CN101914100B - Benzenesulfonyl lupetazin derivative and preparation method thereof - Google Patents
Benzenesulfonyl lupetazin derivative and preparation method thereof Download PDFInfo
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- CN101914100B CN101914100B CN 201010145986 CN201010145986A CN101914100B CN 101914100 B CN101914100 B CN 101914100B CN 201010145986 CN201010145986 CN 201010145986 CN 201010145986 A CN201010145986 A CN 201010145986A CN 101914100 B CN101914100 B CN 101914100B
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- 0 CCOc(c(C(NC1=O)=NC(C(*)=N)=C1[N+]C)c1)ccc1S(N1CC(C)NC(C)C1)(=O)=O Chemical compound CCOc(c(C(NC1=O)=NC(C(*)=N)=C1[N+]C)c1)ccc1S(N1CC(C)NC(C)C1)(=O)=O 0.000 description 2
Abstract
The invention provides a benzenesulfonyl lupetazin derivative, which is obtained by reacting benzenesulfonyl lupetazin with acid and alkali metal elements or an ammonia (ammonium) compound or amino acid or amino alcohol in turn or directly reacting the benzenesulfonyl lupetazin with acid salt. When acid or the acid salt is a sulfate radical, benzenesulfonyl lupetazin complex bisulfate is obtained; and when acid or the acid salt is a phosphate radical, benzenesulfonyl lupetazin complex dihydric phosphate is obtained. A method of the invention has the advantages of reasonable design, stable process and high production practicability. The benzenesulfonyl lupetazin derivative provided by the invention has the remarkable advantages of high solubility, high bioavailability and the like and can be prepared into a preparation. After the preparation is taken orally, benzenesulfonyl lupetazin goes into blood, so that a better effect for treating male erectile dysfunction is achieved. The derivative has the structural formula shown in the specifications.
Description
Technical field
The invention belongs to the compound preparation, relate to benzenesulfonyl lupetazin derivative and preparation method and effect.
Background technology
The benzenesulfonyl lupetazin clinical application is its Citrate trianion, and also name citric acid edenaphy is the synthetic new drug of Oral Chemical of China's autonomous design development.
Experimentation on animals shows; the benzenesulfonyl lupetazin Citrate trianion can obviously promote rat erection activity; show: the first response latency obviously shortens; the erectile response number of times obviously increases; the erection time length obviously prolongs; area obviously increases under intracavernous pressure-time curve, and its effect and intensity are similar to sildenafil citrate.The mechanism of action of benzenesulfonyl lupetazin Citrate trianion is the PDE that selectivity suppresses to decompose cGMP
5, improve the cGMP level, strengthen the effect of NO.One, the second stage of clinical study confirms that all it has obvious therapeutic action to ED.
Erection function scoring score was obviously greater than placebo after clinical experimental study showed benzenesulfonyl lupetazin Citrate trianion 60mg treatment; treatment group relatively has utmost point significant difference before and after taking medicine, and illustrates that benzenesulfonyl lupetazin Citrate trianion 60mg treatment ED is effective.The untoward reaction that single is taken the benzenesulfonyl lupetazin Citrate trianion is visual abnormality, flushed face, headache or dizziness etc.The incidence of untoward reaction increases with dosage.Structure and the preparation method of benzenesulfonyl lupetazin are disclosed among the CN1393444.
Summary of the invention
The object of the present invention is to provide a kind of quality height, good stability, solubleness is good, bioavailability is high benzenesulfonyl lupetazin derivative.
Benzenesulfonyl lupetazin derivative of the present invention has formula (I) general structure:
Wherein:
M is a kind of in basic metal, ammonia (or ammonium), amino acid, the amino alcohol, and described basic metal is Na
+, K
+Or Cs
+, amino acid is arginine, ornithine, citrulline or Methionin, amino alcohol is tromethane, amino-propanediol, monoethanolamine or glucosamine.
Y is SO4
2-(sulfate radical) or HPO4
2-(phosphoric acid one hydrogen root).
