CN101899008B - N-substituted pyrimidine sulfonyl-substituted benzamide type small molecular inhibitor for Bcl-2 protein and application thereof - Google Patents
N-substituted pyrimidine sulfonyl-substituted benzamide type small molecular inhibitor for Bcl-2 protein and application thereof Download PDFInfo
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Abstract
The invention relates to an N-substituted pyrimidine sulfonyl-substituted benzamide type small molecular inhibitor for an antiapoptotic member of Bcl-2 protein family and an application thereof. The N-substituted pyrimidine sulfonyl-substituted benzamide type compounds related in the invention are represented in the formula 1 and have the action of inhibiting the antiapoptotic member of Bcl-2 protein family (such as Bcl-2, Bcl-xL, Mcl-1 and the like), and the detailed definition of each group is shown in the specifications. The compounds (and stereoisomers thereof if existing), medicinal salts thereof, hydrates thereof, solvates thereof and medicinal compositions thereof can be used for treating diseases or symptoms related to the high expression of the antiapoptotic member of Bcl-2 protein family, or can be used for treating tumors or can be used as an synergist or used together with other antitumor medicines for treating tumors. The invention also relates to compounds represented in the formula 1 and a preparation method of the medicinal salts.
Description
The present invention relates to the pyrimidine sulfonyl-substituted base of N--substituted benzene formyl aminated compounds, relate to its preparation method, relate to its as Bcl-2 protein family anti-apoptotic members (like Bcl-2, Bcl-x
L, Mcl-1 etc.) purposes of suppressor factor; Be used for treating purposes with Bcl-2 protein family anti-apoptotic members high expression level diseases associated or symptom; Be used for treating the purposes of tumour, and share the purposes in the treatment tumour as synergistic agent and other antitumor drug.
Discovering in recent years, natural death of cerebral cells and tumour are taken place and the resistance generation has substantial connection.And the Bcl-2 protein family plays important regulatory role at the apoptosis path.It can be divided into anti-apoptosis member (like Bcl-2, Bcl-x
L, Mcl-1 etc.) and two types of short apoptosis members.Research shows that anti-apoptosis member combines to interact with short apoptosis member's Bcl-2 protein family conservative region (BH) 3 through its surperficial hydrophobic groove, regulates the normal physiology apoptosis of cell.
Bcl-2 protein family anti-apoptotic members is found in over-expresses in many tumours, is that tumour produces and one of drug-fast major reason takes place.Through suppressing the anti-apoptotic effect of the anti-apoptotic members of over-expresses in the tumour cell, recover its normal apoptosis pathway and increase the New Policy that its susceptibility to chemotherapy radiotherapy is the treatment tumour.GEM 132 medicine (Genasense) to Bcl-2 has got into III phase clinical study at present, and its clinical data has confirmed the good selectivity of this therapeutic strategy and had the effect that improves the chemotherapy radiotherapy drug susceptibility.But because the GEM 132 medicine has vice proper, micromolecular inhibitor will be more suitable for clinical application.
Visible from the molecular mechanism that the Bcl-2 protein family plays a role, micromolecular inhibitor can disturb short apoptosis member BH3 zone to combine with it to play and promote apoptotic effect through being incorporated into anti-apoptosis member surface hydrophobicity groove.At present, antineoplastic Bcl-2 protein micromolecular inhibitor research becomes focus, has reported the micromolecular inhibitor of some different types of structure successively.Allied compound among the present invention as Bcl-2 protein family anti-apoptotic members suppressor factor, and does not appear in the newspapers in the application of anti-tumor aspect.
The object of the present invention is to provide and selectivity to suppress Bcl-2 protein family anti-apoptotic members (like Bcl-2, Bcl-x
L, Mcl-1 etc.), recover the normal apoptosis pathway of tumour cell and increase its compound the susceptibility of chemotherapy radiotherapy.
More specifically, first aspect present invention relates to N-substituted benzoyl-pyrimidine sulfonyl aminated compounds of formula I, its steric isomer, and its pharmaceutical salts, its hydrate or its solvolyte,
Wherein
R
1The position of substitution can be positioned at two or three-digit, is Wasserstoffatoms, hydroxyl, amino, halogen, C
1～C
5The straight or branched alkyl, C
1～C
5Alkyloyl, C
1～C
5Alkoxy grp, C
1～C
5Alkyl amide.
R
2Group is a Wasserstoffatoms, C
1～C
7The straight or branched alkyl does not replace or replaces five～hexa-atomic fragrant monocycle or condensed ring aryl radical (preferred naphthyl, indyl), C
3～C
6Cycloalkyl group, or XR
5Or NR (II),
5R
6(III).Wherein, X is O, S, carbonyl, sulfuryl or sulfoxide group; R
5, R
6Independently be Wasserstoffatoms separately, C
1～C
7The straight or branched alkyl does not replace or substituted aroma alkyl (preferred five～hexa-atomic fragrant monocycle, naphthyl, indyl) C
3～C
6Cycloalkyl group, or group shown in the formula IV:
(CH2)
nYR
7 (IV)
Wherein, n=1-7; Y is O, S, NH, carbonyl, sulfuryl or sulfoxide group; R
7Be Wasserstoffatoms, C
1～C
7The straight or branched alkyl does not replace or replaces five～hexa-atomic fragrant monocycle or condensed ring aryl radical (preferred naphthyl, indyl).
R
3Group is a Wasserstoffatoms, C
1～C
7The straight or branched alkyl does not replace or replaces five～hexa-atomic fragrant monocycle or condensed ring aryl radical (preferred naphthyl, indyl), heterocycle (preferred piperidines, piperazine, Pyrrolidine, morpholine), C
3～C
6Cycloalkyl group, or ZR
8Or NR (V),
8R
9(VI).Wherein, Z is O, S, carbonyl, sulfuryl or sulfoxide group; R
8, R
9Independently be Wasserstoffatoms separately, C
1～C
7The straight or branched alkyl does not replace or replaces five～hexa-atomic fragrant monocycle or condensed ring aryl radical (preferred naphthyl, indyl), C
3～C
6Cycloalkyl group, or group shown in the formula VII:
WR
10 (VII)
Wherein, W is a carbonyl, sulfuryl or sulfoxide group.
