CN100342851C - Pharmaceutical composition comprising crystalline sibutramine methanesulfonate hemihydrate - Google Patents
Pharmaceutical composition comprising crystalline sibutramine methanesulfonate hemihydrate Download PDFInfo
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Abstract
The present invention relates to a pharmaceutical composition for treating or preventing obesity, comprising novel crystalline sibutramine methanesulfonate hemihydrate of formula (I). The crystalline sibutramine methanesulfonate hemihydrate according to the present invention has a much higher solubility in water, and enhanced stability under a high humidity/temperature condition, as compared with sibutramine hydrochloride monohydrate.
Description
Technical field
The present invention relates to be used for the treatment of the pharmaceutical composition with prevention of obesity, it comprises the semihydrate crystal of sibutramine acid-addition salts.
Background technology
Sibutramine, with the N of following formula, N-dimethyl-1-[1-(4-chlorphenyl)-cyclobutyl]-the 3-methylbutylamine,
Can be used for that prevention or treatment are depressed, parkinson disease and obesity (referring to: GB patent 2,098,602, Korean Patent are announced 90-00274 and 99-164435 number and the open WO88/06444 of international patent application).In addition, sibutramine can be used for reducing to resistance of insulin and reducing or strengthens repellence to sugar, and be used for prevention or treatment such as gout, hyperuricemia, hyperlipemia, osteoarthritis, anxiety disorder, sleep disease, sexual dysfunction, chronic fatigue syndrome and cholelithiasis (referring to the 6th, 174,925,5,459,164,6,187,820,6,162,831,6,232,347,6,355,685,6,365,631,6,376,554,6,376,551 and 6,376, No. 552 United States Patent (USP)s).
Yet, because sibutramine has low melting point, so it is to use with the form of acid-addition salts in medicinal application.
GB patent 2,098,302 and Korean Patent bulletin 90-00274 has disclosed the preparation sibutramine and as the method for the anhydrous salt hydrochlorate of the acceptable acid-addition salts form of materia medica.But anhydrous sibutramine hydrochlorate is highly hygroscopic.Therefore, in pharmaceutical composition, be difficult to use anhydrous sibutramine hydrochlorate.
For addressing the above problem, develop the non-hygroscopic sibutramine hydrochloride monohydrate (referring to GB patent 2,184,122 and Korean Patent bulletin 94-08913) of formula (IV), for example be used for the treatment of obesity.
But, the sibutramine hydrochloride monohydrate that is used for the treatment of fat formula (IV), for example Meridia and Reductil, in water, has lower dissolubility, for example when pH 5.2 2.9mg/ml, this active component needed minimum solubility values that does not meet pharmaceutical composition is (referring to Merck Index, 13
ThEd, p 1522).
Therefore, still need to develop novel sibutramine salt or the hydrate crystal that is suitable in the pharmaceutical composition.The present inventor thereby develop sibutramine methanesulfonate hemihydrate hardy, it has high dissolubility in water, and is non-hygroscopic, is stable under high-temperature/damp condition.
Summary of the invention
Therefore, the purpose of this invention is to provide and be used for the treatment of or the pharmaceutical composition of prevention of obesity, it comprises the acid-addition salts of sibutramine, and this acid-addition salts has high-dissolvability in water, and is stable under high-temperature/damp condition.
Another object of the present invention provides the method for this acid-addition salts of preparation.
Description of drawings
By below in conjunction with the present invention of accompanying drawing explanation, above-mentioned and other purposes of the present invention and feature will become obviously, and these accompanying drawings show respectively:
Fig. 1 to Fig. 3 is respectively the x-ray diffractogram of powder spectrum of the sibutramine methanesulfonate monohydrate of the anhydrous sibutramine methanesulfonate of formula (I) crystalline sibutramine methanesulfonate hemihydrate, formula (II) according to the present invention and formula (IV).
Fig. 4 and Fig. 5 are respectively the differential thermograms of differential scanning calorimeter of the anhydrous sibutramine methanesulfonate of formula (I) crystalline sibutramine methanesulfonate hemihydrate according to the present invention and formula (II).
The specific embodiment
The invention provides and be used for the treatment of or the pharmaceutical composition of prevention of obesity, it comprises the novel crystalline sibutramine methanesulfonate hemihydrate of formula (I), and this crystal has high-dissolvability in water, and has high stability under humidity.
In addition, the present invention also provides crystalline sibutramine methanesulfonate hemihydrate of formula (I) and preparation method thereof.
At this, term " sibutramine " is meant the sibutramine of racemic modification, except as otherwise noted.