The present invention also provides two kinds of preparation methods of described benzenesulfonyl lupetazin derivative:
The first preparation method realizes by following steps: benzenesulfonyl lupetazin and equimolar acid (H
2Y) in polar solvent, mix after; make benzenesulfonyl lupetazin acid salt; after the compound of adding and the equimolar alkali metal containing of benzenesulfonyl lupetazin or ammonium compound or amino acid or amino alcohol react completely again; concentrated; add the weak polar solvent crystallization; filter, with solid drying, namely get benzenesulfonyl lupetazin derivative.
Reaction formula is
Wherein M, Y in the compound (I) definition.
Alkali metal compound comprises in the method for making: a kind of in sodium methylate, potassium methylate, methyl alcohol caesium, sodium ethylate, potassium ethylate, ethanol caesium, sodium propylate, potassium propylate, propyl alcohol caesium, sodium butylate, butanols potassium, butanols caesium, sodium isopropylate, potassium isopropoxide, Virahol caesium, butyl alcohol-tert sodium, butyl alcohol-tert potassium, butyl alcohol-tert caesium, sodium-acetate, Potassium ethanoate, cesium acetate, Sodium Propionate, potassium propionate, propionic acid caesium, Sodium propanecarboxylate, potassium butyrate, butyric acid caesium, sodium hydroxide, potassium hydroxide or the cesium hydroxide.Ammonium or ammoniate are selected a kind of in ammonia, ammoniacal liquor, ammonium acetate, propionic acid ammonium or the butyric acid ammonium.
R is CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, CH
3CH
2CH
2CH
2-, (CH
3)
2CH-, (CH
3)
3C-, CH
3CO-, CH
3CH
2CO-, CH
3CH
2CH
2A kind of among CO-, the H.
The second is the preparation method realize by following steps: with benzenesulfonyl lupetazin with after acid salt MHY mixes in polar solvent, reacts completely with 1: 1 mol ratio; concentrated, add the weak polar solvent crystallization, filter; with solid drying, namely get benzenesulfonyl lupetazin derivative.
Reaction formula is
Wherein M, Y in the compound (I) definition.
Acid salt described in the preparation method (MHY) is selected a kind of in sodium pyrosulfate, sal enixum, monoammonium sulfate, cesium hydrogen sulfate, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate, primary ammonium phosphate or the cesium dihydrogen phosphate.
Described polar solvent is selected a kind of among water, ethanol, methyl alcohol, Virahol, acetone, DMF (DMF) or the DMSO (dimethyl sulfoxide (DMSO)) during reaction.
The weak polar solvent that described its crystallization is used is a kind of in ether, sherwood oil, normal hexane or the hexanaphthene.
Benzenesulfonyl lupetazin derivative of the present invention comprises benzenesulfonyl lupetazin hydrogen sulfate double salt and benzenesulfonyl lupetazin biphosphate double salt.
The method for making of benzenesulfonyl lupetazin hydrogen sulfate double salt of the present invention is:
1. benzenesulfonyl lupetazin is with after equimolar sulfuric acid mixes in polar solvent, add and the equimolar alkali metal-containing compound of benzenesulfonyl lupetazin or ammonium compound or amino acid or amino alcohol again, after reacting completely, concentrated, add the weak polar solvent crystallization, filter, with solid drying, namely get benzenesulfonyl lupetazin hydrogen sulfate double salt;
2. benzenesulfonyl lupetazin and equimolar sodium pyrosulfate or sal enixum or cesium dihydrogen phosphate or monoammonium sulfate mix, and be concentrated after reacting completely, and adds the weak polar solvent crystallization, filters, and with solid drying, namely gets benzenesulfonyl lupetazin hydrogen sulfate double salt.
The method for making of benzenesulfonyl lupetazin biphosphate double salt of the present invention is:
1. benzenesulfonyl lupetazin is with after equimolar phosphoric acid mixes in polar solvent, add and the equimolar alkali metal-containing compound of benzenesulfonyl lupetazin or ammonium compound or amino acid or amino alcohol again, after reacting completely, concentrated, add the weak polar solvent crystallization, filter, with solid drying, namely get benzenesulfonyl lupetazin biphosphate double salt;
2. benzenesulfonyl lupetazin and equimolar SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate or cesium dihydrogen phosphate or primary ammonium phosphate mix, and be after reacting completely, concentrated; add the weak polar solvent crystallization; separate out solid filtering, with solid drying, namely get benzenesulfonyl lupetazin biphosphate double salt.
