JP2014098017A - 4-[2-(4-methylphenylsulfanyl)phenyl]piperidine for treatment of irritable bowel syndrome (ibs) - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutically effective amount of 4-[2-(4-methylphenylsulfanyl)-phenyl]piperidine or a pharmaceutically acceptable salt thereof for treatment of irritable bowel syndrome.SOLUTION: A pharmaceutical composition is administered in a crystalline form of a HBr addition salt of the specified compound characterized by peaks in an XRPD at approximately 6.08, 14.81, 19.26 and 25.38° 2θ (all ±0.1°). A medical treatment includes administration of the compound of 1-20 mg/day.

Description

  The present invention provides the use of 4- [2- (4-methylphenylsulfanyl) phenyl] piperidine to treat irritable bowel syndrome (IBS).

  Irritable bowel syndrome is a chronic disorder of the intestine that causes flatulence, abdominal pain, constipation and / or diarrhea. Symptoms of IBS are not explained by anatomical or metabolic abnormalities. Rather, IBS is thought to be a biopsycho-social disorder resulting from a combination of three interacting mechanisms: changes in gut motility, increased visceral perception, and psychosocial factors [Non-Patent Document 1].

  Irritable bowel disease is a common disease that primarily affects women, with an estimated prevalence of 10-15% in Europe and North America. However, the disease is not well recognized, and only some of those affected are actually diagnosed. The average prevalence of patients diagnosed with IBS in 8 European countries is only 2.8% [Non-Patent Document 2]

  Irritable bowel syndrome usually consists of three subgroups depending on the main defecation habits: constipation type (c-IBS), diarrhea type (d-IBS), and IBS (a-IBS) in which both constipation and diarrhea alternate ).

Irritable bowel syndrome has been treated with various therapeutic agents including antispasmodic drugs, laxatives, antidiarrheals, tricyclic antidepressants and 5-HT ₃ antagonists. Odansetron is a 5-HT ₃ antagonist, and this compound has been shown in clinical trials to improve stool hardness, defecation frequency, and reduce the number of pain episodes. Alosetron, also a 5-HT ₃ antagonist, has been shown to improve abdominal pain or abdominal discomfort and urgency [Non-Patent Document 2]. Alosetron is approved by the FDA for the treatment of women with severe diarrhea-type IBS.

The compound 4- [2- (4-methylphenylsulfanyl) phenyl] piperidine was first disclosed in an international patent application published as Patent Document 1, in which the compound is a serotonin transport inhibitor. Indicated. Subsequently, in an international patent application published as WO 2004/058400, crystalline salts of said compounds were disclosed with a broader pharmacological profile including 5-HT ₃ antagonism.

International Publication No. 2003/029232 International Publication No. 2007/144006

Gastroenterol., 120, 652-668, 2001 Aliment. Pharmacol. Ther., 24, 183-205, 2006

  In certain embodiments, the present invention provides a method for treating irritable bowel syndrome (IBS), wherein a therapeutically effective amount of 4- [2- (4-methylphenylsulfanyl) phenyl] piperidine is applied to a patient in need thereof. Or a method comprising administering a therapeutically acceptable salt thereof (hereinafter Compound I).

  In certain embodiments, the present invention provides Compound I for use in the treatment of IBS.

  In certain embodiments, the present invention provides the use of Compound I in the manufacture of a medicament for treating IBS.

X-ray diffraction pattern of HBr addition salt of Compound I. X-ray diffraction pattern of HBr addition salt solvate of Compound I. X-ray diffraction pattern of palmitic acid addition salt of Compound I. X-ray diffraction pattern of DL-lactic acid addition salt of Compound I. X-ray diffraction pattern of adipic acid addition salt of compound I (1: 1) (α + β form). X-ray diffraction pattern of adipic acid addition salt of Compound I (2: 1). X-ray diffraction pattern of the fumaric acid addition salt of Compound I (1: 1). X-ray diffraction pattern of glutaric acid addition salt of compound I (1: 1). X-ray diffraction pattern of malonic acid addition salt (1: 1) α form of Compound I. X-ray diffraction pattern of malonic acid addition salt β form of Compound I. X-ray diffraction pattern of the oxalic acid addition salt of Compound I (1: 1). X-ray diffraction pattern of sebacoinic acid addition salt (2: 1) of Compound I. X-ray diffraction pattern of succinic acid addition salt of Compound I (2: 1). X-ray diffraction pattern of L-malic acid addition salt (1: 1) α form of Compound I. X-ray diffraction pattern of L-malic acid addition salt (1: 1) β form of Compound I. X-ray diffraction pattern of D-tartaric acid addition salt of compound I (1: 1). X-ray diffraction pattern of L-aspartic acid addition salt of compound I (1: 1) in a mixed state with L-aspartic acid. X-ray diffraction pattern of L-aspartic acid addition salt hydrate (1: 1) of Compound I in a mixed state with L-aspartic acid. X-ray diffraction pattern of glutamic acid addition salt (1: 1) of compound I in a mixed state with glutamic acid monohydrate. X-ray diffraction pattern of citric acid addition salt of compound I (2: 1). X-ray diffraction pattern of HCl acid addition salt of Compound I. X-ray diffraction pattern of Compound I phosphate addition salt (1: 1).

