CN101851199A - Substituted piperazine N-ethyl sulfonamide derivative and preparation and application thereof - Google Patents
Substituted piperazine N-ethyl sulfonamide derivative and preparation and application thereof Download PDFInfo
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Abstract
The invention provides a substituted piperazine N-ethyl sulfonamide derivative and medicinal salt thereof. The acyl chloride derivative thereof is obtained by chlorination of substituted sulfoacid by thionyl chloride; substituted L-type amino acid is reduced by lithium aluminium hydride reduction to obtain L-type alkamines compound; the L-type alkamines compound and the substituted sulfoacid derivative are carried out with coupling reaction and protected by mesyl chloride to obtain methanesulfonate derivative; mono-Boc protection piperazine is performed with substitution reaction and trifluoroacetic acid deprotection to obtain monosubstitution piperazine; and the monosubstitution piperazine is carried out with substitution reaction under the catalysis of organic amine to obtain the substituted piperazine N-Ethyl sulfonamide derivative. The virus activity test to five tumour cells in vitro by the compound provided by the invention shows that the in vitro virus activity test of the derivative shows the activity of parts of compound is higher than or comparative to positive control antitumor drug. The invention can be applied in preparing drug for preventing and curing tumour. The general formula of the compound of the invention is shown in the specification.
Description
Invention field
The invention belongs to pharmaceutical chemistry and area of pharmacology, relate to substituted piperazine N-ethyl sulfonamide derivative and preparation, and the purposes of this compounds in the preparation antitumor drug.
Background of invention
Apoptosis is important biological phenomena, apoptosis process be unusually tumour take place and evolution in an important step.Protein kinase PKB is as a kind of important molecule of mediated cell survival signal, and the regulating effect in apoptosis process is very important.The reactivation process of PKB is the key link of cell survival signal transduction pathway, and the activity of utilizing variety of way to suppress PKB can promote apoptosis process.Protein kinase PKB will be new, a good antitumor drug target position.In the research of present kinases inhibitor, the Iressa of the Gleevec of Novartis company and Astrazenca company enters clinical application as treatment chronic leukemia and treatment lung cancer drugs.In addition, also have tens compounds carrying out preclinical test.Though the research to kinases inhibitor obtains some progress recently, but also do not enter compound (Levitzki, A., the Protein Kinase Inhibitors as a Therapeutic Modality.Acc.Chem.Res.2003 of clinical trial, 36,462).The activity of having reported at present inhibitor preferably is isoquinoline sulfonaide compounds H-89, the scientist of Israel has synthesized a large amount of micromolecular inhibitors with Ser/Thr kinases inhibitor H-89 as lead compound, and preliminary study the structure activity relationship (Reuveni of H-89, H., et al.Modification of a Selective PKA Inhibitor by Rational Design.Biochemistry, 2002,41,1030).But it is not, high to the selectivity of PKB because this compounds has effect to multiple target.Therefore, need further develop and optimize high reactivity, specific inhibitor at PKB, exploitation is efficient, the antineoplaston medicine of low toxicity.
Summary of the invention
The purpose of this invention is to provide a kind of substituted piperazine N-ethyl sulfonamide derivative, and their pharmacologically acceptable salt, have following general structure:
Formula (1)
Wherein: the sulfamic of replacement can be 1 or 2 of dicyclo; A, B, D, E is identical or different, selects carbon for use, nitrogen; R
1Can select saturated or unsaturated alkyl, alkanamine methyl, the hydroxyalkyl of 1-5 carbon for use, also can select for use to replace or unsubstituted benzyl; R
2Can select saturated or unsaturated alkyl, replacement or unsubstituted benzyl and five yuan, the hexa-member heterocycle of 1-15 carbon for use.Its preferred formula (1) compound is:
I-a:N-{ (1R)-2-[4-(4-benzyl chloride base) piperazine-1-yl]-the 1-methylethyl } isoquinoline 99.9-5-sulphonamide
I-b:N-[(1R)-and 2-(4-benzyl diethylenediamine-1-yl)-1-methylethyl] isoquinoline 99.9-5-sulphonamide
I-c:N-((1R)-1-methyl-2-{4-[4-(trifluoroethyl) benzyl] piperazine-1-yl } ethyl) isoquinoline 99.9-5-sulphonamide
I-d:N-{ (1R)-2-[4-(3-bromobenzyl) piperazine-1-yl]-the 1-methylethyl } isoquinoline 99.9-5-sulphonamide
I-e:N-{ (1R)-2-[4-(2, the 4-difluorobenzyl) piperazine-1-yl]-the 1-methylethyl } isoquinoline 99.9-5-sulphonamide
I-f:N-((1R)-2-{4-[(2-chloro-1,3-thiazoles-5-yl) methyl] piperazine-1-yl }-the 1-methylethyl) isoquinoline 99.9-5-sulphonamide
I-g:N-((1R)-2-{4-[(6-chloropyridine-3-yl) methyl] piperazine-1-yl }-the 1-methylethyl) isoquinoline 99.9-5-sulphonamide
I-h:N-[(1R)-and 1-methyl-2-(4-methylpiperazine-1-yl) ethyl] isoquinoline 99.9-5-sulphonamide
I-i:N-[(1R)-and 1-methyl-2-(4-amyl group piperazine-1-yl) ethyl] isoquinoline 99.9-5-sulphonamide
I-j:N-[(1R)-and 1-methyl-2-(4-octyl group piperazine-1-yl) ethyl] isoquinoline 99.9-5-sulphonamide