R
10Group is C
1～C
7The straight or branched alkyl, C
3～C
6Cycloalkyl group does not replace or replaces five～hexa-atomic fragrant monocycle or condensed ring aryl radical (preferred naphthyl, indyl), and wherein substituting group can be single replacement, also can be polysubstituted, is halogen, does not replace or halo C
1～C
5The straight or branched alkyl, C
1～C
5Alkoxy grp, nitro, trifluoromethyl, cyanic acid, sulfonic group, carboxyl, C
1～C
5Alkyloyl, C
1～C
5Alkyl amide, hydroxyl, amino.
R
10Group can also be CHR
11R
12(VIII), wherein, R
11, R
12Independently be hydrogen separately, C
1～C
7The straight or branched alkyl, sulfo-C
1～C
7The straight or branched alkyl does not replace or replaces five～hexa-atomic fragrant monocycle or condensed ring aryl radical, heterocycle, C
3～C
6Cycloalkyl group does not replace or substituted-amino (substituting group is preferably ethanoyl, methoxycarbonyl base, formyl radical, ethoxy ethanoyl, methyl, ethyl), or (CH
2)
nR
13(IX).Wherein, n=1-3, R
13Be not replace or replace five～hexa-atomic fragrant monocycle or condensed ring aryl radical, heterocycle, C
3～C
6Cycloalkyl group.
Second section of the present invention relates to pharmaceutical composition, comprises compound or its steric isomer of at least a formula I, its pharmaceutical salts, its hydrate or its solvolyte and pharmaceutical excipient or pharmaceutical carrier.
Third part of the present invention relates to the compound of arbitrary formula I, its steric isomer, its pharmaceutical salts, its hydrate, its solvolyte, and their pharmaceutical composition, as Bcl-2 protein family anti-apoptotic members (like Bcl-2, Bcl-x
L, Mcl-1 etc.) purposes of suppressor factor; Be used for treating purposes with Bcl-2 protein family anti-apoptotic members high expression level diseases associated or symptom; Be used for treating the purposes of tumour, and share the purposes in the treatment tumour as synergistic agent and other antitumor drug.
According to the present invention, R
1, R
2, R
3Preferred following especially group, but these preferred group and not meaning that to any restriction of the present invention.
According to the present invention, contain in the substituent group, but the substituting group halogen of not explaining does not replace or halo C
1～C
5The straight or branched alkyl, C
1～C
5Alkoxy grp, C
1～C
5Alkylthio group, nitro, trifluoromethyl, cyanic acid, sulfonic group, carboxyl, C
1～C
5Alkyloyl, C
1～C
5Alkyl amide, hydroxyl, amino etc.
According to the present invention, term " halogen " is meant fluorine, chlorine, bromine or iodine.
According to the present invention, R
1The position of substitution can be positioned at two or three-digit, is preferably Wasserstoffatoms, hydroxyl, amino.
R
2Group is preferably NR
5R
6(III).Wherein, R
5, R
6Independently be Wasserstoffatoms separately, C
1～C
7The straight or branched alkyl does not replace or replaces five～hexa-atomic fragrant monocycle, naphthyl, and indyl, or group shown in the formula IV:
(CH
2)
nYR
7(Ⅳ)
Wherein, n=1-7; Y is S; R
7Be Wasserstoffatoms, C
1～C
7The straight or branched alkyl does not replace or replaces five～hexa-atomic fragrant monocycle, naphthyl, indyl.
R
3Group is a Wasserstoffatoms, C
1～C
7The straight or branched alkyl does not replace or replaces five～hexa-atomic fragrant monocycle, naphthyl, indyl, piperidines, piperazine, Pyrrolidine, morpholine, or NR
8R
9(VI).Wherein, R
8, R
9Independently be Wasserstoffatoms separately, C
1～C
7The straight or branched alkyl does not replace or replaces five～hexa-atomic fragrant monocycle, naphthyl, and indyl, or group shown in the formula VII:
WR
10(Ⅶ)
Wherein, W is a carbonyl, sulfuryl.
R
10Group is C
1～C
7The straight or branched alkyl does not replace or replaces five～hexa-atomic fragrant monocycle, naphthyl, and indyl, wherein substituting group can be single replacement, also can be polysubstituted, is halogen, does not replace or halo C
1～C
5The straight or branched alkyl, C
1～C
5Alkoxy grp, nitro, trifluoromethyl, cyanic acid, sulfonic group, carboxyl, ethanoyl, acetamido, hydroxyl, amino.
R
10Group can also be CHR
11R
12(VIII), wherein, R
11, R
12Independently be hydrogen separately, C
1～C
7The straight or branched alkyl, sulfo-C
1～C
7The straight or branched alkyl does not replace or replaces five～hexa-atomic fragrant monocycle or condensed ring aryl radical, heterocycle, C
3～C
6Cycloalkyl group does not replace or substituted-amino (substituting group is an ethanoyl, methoxycarbonyl base, formyl radical, ethoxy ethanoyl, methyl, ethyl), or (CH
2)
nR
13(IX).Wherein, n=1-3, R
13Be not replace or replace five～hexa-atomic fragrant monocycle or condensed ring aryl radical, heterocycle, C
3～C
6Cycloalkyl group.
According to the present invention, the formula I compound in the preferred especially table 1,2,3, but these compounds and not meaning that to any restriction of the present invention.
