CN1176077C - Tegaserod maleate-water crystal - Google Patents
Tegaserod maleate-water crystal Download PDFInfo
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- CN1176077C CN1176077C CNB031126219A CN03112621A CN1176077C CN 1176077 C CN1176077 C CN 1176077C CN B031126219 A CNB031126219 A CN B031126219A CN 03112621 A CN03112621 A CN 03112621A CN 1176077 C CN1176077 C CN 1176077C
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- zelnorm
- crystallization
- water crystallization
- water
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Abstract
The present invention relates to a structural formula 2 active compound tegaserod maleate-water crystal. The crystal has good stability, and is more suitable for medicinal use than other crystal forms of tegaserod maleate. The present invention which is used as a part of excitomotors of a 5-HT#-[4] acceptor can be used for treating gastrointestinal tract diseases.
Description
Technical field
The present invention relates to toxilic acid 1-(5-methoxyl group-1H-indol-3-yl-methene amino)-3-n-pentyl guanidine one water crystallization.Toxilic acid 1-(5-methoxyl group-1H-indol-3-yl-methene amino)-3-n-pentyl guanidine one water crystallization is commonly called as Zelnorm one water crystallization.In addition, the invention still further relates to Zelnorm one water crystallization treatment in the gastrointestinal tract disease application and prepare the method for Zelnorm one water crystallization.
Background technology
Zelnorm is indoles aminoguanidine compounds (structural formula I), with 5-HT
4Receptor binding capacity is and more than 25 times of other 5-HT subtype acceptor binding ability.By selectively acting in 5-HT
4Acceptor promotes gastrointestinal peristalsis, reaches the effect of regulating gastrointestinal function, and its two kinds of cardinal symptom enteron aisle kinetics and sensitivity to pain to the emergent syndromes (IBS) of intestines all has effect, is a kind of brand-new IBS curative.
The Crystal forms of Tegaserod Maleate structure is not also studied report.
Summary of the invention
Purpose of the present invention provides a kind of Zelnorm that contains a water crystallization.
Another object of the present invention provides the method that preparation contains the Zelnorm of a water crystallization.
In addition, a further object of the invention is the application of Zelnorm in the treatment gastrointestinal tract disease that contains a water crystallization.
We find that it has two kinds of crystal habits at least when research Zelnorm process for purification and crystallization condition, the one, and anhydrous crystal (being called for short the crystallization of W type) is in addition for containing a water crystallization (being called for short the crystallization of S type, structural formula II).
Discover that at present as oral pharmaceutical, the crystallization of Zelnorm S type is than the easier stripping of W type crystallization in pharmaceutical preparation.There were significant differences for crystallization of S type and W type crystalline biological characteristics, and S type crystalline bioavailability is apparently higher than the crystallization of W type in mouse.With W type crystallization phases ratio, the crystallization of S type is preferably medicinal.
S type crystalline thermodynamics is stable, at 105 ℃ of dry 4h almost without any variation.Thermogravimetric analysis (TGA) is 145～155 ℃ of weightlessness 3.7～4.2%, and is in full accord with the theoretical water ratio of S type crystalline.
Different with the Zelnorm anhydrous crystal, in differential scanning calorimetry (DSC), the crystallization of S type has two endotherm(ic)peaks, is respectively 143 ℃ and 186 ℃.And anhydrous crystal has only 186 ℃ of endotherm(ic)peaks.
Zelnorm S type crystalline powder X ray diffracting data is as follows:
Diffraction angle (2 θ) d-value intensity (cps) relative intensity
6.98 12.65 1472 35
7.82 11.29 1760 42
10.23 8.64 2208 52
15.88 5.58 1696 40
16.78 5.28 1712 41
19.48 4.55 1520 36
20.62 4.30 1552 37
21.40 4.15 2176 52
23.27 3.82 2224 53
25.37 3.51 4224 100
The present invention can pass through crystallization in water-containing organic solvent, be easy to obtain the crystallization of Zelnorm S type, wherein, organic solvent is the organic solvent that dissolves each other with water, as 50%～95% ethanol, methyl alcohol, Virahol and acetone, acetonitrile, dimethyl formamide etc., preferably at 75% ethanol and 80% methyl alcohol.
Prepared Zelnorm one water crystallization of the present invention, as the gastrointestinal tract disease curative, by selectively acting in 5-HT
4Acceptor promotes gastrointestinal peristalsis, reaches the effect of regulating gastrointestinal function.
Description of drawings
Fig. 1 is Zelnorm S type heat of crystallization weight analysis figure of the present invention.
