltd. | Sulfonanilide compounds |
| US5374764A (en) * | 1991-08-08 | 1994-12-20 | Taisho Pharmaceutical Co., Ltd. | 5-aminosulfonanilide compounds |
| CN1247529A (en) * | 1996-12-18 | 2000-03-15 | 小野药品工业株式会社 | Sulfonamide and carboxamide derivatives and drugs containing same as active ingredient |
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