Preferred especially compound structure in the table 1 formula I
Preferred especially compound structure (R in the table 2 formula I
3Be N R
8R
9, R
8Be H, R
9Be WR
10)
Preferred especially compound structure (R in the table 3 formula I
3Be N R
8R
9, R
8Be H, R
9Be WR
10, R
10Be CHR
11R
12)
The compound that has acidic-group according to the present invention in the I can form the basic metal pharmaceutical salts, like sodium salt, and sylvite, magnesium salts or calcium salt.
According to the present invention, term among the present invention " steric isomer " means the various stereoisomer forms that generalformula exists, like racemic isomer, optical isomer.
According to the present invention, the drug regimen among the present invention can prepare by means known in the art, as with the compound in the formula I, its steric isomer, its pharmaceutical salts or their hydrate or solvolyte and pharmaceutical carrier or mixed with excipients.
The present invention relates to provide to the compound in the formula I carry out with Bcl-2 albumen (with and homologous protein Bcl-xL, Mcl-1) carry out the result of protein binding active testing, the test result of anti-tumor activity, and the test result of synergism test.
According to the present invention, the compound among the present invention can be separately or the pharmaceutical combination administration, and route of administration can be oral, non-enteron aisle or topical.Pharmaceutical composition can be made into various suitable formulations according to route of administration.
Preparation, its steric isomer, its pharmaceutical salts, its hydrate, the method for its solvolyte, it comprises the compound of (1) formula X
Adding 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI) and 4-Dimethylamino pyridine (DMAP), normal temperature condition compound following and the formula XI reacts
R wherein
2, R
1, R
3As above define, or
(2) like needs, gained formula I compound and medicinal basic in (1) step are formed the pharmaceutical salts of formula I compound, or
(3) like needs, by stereochemistry separation method such as fractionation, recrystallization, chromatogram etc. split the pure optical isomer of accepted way of doing sth I compound with gained formula I compound in (1) or (2) step.
Bright according to we, the formula I compound can exist by stereoisomer form, has asymmetric center in the formula I compound part, can have S configuration or R configuration.We are bright to comprise all possible steric isomer such as enantiomorph or diastereomer, and the mixture of two or more steric isomers, the for example mixture of any required ratio of enantiomorph and/or diastereomer.Therefore, the present invention designs enantiomorph, left-handed-and the mixture or the racemoid of two kinds of enantiomorphs existing of dextrorotation-enantiomorph and different ratios that for example exists with enantiopure form.
According to the present invention, the formula I compound can disturb short apoptosis member BH3 zone to combine with it to play and promote apoptotic effect through being incorporated into anti-apoptosis member surface hydrophobicity groove.Therefore can be used as anti-tumor disease or the symptom medicine is used for animal, be preferred for Mammals, particularly the people.
Therefore the present invention also relates to and containing as at least a formula I compound of the effective dose of active ingredient and/or the pharmaceutical composition of its steric isomer and conventional medicine vehicle or assistant agent.Usually pharmaceutical composition of the present invention contains formula I compound and/or its physiologically acceptable salt of 0.1-90 weight %.Pharmaceutical composition can be according to the known method preparation of this area.When being used for this purpose, if desired, can formula I compound and/or steric isomer and one or more solids or liquid medicine vehicle and/or assistant agent be combined, process the suitable administration form or the dosage form that can be used as human.
Formula of the present invention (1) compound or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, like oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.Form of administration is tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, lipid agent, transdermal agent, buccal tablet, suppository, freeze-dried powder etc. for example.Can be ordinary preparation, sustained release preparation, controlled release preparation and various particle drug delivery system.For the unit form of administration is processed tablet; Various carrier well known in the art can be widely used; Example about carrier is; For example thinner and absorption agent are like starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, calcium chloride, glucose, urea, lime carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent are like water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, Vinylpyrrolidone polymer etc.; Disintegrating agent, for example dry starch, alginates, agar powder, laminaran, sodium hydrogencarbonate, methylcellulose gum, TKK 021 etc.; Disintegration suppressor factor, for example sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.Can also tablet further be processed coating tablet, for example sugar coated tablet, thin membrane coated tablet, long flourish coating tablet or double-layer tablet and multilayer tablet.For pill is processed in the administration unit, various carrier well known in the art can be widely used.Example about carrier is, for example thinner and absorption agent.Like glucose, lactose, starch, theobroma oil, Wecobee M, Vinylpyrrolidone polymer, Gelucire, kaolin, talcum powder etc.; Tackiness agent such as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent is like agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, TKK 021 etc.For suppository is processed in the administration unit, various carrier well known in the art can be widely used.Example about carrier is, for example the fat of polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols, gelatin, semi-synthetic glyceryl ester etc.For capsule is processed in the administration unit, effective constituent formula (1) compound or its steric isomer are mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard obviously capsule or soft capsule.Also can effective constituent formula (1) compound or its steric isomer be processed microcapsule; Be suspended in and form suspensoid in the aqueous medium,, can use this area all thinners commonly used like solution, emulsion, lyophilized injectable powder and suspensoid; For example; Water, ethanol, polyoxyethylene glycol, 1, ammediol, the isooctadecanol of ethoxylation, the isooctadecanol of polyoxyization, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, ooze injection liquid in order to prepare etc., can in injection preparation, add proper amount of sodium chloride, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, PH regulator etc.
In addition, like needs, also can in pharmaceutical prepn, add tinting material, sanitas, spices, correctives, sweeting agent or other materials.
The dosage of formula of the present invention (1) compound or its steric isomer depends on many factors; For example to prevent or treat the character and the severity of disease; The sex of patient or animal, age, body weight and individual reaction, used particular compound, route of administration and administration number of times etc.Above-mentioned dosage can the single dose form be divided into several, for example two, three or four dosage form administrations.
Embodiment
The present invention can be able to explanation through following embodiment, but these embodiment do not mean that the present invention is had any restriction.