である。 The structure of 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine is

It is.

  In certain embodiments, the pharmaceutically acceptable salts used in the present invention are acid addition salts of acids that are non-toxic. These salts include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, glucone Acid, lactic acid, malic acid, malonic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, theophylline acetic acid, And salts prepared from organic acids such as 8-halotheophylline, such as 8-bromotheophylline. Said salts can also be prepared from inorganic salts such as hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid. Other useful salts are listed in the table of Example 1d (Table 1).

  In certain embodiments, Compound I is an HBr addition salt.

  In certain embodiments, Compound I is a DL-lactic acid addition salt, particularly a 1: 1 salt thereof.

  In certain embodiments, Compound I is an L-aspartic acid addition salt, particularly a 1: 1 salt thereof.

  In certain embodiments, Compound I is a glutamic acid addition salt, particularly a 1: 1 salt thereof.

  In certain embodiments, Compound I is a glutaric acid addition salt, particularly a 1: 1 salt thereof.

  In certain embodiments, Compound I is found to exist in malonic acid addition salts, particularly its 1: 1 salt, which are present in two polymorphic modifications α and β, of which the β form is Based on lower solubility, it is considered the most stable).

  In certain embodiments, Compound I is in a purified form. The term “purified form” is intended to indicate that the compound is essentially free of other compounds, or optionally other forms, ie, free of polymorphs of said compounds.

  Oral dosage forms, especially tablets and capsules, are often preferred by patients and physicians because they are easy to administer, resulting in better dosing rates. In the case of tablets and capsules, the active ingredient is preferably crystalline.

  The crystals of Compound I can exist as solvates, ie, crystals in which solvent molecules form part of the crystal structure. Solvates can be formed from water, in which case the solvates are often referred to as hydrates. Alternatively, solvates can be formed from other solvents such as ethanol, acetone, or ethyl acetate. The exact amount of solvate often depends on the conditions. For example, hydrates will typically lose water as the temperature increases or as the relative humidity decreases. For pharmaceutical formulations, it is generally considered that a compound that does not change or changes slightly even when conditions such as humidity change is more suitable. Note that HBr addition salts do not form hydrates when precipitated from water, whereas compounds such as succinic acid addition salt, malic acid addition salt and tartaric acid addition salt form hydrates. .

  Some compounds are hygroscopic (ie they absorb water when exposed to moisture). Hygroscopicity is generally regarded as an undesirable property for compounds intended to be presented as pharmaceutical formulations (especially dry formulations such as tablets or capsules). In certain embodiments, the present invention uses crystals that are less hygroscopic.

  In the case of oral dosage forms using crystalline active ingredients, it is also beneficial for the crystals to be clearly defined. In this context, the term “well-defined” means that, in particular, the stoichiometry is clearly defined, ie the ratio between the ions forming the salt is a small integer ratio. For example, 1: 1, 1: 2, 2: 1, 1: 1: 1, etc. In certain embodiments, the compounds used in the present invention are clearly defined crystals.

  The solubility of the active ingredient is also important for the choice of dosage form as it can have a direct impact on bioavailability. In the case of oral dosage forms, it is generally considered that higher solubility of the active ingredient is beneficial because of increased bioavailability. Some patients, such as older patients, may have difficulty swallowing tablets, and oral drop solutions may be a suitable alternative to avoid the need to swallow tablets. In order to limit the volume of drops for internal use, it is necessary to increase the concentration of the active ingredient in the solution, which again requires a high solubility of the compound. As shown in Table 3, DL-lactic acid, L-aspartic acid, glutamic acid, glutaric acid, and malonic acid addition salts have exceptionally high solubility.

