KR100800561B1 - A method for preparation of Sibutramine sulfonate salt and a composition containing the same for treating and preventing obesity disease - Google Patents

Abstract

The present invention relates to a novel sibutramine sulfonyl salt useful as an agent for preventing and treating obesity-related diseases, a method for preparing the same, and a pharmaceutical composition for treating and preventing obesity-related diseases containing the same. Since the compound having hygroscopicity is easy to move in the patient's body and has excellent long-term storage, the composition including the same may be usefully used as a pharmaceutical composition for the treatment and prevention of obesity-related diseases.

Sibutramine sulfonyl salt, obesity related disease, pharmaceutical composition

Description

A method for preparation of Sibutramine sulfonate salt and a composition containing the same for treating and preventing obesity disease}

1 is a diagram showing a thin film X-ray diffraction spectrum of crystalline sibutramine methosulfuric anhydride (Thin Film X-ray Diffraction Spectrum)

2 is a diagram showing a thin film X-ray diffraction spectrum of crystalline sibutramine aminosulfate anhydride,

3 is a diagram showing a differential scanning calorimeter thermogram of crystalline sibutramine methosulfuric anhydride,

4 is a diagram showing the differential scanning calorimetry of crystalline sibutramine aminosulfate anhydride.

The present invention relates to a method for preparing a novel sibutramine sulfonyl salt useful as an agent for preventing and treating obesity-related diseases.

Recently, as the standard of living improves, the hygiene environment is improved, and the dietary life is westernized, and the average life span is extended. As a result, geriatric disease has emerged as the biggest medical task today, and obesity, which is a major cause of geriatric disease, is rapidly increasing. Obesity refers to a phenomenon in which excess calories are accumulated in the form of fat in the body by ingesting excessive calories compared to calories consumed. Obesity is thought to be caused by a variety of causes, including genetic effects, environmental effects of westernized diets, and psychological effects of stress, but the exact cause and mechanisms are not clearly established. However, because obesity can act not only as a problem of obesity itself, but also as a cause of diseases such as cardiovascular disease and diabetes (Manson et al., New England J. Med ., 333, pp 677-685, 1995 Kopleman PG, Nature, 404 pp 635-643, 2000; Must et al., JAMA , 282 , pp 1523-1529, 1999).

On the other hand, cholesterol is mainly produced in the liver and is present in the blood in the form of small round particles called lipoproteins, which carry cholesterol throughout the body. There are two types of lipoproteins, low density lipoprotein (LDL) and high density lipoprotein (HDL), and because HDL carries cholesterol from other tissues to the liver, high HDL removes cholesterol from blood vessels. On the other hand, LDL is produced mainly in the liver and carries cholesterol to other tissues of the human body. Therefore, a large amount of LDL causes a lot of cholesterol in blood vessels to promote atherosclerosis, and about 70% of blood cholesterol is present as harmful cholesterol. (Kim Kyung-hwan, Lee Woo-joo's Pharmacology Lecture, 4th edition, pp. 466-481, 2001).

In fact, cholesterol is an essential ingredient necessary for the normal functioning of the human body, nutrients necessary to make cells, and a component of various hormones such as corticosteroids, male hormones, and female hormones. It can help you digest fatty foods. In addition, it is a nutrient necessary for the human body, such as a component of a biological membrane and used as a starting material for hormonal synthesis. However, excessive intake of such cholesterol accumulates in blood vessels and is known to cause heart disease. So far, there is no preventive method other than low cholesterol diet, and taking drugs such as cholesterol-lowering drugs are effective, but their use is extremely limited because of causing side effects such as liver dysfunction due to inhibition of cholesterol synthase.

Homeostasis of fat is maintained by the balance between production and breakdown of fat. ADD1 / SREBP1 is a transcription factor that regulates fat production and regulates the synthesis and absorption of fatty acids, triglycerides, cholesterol, phospholipids (Horton JD et al., J. Clin . Invest., 109, pp 1125-1131, 2002). SREBPs are synthesized as an inert precursor bound to the endoplasmic reticulum membrane, and after the N terminus is cut off, it is activated and moved to the nucleus and binds to the SRE (sterol regulatory elements) of the regulatory gene promoter. Among these isoforms, SREBP1c mainly regulates the synthesis of neutral lipids, while SREBP2 is known to be involved in cholesterol synthesis. Genes regulated by SREBP1c are ATP citrate lyase (ACL), acetyl CoA carboxylase (ACC), fatty acid synthase (FAS) and stearoyl-CoA desarurase (SCD), and others (Osborn TF et al., J. Biol . Chem ., 275 , pp 32379-32382, 2000; Soazig L. L et al., J. Biol . Chem ., 277 , pp 35625-35634, 2002).