The preparation of embodiment 1:2-bromo ethyl phenenyl sulfane
Phosphorus tribromide 7.2ml (0.076mol) is added drop-wise among the 2-thiophenyl ethanol 30ml (0.22mol), and reaction adds entry 50ml after finishing; Ether 100ml separates two phases, adds dried over mgso to organic phase; Filter, concentrate water white transparency oily thing 33g, yield: 98%.
The preparation of embodiment 2:2-(thiophenyl) ethamine
(2-bromotrifluoromethane) benzene sulfane 8.68g (0.040mol) and 4-nitro potassium phthalimide 9.11g (0.040mol) add among the dry DMF 70ml, 35 ℃ of reaction 1h.Add methylene dichloride 100ml, water 250ml separates two phases, and water extracts with methylene dichloride (80ml * 2).Merge organic phase, successively with 0.2mol/L aqueous sodium hydroxide solution 80ml and water 80ml washing.Anhydrous magnesium sulfate drying filters, filtrating concentrate yellow solid, add a small amount of ether and grind, place, separate out solid.Filter, filter cake is used re-crystallizing in ethyl acetate, gets yellow crystals 4-nitro-2-[2-(thiophenyl) ethyl] isoindoline-1, the 3-diketone.
(11.4g, 0.035mol) (6.3ml 0.108mol) adds among the methyl alcohol 200ml with 85% Hydrazine Hydrate 80 with the top yellow crystals that obtains.Be heated to 65 ℃ of reaction 1h.Filter, remove filter cake.In filtrating, add 6% hydrochloric acid (about 60ml) and transfer to pH=4, refrigerator leaves standstill, and separates out yellow solid.Filter, remove filter cake.Filtrating is concentrated into dried, faint yellow solid, add entry 250ml, ether (100ml * 2 time) washing.Water layer adds saturated aqueous sodium hydroxide solution (about 30ml) and transfers to pH＞12, extracts with ether (100ml * 3).Combined ether layer, filtrating concentrate 2-(thiophenyl) ethamine 4.65g, yield: 73.45%, 65～68 ℃ of mp.
Synthesizing of embodiment 3:2-aminopyrimidine-5-sulfonic acid
In chlorsulfonic acid 50mL, slowly add 2-aminopyrimidine 8.00g (0.0840mol) after, 150 ℃ of refluxed reaction 8 hours.Reaction boils off the part chlorsulfonic acid after finishing, and pours in the 50g frozen water after the residue cooling, separates out solid.Filter, the water recrystallization obtains white crystal 8.60g, yield 58.2%.
Synthesizing of embodiment 4:2-hydroxy pyrimidine-5-sulfonic acid
2-aminopyrimidine-5-sulfonic acid 8.60g (0.049mol), sulfuric acid 50mL and water 2mL place 250mL round bottom three-necked bottle, 180 ℃ of back flow reaction 5 hours.Pour in about 200g frozen water after the reaction solution cooling, separate out solid.Filter, the water recrystallization obtains white crystal 4.66g, yield 57.8%.
Synthesizing of embodiment 5:2-chloropyrimide-5-SULPHURYL CHLORIDE
2-hydroxy pyrimidine-5-sulfonic acid 2.64g (0.0150mol) and phosphorus pentachloride 10.9g (0.0525mol), 180 ℃ of back flow reaction 8 hours.Add 60mL toluene in the reaction solution, filter, evaporated under reduced pressure solvent, residual yellow solid place apparatus,Soxhlet's to extract 16 hours continuously with the 100mL sherwood oil.Extracting solution boils off half the, and solid is separated out in cooling, filters, and obtains white crystal 2.40g, yield 75.1%.
Synthesizing of embodiment 6:2-chloropyrimide-5-sulphonamide
After 2-chloropyrimide-5-SULPHURYL CHLORIDE 32.9g (0.150mol) dissolved with the 150mL anhydrous tetrahydro furan, ice bath fed the exsiccant ammonia down.Reacted 1.5 hours, TCL monitors to the raw material reaction stopped reaction immediately that finishes.Reaction finishes the back and transfers PH＜6, filters, and the evaporated under reduced pressure solvent adds the 150mL methylene dichloride in the resistates; Filter, the evaporated under reduced pressure solvent, resistates is through purification by silica gel column chromatography; Eluent is: methylene dichloride: ETHYLE ACETATE=50: 3 obtains white solid 16.1g, yield 54.0%
Synthesizing of embodiment 7:2-[2-(thiophenyl) ethamine] pyrimidine-5-sulphonamide
2-chloropyrimide-5-sulphonamide 5.80g (0.0300mol) and 2-(thiophenyl) ethamine 4.60g (0.03mol), N, N-diisopropylethylamine (DIEA); Carry out normal-temperature reaction 5h with methyl-sulphoxide as solvent; Reaction finishes the 1M hydrochloric acid soln that the back adds 80ml, and the adularescent solid is separated out, refrigeration.Filter, the solid water is given a baby a bath on the third day after its birth inferior, and re-crystallizing in ethyl acetate gets white crystal 7.7g.Yield 82.7%, mp:172～176 ℃.
Embodiment 8: the preparation of benzoylamino ethyl benzoate
Phenylformic acid 1.22g (0.01mol) and parathesin 1.65g (0.01mol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI) 2.3g (0.012mol), 4-Dimethylamino pyridine (DMAP) is a small amount of; With the methylene dichloride is solvent normal-temperature reaction 3h, after reaction finishes, adds the hydrochloric acid 100ml of 0.5M; Have solid to separate out, leach, methylene dichloride is washed with sodium hydrogencarbonate mutually again; Saturated sodium-chloride is washed, and anhydrous magnesium sulfate drying concentrates.Product after concentrating and the above-mentioned solid that leaches merge, and get bullion 2.5g, directly are used for next step reaction.