I-k:N-[(1R)-and 2-(4-dodecyl piperazine-1-yl)-1-methylethyl] isoquinoline 99.9-5-sulphonamide
I-l:N-{ (1R)-2-[4-(4-luorobenzyl) piperazine-1-yl]-the 1-methylethyl } isoquinoline 99.9-5-sulphonamide
I-m:N-{ (1R)-2-[4-(4-bromobenzyl) piperazine-1-yl]-the 1-methylethyl } isoquinoline 99.9-5-sulphonamide
I-n:N-[(1R)-and 1-benzyl-2-(4-methylpiperazine-1-yl) ethyl] isoquinoline 99.9-5-sulphonamide
I-o:N-[(1R)-and 1-benzyl-2-(4-benzyl diethylenediamine-1-yl) ethyl] isoquinoline 99.9-5-sulphonamide
I-p:N-((1R)-1-methyl-2-{4-[4-(trifluoromethyl) benzyl] piperazine-1-yl } ethyl) naphthalene-2-sulphonamide
I-q:N-{ (1R)-2-[4-(3-luorobenzyl) piperazine-1-yl]-the 1-methylethyl } naphthalene-2-sulphonamide
I-r:N-{ (1R)-2-[4-(3-benzyl chloride base) piperazine-1-yl]-the 1-methylethyl } naphthalene-2-sulphonamide
I-s:N-{ (1R)-2-[4-(3-bromobenzyl) piperazine-1-yl]-the 1-methylethyl } naphthalene-2-sulphonamide
I-t:N-((1R)-2-{4-[(2-chloro-1,3-thiazoles-5-yl) methyl] piperazine-1-yl }-the 1-methylethyl) naphthalene-2-sulphonamide
I-u:N-((1R)-2-{4-[(6-chloropyridine-3-ylmethyl] piperazine-1-yl }-the 1-methylethyl) naphthalene-2-sulphonamide
I-v:N-[(1R)-and 1-methyl-2-(4-methylpiperazine-1-yl) ethyl] naphthalene-2-sulphonamide
I-w:N-[(1R)-and 1-methyl-2-(4-amyl group piperazine-1-yl) ethyl] naphthalene-2-sulphonamide
I-x:N-{ (1R)-1-methyl 1-2-[4-(3-methyl butyl) piperazine-1-yl] ethyl } naphthalene-2-sulphonamide
I-y:N-[(1R)-and 1-methyl-2-(4-octyl group piperazine-1-yl) ethyl] naphthalene-2-sulphonamide
I-z:N-[(1R)-and 2-(4-dodecyl piperazine-1-yl)-1-methylethyl] naphthalene-2-sulphonamide
Preferred formula (1) compound structure table
Another object of the present invention provides the preparation method of described substituted piperazine N-ethyl sulfonamide derivative; realize by following scheme: substituted sulfonic acid obtains its chloride derivative through the thionyl chloride chlorination; replace L type amino acid and obtain L type amido alcohol compound through lithium aluminium hydride reduction; obtain compound IV with the sulfonyl chloride derivatives generation linked reaction that replaces; compound IV obtains its mesylate derivatives III through the methylsulfonyl chloride protection; this derivative III be substituted single substituted-piperazinyl II that reaction and trifluoracetic acid deprotection obtain by single tertbutyloxycarbonyl (BOC) protection piperazine and substitution reaction takes place under organic amine catalysis obtain substituted piperazine N-ethyl sulfonamide derivative I, this organic amine can be a Trimethylamine 99; triethylamine; any one of trimethylamines such as diisopropylethylamine.Reaction formula is:
Wherein: A, B, D, E and radicals R
1, R
2Definition and formula (1) in identical.
Another purpose of the present invention provides substituted piperazine N-ethyl sulfonamide derivative and the application of pharmacologically acceptable salt in control tumor disease medicine thereof.Preliminary pharmacological evaluation shows that formula of the present invention (1) compound is external to human lung carcinoma cell (A549), human liver cancer cell (HepG2), the chronic myelogone leukemia cell of people (K562), cervical cancer cell (Hela), people's acute leukemia cells (HL60) growth-inhibiting effect preferably, external activity half-inhibition concentration (IC arranged
50Value) shows, its anti-tumor activity of part of compounds is higher than guide's thing H89, even be higher than a line arrestin kinases antitumor drug Sutent, the Dasatinib or suitable of listing with it, show that this analog derivative might develop into new control tumour medicine.
Usefulness of the present invention is: with the protein kinase B inhibitor H89 that found is lead compound, obtains substituted piperazine N-ethyl sulfonamide derivative by appropriate design.Emphatically this substituted piperazine N-ethyl sulfonamide derivative is explored, the preparation method of this compounds is provided; This substituted piperazine N-ethyl sulfonamide derivative that provides has important biological, and external have restraining effect to many strains tumour cell, is expected to become new control tumour medicine.
Embodiment
Further specify the present invention below by specific embodiment.Following embodiment has provided the synthetic and dependency structure appraising datum of representative compounds.Mandatory declaration, following embodiment is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1: N-[(1R)-and 2-hydroxyl-1-methylethyl] preparation of isoquinoline 99.9-5-sulphonamide (IV)
This example relates to the general synthetic method of substituted piperazidine N-ethyl sulfonamide derivative intermediate (IV).Be specifically related to N-[(1R)-2-hydroxyl-1-methylethyl] isoquinoline 99.9-5-sulphonamide synthetic.This compound is formed with isoquinoline 99.9-5-SULPHURYL CHLORIDE condensation by L-propylamine alcohol.
Under the ice bath with L-L-Ala (4.85g, 55.0mmol) (3.0g in the tetrahydrofuran (THF) reaction solution (150mL) 78.9mmol), reacts and adds entry and 15%NaOH solution stopped reaction after 20 hours slowly to join lithium aluminum hydride, filter, filtrate decompression is steamed to desolventize and is obtained faint yellow solid.Crude product gets colorless oil L-propylamine alcohol 3.41g, yield 82.5% behind silica gel column chromatography.