  Crystal form affects the filtration and processing properties of the compound. Acicular crystals tend to be more difficult to handle in a manufacturing environment because they are more difficult to filter and time consuming. The exact crystal form of a given salt can depend on, for example, the conditions under which the salt is precipitated. The HBr acid addition salt of the present invention grows acicular solvated crystals when precipitated from ethanol, acetic acid and propanol, but is not acicular when it is precipitated from water. To give excellent filtration properties.

  Table 3 also describes the pH of the solution, that is, the pH of the saturated salt solution. This property is important. Because it is impossible to completely avoid moisture during storage, the accumulation of moisture can cause a pH drop in or on tablets containing low solution pH salts, which can reduce shelf life Because. In addition, salts with low solution pH can cause corrosion of processing equipment when tablets are made by wet granulation. The data in Table 3 suggests that HBr, HCl and adipic acid addition salts can be excellent in this regard.

  In certain embodiments, Compound I is a crystalline form of an HBr addition salt, particularly in a purified form. In yet another embodiment, the HBr salt has peaks in the X-ray powder diffractogram (XRPD) at about 6.08 °, 14.81 °, 19.26 ° and 25.38 ° 2θ, particularly when the HBr salt is shown in FIG. Has the XRPD shown.

  In certain embodiments, Compound I is a crystalline form of DL-lactic acid addition salt (1: 1), particularly in a purified form. In yet another embodiment, the DL-lactic acid addition salt has peaks at about 5.30 °, 8.81 °, 9.44 °, and 17.24 ° 2θ in XRPD, and in particular, the DL lactic acid addition salt is XRPD illustrated in FIG. have.

  In certain embodiments, Compound I is a crystalline form of L-aspartic acid addition salt (1: 1), particularly in a purified form. In yet another embodiment, the L-aspartic acid addition salt is a non-solvate and has peaks at about 11.05 °, 20.16 °, 20.60 °, 25.00 ° 2θ in XRPD, especially the L-aspartate. Has XRPD illustrated in FIG. 17 when mixed with L-aspartic acid. In one embodiment, the L-aspartic acid addition salt is a hydrate (especially in a purified form). In yet another embodiment, the L-aspartic acid addition salt hydrate has peaks at about 7.80 °, 13.80 °, 14.10 °, 19.63 ° 2θ in XRPD, in particular the L-aspartic acid addition salt hydrate When mixed with L-aspartic acid, it has XRPD illustrated in FIG.

  In certain embodiments, Compound I is a crystalline form of glutamic acid addition salt (1: 1), particularly in a purified form. In yet another embodiment, the glutamic acid addition salt has peaks at about 7.71 °, 14.01 °, 19.26 °, 22.57 ° 2θ in XRPD, especially when the glutamate is mixed with glutamic acid monohydrate. The XRPD shown in FIG.

  In certain embodiments, Compound I is a malonic acid addition salt (1: 1) in crystalline form (particularly in purified form). In yet another embodiment, the malonic acid addition salt is in alpha form and has peaks at about 10.77 °, 16.70 °, 19.93 °, 24.01 ° 2θ in XRPD, or the malonic acid addition salt is in beta form. The XRPD has peaks at about 6.08 °, 10.11 °, 18.25 °, and 20.26 ° 2θ. In particular, the malonic acid addition salt has the XRPD shown in FIG. 9 or FIG.

  In certain embodiments, Compound I is a crystalline form of glutaric acid addition salt (1: 1), particularly in a purified form. In yet another embodiment, the glutaric acid addition salt has peaks at about 9.39 °, 11.70 °, 14.05 °, and 14.58 ° 2θ in XRPD, in particular, the glutaric acid addition salt is XRPD illustrated in FIG. have.

  The pharmacological profile of Compound I is discussed in the international patent application published as WO 2007/144006, which can be summarized as follows. This compound is an inhibitor of serotonin and norepinephrine reuptake, an inhibitor of serotonin receptors 2A, 2C and 3 and an inhibitor of α-1 adrenergic receptors.

Compound I is thought to be useful in the treatment of IBS because it potently inhibits the 5-HT ₃ receptor. As shown in the Examples, Compound I has a strong effect on pain, which is a significant symptom of IBS as described above.

  In certain embodiments, Compound I is administered in an amount of about 0.001 to about 100 mg / kg body weight per day.

  A typical oral dosage is in the range of about 0.001 to about 100 mg / kg body weight per day, preferably about 0.01 to about 50 mg / kg body weight per day, which is one or more dosages, such as 1 to Administered in 3 doses. The exact dosage will be apparent to the frequency and mode of administration, sex, age, weight and general condition of the subject being treated, the nature and severity of the condition being treated, and the concomitant disease to be treated and to those skilled in the art. Will depend on other factors.