Other substituted benzoylamino ethyl benzoate is with the reaction of the substituted phenylformic acid of difference and parathesin, repeats to implement 8 step and makes.
Other 4-(2 replace-3 replace) ethyl benzoate reacts with parathesin with the hydrophobic amino acid of different N protections, repeats to implement 8 step and makes.
Embodiment 9: the benzoic preparation of benzoylamino
Embodiment 8 resulting benzoylamino ethyl benzoate 2.5g are dissolved in the 60ml THF: the solution of methyl alcohol=1: 1 after the dissolving, adds aqueous sodium hydroxide solution (1g sodium hydroxide is dissolved in 10ml water) fully; After reaction finishes,, add the hydrochloric acid soln 30ml of 1M with the organic solvent evaporate to dryness; The adularescent deposition is separated out, sedimentation and filtration, oven dry; Filtrating is extracted with ETHYLE ACETATE 50ml, and anhydrous magnesium sulfate drying concentrates.Product after concentrating and the above-mentioned solid that leaches merge the THF recrystallization.Obtain white crystal 2g.Yield 90%, mp:280～284 ℃.
Other substituted BM yl benzoic acid, repeats to implement 9 step and makes through macromolecule alkali for hydrolysis with the substituted benzoylamino ethyl benzoate of difference.
Other 4-(2 replace-3 replace) phenylformic acid, repeats to implement 9 step and makes through macromolecule alkali for hydrolysis with the substituted 4-of difference (2 replace-3 replaces) ethyl benzoate.
Other phenylformic acid, p-methylbenzoic acid, 4-fluorophenyl phenylformic acid obtains for buying.
Embodiment 10: the preparation of target compound
BM yl benzoic acid 0.14g (0.57mmol) and 2-[2-(thiophenyl) ethamine] pyrimidine-5-sulphonamide 0.17g (0.57mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI) 0.24g (1.14mmol), the 4-Dimethylamino pyridine is a small amount of; With the methylene dichloride is solvent normal-temperature reaction 3h, after reaction finishes, adds the hydrochloric acid 20ml of 0.5M; The adularescent deposition is separated out, sedimentation and filtration, oven dry; Filtrating is extracted with ETHYLE ACETATE 50ml, and anhydrous magnesium sulfate drying concentrates.Product after concentrating and the above-mentioned solid that leaches merge, and cross gel column.(developping agent is: methylene dichloride: methyl alcohol=1: 4) yield 88%, mp:246～247.
2-[2-(thiophenyl) ethamine] pyrimidine-5-sulfuryl amine reaction that compound that other target compound is obtained by embodiment 9 and embodiment 7 obtain, the step that repeats embodiment 10 makes.
The present invention's fusing point, productive rate and spectroscopic data of synthetic part preferred compound sees table 4.
Fusing point, productive rate and the spectroscopic data of table 4 part preferred compound
| No. | Fusing point | Yield | MS(m/z) (M-H)- | 1H-NMR(DMSO)/δ |
| 1 | 183-185 | 8.1％ | 413.4 | 3.14-3.16(t，2H，S-CH 2)，3.53-3.57(t，2H，N-CH 2)， 7.16-7.38(m，5H，S-Ar-H)，7.46-7.88(m，5H，COAr-H)， 8.46(s，1H，NH)，8.70-8.74(d，2H，pyrimidine)，12.50(s， 1H，SO 2NHCO) |
| 2 | 196-200 | 8.0％ | 427.74 | 2.34(s，3H，Ar-CH 3)，3.12-3.17(t，2H，S-CH 2)， 3.52-3.56(t，2H，N-CH 2)，7.13-7.35(m，5H，S-Ar-H)， 7.37-7.88(m，4H，COAr-H)，8.55(s，1H，NH)，8.70-8.75(d， 2H，pyrimidine)，12.47(s，1H，SO 2NHCO) |
| 3 | 222-224 | 8.0％ | 507.5 | 3.15-3.10(t，2H，S-CH 2)，3.53-3.48(t，2H，N-CH 2)， 7.14-7.17(t，1H，S-Ar-H)，7.25-7.36(d，2H，F-Ar-H?and?4H， dd，S-Ar-H)，7.74-7.78(dd，4H，H-Ar-Ar-H)，7.92-7.95(d，2 H，COAr-H)，8.55(s，1H，NH)，8.69-8.75(d，2H， pyrimidine)，12.58(s，1H，SO 2NHCO) |
| 4 | 246-247 | 7.3％ | 532.91 | 3.14-3.19(t，2H，J＝6.3Hz，S-CH 2)，3.52-3.57(t，2H，J＝6.3Hz， N-CH 2)，7.18-7.94(m，14H，Ar-H)，8.54(s，1H，NH)，8.69-8.75 (d，2H，pyrimidine)，10.54(s，1H，ArNHCO)，12.45(s，1H， SO 2NHCO) |