The crystalline sibutramine methanesulfonate hemihydrate of formula (I) has high-dissolvability in water, and is stable under high-temperature/damp condition, and is non-hygroscopic, and it is suitable in the pharmaceutical composition.
2 θ values of observed main peak are in the X-ray diffraction spectrum of the crystalline sibutramine methanesulfonate hemihydrate of the present invention's formula (I): 8.2 ± 0.2,10.8 ± 0.2,11.7 ± 0.2,12.0 ± 0.2,12.3 ± 0.2,15.8 ± 0.2,16.4 ± 0.2,17.4 ± 0.2,17.8 ± 0.2,19.0 ± 0.2,21.2 ± 0.2,21.9 ± 0.2,22.2 ± 0.2,22.8 ± 0.2,23.3 ± 0.2,24.4 ± 0.2,24.9 ± 0.2,25.3 ± 0.2,25.6 ± 0.2 and 26.8 ± 0.2.
The present invention also provides the method for the crystalline sibutramine methanesulfonate hemihydrate of two kinds of preparation formulas (I).
At first, sibutramine that the crystalline sibutramine methanesulfonate hemihydrate of formula (I) can be by making formula (II) and methanesulfonic acid react in the mixture of organic solvent and water and prepare (hereinafter referred to as first method).
In first method, the sibutramine of the formula with respect to 1 mole (II), the use amount of methanesulfonic acid can be preferably the 1-1.2 molar equivalent in the scope of 1-2 molar equivalent.Generally, methanesulfonic acid is dropped in the substrate, this substrate can be that purified sibutramine or its are dissolved in the solution in the organic solvent.
Described organic solvent can be ester, ether, ketone or their mixture.Described ester can be selected from following group: ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate.Ether can be selected from following group: diethyl ether, Di Iso Propyl Ether and t-butyl methyl ether.Ketone can be selected from following group: acetone, methyl ethyl ketone and methyl iso-butyl ketone (MIBK).When using the mixture of ketone and ether, the ratio of described ketone and ether is preferably 1: 0.5-1: in 1.5 the scope, and more preferably 1: 2-1: 3.
In the method, the sibutramine of the formula with respect to 1 mole (II), the use amount of water is in the scope of 0.5-5 molar equivalent, and behind the interpolation methanesulfonic acid, be reflected at 0 ℃ and to the reaction temperature of solvent boiling point, carry out, preferably under 15-35 ℃, carried out altogether 0.5-5 hour.
Secondly, the crystalline sibutramine methanesulfonate hemihydrate of formula (I) can be prepared as follows: the sibutramine and the methanesulfonic acid of formula (II) are reacted in anhydrous organic solvent, obtain the anhydrous sibutramine methanesulfonate of formula (III); And (ii) make the sibutramine methanesulfonate of formula (III) in organic solvent, contact (hereinafter referred to as second method) with water.
In the second approach, the sibutramine of the formula with respect to 1 mole (II), the use amount of methanesulfonic acid can be preferably the 1-1.2 molar equivalent in the scope of 1-2 molar equivalent.Generally, methanesulfonic acid being dropped to purified formula (II) sibutramine or its is dissolved in the solution in the organic solvent.
Described organic solvent can be ester, ketone, ether, toluene or their mixture.Described ester can be selected from following group: ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate.Ketone can be selected from following group: acetone, methyl ethyl ketone and methyl iso-butyl ketone (MIBK).Ether can be selected from following group: diethyl ether, Di Iso Propyl Ether and t-butyl methyl ether.
When described organic solvent was the mixture of ketone and ether, the ratio of described ketone and ether was preferably 1: 0.5-1: in 1.5 the scope, and more preferably 1: 2-1: 3.
In the second approach, the anhydrous sibutramine methanesulfonate of the formula with respect to 1 mole (III), the use amount of water is in the scope of 0.5-5 molar equivalent, and behind the interpolation methanesulfonic acid, be reflected at 0 ℃ and to the reaction temperature of solvent boiling point, carry out, preferably under 15-35 ℃, carried out altogether 0.5-5 hour.Preferably, the anhydrous sibutramine methanesulfonate of formula (III) contacts 2 hours to 5 days with water.
Crystalline sibutramine methanesulfonate hemihydrate according to the formula (I) of first method or second method preparation has high-dissolvability in water, and is non-hygroscopic, is high stability under humidity.
For comparing, checked enantiomer by sibutramine, whether (+) and (-) sibutramine can prepare crystalline sibutramine methanesulfonate hemihydrate.But, all do not make crystalline sibutramine methanesulfonate hemihydrate by (+) and (-) sibutramine.