  For adults, typical oral dosages are in the range of 1-100 mg / day of Compound I, such as 1-30 mg / day, or 5-25 mg / day. This can typically be achieved by administering 0.1 to 50 mg, eg 1 to 25 mg, eg 1, 5, 10, 15, 20 or 25 mg of Compound I once or twice daily.

  As used herein, a “therapeutically effective amount” of a compound is sufficient to cure, reduce or partially inhibit the clinical symptoms of a given disease and its complications in a therapeutic intervention involving administration of the compound. Means a large amount. An amount adequate to accomplish this is defined as “therapeutically effective amount”. The term also encompasses an amount sufficient to cure, reduce or partially abrogate the clinical symptoms of a given disease and its complications in a treatment involving administration of said compound. The effective amount for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. Determination of the appropriate dosage can be accomplished using routine experimentation by creating a matrix of values and testing different points in the matrix, all of which are routinely performed by a skilled physician. It will be understood that it is included in the workmanship.

  As used herein, the terms “treatment” and “treating” refer to the management and medical care of a patient made to combat a condition such as a disease or disorder. This term refers to the full range of treatments for a given condition that a patient is suffering from, such as reducing the symptoms or complications, reducing the progression of the disease, disorder or condition, and reducing the symptoms and complications. And / or alleviation and / or to cure or eliminate the disease, disorder or condition, and to administer the active compound to prevent the condition, etc. Interpreted as patient care and medical care to combat the disease, condition, or disorder, including administration of active compounds to prevent the occurrence of symptoms or complications. Nevertheless, prophylactic (preventive) treatment and therapeutic (curative) treatment are two separate aspects of the present invention. The patient to be treated is preferably a mammal, in particular a human. In particular, the patient being treated is diagnosed with IBS.

  Compound I can be administered as a pure compound alone or in combination with a pharmaceutically acceptable carrier or excipient in a single dose or multiple doses. The pharmaceutical composition of the present invention can be prepared according to conventional techniques such as disclosed in, for example, “Remington: The Science and Practice of Pharmacy” (19th edition, edited by Gennaro, Mack Publishing Co., Easton, Pa., 1995). It can be formulated with pharmaceutically acceptable carriers or diluents and any other known adjuvants and excipients.

  Pharmaceutical compositions are oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (subcutaneous, intramuscular, intrathecal, intravenous And can be formulated separately for administration by any suitable route, including the intradermal route, with the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject being treated, the nature of the condition being treated and the active ingredient chosen.

  Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. They can be prepared by appropriately applying a coating.

  Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

  Pharmaceutical compositions for parenteral administration are reconstituted into sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions and sterile injectable solutions or dispersions prior to use. Sterile powder is included.

  Other suitable dosage forms include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants and the like.

  Compound I is conveniently administered in unit dosage form containing an amount of said compound (eg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg or 25 mg of Compound I) in an amount of about 0.1-50 mg.

  In the case of a parenteral route such as intravenous administration, intrathecal administration, intramuscular administration, etc., the dose is usually about half of the dose used for oral administration.

  For parenteral administration, sterile aqueous solutions, aqueous propylene glycol, aqueous vitamin E, or solutions of Compound I in sesame oil or peanut oil can be used. Such aqueous solutions should be appropriately buffered if necessary, and first make the diluent isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. All sterile aqueous media used are readily available by standard techniques known to those skilled in the art.

  Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lactose, clay, sucrose, cyclodextrin, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. The pharmaceutical compositions formed by combining Compound I with a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed route of administration.

  Formulations used in the present invention suitable for oral administration are as discrete units, such as capsules or tablets, each containing a predetermined amount of active ingredient and may contain appropriate excipients. Can be presented. Furthermore, the orally available preparation may be a powder or granule, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion. it can.

  When a solid carrier is used for oral administration, the preparation can be a tablet, for example, in the form of a powder or pellet, placed in a hard gelatin capsule, or in the form of a troche or lozenge. The amount of solid carrier may vary but will usually be from about 25 mg to about 1 g.

  If a liquid carrier is used, the preparation may take the form of a syrup, emulsion, soft gelatin capsule or sterile injectable solution, such as an aqueous or non-aqueous liquid suspension or solution.

  Tablets can be prepared by mixing the active ingredient with conventional adjuvants and / or diluents and then compressing the mixture on a conventional tablet press. Examples of adjuvants or diluents include corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gum and the like. Any other adjuvants or additives commonly used for such purposes, such as colorants, flavoring agents, preservatives and the like, can be used provided they are compatible with the active ingredient.