| 5 | 248-250 | 6.6％ | 550.58 | 3.15-3.18(t，2H，S-CH 2)，3.53-3.56(t，2H，N-CH 2)， 7.18-7.91(m，13H，Ar-H)，8.71(s，1H，NH)，8.72-8.76(d，2H， pyrimidine)，10.74(s，1H，ArNHCO)，12.42(s，1H， SO 2NHCO) |
| 6 | 242-244 | 6.5％ | 550.95 | 3.14-3.17(t，2H，S-CH 2)，3.54-3.56(t，2H，N-CH 2)， 7.18-7.92(m，13H，Ar-H)，8.71(s，1H，NH)，8.72-8.76(d，2H， pyrimidine)，10.57(s，1H，ArNHCO)，12.42(s，1H， SO 2NHCO) |
| 7 | 251-252 | 6.4％ | 550.49 | 3.15-3.17(t，2H，S-CH 2)，3.54-3.57(t，2H，N-CH 2)， 7.18-7.92(m，13H，Ar-H)，8.71(s，1H，NH)，8.72-8.76(d，2H， pyrimidine)，10.54(s，1H，ArNHCO)，12.40(s，1H， SO 2NHCO) |
| 8 | 178-182 | 6.5％ | 566.33 | 3.12-3.17(t，2H，S-CH 2)，3.50-3.57(t，2H，N-CH 2)， 7.14-7.91(m，13H，Ar-H)，8.70(s，1H，NH)，8.75-8.76(d，2H， pyrimidine)，10.84(s，1H，ArNHCO)，12.45(s，1H， SO 2NHCO) |
| 9 | 228-231 | 6.5％ | 566.32 | 3.11-3.17(t，2H，S-CH 2)，3.48-3.52(t，2H，N-CH 2)， 7.16-7.99(m，13H，Ar-H)，8.20(s，1H，NH)，8.66-8.69(d，2H， pyrimidine)，10.53(s，1H，ArNHCO)，12.48(s，1H， SO 2NHCO) |
| 10 | 268-271 | 6.4％ | 566.37 | 3.12-3.17(t，2H，S-CH 2)，3.52-3.54(t，2H，N-CH 2)， 7.14-7.99(m，13H，Ar-H)，8.71(s，1H，NH)，8.70-8.76(d，2H， pyrimidine)，10.53(s，1H，ArNHCO)，12.45(s，1H， SO 2NHCO) |
| 11 | 192-196 | 5.5％ | 546.90 | 2.36-2.37(s，3H，CH 3)，3.15-3.16(t，2H，S-CH 2)， 3.53-3.57(t，2H，N-CH 2)，7.18-7.90(m，13H，Ar-H)，8.61(s， 1H，NH)，8.72-8.76(d，2H，pyrimidine)，10.61(s，1H， ArNHCO)，12.41(s，1H，SO 2NHCO) |
| 12 | 235-244 | 5.5％ | 546.62 | 2.40(s，3H，CH 3)，3.15-3.18(t，2H，S-CH 2)，3.55-3.57(t，2H， N-CH 2)，7.16-7.90(m，13H，Ar-H)，8.72(s，1H，NH)，8.72-8.78 (d，2H，pyrimidine)，10.50(s，1H，ArNHCO)，12.40(s，1H， SO 2NHCO) |
| 13 | 257-260 | 5.4％ | 546.77 | 2.39(s，3H，CH 3)，3.15-3.18(t，2H，S-CH 2)，3.55-3.58(t，2H， N-CH 2)，7.16-7.90(m，13H，Ar-H)，8.72(s，1H，NH)， 8.72-8.77(d，2H，pyrimidine)，10.45(s，1H，ArNHCO)， 12.39(s，1H，SO 2NHCO) |
| 14 | 218-220 | 7.3％ | 600.28 | 3.12-3.17(t，2H，J＝6.3Hz，S-CH 2)，3.50-3.57(t，2H， J＝6.3Hz，N-CH 2)，7.18-7.94(m，13H，Ar-H)，8.48(s， 1H，NH)，8.70-8.74(d，2H，pyrimidine)，10.72(s，1H， ArNHCO)，12.45(s，1H，SO 2NHCO) |
| 15 | 180-182 | 6.1％ | 622.44 | 3.16-3.18(t，2H，J＝6.5Hz，S-CH 2)，3.54-3.56(t，2H， J＝6.5Hz，N-CH 2)，3.58-3.88(m，9H，OCH 3)，6.93-7.90(m，11H， Ar-H)，8.56(s，1H，NH)，8.71-8.77(d，2H，pyrimidine)， 10.41(s，1H，ArNHCO)，12.40(s，1H，SO 2NHCO) |
| 16 | 250-252 | 6.1％ | 623.24 | 3.15-3.18(t，2H，J＝6.5Hz，S-CH 2)，3.51-3.55(t，2H，J＝6.5Hz， N-CH 2)，3.73-3.89(m，9H，OCH 3)，6.97-7.89(m，11H， Ar-H)，8.20(s，1H，NH)，8.67-8.71(d，2H，pyrimidine)， 10.31(s，1H，ArNHCO)，12.45(s，1H，SO 2NHCO) |
| 17 | 292-296 | 6.8％ | 578.1 | 3.12-3.17(t，2H，J＝6.3Hz，S-CH 2)，3.50-3.56(t，2H， J＝6.3Hz，N-CH 2)，7.18-7.94(m，13H，Ar-H)，8.48(s， 1H，NH)，8.70-8.74(d，2H，pyrimidine)，10.72(s，1H， ArNHCO)，12.49(s，1H，SO 2NHCO) |
| 18 | 240-244 | 5.2％ | 617.2 | 2.84-3.01(dd，2H，CH 2Ar)，3.13-3.16(m，2H，S-CH 2)， 3.57-3.54(m，2H，N-CH2)，4.61-4.65(m，1H，COC-H-N)， 7.16-7.38(m，10H，Ar-H)，7.85(dd，4H，COAr-H-N)，7.65- 1.75(s，1H，NHCOCH 3)，8.34(d，1H，NHCO)，8.50(s，1H， NH)，8.69-8.74(d，2H，rimidine)，10.4(s，1H，ArNHCO)， 12.37(s，1H，SO 2NHCO) |
| 19 | 100-118 | 4.7％ | 583.9 | 0.84-0.90(m，6H，C(CH 3) 2)，1.46-1.49(m，2H，CCH 2C)， 1.56-1.64(m，1H，CCH(C)2)，1.83(s，1H，NHCOCH 3)，3.12- 3.17(2H，t，ArSCH 2)，3.50-3.57(m，2H，N-CH 2)，4.40(s，1H， COC-H-N)，4.41-4.42(m，1H，COC-H-N)，7.14-7.39(m， 5H，Ar-H)，7.68-7.86(dd，4H，COAr-H-N)，8.19(d，1H， NHCO)，8.54(s，1H，NH)，8.68-8.74(d，2H，pyrimidine)， 10.4(s，1H，ArNHCO)，12.42(s，1H，SO 2NHCO) |
| 20 | 110-116 | 4.6％ | 601.5 | 1.86(s，1H，NHCOCH 3)，1.89-1.98(m，2H，SCH 2)，2.04 (s，3H，SCH 3)，2.45-2.50m，2H，SCH2CH 2)，3.16-3.14 (t，2H，ArSCH 2)，3.57-3.54(m，2H，N-CH 2)，4.40(m，1H， COC-H-N)，7.15-7.35(m，5H，S-Ar-H)，7.65-7.85(dd，4H， COAr-H-N)，8.25(d，1H，NHCO)，8.50(s，1H，NH)，8.68-8.71 (d，2H，pyrimidine)，10.34(s，1H，ArNHCO)，12.39 (s，1H，SO 2NHCO) |