1H-NMR(CDCl
3)：δ3.40(1H，dd，J
1＝8.0Hz，J
2＝2.8Hz)；3.12(1H，dd，J
1＝8.4Hz，J
2＝6.4Hz)；2.91-2.87(1H，m)；0.93(3H，d，J＝5.2Hz).ESI-MS：76[M+1]
+。
With isoquinoline-5-sulfonic acid (4g, 19.0mmol) with sulfur oxychloride (25mL) reflux after 2 hours, remove excessive sulfur oxychloride under reduced pressure, residue is suspended in the methylene dichloride, filter and the collection filter cake, vacuum-drying obtains isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride 5.28g (yield 95.6%).In the 5.28g isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride (0.02mol) water-soluble (53mL) that obtains, and adding sodium bicarbonate under the ice bath (1.68g, 0.02mol), chloroform extraction, gained organic layer wash through saturated sodium-chloride, and anhydrous magnesium sulfate drying is standby.With L-propylamine alcohol (1.50g, 0.02mol) and exsiccant triethylamine (2.02g, 0.02mol) be dissolved in the exsiccant methylene dichloride (60mL), under ice bath, drip the solution of previous step preparation, room temperature reaction adds entry (50mL) after 30 minutes, organic layer washs through saturated sodium-chloride, anhydrous sodium sulfate drying, remove solvent under reduced pressure and get white solid N-[(1R)-2-hydroxyl-1-methylethyl] isoquinoline 99.9-5-sulphonamide 3.86g, yield 72.6%;
1H-NMR (CDCl
3): δ 9.34 (1H, s), 8.67 (1H, d, J=8.0Hz), 8.50 (1H, d, J=9.0Hz), 8.47 (1H, d, J=7.5Hz), 8.22 (1H, d, J=10.0Hz), 7.72 (1H, t, J=9.0Hz), 3.44-3.38 (2H, m), 3.19-3.14 (1H, m), 0.99 (3H, d, J=6.0Hz); ESI-MS:267[M+1]
+
Embodiment 2: (2R)-2-[(isoquinoline 99.9-and 5-base alkylsulfonyl) amido] preparation of propyl group methanesulfonates (III)
This example relates to the general synthetic method of substituted piperazidine N-ethyl sulfonamide derivative intermediate (III).Be specifically related to (2R)-2-[(isoquinoline 99.9-5-base alkylsulfonyl) amido] propyl group methanesulfonates synthetic.N-[(1R)-and 2-hydroxyl-1-methylethyl] isoquinoline 99.9-5-sulphonamide (3g; 13.0mmol) and triethylamine (2.01g; 19.9mmol) be dissolved in the exsiccant methylene dichloride (120mL); after the ice bath cooling; with methylsulfonyl chloride (1.67g; 15.0mmol) slowly splash into; half an hour after saturated sodium carbonate wash; behind the anhydrous sodium sulfate drying; decompression and solvent recovery gets crude product; crude product gets white solid (2R)-2-[(isoquinoline 99.9-5-base alkylsulfonyl through silica gel column chromatography) amido] propyl group methanesulfonates 3.39g, yield 75.8%.
1H-NMR(CDCl
3)：δ9.41(1H，s)，8.69(1H，d，J＝6.5Hz)，8.50(1H，d，J＝7.5Hz)，8.45(1H，d，J＝6.0Hz)，8.26(1H，d，J＝8.0Hz)，7.74(1H，t，J＝8.0Hz)，4.09-4.05(2H，m)，3.69-3.62(1H，m)，2.88(3H，s)，1.10(3H，d，J＝7.0Hz).ESI-MS：345[M+1]
+。
Embodiment 3: the preparation of 1-(4-benzyl chloride base) piperazine (II)
This example relates to the general synthetic method of substituted piperazidine N-ethyl sulfonamide derivative intermediate (II).Be specifically related to the synthetic of 1-(4-benzyl chloride base) piperazine.Tertiary butyl piperazine-1-carbonic ether (2.34g, 12.6mmol), 4-chlorobenzyl chloride (1.69g, 10.5mmol), triethylamine (2.1g, 20.5mmol) in acetonitrile (40mL) solution in 60 ℃ stir 12 hours after, remove solvent under reduced pressure, residue extracts with chloroform-water dispenser, and organic layer is through the saturated common salt water washing, anhydrous sodium sulfate drying removes solvent under reduced pressure and obtains crude product.With the crude product tertiary butyl-4-(4-benzyl chloride base) piperazine-1-carbonic ether of obtaining (2.1g 0.01mol) is dissolved in the methylene dichloride (4mL), add trifluoroacetic acid (5.80g, 0.08mol) after, continue reaction and removing solvent under reduced pressure, the saturated NaHCO of residue after 2 hours
3Neutralization, dichloromethane extraction gained organic layer, the saturated common salt water washing, anhydrous sodium sulfate drying removes the yellow thick liquid of solvent gained under reduced pressure, obtains white solid 1-(4-benzyl chloride base) piperazine (1.89g, 89.8%) through purification by silica gel column chromatography.M.p.93-97℃。
1H?NMR(CDCl
3)：δ7.15(m，4H)，3.35(s，2H)，2.95-2.65(m，4H)，2.45-2.15(m，5H).ESI-MS：211[M+1]
+。
Embodiment 4: N-{ (1R)-2-[4-(4-benzyl chloride base) piperazine-1-yl]-the 1-methylethyl } preparation of isoquinoline 99.9-5-sulphonamide (I-a)
This example relates to the general synthetic method of substituted piperazidine N-ethyl sulfonamide derivative (I).Be specifically related to N-{ (1R)-2-[4-(4-benzyl chloride base) piperazine-1-yl]-the 1-methylethyl } isoquinoline 99.9-5-sulphonamide (I-a) synthetic.(2R)-and 2-[(isoquinoline 99.9-5-base alkylsulfonyl) amido] propyl group methanesulfonates (50mg, 0.142mmol), 1-(4-benzyl chloride base) piperazine (36mg, 0.17mmol), N, N-diisopropyl ethyl amine (21.8mg, 0.17mmol) in anhydrous acetonitrile (2mL), remove solvent in 60 ℃ of stirrings under reduced pressure after 24 hours, residue extracts back gained organic layer with chloroform-water dispenser, through the saturated common salt water washing, anhydrous sodium sulfate drying, remove the residue that obtains behind the solvent under reduced pressure and get white solid (I-a, 41.1mg, 63.2%) with purification by silica gel column chromatography;
1HNMR (CDCl
3): δ 9.35 (1H, s), 8.74 (1H, d, J=6.0Hz), 8.52 (1H, d, J=6.0Hz), 8.45 (1H, d, J=7.5Hz), 8.18 (1H, d, J=8.0Hz), 7.69 (1H, t, J=7.5Hz), 7.28 (2H, t, J=8.5Hz), 7.18 (2H, d, J=8.0Hz), 3.34 (1H, d, J=13.0Hz), 3.26 (1H, d, J=13.0Hz) 3.08-3.02 (1H, m), 2.22-1.67 (10H, m), 1.12 (3H, d, J=6.0Hz) .ESI-MS:459[M+1]
+
Embodiment 5: N-[(1R)-and 2-(4-benzyl diethylenediamine-1-yl)-1-methylethyl] preparation of isoquinoline 99.9-5-sulphonamide (I-b)
According to the method for embodiment 4, substitute 1-(4-benzyl chloride base) piperazine with benzyl diethylenediamine and get white solid (I-b, 75.1%).