  Capsules containing the compound of the present invention can be prepared by mixing a powder containing the compound with microcrystalline cellulose and magnesium stearate and placing the powder in a hard gelatin capsule. In some cases, the capsule may be colored with a suitable dye. Typically, capsules will contain 0.25-20% of a compound of the invention, for example 0.5-1.0%, 3.0-4.0%, 14.0-16.0% of a compound of the invention. These strengths can be used to conveniently deliver 1, 5, 10, 15, 20, and 25 mg of a compound of the invention in a unit dosage form.

  Injectable solutions are prepared by dissolving the active ingredient and possible additives in a portion of the solvent for injection (preferably sterile water), adjusting the solution to the desired volume, sterilizing the solution, Can be prepared by filling appropriate ampoules or vials. Any suitable additive conventionally used in the art can be added, such as osmotic pressure regulator, preservative, antioxidant and the like.

  Compound I can be prepared as outlined in WO2003 / 029232 or WO2007 / 144006. The salt of Compound I can be prepared by adding a suitable acid and then precipitating. Precipitation can be caused, for example, by cooling, removing the solvent, adding another solvent or mixtures thereof.

  All references cited herein, including publications, patent applications, and patents, are independent of each other, regardless of whether the document is incorporated elsewhere in this specification. It is specifically and specifically indicated that the literature is incorporated by reference, and is incorporated herein by reference as if set forth in its entirety (to the fullest extent permitted by law). .

  The use of the terms “a” and “an” and “the” and similar referents in the description of the present invention, unless otherwise indicated herein or unless clearly contradicted by context, It should be considered to include both singular and plural. For example, the expression “the compound” should be understood to refer to various “compounds” of the present invention or the specific embodiments described, unless otherwise indicated.

  Unless otherwise indicated, all exact values recited herein are representative of the corresponding approximation (eg, all exact typical values recited for a particular factor or measurement correspond to Approximate measurements (those appropriately modified by “about”) may also be considered as listed).

  Any one of the present invention made using terms such as “comprising”, “having”, “including”, or “containing” with respect to one or more elements Or a description of a plurality of aspects, unless otherwise specified, or unless otherwise clearly contradicted by context, is essentially derived from that particular element or elements “cosist of” “ It is intended to provide support for one or more similar aspects of the invention (eg, “consisting essentially of” or “substantially comprising”). (It should be understood that the composition described in the paragraph also describes the composition of the element, unless otherwise specified or unless otherwise clearly contradicted by context).

Analysis method
X-ray powder diffractogram (XRPD) was measured with a PANalytical X'Pert PRO X-ray diffractometer using CuK _α1 radiation. Samples were measured in a 2θ range of 5-40 ° using an X'celerator detector and in reflection mode. Elemental composition (CHN) was measured with Elementar's Elementar Vario EL instrument. Approximately 4 mg of sample is used for each measurement and the results are listed as the average of two measurements.

Example 1a: HBr salt of compound I Stirred and slightly heated (about 45 ° C.) oily 4- (2-p-tolylsulfanyl-phenyl) -piperidine-1-carboxylic acid ethyl ester in 442 grams in AcOH 545 ml of 33 wt% HBr (5.7 M, 2.5 equivalents) was added. This mixing generates an exotherm of 10 ° C. After the final addition, the reaction mixture is heated to 80 ° C. and left for 18 hours. A sample is removed and analyzed by HPLC, and if not complete, 33 wt% HBr in AcOH must be added. Otherwise, the mixture is cooled to 25 ° C. to precipitate the product 4- (2-p-tolylsulfanyl-phenyl) -piperidine hydrobromide. After 1 hour at 25 ° C., 800 ml of diethyl ether are added to the concentrated suspension. Stirring is continued for another hour before the product is isolated by filtration, washed with 400 ml diethyl ether and dried overnight at 40 ° C. under vacuum. The hydrobromide salt of Compound I was isolated as a white solid.