Fig. 2 is Zelnorm W type heat of crystallization weight analysis figure of the present invention
Fig. 3 is Zelnorm S type crystallization differential scanning calorimetry figure of the present invention.
Fig. 4 is Zelnorm W type crystallization differential scanning calorimetry figure of the present invention.
Fig. 5 is Zelnorm S type crystallization X-ray powder diffraction figure of the present invention.
Fig. 6 is Zelnorm W type crystallization X-ray powder diffraction figure of the present invention.
Embodiment
Reference example 1
The preparation of 1-(5-methoxyl group-1H-indol-3-yl-methene amino)-3-n-pentyl guanidine
In the 1000ml reaction flask, add methyl alcohol 750ml, the amino croak 97g (0.352mol) of hydroiodic acid HI N-amyl group-N`-, stir and add 5-methoxyl group indole-3-formaldehyde 62.3g (0.356mol) down, slowly the interior temperature of heating is 35 ℃, drip concentrated hydrochloric acid and transfer reaction solution pH3～4, solution becomes red to red-purple gradually.Room temperature reaction 5h.Add toxilic acid 41g (0.351mol), crystallisation by cooling filters, and methanol wash gets Zelnorm 100g, yield 69%.
Reference example 2
The preparation of Zelnorm W type crystalline
Zelnorm 10g, methyl alcohol 200ml, heating for dissolving, cold slightly, add gac 1g, backflow 15min, filtered while hot, crystallisation by cooling filters, and the small amount of methanol washing gets Zelnorm W crystallization 8.1g, yield 81%.
Embodiment 1
The preparation of Zelnorm S type crystalline
Zelnorm 20g, 75% ethanol 300ml, heating for dissolving, cold slightly, add gac 1g, backflow 15min, filtered while hot, crystallisation by cooling filters, and 75% washing with alcohol gets Zelnorm S crystallization 8.6g, yield 86%.
Embodiment 2
The preparation of Zelnorm S type crystalline
Zelnorm 20g, 80% methyl alcohol 300ml, heating for dissolving, cold slightly, add gac 1g, backflow 15min, filtered while hot, crystallisation by cooling filters, and 80% washing with alcohol gets Zelnorm S crystallization 8.7g, yield 87%.
Claims (8)
1. Zelnorm one water crystallization, it is characterized in that: Zelnorm one water crystallization structural formula is as follows
2. Zelnorm one water crystallization according to claim 1 is characterized in that: in the Zelnorm one water crystallization thermogravimetric analysis, 145～155 ℃ of weightlessness 3.7～4.2%.
3. Zelnorm one water crystallization according to claim 1 is characterized in that: in the Zelnorm one water crystallization differential scanning calorimetry two endotherm(ic)peaks are arranged, be respectively 143 ℃ and 186 ℃.
4. according to claims 1 described Zelnorm one water crystallization, it is characterized in that: have diffraction angle 6.98,7.82,10.23,15.88,16.78,19.48,20.62,21.40,23.27,25.37 among the Zelnorm one water crystallization X-ray powder diffraction figure.
5. a method for preparing each described Zelnorm one water crystallization of claim 1-4 is characterized in that structural formula II crystallization in aqueous organic solvent.
6. the preparation method of Zelnorm one water crystallization according to claim 5 is characterized in that organic solvent is the organic solvent that dissolves each other with water.
7. the preparation method of Zelnorm one water crystallization according to claim 6 is characterized in that this organic solvent is methyl alcohol, ethanol, Virahol, acetone, acetonitrile, dimethyl formamide.
8. any defined Zelnorm one water crystallization of claim 1-4 is as the application of activeconstituents in preparation treatment gastrointestinal tract disease medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031126219A CN1176077C (en) | 2003-01-07 | 2003-01-07 | Tegaserod maleate-water crystal |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031126219A CN1176077C (en) | 2003-01-07 | 2003-01-07 | Tegaserod maleate-water crystal |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1425651A CN1425651A (en) | 2003-06-25 |
| CN1176077C true CN1176077C (en) | 2004-11-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB031126219A Expired - Fee Related CN1176077C (en) | 2003-01-07 | 2003-01-07 | Tegaserod maleate-water crystal |
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Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR045081A1 (en) * | 2003-07-24 | 2005-10-12 | Novartis Ag | STABLE MODIFICATIONS OF TEGASEROD HYDROGEN MALEATE |
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2003
- 2003-01-07 CN CNB031126219A patent/CN1176077C/en not_active Expired - Fee Related
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| CN1425651A (en) | 2003-06-25 |
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