Current strategies for developing obesity treatments include reducing meals, suppressing caloric intake, promoting exothermic reactions, regulating energy metabolism, and regulating signaling through the nervous system (Kopleman PG, Nature, 404 , pp 635-643, 2000). Attempts have been made for the treatment of obesity by developing drugs to function more than one function for such a strategy, but it is not easy to develop drugs that have both safety and efficacy at the same time.

Therefore, attempting to find an ingredient that meets the strategy for treating obesity from natural products with proven safety may be a more efficient approach than developing a therapeutic agent from a synthetic formulation.

Sibutramine (formula A) is named N, N-dimethyl-1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine and has one asymmetric carbon atom, originally intended to treat depression The drug was developed as an anti-obesity drug because it was found to give weight to patients taking this drug.

(A)

(A)

Sibutramine reduces appetite by inhibiting resorption of serotonin and noradrenaline, the neurohormones that regulate appetite in the brain, and sibutramine, a racemic mixture, is known to prevent and treat obesity and depression, incontinence, and Parkinson's disease. 397,831; European Patent 230,742; British Patent 2,098,602; International Patent 0032182; European Patent 282,206). In addition, sibutramine is known to be used to prevent and treat diseases such as hyperlipidemia, cholelithiasis, chronic fatigue syndrome, sexual dysfunction, anxiety disorder, and osteoarthritis (US Pat. Nos. 5,459,164, 6,162,831, 6,232,347, 6,365,631). , 6,376,554, 6,376,551, 6,376,552).

Since the sibutramine has a melting point of 51 to 55 ° C. and low heat stability, and thus it is difficult to handle pharmaceuticals, it was necessary to convert to the acid-addition salt form. In order to solve the above problem, sibutramine hydrochloride monohydrate, which is sibutramine hydrochloride, has been developed (UK Patent No. 2,184,122) and used in medicines, and is currently used in medicines such as Meridia® or Reductil®, which are known as obesity drugs. It is used as an active ingredient.

Sibutramine hydrochloride monohydrate is known to have good non-hygroscopicity and stability but very low solubility in water. In general, the solubility of the active ingredient used in the pharmaceutical composition in water is preferably solubility of 1 mg / ml or more in the pH range of 1 to 7, and considering the disintegration rate in the absorption process, when the solubility is lower than 3 mg / ml It is known that in vivo administration may be limited in the absorption process. However, sibutramine hydrochloride monohydrate has a low solubility of 2.9 mg / ml (Merck Index, 13th Ed, p 1522) in an aqueous solution of pH 5.2, there was a problem to use as a pharmaceutical composition.

Accordingly, the present inventors have completed the present invention by synthesizing a novel sibutramine sulfonyl salt having excellent solubility in water compared to sibutramine hydrochloride monohydrate and having superior nonhygroscopicity and stability.

An object of the present invention is to prepare a novel sibutramine sulfonyl salt by reacting sibutramine with a functional group including a pharmaceutically appropriate sulfone group, having no hygroscopicity against moisture, good thermal stability, and excellent solubility in an aqueous solution of water or a thin pH range. It is to provide a pharmaceutical composition for the prevention and treatment of obesity-related diseases and methods containing the same.

In order to achieve the above object, the present invention is a novel sibutramine sulfonyl salt of the following general formula (I), comprising a sulfone group in sibutramine

To provide.

(Ⅰ)

(Ⅰ)

Where

A is OR ₂ or NR ₃ R ₄ ,

R ₁ is a hydrogen atom or a methyl group,

R ₂ is an alkyl group having 1 to 5 carbon atoms,

R ₃ and R ₄ are each independently a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or R ₃ and R ₄ are interconnected to form a 5 to 7 membered cyclic alkyl group.

Preferably, R ₂ is a methyl group, R ₃ and R ₄ is characterized in that the hydrogen atom.

The present invention provides a process for preparing crystalline sibutramine alkoxy sulfonyl salt of general formula (Ia) by reacting sibutramine with a reaction reagent comprising an alkoxy group and a sulfonyl group in an organic solvent.

The present invention also provides a process for preparing crystalline sibutramine amino sulfonyl salt of general formula (Ib) by reacting sibutramine with a reaction reagent comprising an amino group and a sulfonyl group in an organic solvent.