Preparation method of the present invention is reasonable, and technique is simple.Benzenesulfonyl lupetazin double salt purity, content by the inventive method preparation are high, have good stability, characteristics that quality is high.Described benzenesulfonyl lupetazin derivative bioavailability is high, is converted into benzenesulfonyl lupetazin in the oral rear body, and enters blood with benzenesulfonyl lupetazin, absorbs fast, rapid-action, thereby bring into play better curative effect.
Embodiment
The present invention is further described in conjunction with the embodiments.Present invention is described for following examples, and these examples only are can not be interpreted as limitation of the scope of the invention in order to illustrate.
Embodiment 1
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous methanol; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 556mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 68mg sodium ethylate reaction 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 526mg, yield 91%.
Embodiment 2
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 572mg; benzenesulfonyl lupetazin acid salt is mixing in DMF again; add 84mg potassium ethylate reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain white solid benzenesulfonyl lupetazin sal enixum double salt 458mg, yield 75%.
Embodiment 3
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml dry DMF; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 559mg; benzenesulfonyl lupetazin acid salt is mixing in ethanol again; add 92mg propionic acid ammonium reaction 3 hours, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain white solid benzenesulfonyl lupetazin monoammonium sulfate double salt 403mg, yield 70%.
Embodiment 4
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; with the anhydrous DMSO dissolving of 50ml; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 579mg; benzenesulfonyl lupetazin acid salt is mixing in methyl alcohol again; add 164mg methyl alcohol caesium reaction 3 hours, concentrating under reduced pressure adds an amount of hexanaphthene; separate out solid, filtration; with hexanaphthene washing, drying, obtain white solid benzenesulfonyl lupetazin cesium hydrogen sulfate double salt 248mg, yield 35%.
Embodiment 5
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 577mg; benzenesulfonyl lupetazin acid salt is mixing in methyl alcohol again; add 82mg sodium propylate reaction 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain white solid benzenesulfonyl lupetazin SODIUM PHOSPHATE, MONOBASIC double salt 540mg, yield 82%.
Embodiment 6
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous methanol; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 580mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 98mg potassium propylate reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain white solid benzenesulfonyl lupetazin potassium primary phosphate double salt 445mg, yield 72%.
Embodiment 7
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml dry DMF; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 580mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 77mg ammonium acetate reaction 1 hour, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain white solid benzenesulfonyl lupetazin primary ammonium phosphate double salt 340mg, yield 57%.
Embodiment 8
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 575mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 192mg propyl alcohol caesium reaction 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain white solid benzenesulfonyl lupetazin cesium dihydrogen phosphate double salt 282mg, yield 40%.
Embodiment 9
In the 100ml reaction flask, add 50ml water, sodium pyrosulfate 120mg stirs, and adds benzene sulfonyl again
Base lupetazin 488.6mg, after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 603mg, yield 99%.
Embodiment 10
In the 100ml reaction flask, add 50ml water, sal enixum 136mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 425mg, yield 68%.
Embodiment 11
In the 100ml reaction flask, add 50ml water, monoammonium sulfate 115mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 392mg, yield 65%.
Embodiment 12
In the 100ml reaction flask, add 50ml water, cesium hydrogen sulfate 230mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 273mg, yield 38%.
Embodiment 13
In the 100ml reaction flask, add 50ml water, SODIUM PHOSPHATE, MONOBASIC 120mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 596mg, yield 98%.
Embodiment 14
In the 100ml reaction flask, add 50ml water, potassium primary phosphate 136mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 443mg, yield 71%.
Embodiment 15
In the 100ml reaction flask, add 50ml water, primary ammonium phosphate 115mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 320mg, yield 53%.
Embodiment 16
In the 100ml reaction flask, add 50ml water, cesium dihydrogen phosphate 230mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 302mg, yield 42%.
Embodiment 17
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 556mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 121.14mg tromethane reaction 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate tromethane 623mg, yield 92%.
Embodiment 18
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous methanol; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 556mg; benzenesulfonyl lupetazin acid salt is mixing in DMF again; add 121.14mg tromethane reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain the amino trihydroxybutane 609mg of white solid benzenesulfonyl lupetazin biphosphate, yield 90%.