Particularly, checked whether (+) and (-) sibutramine that is got by the separation of raceme sibutramine can prepare crystalline sibutramine methanesulfonate hemihydrate.Disclose randomly resolution of racemic sibutramine of WO00/10551 according to No. the 2002/0006963rd, 2002/0006964, U.S. Patent Application Publication or international patent application, obtain (+) and (-) sibutramine.Then, the method according to this invention is handled (+) and (-) sibutramine respectively, to observe whether all can make the methanesulfonate hemihydrate crystal by them.
Yet, when using method of the present invention, all do not obtain the methanesulfonate hemihydrate crystal with (+) and (-) sibutramine.Therefore, crystalline sibutramine methanesulfonate hemihydrate of the present invention is not to expect easily for those skilled in the art.
The present invention includes and be used for the treatment of the obesity and the pharmaceutical composition of relevant disease therewith, its crystalline sibutramine methanesulfonate hemihydrate that comprises formula (I) is as active component, and materia medica acceptable carrier, diluent, excipient or other additives.
Preferably, pharmaceutical composition of the present invention is with the oral formulations form administration of tablet or capsule.
Tablet can prepare by mixed active composition and carrier, diluent or excipient.The example of carrier, excipient and the diluent that can use in pharmaceutical composition of the present invention is disintegrating agent (as starch, sugar and mannitol), filler and extender (as calcium phosphate and silica derivative), binding agent (as carboxymethyl cellulose and derivant, gelatin and polyvinylpyrrolidone) and lubricant (as Talcum, calcium stearate and magnesium stearate and Polyethylene Glycol).
According to conventional methods, use or do not use additive, all can prepare the hard or soft capsule that comprises active component such as carrier, diluent and excipient.
Preferably, the content of crystalline sibutramine methanesulfonate hemihydrate in the present invention's pharmaceutical composition of formula (I) is the 1-50 weight portion, in the compositions of 250 weight portions.
For example, prepared pharmaceutical composition can comprise crystalline sibutramine methanesulfonate hemihydrate, 115mg microcrystalline Cellulose, 115mg lactose, 5mg silicon dioxide and the 5mg magnesium stearate of 10mg formula (I).But be understood that, the actual dosage of active component should be determined according to various correlative factors, these factors comprise patient's to be treated situation, age and the body weight and the order of severity of patient's symptom, and therefore above-mentioned proportion of composing never should limit the scope of the invention.
Crystalline sibutramine methanesulfonate hemihydrate of the present invention can be used for treatment or prevention of obesity.
Explanation the present invention will be advanced-be gone on foot to following examples, rather than to the restriction of its scope.
Preparation example 1
The sibutramine hydrochloride monohydrate of preparation formula (IV)
According to GB patent 2,098,602 or Korean Patent bulletin 90-00274 in the method described prepare anhydrous sibutramine hydrochlorate, then according to GB patent 2,184,122 or Korean Patent bulletin 94-08913 with this compound dissolution of 10g in the boiling mixture of acetone (110ml) and water (1.2ml), heat filtering, and distill concentrated filtrate.
Cooling concentration liquid filters then, obtains crystal.This crystal of vacuum drying obtains the title compound (productive rate: 87%) of 9.2g.
Embodiment 1
Crystalline sibutramine methanesulfonate hemihydrate according to first method preparation formula (I)
1-1) technology 1
Formula (II) sibutramine of 30.0g is dissolved in the isopropyl acetate of 120ml, adds the water of 1.94ml, then to the methanesulfonic acid that wherein drips 10.9g.Reactant mixture stirred 1 hour, was cooled to 0 ℃, and about 2 hours of restir filters then and obtains crystal.This crystal sequentially washs with the isopropyl acetate of 30ml and the isopropyl ether of 30ml, and is dry under 50 ℃ then, obtains the title compound of 38.46g, and it is a white solid (productive rate: 92.5%).
Fusing point: 164-165 ℃ (in the time of about 130 ℃, shrinking)
Moisture content: 2.35% (theoretical value: 2.34%)
1H-NMR(δ，DMSO-d6)：8.5(1H，br.s)，7.7-7.2(4H，dd)，3.7(1H，t)，2.8(3H，d)，2.5(2H，d)，2.4(3H，s)，2.3(2H，d)，2.1(3H，d)，1.9(1H，m)，1.7-1.6(2H，m)，1.3(2H，t)，1.0(6H，t).