1HNMR(CDCl
3)：δ9.36(1H，s)，8.74(1H，d，J＝5.5Hz)，8.52(1H，d，J＝7.5Hz)，8.45(1H，d，J＝7.5Hz)，8.18(1H，dd，J＝7.5Hz)，7.69(1H，t，J＝8.0Hz)，7.33-7.30(3H，m)，7.26-7.24(2H，m)，3.38(1H，d，J＝13.0Hz)，3.32(1H，d，J＝13.0Hz)3.06-3.03(1H，m)，2.21-1.96(10H，m)，1.12(3H，d，J＝6.0Hz).ESI-MS：425[M+1]
+。
Embodiment 6: the preparation of N-((1R)-1-methyl-2-{4-[4-(trifluoroethyl) benzyl] piperazine-1-yl } ethyl) isoquinoline 99.9-5-sulphonamide (I-c)
According to the method for embodiment 4, use alternative 1-(the 4-benzyl chloride base) piperazine of trifluoromethyl benzyl piperazine is got white solid (I-c, 68.9%);
1HNMR (CDCl
3): δ 9.35 (1H, s), 8.73 (1H, d, J=5.5Hz), 8.53 (1H, d, J=6.0Hz), 8.45 (1H, d, J=7.5Hz), 8.18 (1H, d, J=7.5Hz), 7.69 (1H, t, J=8.0Hz), 7.50 (2H, t, J=7.5Hz), 7.42 (2H, d, J=7.5Hz), 3.33 (1H, d, J=13.0Hz), 3.25 (1H, d, J=13.0Hz), 3.06-3.01 (1H, m), 2.31-1.79 (10H, m), 1.12 (3H, d, J=6.0Hz) .ESI-MS:493[M+1]
+
Embodiment 7: N-{ (1R)-2-[4-(3-bromobenzyl) piperazine-1-yl]-the 1-methylethyl } preparation of isoquinoline 99.9-5-sulphonamide (I-d)
According to the method for embodiment 4, with between the bromobenzyl piperazine substitute 1-(4-benzyl chloride base) piperazine and get white solid (I-d, 68.7%).
1HNMR(CDCl
3)：δ9.36(1H，s)，8.74(1H，d，J＝6.0Hz)，8.52(1H，d，J＝6.0Hz)，8.46(1H，d，J＝7.5Hz)，8.19(1H，d，J＝8.0Hz)，7.70(1H，t，J＝8.0Hz)，7.26-7.23(1H，m)，7.02-6.97(2H，m)，6.94-6.91(1H，m)，3.34(1H，d，J＝13.0Hz)，3.26(1H，d，J＝13.0Hz)，3.09-3.04(1H，m)，2.26-1.51(10H，m)，1.11(3H，d，J＝6.0Hz).ESI-MS：503[M+1]
+。
Embodiment 8: N-{ (1R)-2-[4-(2, the 4-difluorobenzyl) piperazine-1-yl]-the 1-methylethyl } preparation of isoquinoline 99.9-5-sulphonamide (I-e)
According to the method for embodiment 4, with 2,4-difluorobenzyl piperazine substitutes 1-(4-benzyl chloride base) piperazine and gets white solid (I-e, 67.4%).
1HNMR(CDCl
3)：δ9.37(1H，s)，8.73(1H，d，J＝6.0Hz)，8.51(1H，d，J＝6.0Hz)，8.46(1H，d，J＝7.5Hz)，8.21(1H，d，J＝8.0Hz)，7.71(1H，t，J＝8.0Hz)，7.27-7.21(1H，m)，6.86-6.78(2H，m)，3.40(1H，d，J＝13.0Hz)，3.34(1H，d，J＝13.0Hz)，3.06-3.02(1H，m)，2.21-1.62(10H，m)，1.11(3H，d，J＝6.0Hz).ESI-MS：461[M+1]
+。
Embodiment 9: N-((1R)-2-{4-[(2-chloro-1,3-thiazoles-5-yl) methyl] piperazine-1-yl }-the 1-methylethyl) preparation of isoquinoline 99.9-5-sulphonamide (I-f)
According to the method for embodiment 4, substitute 1-(4-benzyl chloride base) piperazine with 2-chloro-5-(piperazine-1-ylmethyl) thiazole and get white solid (I-f, 68.5%).
1HNMR(CDCl
3)：δ9.37(1H，s)，8.75(1H，d，J＝6.0Hz)，8.52(1H，d，J＝6.0Hz)，8.47(1H，d，J＝7.0Hz)，8.21(1H，d，J＝8.0Hz)，7.72(1H，t，J＝8.0Hz)，7.35(1H，s)，3.48(1H，d，J＝13.5Hz)，3.42(1H，d，J＝13.5Hz)，3.08-3.01(1H，m)，2.25-1.62(10H，m)，1.12(3H，d，J＝6.0Hz).ESI-MS：466[M+1]
+。
Embodiment 10: N-((1R)-2-{4-[(6-chloropyridine-3-yl) methyl] piperazine-1-yl }-the 1-methylethyl) preparation of isoquinoline 99.9-5-sulphonamide (I-g)
According to the method for embodiment 4, substitute 1-(4-benzyl chloride base) piperazine with 1-((6-chloropyridine-3-yl) methyl) piperazine and get white solid (I-g, 71.4%).
1HNMR(CDCl
3)：δ9.35(1H，s)，8.75(1H，d，J＝5.5Hz)，8.52(1H，d，J＝6.0Hz)，8.46(1H，d，J＝7.5Hz)，8.29(1H，d，J＝5.0Hz)，8.20(1H，dd，J＝7.5Hz)，7.71(1H，t，J＝8.0Hz，)，7.26(1H，s)，7.12-7.11(1H，m)，3.34(1H，d，J＝14.0Hz)，3.25(1H，d，J＝14.0Hz)3.09-3.01(1H，m)，2.23-1.63(10H，m)，1.12(3H，d，J＝6.0Hz).ESI-MS：460[M+1]
+。
Embodiment 11: N-[(1R)-and 1-methyl-2-(4-methylpiperazine-1-yl) ethyl] preparation of isoquinoline 99.9-5-sulphonamide (I-h)
According to the method for embodiment 4, substitute 1-(4-benzyl chloride base) piperazine with N methyl piperazine and get white solid (I-h, 78.9%).
1HNMR(CDCl
3)：δ9.37(1H，s)，8.74(1H，d，J＝5.5Hz)，8.51(1H，d，J＝8.0Hz，)，8.47(1H，d，J＝7.5Hz)，8.21(1H，d，J＝7.5Hz)，7.71(1H，t，J＝8.0Hz)，3.09-3.05(1H，m)，2.22-2.14(2H，m)，2.14(3H，s)，2.09-1.65(8H，m)，1.12(3H，d，J＝6.0Hz).ESI-MS：349[M+1]
+。
Embodiment 12: N-[(1R)-and 1-methyl-2-(4-amyl group piperazine-1-yl) ethyl] preparation of isoquinoline 99.9-5-sulphonamide (I-i)
According to the method for embodiment 4, substitute 1-(4-benzyl chloride base) piperazine with the n-pentyl piperazine and get white solid (I-i, 79.4%).