Embodiment 19
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous isopropyl alcohol; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 556mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 91.11mg amino-propanediol reaction 2 hours, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate amino-propanediol 466mg, yield 72%.
Embodiment 20
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml dry DMF; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 550mg; benzenesulfonyl lupetazin acid salt is mixing in methyl alcohol again; add 91.11mg amino-propanediol reaction 2 hours, concentrating under reduced pressure adds an amount of hexanaphthene; separate out solid, filtration; with hexanaphthene washing, drying, obtain the amino propylene glycol 449mg of white solid benzenesulfonyl lupetazin biphosphate, yield 70%.
Embodiment 21
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 553mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 61.08mg monoethanolamine reaction 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate monoethanolamine 430mg, yield 70%.
Embodiment 22
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; with the anhydrous DMSO dissolving of 50ml; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 550mg; benzenesulfonyl lupetazin acid salt is mixing in methyl alcohol again; add 61.08mg monoethanolamine reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain the amino ethanol 446mg of white solid benzenesulfonyl lupetazin biphosphate, yield 73%.
Embodiment 23
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous propanone; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 550mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 179.17mg glucosamine reaction 2 hours, concentrating under reduced pressure adds an amount of hexanaphthene; separate out solid, filtration; with hexanaphthene washing, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate glucosamine 481mg, yield 66%.
Embodiment 24
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous isopropyl alcohol; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 549mg; benzenesulfonyl lupetazin acid salt is mixing in ethanol again; add 179.17mg glucosamine reaction 2 hours, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain the amino glucose 473mg of white solid benzenesulfonyl lupetazin biphosphate, yield 65%.
Embodiment 25
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml dry DMF; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 553mg; benzenesulfonyl lupetazin acid salt is mixing in Virahol again; add the smart sour ammonia react of 174.2mg 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain the smart sour ammonia 676mg of white solid benzenesulfonyl lupetazin hydrogen sulfate, yield 93%.
Embodiment 26
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; with the anhydrous DMSO dissolving of 50ml; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 554mg; benzenesulfonyl lupetazin acid salt is mixing in ethanol again; add the smart sour ammonia react of 174.2mg 2 hours, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain the smart sour ammonia 685mg of white solid benzenesulfonyl lupetazin biphosphate, yield 94%.
Embodiment 27
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous methanol; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 564mg; benzenesulfonyl lupetazin acid salt is mixing in DMF again; add 132.16mg ornithine reaction 2 hours, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate ornithine 404mg, yield 58%.
Embodiment 28
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous propanone; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 564mg; benzenesulfonyl lupetazin acid salt is mixing in DMSO again; add 132.16mg ornithine reaction 2 hours, concentrating under reduced pressure adds an amount of hexanaphthene; separate out solid, filtration; with hexanaphthene washing, drying, obtain white solid benzenesulfonyl lupetazin biphosphate ornithine 348mg, yield 50%.
Embodiment 29
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml dry DMF; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 560mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 175.19mg citrulline reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate citrulline 441mg, yield 60%.
Embodiment 30
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 563mg; benzenesulfonyl lupetazin acid salt is mixing in methyl alcohol again; add 175.19mg citrulline reaction 2 hours, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain white solid benzenesulfonyl lupetazin biphosphate citrulline 480mg, yield 65%.
Embodiment 31
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; with the anhydrous DMSO dissolving of 50ml; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 549mg; benzenesulfonyl lupetazin acid salt is mixing in DMF again; add 146.19mg Methionin reaction 2 hours, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate Methionin 431mg, yield 62%.
Embodiment 32
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 550mg; benzenesulfonyl lupetazin acid salt is mixing in DMF again; add 146.19mg Methionin reaction 2 hours, concentrating under reduced pressure adds an amount of hexanaphthene; separate out solid, filtration; with hexanaphthene washing, drying, obtain white solid benzenesulfonyl lupetazin biphosphate Methionin 404mg, yield 58%.
Embodiment 33
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml water dissolution; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 581mg; benzenesulfonyl lupetazin acid salt is mixing in ethanol again; add 68mg sodium ethylate reaction 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 643mg, yield 99%.