1-2) technology 2
Formula (II) sibutramine of 10.0g is dissolved in the mixture of being made up of ethyl acetate and the 40ml t-butyl methyl ether of 40ml, adds the water of 0.97ml, then to the methanesulfonic acid that wherein drips 3.8g.Reactant mixture stirred 1 hour, was cooled to 0 ℃, and about 2 hours of restir filters then and obtains crystal.This crystal sequentially washs with the isopropyl acetate of 30ml and the isopropyl ether of 30ml, and is dry under 50 ℃ then, obtains the title compound of 12.1g, and it is a white solid (productive rate: 88%).The moisture content of this title compound be 2.38% (theoretical value: 2.34%), and fusing point and
1The H-NMR data all with 1-1) in observed identical.
1-3) technology 3
Repeat above-mentioned technology 1-2) step, make the title compound of 11.7g, difference is: use the acetone of 30ml and the t-butyl methyl ether of 60ml to substitute the ethyl acetate of 40ml and the t-butyl methyl ether of 40ml.The moisture content of this title compound be 2.27% (theoretical value: 2.34%), and fusing point and
1The H-NMR data all with 1-1) in observed identical.
Embodiment 2
Crystalline sibutramine methanesulfonate hemihydrate according to second method preparation formula (I)
2-1) the anhydrous sibutramine methanesulfonate of preparation formula (III) (the step 1) 2-1-1 of second method) technology 1
Formula (II) sibutramine of 10.0g is dissolved in the acetone of 70ml, then at room temperature to the methanesulfonic acid that wherein drips 3.75g.Reaction suspension stirred 1 hour, was cooled to 0 ℃, and about 2 hours of restir filters then and obtains crystal.This crystal is with the ether washing of 30ml, and is dry under 50 ℃ then, obtains the title compound of 11.7g, and it is a white solid (productive rate: 88%).
Fusing point: 164-165 ℃ (in the time of about 130 ℃, shrinking)
Moisture content: 2.35% (theoretical value: 2.34%)
1H-NMR(δ，DMSO-d6)：8.5(1H，br.s)，7.5(4H，dd)，3.7(1H，t)，2.8(3H，d)，2.5(2H，d)，2.4(3H，s)，2.3(2H，d)，2.1(3H，d)，1.9(1H，m)，1.7-1.6(2H，m)，1.3(2H，t)，1.0(6H，t).
2-1-2) technology 2
Formula (II) sibutramine of 10.0g is dissolved in the toluene of 80ml, then at room temperature to the methanesulfonic acid that wherein slowly drips 3.75g.Reaction suspension stirred 2 hours, was cooled to 0 ℃, and about 2 hours of restir filters then and obtains crystal.This crystal is with the ether washing of 20ml, then 50 ℃ dry down, obtain the title compound of 12.8g, its be white solid (productive rate: 95%), and fusing point with
1The H-NMR data all with 2-1-1) in observed identical.
2-1-3) technology 3
Repeat above-mentioned technology 2-1-2) step, (productive rate: 93%), difference is: use the acetic acid isopropyl esters to substitute toluene to make the title compound of 12.5g.The moisture content of this product be 2.27% (theoretical value: 2.34%), and fusing point and
1The H-NMR data all with 2-1-1) in observed identical.
2-2) the sibutramine methanesulfonate hemihydrate (step 2 of second method) of preparation formula (I)
2-2-1) technology 1
With 5.0g at 2-1-1) to 2-1-3) and make in the technology arbitrarily the anhydrous sibutramine methanesulfonate of formula (III) be dissolved in the mixture of 50ml ether and 25ml acetone, then to the water that wherein adds 0.72ml.Reactant mixture at room temperature stirred 18 hours, filtered then and obtained crystal.The mixture that this crystal usefulness 10ml is made up of ether and acetone (2: 1v/v) washing, 50 ℃ of following dryings, obtain the title compound of 3.89g, it is a white solid (productive rate: 76%).The moisture content of gained chemical compound be 2.30% (theoretical value: 2.34%), and fusing point and
1The H-NMR data all with 1-1) in observed identical.
2-2-2) technology 2
With 10.0g at 2-1-1) to 2-1-3) and make in arbitrarily the anhydrous sibutramine methanesulfonate of formula (III) be dissolved in the mixture of 100ml ether and 40ml methyl iso-butyl ketone (MIBK), then to the water that wherein adds 1.44ml.Reactant mixture at room temperature stirred 24 hours, filtered then and obtained crystal.The mixture that this crystal usefulness 30ml is made up of ether and methyl iso-butyl ketone (MIBK) (2: 1v/v) washing, 50 ℃ of following dryings, obtain the title compound of 7.5g, it is a white solid (productive rate: 73%).The moisture content of gained chemical compound be 2.32% (theoretical value: 2.34%), and fusing point and
1The H-NMR data all with 1-1) in observed identical.