1HNMR(CDCl
3)：δ9.36(1H，s)，8.73(1H，d，J＝5.6Hz)，8.50(1H，d，J＝5.6Hz)，8.46(1H，d，J＝7.2Hz)，8.21(1H，d，J＝8.4Hz)，7.71(1H，t，J＝8.0Hz)，3.05-3.01(1H，m)，2.22-1.88(12H，m)，1.41-1.19(6H，m)，1.11(3H，d，J＝6.4Hz)，0.87(3H，t，J＝6.8Hz).ESI-MS：405[M+1]
+。
Embodiment 13: N-[(1R)-and 1-methyl-2-(4-octyl group piperazine-1-yl) ethyl] preparation of isoquinoline 99.9-5-sulphonamide (I-j)
According to the method for embodiment 4, substitute 1-(4-benzyl chloride base) piperazine with the n-octyl piperazine and get white solid (I-j, 75.8%).
1HNMR(CDCl
3)：δ9.37(1H，s)，8.72(1H，d，J＝6.0Hz)，8.50(1H，d，J＝6.0Hz)，8.47(1H，d，J＝7.2Hz)，8.22(1H，d，J＝7.6Hz)，7.72(1H，t，J＝7.6Hz)，3.11-3.08(1H，m)，2.51-1.97(12H，m)，1.52-1.40(2H，m)，1.32-1.19(10H，m)，1.07(3H，d，J＝6.4Hz)，0.87(3H，t，J＝6.0Hz).ESI-MS：447[M+1]
+。
Embodiment 14: N-[(1R)-and 2-(4-dodecyl piperazine-1-yl)-1-methylethyl] preparation of isoquinoline 99.9-5-sulphonamide (I-k)
According to the method for embodiment 4, substitute 1-(4-benzyl chloride base) piperazine with the dodecyl piperazine and get white solid (I-k, 73.6%).
1HNMR(CDCl
3)：δ9.37(1H，s)，8.74(1H，d，J＝6.0Hz)，8.52(1H，d，J＝6.4Hz)，8.47(1H，d，J＝7.2Hz)，8.22(1H，d，J＝8.0Hz)，7.72(1H，t，J＝8.0Hz)，3.08-2.98(1H，m)，2.22-2.08(12H，m)，1.36-1.32(2H，m)，1.32-1.19(18H，m)，1.12(3H，d，J＝5.6Hz)，0.89(3H，t，J＝7.2Hz).ESI-MS：503[M+1]
+。
Embodiment 15: N-{ (1R)-2-[4-(4-luorobenzyl) piperazine-1-yl]-the 1-methylethyl } preparation of isoquinoline 99.9-5-sulphonamide (I-1)
According to the method for embodiment 4, use alternative 1-(the 4-benzyl chloride base) piperazine of luorobenzyl piperazine is got white solid (I-1,75.2%).
1HNMR(CDCl
3)：δ9.35(1H，s)，8.73(1H，d，J＝5.5Hz)，8.53(1H，d，J＝6.0Hz)，8.45(1H，d，J＝7.5Hz)，8.18(1H，d，J＝7.5Hz)，7.69(1H，t，J＝8.0Hz)，7.21-7.18(2H，m)，7.01-6.98(2H，m)，3.33(1H，d，J＝13.0Hz)，3.25(1H，d，J＝13.0Hz)，3.06-3.01(1H，m)，2.21-1.69(10H，m)，1.12(3H，d，J＝6.0Hz).ESI-MS：443[M+1]
+。
Embodiment 16: N-{ (1R)-2-[4-(4-bromobenzyl) piperazine-1-yl]-the 1-methylethyl } preparation of isoquinoline 99.9-5-sulphonamide (I-m)
According to the method for embodiment 4, use alternative 1-(the 4-benzyl chloride base) piperazine of bromobenzyl piperazine is got white solid (I-m, 65.5%).
1HNMR(CDCl
3)：δ9.36(1H，s)，8.74(1H，d，J＝6.0Hz)，8.52(1H，d，J＝6.0Hz)，8.46(1H，d，J＝7.5Hz)，8.19(1H，d，J＝8.0Hz)，7.70(1H，t，J＝8.0Hz)，7.44(2H，d，J＝8.0Hz)，7.16(2H，d，J＝8.0Hz)，3.34(1H，d，J＝13.0Hz)，3.26(1H，d，J＝13.0Hz)，3.09-3.04(1H，m)，2.26-1.51(10H，m)，1.11(3H，d，J＝6.0Hz).ESI-MS：503[M+1]
+。
Embodiment 17: N-[(1R)-and 1-benzyl-2-(4-methylpiperazine-1-yl) ethyl] preparation of isoquinoline 99.9-5-sulphonamide (I-n)
According to the method for embodiment 1 and 4, substitute the L-L-Ala with the L-phenylalanine, N methyl piperazine substitutes 1-(4-benzyl chloride base) piperazine and gets white solid (I-n, 75.2%).
1HNMR(CDCl
3)：δ9.34(1H，s)，8.70(1H，d，J＝6.0Hz)，8.47-8.45(2H，m)，8.20(1H，d，J＝8.5Hz)，7.70(1H，t，J＝8.0Hz)，7.17-7.10(3H，m)，7.03-7.01(2H，m)，3.31-3.28(1H，m)，3.01(1H，dd，J
1＝14.0Hz，J
2＝4.5Hz)，2.75(1H，dd，J
1＝14.0Hz，J
2＝7.5Hz)，2.23-1.97(12H，m).ESI-MS：425[M+1]
+。
Embodiment 18: N-[(1R)-and 1-benzyl-2-(4-benzyl diethylenediamine-1-yl) ethyl] preparation of isoquinoline 99.9-5-sulphonamide (I-o)
According to the method for embodiment 1 and 4, substitute the L-L-Ala with the L-phenylalanine, the N-benzyl diethylenediamine substitutes 1-(4-benzyl chloride base) piperazine and gets white solid (I-o, 73.6%).