Example 1b: HBr salt of compound I
In a stirred reactor covered with 2- (4-tolylsulfanyl) -phenylbromide nitrogen, N-methyl-pyrrolidone, NMP (4.5 L) was bubbled with nitrogen for 20 minutes. 4-Methylbenzenethiol (900 g, 7.25 mol) was added, followed by 1,2-dibromobenzene (1709 g, 7.25 mol). Finally potassium tert-butoxide (813 g, 7.25 mol) was added as the last reactant. The reaction was exothermic and the temperature of the reaction mixture was raised to 70 ° C. The reaction mixture was then heated to 120 ° C. for 2-3 hours. The reaction mixture was cooled to room temperature. Ethyl acetate (4 L) and aqueous sodium chloride solution (15%, 2.5 L) were added. The mixture was stirred for 20 minutes. The aqueous phase was separated and extracted with fresh ethyl acetate (2 L). The aqueous phase was separated and the organic phases were combined and washed with sodium chloride solution (15%, 2.5 L). The organic phase was separated, dried over sodium sulfate and evaporated under reduced pressure to give a red oil containing 20-30% NMP. The oil was diluted to 2 volumes with methanol and the mixture was refluxed. Methanol was added until a clear red solution was obtained. The solution was seeded and cooled slowly to room temperature. The product crystallizes as off-white crystals. They were isolated by filtration, washed with methanol and dried to constant weight at 40 ° C. in a vacuum oven.

In a stirred reactor covered with ethyl 4-hydroxy-4- (2- (4-tolylsulfanyl) phenyl) -piperidine-1-carboxylate nitrogen, 2- (4-tolylsulfanyl) -phenyl bromide (600 g, 2.15 mol) was suspended in heptane (4.5 L). At room temperature, 10M BuLi (235 mL, 2.36 mol) in hexane was added over 10 minutes. Only a slight fever was observed. The suspension was stirred at ambient temperature for 1 hour and then cooled to -40 ° C. 1-carbethoxy-4-piperidone (368 g, 2.15 mol) dissolved in THF (1.5 L) was added at a rate that did not exceed the rate at which the reaction temperature was kept below -40 ° C. When the reaction was complete, it was warmed to 0 ° C. and 1M HCl (1 L) was added while keeping the temperature below 10 ° C. The acidic aqueous phase was separated and extracted with ethyl acetate (1 L). The organic phases were combined and extracted with sodium chloride solution (15%, 1 L). The organic phase was dried over sodium sulfate and evaporated to give a semicrystalline mass. It was slurried with ethyl ether (250 mL) and filtered off. It dried to a constant weight at 40 degreeC in the vacuum dryer.

Reaction of ethyl 4- (2- (4-tolylsulfanyl) phenyl) -piperidine-1-carboxylate trifluoroacetic acid (2.8 kg, 24.9 mol) and triethylsilane (362 g, 3.1 mol) with an efficient stirrer I put it in the vessel. Ethyl 4-hydroxy-4- (2- (4-tolylsulfanyl) phenyl) -piperidine-1-carboxylate (462 g, 1.24 mol) was added in portions from a powder funnel. The reaction was slightly exothermic. The temperature rose to 50 ° C. After the addition was complete, the reaction mixture was warmed to 60 ° C. for 18 hours. The reaction mixture was cooled to room temperature. Toluene (750 mL) and water (750 mL) were added. The organic phase was isolated and the aqueous layer was extracted with fresh toluene (750 mL). The organic phases were combined, washed with sodium chloride solution (15%, 500 mL) and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was evaporated under reduced pressure to a red oil which was further processed in the next step.

4- (2- (4-Tolylsulfanyl) phenyl) -piperidine hydrobromide Crude ethyl 4- (2- (4-tolylsulfanyl) phenyl) -piperidine-1 which is the red oil obtained in Example 3 -Carboxylate was mixed with hydrobromic acid in acetic acid (40%, 545 mL, 3.11 mol) in a stirred reactor. The mixture was heated at 80 ° C. for 18 hours. The reaction mixture was cooled to room temperature. The product crystallized out during cooling. After 1 hour at room temperature, ethyl ether (800 mL) was added to the reaction mixture and the mixture was stirred for an additional hour. The product was filtered off, washed with ethyl ether and dried to constant weight at 50 ° C. in a vacuum oven.

Example 1c: Recrystallization of Compound I HBr Salt A mixture of 10.0 grams of Compound I HBr salt (eg, prepared as described above) was heated to reflux in 100 ml H ₂ O. The mixture became clear at 80-90 ° C. and was completely dissolved. 1 gram of charcoal was added to the clear solution and reflux was continued for 15 minutes, then filtered and allowed to cool to room temperature. A white solid precipitated during cooling and the suspension was stirred at room temperature for 1 hour. Filtration and drying at 40 ° C. under reduced pressure overnight gave 6.9 grams (69%) of the HBr acid addition salt of Compound I. See Figure 1 for XRPD. Elemental analysis: 3.92% N, 59.36% C, 6.16% H (theoretical: 3.85% N, 59.34% C, 6.09% H).