Embodiment 3
The D-M (Determiner-Measure) construction analysis of the crystalline sibutramine methanesulfonate hemihydrate of formula (I)
The differential thermogram of powder X-ray diffraction data and differential scanning calorimeter shows that the crystal shape of the sibutramine methanesulfonate hemihydrate of formula (I) is different from the anhydrous sibutramine methanesulfonate of formula (II) or the sibutramine hydrochloride monohydrate (referring to Fig. 1-5) of formula (IV).
The x-ray diffractogram of powder of the sibutramine methanesulfonate hemihydrate of formula (I) has shown characteristic peak (Fig. 1), and these peak values are shown in Table 1.In table 1, " 2 θ ", " d " and " I/I
o" represent distance and relative peak intensity between the angle of diffraction, the crystal face respectively.
Table 1
| 2θ±0.2 | d | I/I o | 2θ±0.2 | d | I/I o |
| 8.2 | 10.8 | 868 | 21.2 | 4.19 | 785 |
| 10.8 | 8.17 | 218 | 21.9 | 4.06 | 646 |
| 11.7 | 7.53 | 210 | 22.2 | 4.00 | 315 |
| 12.0 | 7.36 | 276 | 22.8 | 3.90 | 286 |
| 12.3 | 7.19 | 661 | 23.3 | 3.81 | 456 |
| 15.8 | 5.61 | 716 | 24.4 | 3.65 | 537 |
| 16.4 | 5.39 | 725 | 24.9 | 3.58 | 596 |
| 17.4 | 5.10 | 792 | 25.3 | 3.52 | 322 |
| 17.8 | 4.97 | 498 | 25.6 | 3.47 | 351 |
| 19.0 | 4.68 | 556 | 26.8 | 3.33 | 1000 |
Experimental example 1: the dissolubility in the water
Sibutramine methanesulfonate hemihydrate and sibutramine hydrochloride monohydrate with formula (I) when pH 5.2 are dissolved to saturation point respectively, carry out high performance liquid chromatography (HPLC) analysis then, to determine meltage (based on anhydrous sibutramine).The results are shown in the table 2.
Table 2
| Chemical compound | Dissolubility in the water (mg/ml, pH 5.2) |
| The sibutramine hydrochloride monohydrate of formula (IV) | 2.8 |
| The sibutramine methanesulfonate hemihydrate of formula (I) | 2500 |
As can be seen from Table 2, the dissolubility of sibutramine methanesulfonate hemihydrate in water of formula (I) is higher than the dissolubility of the sibutramine hydrochloride monohydrate of formula (IV) far away.
Experimental example 2: the stability under humidity
The crystalline sibutramine methanesulfonate hemihydrate of formula (I) and the heat stability of sibutramine hydrochloride monohydrate during long term storage of formula (IV) are compared.60 ℃ store down 1,2,3 and 6 months after the amount of sibutramine hydrochloride monohydrate of the crystalline sibutramine methanesulfonate hemihydrate of unchanged formula (I) and formula (IV) be shown in Table 3.
Table 3
| Chemical compound | Initially | Residual rate after 1 month | Residual rate after 2 months | Residual rate after 3 months | Residual rate after 6 months |
| The sibutramine hydrochloride monohydrate of formula (IV) | 1.000 | 1.000 | 0.999 | 0.999 | 0.992 |
| The sibutramine methanesulfonate hemihydrate of formula (I) | 1.000 | 1.001 | 0.999 | 0.999 | 1.000 |
Above result shows that sibutramine semihydrate crystal and sibutramine hydrochloride monohydrate are stable equally.
Experimental example 3: non-hygroscopic test
The sibutramine hydrochloride monohydrate of the crystalline sibutramine methanesulfonate hemihydrate of formula (I), formula (IV) and anhydrous sibutramine methanesulfonate are exposed under the high-temperature/damp condition of 40 ℃ and 75% relative humidity 1,2 and 5 day respectively, then by using Kaal-Fisher analysis of moisture content instrument to measure their moisture content.The results are shown in the table 4.
Whether carry out the experiment of similar series under 40 ℃ and 10% relative humidity, be stable to check respective compound relatively doing under the condition.