1HNMR(CDCl
3)：δ9.34(1H，s)，8.71(1H，d，J＝6.5Hz)，8.48-8.46(2H，m)，8.17(1H，d，J＝8.5Hz)，7.68(1H，t，J＝7.5Hz)，7.31-7.21(5H，m)，7.18-7.11(3H，m)，7.06-7.03(2H，m)，3.33-3.24(2H，m)，3.03(1H，dd，J
1＝14.0Hz，J
2＝4.5Hz)，2.78(1H，dd，J
1＝13.5Hz，J
2＝7.5Hz)，2.21-2.17(1H，m)，2.12-2.09(1H，m)，2.05-1.72(8H，m).ESI-MS：501[M+1]
+。
Embodiment 19: the preparation of N-((1R)-1-methyl-2-{4-[4-(trifluoromethyl) benzyl] piperazine-1-yl } ethyl) naphthalene-2-sulphonamide (I-p)
According to the method for embodiment 1 and 4, substitute isoquinoline-5-sulfonic acid with naphthalene-2-sulfonic acid, the trifluoromethyl benzyl piperazine is substituted 1-(4-benzyl chloride base) piperazine get white solid (I-p, 72.3%).
1HNMR(CDCl
3)：δ8.44(1H，s)，7.97-7.93(2H，m)，7.89-7.84(2H，m)，7.65-7.60(2H，m)，7.55(2H，d，J＝8.0Hz)，7.36(2H，d，J＝8.0Hz)，3.47(1H，d，J＝13.0Hz)，3.43(1H，d，J＝13.0Hz)3.11-3.07(1H，m)，2.32-1.92(10H，m)，1.20(3H，d，J＝6.0Hz).ESI-MS：492[M+1]
+。
Embodiment 20: N-{ (1R)-2-[4-(3-luorobenzyl) piperazine-1-yl]-the 1-methylethyl } preparation of naphthalene-2-sulphonamide (I-q)
According to the method for embodiment 1 and 4, substitute isoquinoline-5-sulfonic acid with naphthalene-2-sulfonic acid, with between alternative 1-(the 4-benzyl chloride base) piperazine of luorobenzyl piperazine get white solid (I-q, 73.6%).
1HNMR(CDCl
3)：δ8.45(1H，s)，7.98-7.93(2H，m)，7.90-7.84(2H，m)，7.65-7.61(2H，m)，7.27-7.24(1H，m)，7.03-6.99(2H，m)，6.95-6.92(1H，m)，3.43(1H，d，J＝13.0Hz)，3.39(1H，d，J＝13.0Hz)，3.09-3.04(1H，m)，2.34-1.53(10H，m)，1.21(3H，d，J＝6.0Hz).ESI-MS：442[M+1]
+。
Embodiment 21: N-{ (1R)-2-[4-(3-benzyl chloride base) piperazine-1-yl]-the 1-methylethyl } preparation of naphthalene-2-sulphonamide (I-r)
According to the method for embodiment 1 and 4, substitute isoquinoline-5-sulfonic acid with naphthalene-2-sulfonic acid, substitute 1-(4-benzyl chloride base) piperazine with the m-chloro benzyl diethylenediamine and get white solid (I-r, 72.5%).
1HNMR(CDCl
3)：δ8.45(1H，s)，7.98-7.94(2H，m)，7.91-7.84(2H，m)，7.66-7.61(2H，m)，7.24-7.21(3H，m)，7.12-7.10(1H，m)，3.41(1H，d，J＝13.0Hz)，3.34(1H，d，J＝13.0Hz)3.09-3.05(1H，m)，2.24-2.01(10H，m)，1.21(3H，d，J＝6.0Hz).ESI-MS：458[M+1]
+。
Embodiment 22: N-{ (1R)-2-[4-(3-bromobenzyl) piperazine-1-yl]-the 1-methylethyl } preparation of naphthalene-2-sulphonamide (I-s)
According to the method for embodiment 1 and 4, substitute isoquinoline-5-sulfonic acid with naphthalene-2-sulfonic acid, with between alternative 1-(the 4-benzyl chloride base) piperazine of bromobenzyl piperazine get white solid (I-s, 69.7%).
1HNMR(CDCl
3)：δ8.44(1H，s)，7.97-7.94(2H，m)，7.91-7.84(2H，m)，7.66-7.61(2H，m)，7.24-7.20(3H，m)，7.12-7.10(1H，m)，3.41(1H，d，J＝13.0Hz)，3.34(1H，d，J＝13.0Hz)3.09-3.04(1H，m)，2.24-2.01(10H，m)，1.21(3H，d，J＝6.0Hz).ESI-MS：502[M+1]
+。
Embodiment 23: N-((1R)-2-{4-[(2-chloro-1,3-thiazoles-5-yl) methyl] piperazine-1-yl }-the 1-methylethyl) preparation of naphthalene-2-sulphonamide (I-t)
According to the method for embodiment 1 and 4, substitute isoquinoline-5-sulfonic acid with naphthalene-2-sulfonic acid, with 1-[(2-chloro-1,3-thiazoles-5-yl) methyl] alternative 1-(the 4-benzyl chloride base) piperazine of piperazine gets white solid (I-t, 76.7%).
1HNMR(CDCl
3)：δ8.44(1H，s)，7.97-7.93(2H，m)，7.90-7.84(2H，m)，7.65-7.60(2H，m)，7.35(1H，s)，3.56(1H，d，J＝13.0Hz)，3.49(1H，d，J＝13.0Hz)，3.13-3.08(1H，m，)，2.29-1.63(10H，m)，1.20(3H，d，J＝6.0Hz)，7.35(1H，s)，3.48(1H，d，J＝10.8Hz)，3.42(1H，d，J＝10.8Hz).ESI-MS：465[M+1]
+。
Embodiment 24: N-((1R)-2-{4-[(6-chloropyridine-3-ylmethyl] piperazine-1-yl }-the 1-methylethyl) preparation of naphthalene-2-sulphonamide (I-u)
According to the method for embodiment 1 and 4, substitute isoquinoline-5-sulfonic acid with naphthalene-2-sulfonic acid, with 1-[(6-chloropyridine-3-yl) methyl] alternative 1-(the 4-benzyl chloride base) piperazine of piperazine gets white solid (I-u, 77.9%).
1HNMR(CDCl
3)：δ8.44(1H，s)，8.29-8.28(1H，m)，7.97-7.93(2H，m)，7.90-7.84(2H，m)，7.65-7.60(2H，m)，7.26-7.24(1H，m)，7.12-7.11(1H，m)，3.42(1H，d，J＝13.0Hz)，3.34(1H，d，J＝13.0Hz)3.13-3.08(1H，m)，2.29-1.63(10H，m)，1.20(3H，d，J＝6.0Hz).ESI-MS：459[M+1]
+。
Embodiment 25: N-[(1R)-and 1-methyl-2-(4-methylpiperazine-1-yl) ethyl] preparation of naphthalene-2-sulphonamide (I-v)
According to the method for embodiment 1 and 4, substitute isoquinoline-5-sulfonic acid with naphthalene-2-sulfonic acid, substitute 1-(4-benzyl chloride base) piperazine with N methyl piperazine and get white solid (I-v, 74.3%).