Example 1d: Preparation of the free base stock solution To a mixture of 500 ml of ethyl acetate and 200 ml of H ₂ O was added 50 grams of the HBr salt of Compound I to form a two-phase slurry. About 25 ml of concentrated NaOH was added to the slurry, resulting in the formation of a clear biphasic solution (pH was measured as 13-14). The solution was stirred vigorously for 15 minutes and the organic phase was separated. The organic phase was washed with 200 ml H ₂ O, dried over Na ₂ SO ₄ , filtered and evaporated under vacuum at 60 ° C. to give the free base in 38 g yield (99%), almost colorless oil Obtained as a thing.

  A 0.235M stock solution in ethyl acetate was prepared by dissolving 10 grams of oil with ethyl acetate and adjusting the volume to 150 ml, from which 1.5 ml (100 mg of free base) was taken and used.

  A 0.353 M stock solution in EtOH was prepared by dissolving 10 grams of oil using 96 vol% EtOH and adjusting the volume to 100 ml, from which 1.0 ml (100 mg of free base) was taken and used.

Example 1e: Salt formation using a stock solution of free base A given aliquot was placed in a test tube and the appropriate amount of acid as shown in Table 1 was added with stirring. If the acid was a liquid, it was added neat, otherwise it was added after dissolving in the indicated solvent. After mixing and precipitation, stirring was continued overnight and the precipitate was collected by filtration. Before drying at 30 ° C. under vacuum, a small amount of reference sample was removed and dried at room temperature without decompression. This procedure was included to check for solvates. Some results are presented in Table 1. XRPD diffractograms are shown in FIGS. 1-22 and selected peak locations are summarized in Table 2. Table 3 shows the solubility of the compounds of the invention in water along with the pH of the resulting saturated solution. The column “Precipitate” indicates whether the precipitate isolated after the solubility determination is identical to the dissolved compound, which indicates the formation of a hydrate.

Example 2: 5-HT _3A receptor antagonism In an oocyte expressing the human homomeric 5-HT _3A receptor, 5-HT activates current with an EC ₅₀ of 2600 nM. This current can be antagonized with classical 5-HT ₃ antagonists such as ondansetron. Ondansetron exhibits a Ki value of less than 1 nM in this system. Compound I shows potent antagonism at low concentrations (0.1 nM to 100 nM) (IC ₅₀ about 10 nM / Kb about 2 nM) and shows agonist properties when applied at higher concentrations (100,000 to 100,000 nM) ( EC ₅₀ about 2600nM), reaching a maximum current of about 70-80% of the maximum current induced by 5-HT itself. In oocytes expressing the rat homomeric 5-HT _3A receptor, 5-HT activates the current with an EC ₅₀ of 3.3 μM. The experiment was performed as follows. Oocytes were surgically removed from mature female Xenopus laevis anesthetized in 0.4% MS-222 for 10-15 minutes. The oocytes were then incubated with 0.5 mg / ml collagenase (type IA Sigma-Aldrich) in OR2 buffer (82.5 mM NaCl, 2.0 mM KCl, 1.0 mM MgCl ₂ and 5.0 mM HEPES, pH 7.6) at room temperature. Digested for 2-3 hours. Select oocytes from which the follicular layer has been removed and a modified Barth's Saline buffer supplemented with 2 mM sodium pyruvate, 0.1 U / l penicillin and 0.1 μg / l streptomycin [88 mM NaCl, 1 mM KCl , 15 mM HEPES, 2.4 mM NaHCO ₃ , 0.41 mM CaCl ₂ , 0.82 mM MgSO ₄ , 0.3 mM Ca (NO ₃ ) ₂ ] for 24 hours. Stage IV-IV oocytes are identified and injected with 12-48 nl of nuclease-free water containing 14-50 pg of cRNA encoding human 5-HT _3A receptor and used for electrophysiological recording at 18 ° C. (1-7 days after injection). Place oocytes expressing human 5-HT ₃ receptor in a 1 ml bath and use Ringer's buffer (115 mM NaCl, 2.5 mM KCl, 10 mM HEPES, 1.8 mM CaCl ₂ , 0.1 mM MgCl ₂ , pH 7.5) Perfused. The cells were pierced with 0.5-1 MΩ electrodes containing 3M KCl plugged with agar and voltage fixed at −90 mV with a GeneClamp 500B amplifier. The oocytes were kept perfused with Ringer's buffer and the drug was applied to the perfusate. The 5-HT agonist solution was applied for 10-30 seconds. The efficacy of 5-HT ₃ receptor antagonists was examined by measuring the concentration response to 10 μM 5-HT stimulation.