Table 4: moisture content (weight %)
| Temperature (℃) relative humidity (℃) | Storage time (my god) | The sibutramine methanesulfonate hemihydrate of formula (I) | The sibutramine hydrochloride monohydrate of formula (IV) | Anhydrous sibutramine methanesulfonate |
| 40℃ 75％ | 1 2 5 | 2.27 2.30 2.30 | 5.40 5.45 5.48 | 0.60 2.20 2.25 |
| 40℃ 10％ | 1 2 5 | 2.27 2.25 2.26 | 5.40 5.36 5.36 | 0.60 0.71 0.70 |
As can be seen from Table 4, the crystalline sibutramine methanesulfonate hemihydrate of formula (I) is non-hygroscopic under high humidity, does not discharge water of crystallization simultaneously under drying condition.
Experimental example 4: weight saving effect
Overweight Zuker rat (fa/fa) and each 16 thin of Zuker rats (Fa/Fa) are divided into administration group and matched group (8 every group), and before experiment, measure the weight of each rat.To the crystalline sibutramine methanesulfonate hemihydrate of each rat administration every day 3mg/kg dosage of administration group, to the rat drug administration carrier of matched group, carried out altogether 21 days simultaneously.During this period, rat can freely obtain food rich in fat, measures the average weight of administration group and control rats then, increases and alleviates with calculated weight.
Table 5
| Overweight Zuker rat | Thin Zuker rat | |||
| The administration group | Matched group | The administration group | Matched group | |
| Average weight (g:A) before the test | 332.2 | 333.2 | 245.0 | 244.8 |
| Average weight after the test (g:B) | 455.6 | 486.2 | 303.4 | 323.6 |
| Weight increases (g:B-A) | 123.4 | 153.0 | 58.4 | 78.8 |
| Weight saving effect (weight of g:(matched group increases)-(weight of administration group increases)) | 29.6 | 20.4 | ||
As can be seen from Table 5, compare with matched group, the administration group of the crystalline sibutramine methanesulfonate hemihydrate of Medicine-feeding type (I) shows the effect of significantly losing weight.The crystalline sibutramine methanesulfonate hemihydrate of therefore, confirmation formula (I) can be used for treatment or prevention of obesity.
Comparative Examples: attempt preparation (+) and (-) sibutramine methanesulfonate hemihydrate
(1) sibutramine of optical resolution formula (II) ((+) and (-) sibutramine of preparation formula (II))
The raceme sibutramine of 12.3g is dissolved in the ethyl acetate of 85ml, then to wherein adding the L-DBTA that is dissolved in the 85ml ethyl acetate.Reactant mixture is heating under refluxing, and is cooled to room temperature, filters then and obtains crystal (ee: about 85%).Then, this crystal is suspended in the ethyl acetate of 220ml, and reflux, solid obtained.This solid carries out recrystallization with the isopropyl alcohol of 450ml, obtains (-)-the L-DBTA salt (ee: 〉=99.3%) of sibutramine.With the L-DBTA salt of saturated sodium bicarbonate aqueous solution neutralization (-)-sibutramine, use chloroform extraction then, obtain (-)-the sibutramine free alkali.
After reacting with L-DBTA, filter the filtrate that obtains and be neutralized to pH 8.5 with sodium hydroxide, use chloroform extraction then, obtain (+)-sibutramine, it is almost pure (+)-isomer.To wherein adding D-DBTA, obtain crystal, this crystal carries out recrystallization with the isopropyl alcohol of 450ml, obtains (+)-the D-DBTA salt (ee: 〉=99.3%) of sibutramine.To pH 8.5, use chloroform extraction with the D-DBTA salt of saturated sodium bicarbonate aqueous solution neutralization (+)-sibutramine then, obtain (+)-the sibutramine free alkali.
(2) preparation (+) and (-)-sibutramine methanesulfonate
Use 2-1-2 with embodiment 2) in (+) and (-)-sibutramine free alkali of in above-mentioned (1), making of the identical method processing of method described, make corresponding anhydrous mesylate.
(+)-sibutramine methanesulfonate: fusing point 156.5-157.5 ℃, moisture content 0.30%,
(-)-sibutramine methanesulfonate: fusing point 156.5-157.5 ℃, moisture content 0.05%.
(3) attempt preparation (+) and (-)-sibutramine methanesulfonate hemihydrate
According to the 2-2 of embodiment 2) in the identical method of the method described handle anhydrous (+) and (-)-sibutramine methanesulfonate that in above-mentioned (2), makes.Yet, do not observe crystalline formation.