1HNMR(CDCl
3)：δ8.46(1H，s)，7.99-7.96(2H，m)，7.92-7.90(1H，m)，7.87-7.86(1H，m)，7.67-7.61(2H，m)，3.09-3.06(1H，m)，2.27-1.79(13H，m)，1.21(3H，d，J＝4.8Hz).ESI-MS：348[M+1]
+。
Embodiment 26: N-[(1R)-and 1-methyl-2-(4-amyl group piperazine-1-yl) ethyl] preparation of naphthalene-2-sulphonamide (I-w)
According to the method for embodiment 1 and 4, substitute isoquinoline-5-sulfonic acid with naphthalene-2-sulfonic acid, substitute 1-(4-benzyl chloride base) piperazine with the n-pentyl piperazine and get white solid (I-w, 72.4%).
1HNMR(CDCl
3)：δ8.48(1H，s)，7.99-7.88(2H，m)，7.70-7.64(2H，m)，3.39-3.27(1H，m)，2.75-2.27(12H，m)，1.59-1.57(2H，m)，1.32-1.22(4H，m)，1.14(3H，d，J＝6.0Hz)，0.89(3H，d，J＝6.0Hz).ESI-MS：404[M+1]
+。
Embodiment 27: N-{ (1R)-1-methyl 1-2-[4-(3-methyl butyl) piperazine-1-yl] ethyl } preparation of naphthalene-2-sulphonamide (I-x)
According to the method for embodiment 1 and 4, substitute isoquinoline-5-sulfonic acid with naphthalene-2-sulfonic acid, substitute 1-(4-benzyl chloride base) piperazine with the isopentyl piperazine and get white solid (I-x, 75.6%).
1HNMR(CDCl
3)：δ8.48(1H，s)，7.99-7.88(2H，m)，7.70-7.64(2H，m)，3.39-3.27(1H，m)，2.75-2.27(12H，m)，1.56-1.52(1H，m)，1.35-1.31(2H，m)，1.09(3H，d，J＝6.4Hz)，0.87(3H，t，J＝6.4Hz).ESI-MS：404[M+1]
+。
Embodiment 28: N-[(1R)-and 1-methyl-2-(4-octyl group piperazine-1-yl) ethyl] preparation of naphthalene-2-sulphonamide (I-y)
According to the method for embodiment 1 and 4, substitute isoquinoline-5-sulfonic acid with naphthalene-2-sulfonic acid, substitute 1-(4-benzyl chloride base) piperazine with the n-octyl piperazine and get white solid (I-y, 78.6%).
1HNMR(CDCl
3)：δ8.48(1H，s)，7.99-7.88(2H，m)，7.70-7.64(2H，m)，3.39-3.27(1H，m)，2.75-2.27(12H，m)，1.59-1.57(2H，m)，1.32-1.22(10H，m)，1.14(3H，d，J＝6.0Hz)，0.89(3H，d，J＝6.0Hz).ESI-MS：446[M+1]
+。
Embodiment 29: N-[(1R)-and 2-(4-dodecyl piperazine-1-yl)-1-methylethyl] preparation of naphthalene-2-sulphonamide (I-z)
According to the method for embodiment 1 and 4, substitute isoquinoline-5-sulfonic acid with naphthalene-2-sulfonic acid, substitute 1-(4-benzyl chloride base) piperazine with the dodecyl piperazine and get white solid (I-z, 69.5%).
1HNMR(CDCl
3)：δ8.48(1H，s)，7.99-7.88(2H，m)，7.70-7.64(2H，m)，3.31-3.25(1H，m)，2.83-2.12(12H，m)，1.62-1.53(2H，m)，1.29-1.21(18H，m)，1.14(3H，d，J＝6.4Hz)，0.88(3H，d，J＝6.4Hz).ESI-MS：502[M+1]
+。
In order to understand essence of the present invention better, embodiment further specifies the present invention below by pharmacology.Pharmacology embodiment has provided the part activity data of representative compounds.Mandatory declaration, following pharmacology embodiment is used to illustrate the present invention rather than limitation of the present invention, essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 30: Compound I-k is to the cytotoxic activity of A549 cell
A549 (people's lung cancer) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/ ml penicillin and 100U/ milliliter with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay.Cell is through after 24 hours hatch, the dimethyl sulfoxide solution of the Compound I-k that will newly join joins in each hole with concentration gradient respectively, make that the compound ultimate density is respectively 100 mcg/ml in the hole, 33.3 mcg/ml, 11.1 mcg/ml and 3.7 mcg/ml.After 72 hours, the phosphate buffered saline buffer that adds 10 microlitre MTT (5 mg/ml), continue 37 ℃ of cultivations after 4 hours again, removed unconverted MTT in centrifugal 5 minutes, add 200 microlitre methyl-sulphoxides in every hole, with the MTT crystal Jia Za (formazan) of dissolving and reducing, formed formazan microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample with respect to reference substance.
Wherein Compound I-k is to A549 cell 503nhibiting concentration IC
50Obtain by dose effect curve.The IC of Compound I-k
50Be 25.2 μ M.
As positive control, Sutent and H-89 are to the 503nhibiting concentration IC of people's lung cancer A549 cell with an antitumor line medication Sutent and the PKB inhibitor H-89 that reported in this test
50Be respectively 23.6 μ M and 58.9 μ M.
This test shows that this type of new substituted piperazine N-ethyl sulfonamide derivative has stronger cytotoxicity to people's lung cancer A549 cell, might develop into the new medicine with effect of anti-lung cancer.
Embodiment 31:Compound I-k is to the chronic myelogone leukemia cell's of people (K562) cytotoxic activity
The chronic myelogone leukemia cell of people (K562) contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter Streptomycin sulphate with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 1 * 10
4Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO
2Cultivated 24 hours in the incubator of damp atmosphere.
The measuring method of cell survival rate is with improveing mtt assay.Cell is after 24 hours hatch, and the dimethyl sulfoxide solution of the Compound I-k that will newly join joins in each hole with concentration gradient respectively, makes that the ultimate density of compound is respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml in the hole.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 mg/ml), continue at 37 ℃ 5%CO again
2Cultivated 3 hours in the incubator of damp atmosphere, add 150 milliliters of methyl-sulphoxides in every hole, the MTT crystal Jia Za (formazan) that the vibration dissolving generates, formed Jia Za microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Wherein Compound I-k is to the half-inhibition concentration (IC of K562 cell
50) obtain by dose effect curve.