(Ia)

(Ia)

(Ib)

(Ib)

In the preparation step, the reaction reagent containing an alkoxy group and a sulfonyl group is most preferably dimethyl sulfate, and it is a conventional method to be injected into the reaction solution as a stock solution or a mixed solution with an organic solvent, and the amount of sulfonyl group is 1 mol equivalent of sibutramine. It is preferable to use 1 to 2 molar equivalents, preferably 1 to 1.5 molar equivalents, relative to each other.

In addition, the reaction reagent containing the amino group and the sulfonyl group in the preparation step is most preferably amino sulfuric acid, it is a common method to be injected into the reaction solution as a stock solution or a mixed solution with an organic solvent and the amount of sulfonyl group is 1 molar equivalent of sibutramine It is preferable to use 1 to 2 molar equivalents, preferably 1 to 1.5 molar equivalents, relative to each other.

In the preparation step, it is preferable to use methylene chloride, chloroform, acetone, tetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate or a mixed solvent thereof, and more preferably methylene chloride or ethyl. Acetate can be used.

The amount of the organic solvent used in the preparation step may be used in a ratio of 1 to 20ml, preferably 3 to 10ml based on 1 g of sibutramine.

In the preparation step, the reaction temperature is 25 to 120 ℃, preferably carried out in the boiling point of the solvent, the reaction time is preferably maintained for 10 to 24 hours.

Sibutramine sulfonyl salt prepared by the manufacturing step is superior to the conventional sibutramine hydrochloride monohydrate has excellent solubility in water and excellent in non-hygroscopicity and stability.

The present method provides a pharmaceutical composition containing the crystalline sibutramine sulfonyl salt obtained by the above method as an active ingredient and effective in preventing or treating obesity-related diseases.

The obesity-related diseases include overeating, hypereating and bulimia, hypertension, diabetes, increased plasma insulin concentrations, insulin resistance, hemostatic abnormalities, hyperlipidemia, metabolic syndrome, insulin resistance syndrome, obesity-related gastroesophageal reflux, arteriosclerosis, hypercholesterolemia, Hyperuricemia, lower back pain, hypertrophy of the heart or left ventricular hypertrophy, more specifically obesity.

Compositions comprising a compound of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.

Compositions comprising the compounds of the invention are each formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories, and sterile injectable solutions, according to conventional methods. Carriers, excipients and diluents that may be included in the composition comprising the compound include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, Calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose, or the like. ) Or lactose, gelatin and the like are mixed. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Oral liquid preparations include suspending agents, liquid solutions, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Preferred dosages of the compounds of the present invention depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention is preferably administered at 0.0001 to 100 mg / kg, preferably 1 to 20 mg / kg. Administration may be administered once a day or may be divided several times. Therefore, the above dosage does not limit the scope of the present invention in any aspect.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.

However, the following Examples and Experimental Examples are only illustrative of the present invention, and the content of the present invention is not limited to the following Examples and Experimental Examples.

Comparative Example 1. Preparation of Sibutramine Hydrochloride Monohydrate

Dissolve 50.0 g of sibutramine in 150 ml of ethyl acetate and adjust to pH 2.0 by injecting 6N dilute hydrochloric acid. After stirring for 1 hour at room temperature, the precipitated crystals are filtered off and washed with 100 ml of ethyl acetate. Drying in vacuo gave 56.0 g (yield 93.8%) of sibutramine hydrochloride monohydrate of formula B having a melting point of 195 ° C.

(B)

(B)

Example 1 Preparation of Sibutramine Methosulfate 1

100.0 g of sibutramine are dissolved in 300 ml of methylene chloride, and 49.58 g of dimethyl sulfate are injected at room temperature and then refluxed for 14 hours. After cooling to room temperature, 300 ml of ethyl acetate was injected and stirred for 1 hour, after which the precipitated crystals were filtered and washed with 100 ml of ethyl acetate. It dried at 70 degreeC and obtained 139.2g (yield: 96.0%) of the white sibutramine methosulfates of the following structural formula C which have the following physical properties.