Example 3: Effect on neuropathic pain To demonstrate efficacy against neuropathic pain, Compound I was treated with a formalin model of neuropathic pain [ Neuropharm. , 48, 252-263, 2005; Pain , 51, 5- 17, 1992]. In this model, formalin (4.5%, 20 μl) is injected into the plantar surface of the left hind paw of the mouse, and then the mouse is individually placed in a glass beaker (2 liter capacity) for observation. The stimulus caused by formalin injection induces a characteristic biphasic behavioral response that is quantified as the amount of time spent licking the injured paw. The first phase (about 0 to 10 minutes) represents direct chemical stimulation and nociception, whereas the second phase (about 20 to 30 minutes) is thought to represent neuropathic pain. These two phases are separated by rest time, during which behavior returns to normal. By measuring the amount of time spent licking the injured paw in two phases, the effectiveness of the test compound in reducing pain stimulation is assessed.

Eight C57 / B6 mice (approximately 25 g) were tested in each group. Table 4 below shows the amount of time spent licking the injured paw in two phases, 0-5 minutes and 20-30 minutes after formalin injection. The amount of compound administered is calculated as the free base.

  The data in Table 4 reveals that Compound I has little effect in the first phase, which represents direct chemical stimulation and nociception. More notably, the data also reveals a clear and dose-dependent shortening of the time spent licking the feet in phase 2, which in the treatment of neuropathic pain The effect of the compound of the present invention is shown.

  Furthermore, the potential analgesic effect of Compound I in an animal model of neuropathic pain was evaluated. Peripheral mononeuropathy secondary to chronic strangulated nerve injury is induced in the rat right hind limb using established behavioral tests (Von Frey filaments and Hargreaves Plantar Device, respectively) The occurrence of mechanical allodynia and thermal hyperalgesia was monitored. Subcutaneous administration of Compound I in 10% hydroxypropyl-betacyclodextrin at doses of 1.9, 4.8 and 7.9 mg / kg did not increase the right hind paw escape threshold when challenged with von Frey hair. However, thermal hyperalgesia showed a significant increase in foot escape latency at 4.8 and 7.8 mg / kg, indicating an analgesic response.

Claims (18)

  A method for treating irritable bowel syndrome, wherein a therapeutically effective amount of 4- [2- (4-methylphenylsulfanyl) phenyl] piperidine or a pharmaceutically acceptable salt thereof (compound I) ).   The method of claim 1, wherein Compound I is administered in crystalline form.   The method of claim 2, wherein compound I is an HBr addition salt.   4. The method of claim 3, wherein the HBr addition salt is characterized by peaks at about 6.08, 14.81, 19.26 and 25.38 ° 2θ (all ± 0.1 °) in XRPD.   5. The method of claim 4, wherein the HBr addition salt is characterized by XRPD illustrated in FIG.   6. The method according to any one of claims 1-5, wherein Compound I is administered at 1-20 mg / day.   4- [2- (4-Methylphenylsulfanyl) phenyl] piperidine or a pharmaceutically acceptable salt thereof (Compound I) for use in the treatment of irritable bowel syndrome.   8. Compound I according to claim 7, which is administered in crystalline form.   9. Compound I according to claim 8, which is an HBr addition salt.   9. Compound I according to claim 8, characterized in that the HBr addition salt is characterized by peaks at about 6.08, 14.81, 19.26 and 25.38 ° 2θ (all ± 0.1 °) in XRPD.   11. Compound I according to claim 10, characterized in that the HBr addition salt is characterized by the XRPD illustrated in FIG.   12. Compound I according to any one of claims 7-11, wherein Compound I is administered at 1-20 mg / day.   Use of 4- [2- (4-methylphenylsulfanyl) phenyl] piperidine or a pharmaceutically acceptable salt thereof (Compound I) in the manufacture of a medicament for treating irritable bowel syndrome.   14. Use according to claim 13, wherein compound I is administered in crystalline form.   15. Use according to claim 14, wherein compound I is an HBr addition salt.   16. Use according to claim 15, characterized in that the HBr addition salt is characterized by peaks of about 6.08, 14.81, 19.26 and 25.38 ° 2θ (all ± 0.1 °) in XRPD.   Use according to claim 16, characterized in that the HBr addition salt is characterized by the XRPD illustrated in FIG.   17. Use according to any one of claims 13 to 16, wherein Compound I is administered at 1-20 mg / day.

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