Embodiment 34
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml water dissolution; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 580mg; benzenesulfonyl lupetazin acid salt is mixing in Virahol again; add 82mg n-propyl alcohol sodium reaction 1 hour, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain white solid benzenesulfonyl lupetazin SODIUM PHOSPHATE, MONOBASIC double salt 649mg, yield 98%.
Embodiment 35
Pressing 2005 editions solubleness vocabularies of terms of Chinese Pharmacopoeia explains; the solubleness of new compound of the present invention in water sees Table 1; benzenesulfonyl lupetazin is insoluble in water, benzenesulfonyl lupetazin Citrate trianion slightly soluble in water, and compound dissolution degree of the present invention all reaches slightly molten.
Table 1
| Sequence number | New compound | Solubleness |
| 1 | Benzenesulfonyl lupetazin sodium pyrosulfate double salt | Slightly molten |
| 2 | Benzenesulfonyl lupetazin sal enixum double salt | Slightly molten |
| 3 | Benzenesulfonyl lupetazin hydrogen sulfate Arginine Salts | Slightly molten |
| 4 | Benzenesulfonyl lupetazin hydrogen sulfate tromethane double salt | Slightly molten |
| 5 | Benzenesulfonyl lupetazin SODIUM PHOSPHATE, MONOBASIC double salt | Slightly molten |
| 6 | Benzenesulfonyl lupetazin potassium primary phosphate double salt | Slightly molten |
| 7 | The amino trihydroxybutane double salt of benzenesulfonyl lupetazin biphosphate | Slightly molten |
Embodiment 36
The beagle dog is adopted in the bioavailability test, and is complete male, body weight 10kg, and fasting 12h can't help water; Control group benzenesulfonyl lupetazin Citrate trianion capsule.Medicine of the present invention is directly overlapped into capsule (being 20mg in the benzenesulfonyl lupetazin Citrate trianion) gavage; feed in about 3 hours after the gavage; respectively 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h and the about 0.5mL of 10h venous blood collection after gavage; measure the benzenesulfonyl lupetazin Plasma Concentration, the results are shown in Table 2.Illustrate that compound of the present invention is significantly improved than benzenesulfonyl lupetazin Citrate trianion bioavailability.Peak time significantly shifts to an earlier date, and the results are shown in Table 3.
Table 2 compares with the benzenesulfonyl lupetazin Citrate trianion, and the relative bioavailability of the compounds of this invention is:
| Medicine | Relative bioavailability |
| Benzenesulfonyl lupetazin sodium pyrosulfate double salt | 130％ |
| Benzenesulfonyl lupetazin sulfuric acid Arginine Salts | 125％ |
| Benzenesulfonyl lupetazin sulfuric acid tromethane double salt | 126％ |
| Benzenesulfonyl lupetazin SODIUM PHOSPHATE, MONOBASIC double salt | 128％ |
| Benzenesulfonyl lupetazin phosphoric acid hydrogen tromethane double salt | 124％ |
| Benzenesulfonyl lupetazin phosphoric acid hydrogen Arginine Salts | 123％ |
The peak time of table 3 the compounds of this invention and benzenesulfonyl lupetazin Citrate trianion compares:
| Medicine | Peak time |
| The benzenesulfonyl lupetazin Citrate trianion | 2 hours |
| Benzenesulfonyl lupetazin sodium pyrosulfate double salt | 0.9 hour |
| Benzenesulfonyl lupetazin sulfuric acid tromethane double salt | 1 o'clock |
Claims (5)
1. a class benzenesulfonyl lupetazin derivative has following general structure:
Wherein:
M is a kind of in basic metal, the ammonium ion,
Described basic metal is Na
+, K
+Or Cs
+
Y is SO
4 2-Or HPO
4 2-
2. the preparation method of benzenesulfonyl lupetazin derivative according to claim 1 is characterized in that realizing by following steps:
1-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3,5-lupetazin and equimolar H
2After Y mixes in polar solvent; make acid salt, add and 1-［ 3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4 again; 3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3; after the equimolar alkali metal compound of 5-lupetazin or ammonium compound react completely, concentrated, add the weak polar solvent crystallization; filter; with solid drying, namely get the purpose derivative
Reaction formula is:
Wherein the definition of M, Y is with claim 1,