Particle Distribution: X10 = 8.0μm, X50 = 28.0μm, X90 = 100.0μm

(Xn = A: n = particle distribution, A = particle density, Sympatec GmbH particle size analyzer)

Melting Point: 149.5 ~ 150.5 ℃

Moisture content: 0.10%

MS m / z Theoretical 294.81 (M-Me) ⁺ Found 294.36 (M-Me) ⁺

Elemental Analysis (C ₁₉ H ₃₂ ClNO ₄ S): Theoretical- C: 56.2 H: 7.9 N: 3.45 S: 7.9

                               Found: C: 54.1 H: 7.8 N: 3.11 S: 7.5

¹ H-NMR (δ, CDCl 3): 7.5 to 7.2 (4H, dd), 4.1 (1H, t), 3.7 (3H, s), 2.9 (9H, s), 2.7 (2H, d), 2.2 (2H , d), 1.9 (1H, m), 1.7 to 1.6 (2H, m), 1.5 (2H, t), 1.1 (6H, t)

X-ray diffraction analysis (I / Io≥200): 5.6 ± 0.2, 11.4 ± 0.2, 13.9 ± 0.2, 16.1 ± 0.2, 18.0 ± 0.2, 19.7 ± 0.2, 21.1 ± 0.2, 21.5 ± 0.2, 22.0 ± 0.2, 22.5 ± 0.2, 28.3 ± 0.2

(C)

(C)

Example 2 Preparation of Sibutramine Methosulfate

100.0 g of sibutramine are dissolved in 300 ml of ethyl acetate, and 49.58 g of dimethyl sulfate is injected at room temperature and then refluxed for 15 hours. After cooling to room temperature, the precipitated crystals are filtered and washed with 100 ml of ethyl acetate. Drying at 70 ° C. yielded 130.5 g (yield: 90.0%) of white sibutramine methosulfate.

Melting Point: 149.5 ~ 150.5 ℃

Moisture content: 0.07%

¹ H-NMR: same as the data of Example 1 above.

Example 3 Preparation of Sibutramine Amino Sulfate 1

100.0 g of sibutramine is dissolved in 300 ml of methylene chloride, and 34.7 g of amino sulfate is injected at room temperature, followed by reflux for 14 hours. After cooling to room temperature, 300 ml of ethyl acetate was injected and stirred for 1 hour, after which the precipitated crystals were filtered and washed with 100 ml of ethyl acetate. It dried at 70 degreeC and obtained 125.2 g (yield: 96.0%) of the white sibutramine aminosulfates of the following structural formula D which have the following physical properties.

Particle Distribution: X10 = 4.5μm, X50 = 18.0μm, X90 = 45.0μm

(Xn = A: n = particle distribution, A = particle density, Sympatec GmbH particle size analyzer)

Melting Point: 136.3 ~ 136.5 ℃

Moisture content: 0.01%

MS m / z: Theoretical 280.81 (MH) ⁺ Found 280.41 (MH) ⁺

Elemental Analysis (C ₁₇ H ₂₉ ClN ₂ O ₃ S): Theoretical- C: 54.1 H: 7.7 N: 7.4 S: 8.5

                                Found: C: 54.2 H: 7.9 N: 7.0 S: 8.5

¹ H-NMR (δ, CDCl ₃ ): 9.5 (2H, br, s), 7.5-7.2 (4H, dd), 3.5 (1H, t), 3.0 (3H, s), 2.9 (2H, m), 2.6 (2H, m), 2.3 (3H, s), 2.0 (1H, m), 1.8 (2H, m), 1.5 (2H, t), 1.0 (6H, t)

X-ray diffraction analysis (I / Io≥200): 5.7 ± 0.2, 11.5 ± 0.2, 12.0 ± 0.2, 14.8 ± 0.2, 17.3 ± 0.2, 19.2 ± 0.2, 20.5 ± 0.2, 22.1 ± 0.2, 24.6 ± 0.2, 25.9 ± 0.2, 29.4 ± 0.2

(D)

(D)

Example 4 Preparation of Sibutramine Amino Sulfate

100.0 g of sibutramine is dissolved in 300 ml of methanol, and 49.58 g of aminosulfuric acid is injected at room temperature, followed by reflux for 14 hours. After distillation under reduced pressure to remove methanol, 300 ml of ethyl acetate was injected and stirred for 1 hour, after which the precipitated crystals were filtered and washed with 100 ml of ethyl acetate. It dried at 70 degreeC and obtained 119.8g (yield: 89.0%) of white sibutramine aminosulfates which have the following physical properties.

Melting Point: 136.0 ~ 136.5 ℃

Moisture content: 0.03%

¹ H-NMR: same as the data of Example 3 above.

Experimental Example 1. Stability test for moisture and heat

Thermal stability test is an important factor in the long-term storage of the product, as well as product manufacturing process, such as tablets and capsules of the active ingredient used in the pharmaceutical composition and the sibutramine sulfonyl salts of formula C and D prepared in the above examples The stability of sibutramine hydrochloride monohydrate (formula A above) prepared in Comparative Example was compared.