The mensuration of cell survival rate is with improveing mtt assay, and concrete grammar is with embodiment 30.
To the chronic myelogone leukemia K 562 of people cell 503nhibiting concentration IC
50Obtain by dose effect curve.The IC of Compound I-k
50For: 34.5 μ M.
As positive control, Dasatinib and H-89 are to the chronic myelogone leukemia cell's of people 503nhibiting concentration IC with an antitumor line medication Dasatinib and the PKB inhibitor H-89 that reported in this test
50Be respectively 35.2 and 49.6 μ M.
This experiment shows that this type of new substituted piperazine N-ethyl sulfonamide derivative has cytotoxicity to the chronic myelogone leukaemia cancer cell of people K562 cell, might develop into the new medicine with anti-chronic myelogone leukemia effect.
Embodiment 32: Compound I-y is to the cytotoxic activity of human liver cancer cell (HepG2)
According to the method for embodiment 30, as positive control, Sutent and H-89 are to human hepatoma HepG2 cell's 503nhibiting concentration IC with an antitumor line medication Sutent and the PKB inhibitor H-89 that reported in this test
50Be respectively 20.1 μ M and 40.4 μ M.
Wherein Compound I-y is to human hepatoma HepG2 cell's 503nhibiting concentration IC
50Obtain by dose effect curve.The IC of Compound I-k
50Be 17.6 μ M.
This test shows that this type of new substituted piperazine N-ethyl sulfonamide derivative has stronger cytotoxicity to the human hepatoma HepG2 cell, might develop into the new medicine with antihepatocarcinoma effect.
Embodiment 33: Compound I-j is to the cytotoxic activity of human cervical carcinoma cell (Hela)
According to the method for embodiment 30, as positive control, Sutent and H-89 are to the 503nhibiting concentration IC of human cervical carcinoma Hela cell with an antitumor line medication Sutent and the PKB inhibitor H-89 that reported in this test
50Be respectively 19.4 μ M and 51.8 μ M.
Wherein Compound I-j is to Hela cell 503nhibiting concentration IC
50Obtain by dose effect curve.The IC of Compound I-j
50Be 20.6 μ M.
This test shows that this type of new substituted piperazine N-ethyl sulfonamide derivative has stronger cytotoxicity to human cervical carcinoma Hela cell, might develop into the new medicine with anti-cervical cancer effect.
Embodiment 34:Compound I-z is to the cytotoxic activity of human leukemia cell (HL60)
According to the method for embodiment 31, as positive control, Dasatinib and H-89 are to human leukemia cell's (HL60) 503nhibiting concentration IC with an antitumor line medication Dasatinib and the PKB inhibitor H-89 that reported in this test
50Be respectively 20.8 μ M and 51.4 μ M.
Wherein Compound I-z is to HL60 cell 503nhibiting concentration IC
50Obtain by dose effect curve.The IC of Compound I-z
50Be 18.1 μ M.
This test shows that this type of substituted piperazine N-ethyl sulfonamide derivative to human leukemia cell (HL60) is had stronger cytotoxicity, might develop into the new medicine with leukemia resisting action.
Claims (4)
1. substituted piperazine N-ethyl sulfonamide derivative, and their pharmacologically acceptable salt has following general structure:
Wherein: the sulfamic of replacement is at 1 or 2 of dicyclo; A, B, D, E is identical or different, selects carbon for use, nitrogen; R
1Select saturated or unsaturated alkyl, alkanamine methyl, the hydroxyalkyl of 1-5 carbon for use, or select replacement or unsubstituted benzyl for use; R
2Select saturated or unsaturated alkyl, replacement or unsubstituted benzyl and five yuan or the hexa-member heterocycle of 1-15 carbon for use.
2. the preparation method of substituted piperazine N-ethyl sulfonamide derivative according to claim 1, it is characterized in that realizing by following steps: substituted sulfonic acid obtains its chloride derivative through the thionyl chloride chlorination, replace L type amino acid and obtain L type amido alcohol compound through lithium aluminium hydride reduction, obtain compound IV with the sulfonyl chloride derivatives generation linked reaction that replaces, compound IV obtains its mesylate derivatives III through methylsulfonyl chloride protection, this derivative III be substituted single substituted-piperazinyl II that reaction and trifluoracetic acid deprotection obtain by single tertbutyloxycarbonyl protection piperazine and substitution reaction takes place under organic amine catalysis obtain substituted piperazine N-ethyl sulfonamide derivative I; Reaction formula is:
Wherein: A, B, D, E and radicals R
1, R
2Definition and claim 1 in identical.
3. the preparation method of substituted piperazine N-ethyl sulfonamide derivative according to claim 2 is characterized in that, preparing by Compound I I and III that the used organic amine of I selects for use is in Trimethylamine 99, triethylamine or the diisopropylethylamine any one.
4. the application in preparation control tumour medicine of substituted piperazine N-ethyl sulfonamide derivative according to claim 1 and their pharmacologically acceptable salt.
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| CN105566220A (en) * | 2016-01-22 | 2016-05-11 | 浙江工业大学 | Long-chain piperazine ethyl sulfonamide derivative or medicinal salt thereof and preparation method and application of long-chain piperazine ethyl sulfonamide derivative |
| CN113968816A (en) * | 2020-07-23 | 2022-01-25 | 合肥久诺医药科技有限公司 | Preparation method of isoquinoline-5-sulfonyl chloride hydrochloride |
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2010
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1642912A (en) * | 2002-03-13 | 2005-07-20 | 詹森药业有限公司 | Sulfonylamino-derivatives as novel inhibitors of histone deacetylase |
| WO2005030704A1 (en) * | 2003-09-24 | 2005-04-07 | Methylgene, Inc. | Inhibitors of histone deacetylase |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566220A (en) * | 2016-01-22 | 2016-05-11 | 浙江工业大学 | Long-chain piperazine ethyl sulfonamide derivative or medicinal salt thereof and preparation method and application of long-chain piperazine ethyl sulfonamide derivative |
| CN113968816A (en) * | 2020-07-23 | 2022-01-25 | 合肥久诺医药科技有限公司 | Preparation method of isoquinoline-5-sulfonyl chloride hydrochloride |
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| CN101851199B (en) | 2012-07-04 |
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