Therefore, with the solvent of toluene replacement (+) or (-)-sibutramine methanesulfonate, to induce crystalline formation.But the crystal of gained has identical with (-)-sibutramine methanesulfonate with anhydrous (+) that make respectively fusing point/moisture content in above-mentioned (2).
In addition, anhydrous (+) and (-)-sibutramine methanesulfonate was placed 1 day under the condition of room temperature and 75% relative humidity.Happy and harmonious in each comfortable 2 hours, and in 1 day, become transparent liquid.
The above results shows that the sibutramine methanesulfonate hemihydrate of formula (I) can not be made by each enantiomer.
Though described the present invention with respect to above-mentioned specific embodiments, it should be understood that those skilled in the art still can carry out various improvement and modification to the present invention, they also fall in the appended claims institute restricted portion.
Claims (9)
1, be used for the treatment of or the pharmaceutical composition of prevention of obesity, it comprises the crystalline sibutramine methanesulfonate hemihydrate of formula (I),
2 θ values of the main peak in the X-ray diffraction spectrum of wherein said crystalline sibutramine methanesulfonate hemihydrate are:
8.2 ± 0.2,10.8 ± 0.2,11.7 ± 0.2,12.0 ± 0.2,12.3 ± 0.2,15.8 ± 0.2,16.4 ± 0.2,17.4 ± 0.2,17.8 ± 0.2,19.0 ± 0.2,21.2 ± 0.2,21.9 ± 0.2,22.2 ± 0.2,22.8 ± 0.2,23.3 ± 0.2,24.4 ± 0.2,24.9 ± 0.2,25.3 ± 0.2,25.6 ± 0.2 and 26.8 ± 0.2.
2, pharmaceutical composition as claimed in claim 1, it further comprises materia medica acceptable carrier, diluent or excipient.
3, pharmaceutical composition as claimed in claim 1, the content of the crystalline sibutramine methanesulfonate hemihydrate of its Chinese style (I) is the 1-50 weight portion, in the compositions of 250 weight portions.
4, the crystalline sibutramine methanesulfonate hemihydrate of formula (I),
2 θ values of its main peak in X-ray diffraction spectrum are:
8.2 ± 0.2,10.8 ± 0.2,11.7 ± 0.2,12.0 ± 0.2,12.3 ± 0.2,15.8 ± 0.2,16.4 ± 0.2,17.4 ± 0.2,17.8 ± 0.2,19.0 ± 0.2,21.2 ± 0.2,21.9 ± 0.2,22.2 ± 0.2,22.8 ± 0.2,23.3 ± 0.2,24.4 ± 0.2,24.9 ± 0.2,25.3 ± 0.2,25.6 ± 0.2 and 26.8 ± 0.2.
5, the method for preparation crystalline sibutramine methanesulfonate hemihydrate as claimed in claim 4, it comprises the methanesulfonic acid reaction in the sibutramine that makes formula (II) and the mixture that is dissolved in the organic solvent that is selected from ester, ether, ketone and mixture thereof and water,
Wherein, the sibutramine of the formula with respect to 1 mole (II), the use amount of methanesulfonic acid and water is respectively in the scope of 1-2 molar equivalent and 0.5-5 molar equivalent.
6, method as claimed in claim 5, wherein said ester is selected from ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate, and described ether is selected from diethyl ether, Di Iso Propyl Ether and t-butyl methyl ether, and described ketone is acetone or methyl ethyl ketone.
7, the method for preparation crystalline sibutramine methanesulfonate hemihydrate as claimed in claim 4, it comprises: the sibutramine of formula (II) and methanesulfonic acid are reacted in the anhydrous organic solvent that is selected from ester, ether, ketone, toluene and mixture thereof, obtain the anhydrous sibutramine methanesulfonate of formula (III), the sibutramine of the formula with respect to 1 mole (II) wherein, the use amount of methanesulfonic acid is in the scope of 1-2 molar equivalent; And the sibutramine methanesulfonate of formula (III) is contacted in the organic solvent that is selected from ester, ether, ketone and mixture thereof with water, the anhydrous sibutramine methanesulfonate of the formula with respect to 1 mole (III) wherein, the use amount of water is in the scope of 0.5-5 molar equivalent
8, method as claimed in claim 7, wherein, in step (i), described ester is selected from ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate, described ketone is selected from acetone, methyl ethyl ketone and methyl iso-butyl ketone (MIBK), and described ether is selected from diethyl ether, Di Iso Propyl Ether and t-butyl methyl ether.