Each salt was stored at a temperature of 60 ° C. and the relative stability was determined by high performance liquid chromatography (HPLC) after 1 month, 2 months, 3 months and 6 months and the residual ratios for the initial active ingredient values were determined.

salt Early 1 month 2 months 3 months 6 months Sibutramine Hydrochloride Monohydrate 1.000 0.999 1.000 0.998 0.995 Sibutramine Methosulfate 1.000 1.000 0.999 1.000 1.000 Sibutramine aminosulfate 1.000 1.000 1.000 0.999 0.999

As shown in Table 1, the sibutramine hydrochloride monohydrate showed a tendency to decompose in a very small amount after 6 months, while the sibutramine sulfonyl salts could be confirmed that no degradation occurred after 6 months. From the above results, it was confirmed that the sibutramine sulfonyl salts of the present invention have better chemical stability due to temperature than sibutramine hydrochloride monohydrate.

Experimental Example 2 Measurement of Solubility in Water

The solubility in water of the sibutramine sulfonyl salts prepared in the above example and the sibutramine hydrochloride monohydrate prepared in the comparative example was compared. Solubility specified in the Korean Pharmacopoeia refers to the degree of dissolution within 30 minutes when the medicine is solid, powdered, and then dissolved in a solvent and mixed vigorously for 30 seconds every 5 minutes at 20 ㅁ 6 ℃. The solubility test was measured based on this until the sibutramine sulfonyl salts and sibutramine hydrochloride monohydrate were saturated in 100 ml of purified water at pH 5.2.

salt Solubility in water (mg / ml, pH5.2) Sibutramine Hydrochloride Monohydrate 2.9 Sibutramine Methosulfate 140 Sibutramine aminosulfate 1,500

As shown in Table 2, the solubility of sibutramine sulfonyl salts in purified water at pH 5.2 was significantly higher than that of sibutramine hydrochloride monohydrate. Therefore, the sibutramine sulfonyl salts of the present invention are expected to be more effective in terms of bioavailability because they have very excellent properties in terms of solubility compared to sibutramine hydrochloride monohydrate.

Experimental Example 3. Nonhygroscopic Experiment

The sibutramine sulfonyl salts prepared in the above examples and the sibutramine hydrochloride monohydrate prepared in the comparative example were respectively 1 day and 2 days at 40 ° C. under relative humidity conditions of 80% and 0% (using a desiccator exposed to calcium chloride). And 4 days of continuous exposure, each moisture content was measured by Karl-Fisher moisture meter. As a result, Table 3 shows the water content in the active ingredient (% by weight) contained in the active ingredient.

Temperature relative humidity Hours Sibutramine Methosulfate Sibutramine Hydrochloride Monohydrate Sibutramine Amino Sulfate - Early 0.09 5.29 0.03 40 ℃ 80% 1 2 4 0.08 0.10 0.10 5.18 5.13 5.13 0.03 0.04 0.04 40 ℃ 0% 1 2 4 0.08 0.10 0.11 4.83 4.57 4.08 0.04 0.03 0.03

As shown in Table 3, the sibutramine sulfonyl salts were confirmed to be non-hygroscopic salts that did not absorb moisture in the same manner as the sibutramine hydrochloride monohydrate under high humidity conditions. Sibutramine hydrochloride monohydrate was found to be an unstable salt that releases crystallized water over time.

Sibutramine sulfonyl salts prepared according to the method of the present invention are compounds having excellent solubility, stability, and hygroscopicity, and thus can be conveniently used for preventing and treating obesity-related diseases because they are easy to move in the patient's body and have excellent long-term storage. .

Claims (10)

delete delete delete A process for producing crystalline sibutramine metho sulfate of formula (I) by reacting sibutramine with a reaction reagent comprising an alkoxy group and a sulfonyl group in an organic solvent.

(Ⅰ) A process for producing crystalline sibutramine amino sulfate of formula (II) by reacting sibutramine with a reaction reagent comprising an amino group and a sulfonyl group on an organic solvent.

(Ⅱ) The method according to claim 4 or 5, wherein the organic solvent is methylene chloride, chloroform, acetone, tetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate or a mixed solvent thereof. The method according to claim 4 or 5, wherein the reaction reagent is used in 1 to 2 molar equivalents to 1 molar equivalent of sibutramine. The method according to claim 4 or 5, wherein the use ratio of the organic solvent is used at a ratio of 1 to 20 ml based on 1 g of sibutramine. delete delete

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