Embodiment 11: The compounds of this invention is for Bcl-2, Bcl-xL, three kinds of proteic avidity of Mcl-1
(sequence: EDIIRNIARHLAQVGDSMDR), the N-end is used marked by fluorescein isothiocyanate with Bid BH3 zone peptide.The Bcl-xL of 200nM; The BH3 peptide of the marked by fluorescein isothiocyanate of the 200nM of Bcl-2 or Mcl-1 albumen and equivalent; And the PBS of different concns (pH7.4); After compound of the present invention is at room temperature cultivated 10 minutes together, be under 485nm and the absorbing wavelength 520nm in excitation wavelength respectively, the record fluorescence polarization.All tests all repeat 3 times.IC
50Obtain through dose effect curve.Compound 3 suppresses the proteic IC of Bcl-2
50: 41.4 μ M.Compound 18 is respectively Bcl-2, Bcl-xL, three kinds of proteic inhibiting rates of Mcl-1 when 100 μ M: 32%, 50%, 34%.
Embodiment 12: The compounds of this invention is for the in-vitro multiplication restraining effect of human body tumour cell
This compound with after the DMSO dissolving, is added PBS (-) and is made into the solution of 1000ug/mL or suspension uniformly, and then be diluted to 5 concentration gradients with the PBS (-) that contains DMSO.With gossypol (Gossypol) as the contrast.Select five kinds of tumour cell: NCI-H446 (people's non-small cell lung cancer cell); HCT116 (human colon cancer cell); PC-3M (Human Prostate Cancer Cells, MDA-MB-435 (human breast cancer cell), Raji (human lymphoma cell) by Shanghai Institute of Pharmaceutical Industry's Pharmacology Lab frozen with go down to posterity.In the nutrient solution of RPMI1640+15%NBS+ two anti-(penicillium mould 100 units/mL, Streptomycin sulphate 100ug/mL), cultivate.It is the cell suspension 100 μ l of 4～5 * 104/ml that the every hole of 96 orifice plates adds concentration, puts 37 ℃, 5%CO
2In the incubator.Behind the 24h, add sample liquid, two multiple holes are established in l0 μ l/ hole, and 37 ℃, 5%CO2 effect 72h.Every hole adds the MTT solution 20 μ l of 5mg/ml, adds lysate behind the effect 4h, and put in the incubator in 100 μ l/ holes, and 570nm OD value is surveyed with the full-automatic ELIASA of MK-2 in the dissolving back, through relatively estimating its cell inhibitory effect situation with blank, calculates IC
50The in-vitro multiplication restraining effect that is The compounds of this invention and positive control gossypol acetic acid (GA) for five kinds of human body tumour cells as shown in table 5.
Embodiment 13: The compounds of this invention has the synergy synergism for the cell levels of cell toxicant antitumor drug
Compound concentration is 10 μ g/ml, 1 μ g/ml, and 0.1 μ g/ml, 0.01 μ g/ml, 0.001 μ g/ml, 0.0001 μ g/ml, the paclitaxel solution of 0.00001 μ g/ml as reference substance solution, is measured the IC of this moment
50Value in the paclitaxel solution solution of each concentration, adds 100 μ g/ml respectively then, and the compound 18 of 50 μ g/ml is measured IC
50Value.(Q=ICa+b/ ((ICa+ICb)-ICa*ICb)) calculates Q value, and for merging, for working in coordination with, explaining for the cell toxicant antitumor drug has synergism when Q＞1.15 when Q＞0.85 through golden formula formula.When the concentration of paclitaxel solution is 0.01 μ g/ml; The Q value that the compound 18 of 100 μ g/ml share with it is 1.277; The Q value that the compound 18 of 50 μ g/ml share with it is 1.264, in addition, and when the concentration of paclitaxel solution is 0.001 μ g/ml; The Q value that the compound 18 of 100 μ g/ml share with it is 1.275, explains that have synergism for the cell toxicant antitumor drug this moment.