9, method as claimed in claim 7, wherein, step (ii) in, described ester is selected from ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate, described ether is selected from diethyl ether, Di Iso Propyl Ether and t-butyl methyl ether, and described ketone is selected from acetone, methyl ethyl ketone and methyl iso-butyl ketone (MIBK).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20020060798 | 2002-10-05 | ||
| KR1020020060798 | 2002-10-05 | ||
| KR1020030053752 | 2003-08-04 |
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| CN1688297A CN1688297A (en) | 2005-10-26 |
| CN100342851C true CN100342851C (en) | 2007-10-17 |
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Country Status (6)
| Country | Link |
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| KR (1) | KR100536750B1 (en) |
| CN (1) | CN100342851C (en) |
| IL (1) | IL167659A (en) |
| RS (1) | RS20050272A (en) |
| UA (1) | UA76913C2 (en) |
| ZA (1) | ZA200502691B (en) |
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| KR100618176B1 (en) * | 2004-12-02 | 2006-09-01 | 휴먼팜 주식회사 | Sibutramine tartrate, its preparation process and phamaceutical composition comprising it |
| WO2006073292A1 (en) * | 2005-01-06 | 2006-07-13 | Cj Corporation | Inorganic acid salts of sibutramine |
| KR100632470B1 (en) * | 2005-02-25 | 2006-10-12 | 민연식 | Crystalline Sibutramin Camsylate and Process for Preparing it |
| KR100814384B1 (en) * | 2006-02-10 | 2008-03-18 | 대화제약 주식회사 | Pharmaceutical composition containing sibutramine salt, and manufacturing method thereof |
| KR100800561B1 (en) * | 2006-03-29 | 2008-02-04 | 주식회사 삼오제약 | A method for preparation of Sibutramine sulfonate salt and a composition containing the same for treating and preventing obesity disease |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2098602A (en) * | 1981-04-06 | 1982-11-24 | Boots Co Plc | Therapeutic agents |
| US4746680A (en) * | 1981-04-06 | 1988-05-24 | The Boots Company P.L.C. | Therapeutic agents |
| CN1016245B (en) * | 1985-12-17 | 1992-04-15 | 布茨公司 | Process for N.N.-dimethyl-1-[1-4-chlorobenzene) cyclobutyl]-3-methyl butyl hydrochloric acid salt-hydrate |
| WO2002036540A2 (en) * | 2000-11-02 | 2002-05-10 | Torrent Pharmaceuticals Ltd | PROCESS FOR PREPARATION OF β-PHENETHYLAMINE DERIVATIVE |
| US6399826B1 (en) * | 1999-08-11 | 2002-06-04 | Sepracor Inc. | Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain |
-
2003
- 2003-08-04 KR KR10-2003-0053752A patent/KR100536750B1/en not_active IP Right Cessation
- 2003-09-25 UA UAA200503096A patent/UA76913C2/en unknown
- 2003-09-25 RS YUP-2005/0272A patent/RS20050272A/en unknown
- 2003-09-25 CN CNB038238195A patent/CN100342851C/en not_active Expired - Fee Related
-
2005
- 2005-03-24 IL IL167659A patent/IL167659A/en not_active IP Right Cessation
- 2005-04-04 ZA ZA200502691A patent/ZA200502691B/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2098602A (en) * | 1981-04-06 | 1982-11-24 | Boots Co Plc | Therapeutic agents |
| US4746680A (en) * | 1981-04-06 | 1988-05-24 | The Boots Company P.L.C. | Therapeutic agents |
| CN1016245B (en) * | 1985-12-17 | 1992-04-15 | 布茨公司 | Process for N.N.-dimethyl-1-[1-4-chlorobenzene) cyclobutyl]-3-methyl butyl hydrochloric acid salt-hydrate |
| US6399826B1 (en) * | 1999-08-11 | 2002-06-04 | Sepracor Inc. | Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain |
| WO2002036540A2 (en) * | 2000-11-02 | 2002-05-10 | Torrent Pharmaceuticals Ltd | PROCESS FOR PREPARATION OF β-PHENETHYLAMINE DERIVATIVE |
Also Published As
| Publication number | Publication date |
|---|---|
| RS20050272A (en) | 2007-09-21 |
| UA76913C2 (en) | 2006-09-15 |
| KR100536750B1 (en) | 2005-12-16 |
| CN1688297A (en) | 2005-10-26 |
| ZA200502691B (en) | 2005-11-02 |
| KR20040031574A (en) | 2004-04-13 |
| IL167659A (en) | 2010-04-29 |
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