Described alkali metal compound is selected: sodium methylate, potassium methylate, the methyl alcohol caesium, sodium ethylate, potassium ethylate, the ethanol caesium, sodium propylate, potassium propylate, the propyl alcohol caesium, sodium butylate, butanols potassium, the butanols caesium, sodium isopropylate, potassium isopropoxide, the Virahol caesium, butyl alcohol-tert sodium, butyl alcohol-tert potassium, the butyl alcohol-tert caesium, sodium-acetate, Potassium ethanoate, cesium acetate, Sodium Propionate, potassium propionate, the propionic acid caesium, Sodium propanecarboxylate, potassium butyrate, the butyric acid caesium, sodium hydroxide, a kind of in potassium hydroxide or the cesium hydroxide, described ammonium compound is selected ammonium acetate, a kind of in propionic acid ammonium or the butyric acid ammonium, described polar solvent is selected water, ethanol, methyl alcohol, Virahol, acetone, a kind of among DMF or the DMSO; The weak polar solvent that crystallization is used is selected a kind of in ether, sherwood oil, normal hexane or the hexanaphthene;
R is CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, CH
3CH
2CH
2CH
2-, (CH
3)
2CH-, (CH
3)
3C-, CH
3CO-, CH
3CH
2CO-, CH
3CH
2CH
2A kind of among CO-or the H.
3. the preparation method of benzenesulfonyl lupetazin derivative according to claim 1 is characterized in that realizing by following steps:
With 1-［ 3-(6; 7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4; 3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3; the 5-lupetazin is with after acid salt MHY mixes in polar solvent, reacts completely with the mol ratio of 1:1, and is concentrated, adds the weak polar solvent crystallization; filter; with solid drying, namely get the purpose derivative
Reaction formula is
Wherein the definition of M, Y is with claim 1,
Described acid salt selects a kind of in sodium pyrosulfate, sal enixum, monoammonium sulfate, cesium hydrogen sulfate, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate, primary ammonium phosphate or the cesium dihydrogen phosphate, described polar solvent to select a kind of among water, ethanol, methyl alcohol, Virahol, acetone, DMF or the DMSO; The weak polar solvent that crystallization is used is selected a kind of in ether, sherwood oil, normal hexane or the hexanaphthene.
4. according to claim 2 or the preparation method of 3 described benzenesulfonyl lupetazin derivatives, it is characterized in that the hydrogen sulfate double salt of described derivative is realized by following steps respectively:
1. 1-［ 3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3, the 5-lupetazin is with after equimolar sulfuric acid mixes in polar solvent, add and 1-［ 3-(6 again, 7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3, the equimolar alkali metal compound of 5-lupetazin or ammonium compound, after reacting completely, concentrated, add the weak polar solvent crystallization, filter, with solid drying, namely get hydrogen sulfate double salt;
2. 1-［ 3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3,5-lupetazin and equimolar sodium pyrosulfate or sal enixum or cesium hydrogen sulfate or monoammonium sulfate mix, and be after reacting completely, concentrated, add the weak polar solvent crystallization, filter, with solid drying, namely get hydrogen sulfate double salt;
Described polar solvent and weak polar solvent are with claim 2 or 3.
5. according to claim 2 or the preparation method of 3 described benzenesulfonyl lupetazin derivatives, it is characterized in that the biphosphate double salt of described derivative is realized by following steps respectively:
1. 1-［ 3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3, the 5-lupetazin is with after equimolar phosphoric acid mixes in polar solvent, add and 1-［ 3-(6 again, 7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3, the equimolar alkali metal compound of 5-lupetazin or ammonium compound, after reacting completely, concentrated, add the weak polar solvent crystallization, filter, with solid drying, namely get biphosphate double salt;
2. 1-［ 3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3,5-lupetazin and equimolar SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate or cesium dihydrogen phosphate or primary ammonium phosphate mix, and be after reacting completely, concentrated, add the weak polar solvent crystallization, separate out solid filtering, with solid drying, namely get biphosphate double salt;
Described polar solvent and weak polar solvent are with claim 2 or 3.
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