Claims (7)
1. the pyrimidine sulfonyl-substituted base of the N-of formula I-substituted benzene formyl aminated compounds, its steric isomer, its pharmaceutical salts,
Wherein
R
1Group is a Wasserstoffatoms,
R
2Group is NR
5R
6(III), wherein, R
5, R
6Independently be group shown in Wasserstoffatoms or the formula IV separately:
(CH2)
nYR
7(IV)
Wherein, n=1-7; Y is S, R
7Be Wasserstoffatoms, C
1～C
7The straight or branched alkyl does not replace five～hexa-atomic fragrant monocycle,
R
3Group is a Wasserstoffatoms, C
1～C
7The straight or branched alkyl does not replace or replaces five～hexa-atomic fragrant monocycle, or NR
8R
9(VI), R wherein
8, R
9Independently be Wasserstoffatoms separately, or group shown in the formula VII:
WR
10(VII)
Wherein, W is a carbonyl;
R
10Group is not replace or replace five～hexa-atomic fragrant monocycle, and wherein substituting group can be single replacement, also can be polysubstituted, is halogen, does not replace or halo C
1～C
5The straight or branched alkyl, C
1～C
5Alkoxy grp, nitro;
R
10Group can also be CHR
11R
12(VIII), wherein, R
11, R
12Independently be C separately
1～C
7The straight or branched alkyl, sulfo-C
1～C
7The straight or branched alkyl, by the substituted amino of ethanoyl, or (CH
2)
nR
13(IX); N=1-3 wherein, R
13Be not replace five～hexa-atomic fragrant monocycle,
In containing substituent group, substituting group is a halogen, does not replace or halo C
1～C
5The straight or branched alkyl, C
1～C
5Alkoxy grp, nitro.
2. the compound of claim 1, wherein said formula I compound is selected from following compound:
(1) N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(2) 4-methyl-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(3) 4-is to fluorophenyl-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(4) 4-(phenyl formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(5) 4-(2-fluorophenyl formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(6) 4-(3-fluorophenyl formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(7) 4-(4-fluorophenyl formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(8) 4-(2-chloro-phenyl-formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(9) 4-(3-chloro-phenyl-formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(10) 4-(4-chloro-phenyl-formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(11) 4-(2-aminomethyl phenyl formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(12) 4-(3-aminomethyl phenyl formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(13) 4-(4-aminomethyl phenyl formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(14) 4-(4-trifluoromethyl formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(15) 4-(2,3,4-trimethoxyphenyl formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(16) 4-(3,4,5-trimethoxyphenyl formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(17) 4-(4-nitrophenyl formamido group)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(18) 4-(2-acetylaminohydroxyphenylarsonic acid 3-phenyl third amino)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(19) 4-(2-acetylaminohydroxyphenylarsonic acid 4-methylpent is amino)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide
(20) 4-(2-acetylaminohydroxyphenylarsonic acid 4-(first sulfydryl) fourth is amino)-N-(2-(2-(benzene sulfydryl) ethylamino) pyrimidine-5-alkylsulfonyl) benzamide.
3. pharmaceutical composition, it comprises formula I compound and the pharmaceutical carrier that at least a claim 1～2 is arbitrary.
4. the arbitrary formula I compound of claim 1～2 is used for treating the purposes with the medicine of Bcl-2 protein family anti-apoptotic members high expression level diseases associated or symptom in preparation.
5. the arbitrary formula I compound of claim 1～2 is used for the purposes of medicine for treating tumor thing in preparation.
6. the purposes of the arbitrary formula I compound of claim 1～2 in the preparation synergistic agent, said synergistic agent and other antitumor drug share to treat tumour.
7. prepare the said formula I compound of claim 1, the method for its steric isomer and pharmaceutical salts thereof, it comprises
(1) compound of formula X
Adding 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI) and 4-Dimethylamino pyridine (DMAP), normal temperature condition compound following and formula XI reacts
R wherein
2, R
1, R
3Like definition in the claim 1, or
(2) like needs, gained formula I compound and medicinal basic in (1) step are formed the pharmaceutical salts of formula I compound, or
(3) like needs, with gained formula I compound in (1) or (2) step by being selected from the pure optical isomer that fractionation, recrystallization or stratographic stereochemistry separation method split accepted way of doing sth I compound.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1219840A (en) * | 1996-05-29 | 1999-06-16 | 赫彻斯特-舍林农业发展有限公司 | Novel N-acyl sulphonamides, novel mixtures of herbicides and antidotes and their use |
| CN1272106A (en) * | 1997-09-29 | 2000-11-01 | 阿温提斯作物科学有限公司 | Acylsulfamoyl benzoic acid amides, plant protection agents containing same, and method for producing same |
| CN1575286A (en) * | 2001-10-25 | 2005-02-02 | 伊莱利利公司 | Thiophene-amd thiazolesulfonamides as antineoplastic agents |
| EP2015070A1 (en) * | 2006-04-20 | 2009-01-14 | Eisai R&D Management Co., Ltd. | Novel marker for sensitivity against sulfonamide compound |
-
2010
- 2010-05-20 CN CN201010180165A patent/CN101899008B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1219840A (en) * | 1996-05-29 | 1999-06-16 | 赫彻斯特-舍林农业发展有限公司 | Novel N-acyl sulphonamides, novel mixtures of herbicides and antidotes and their use |
| CN1272106A (en) * | 1997-09-29 | 2000-11-01 | 阿温提斯作物科学有限公司 | Acylsulfamoyl benzoic acid amides, plant protection agents containing same, and method for producing same |
| CN1575286A (en) * | 2001-10-25 | 2005-02-02 | 伊莱利利公司 | Thiophene-amd thiazolesulfonamides as antineoplastic agents |
| EP2015070A1 (en) * | 2006-04-20 | 2009-01-14 | Eisai R&D Management Co., Ltd. | Novel marker for sensitivity against sulfonamide compound |
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Inventor after: Zheng Canhui Inventor after: Zhou Feng Inventor after: Wang Mingping Inventor after: Liu Tiantian Inventor after: Hu Jinlian Inventor after: Zhou Youjun Inventor after: Yang Hui Inventor after: Zhu Ju Inventor after: Lv Jiaguo Inventor after: Shu Chang Inventor after: Tang Hui Inventor after: Fu Bingyue Inventor after: Liu Jia Inventor before: Zheng Canhui Inventor before: Zhou Feng Inventor before: Zhou Youjun Inventor before: Yang Hui Inventor before: Zhu Ju Inventor before: Lv Jiaguo Inventor before: Shu Chang Inventor before: Tang Hui Inventor before: Fu Bingyue Inventor before: Liu Jia |
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