JP2006111531A - 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salt - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To improve the instability and low biological effects during storage of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea as a free base. <P>SOLUTION: The 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea is converted into a crystalline salt or a non-crystalline salt hydrate with sulfuric acid, malic acid or citric acid. Furthermore, a method for producing the crystalline salt or non-crystalline salt hydrate is provided. The use of the crystalline salt or non-crystalline salt hydrate alone or in combination with other compounds for treatment of various diseases associated with dysregulation of urotensin II or urotensin II receptors or the use of the crystalline salt or non-crystalline salt hydrate in the preparation of pharmaceutical compositions is provided. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) as crystalline or amorphous salt hydrate -Relates to urea and its production process. Furthermore, the present invention provides the above 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-) alone as a crystalline salt or in combination with other compounds. It relates to the use of quinolin-4-yl) -urea. The present invention also provides 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea and urotensin II as crystalline salts. It relates to a composition comprising an inert carrier material useful as an antagonist.

1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea of general formula I and its preparation as free base The method is known from the description of WO-20024026836 (see Patent Document 1). 1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea of general formula I is a potent urotensin II receptor It is already known to be a body antagonist (see Non-Patent Document 1).
International Publication No. 2004/026836 Pamphlet Martine Clozel et al. J. et al. Pharmcol. Exp. Ther. 2004, 311, 204-212

  1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea of general formula I as the free base is hygroscopic , And discolors at high temperature and high humidity, and also has the disadvantage of becoming lumps under such conditions. 1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea of general formula I as free base has a pH of 7 Slightly soluble in water (see Example 9). Said compound of general formula I as the free base is shown to have a low biological effect after administration to rats (see Example 10). Therefore, the compound of general formula I as the free base is unsuitable as a pharmaceutical because it is not easy to handle in the manufacture of the pharmaceutical. Moreover, large scale production and storage of the compounds of general formula I cause various problems due to the above properties.

  The present invention relates to a crystalline form of 1- [2- (4-benzyl-4-hydroxy-piperidine-1-] of the formula I which exhibits improved properties suitable for pharmaceuticals or for large-scale production, production and storage. Yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea.

  The present invention relates to 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl- of general formula I as sulfate or amorphous sulfate hydrate It relates to quinolin-4-yl) -urea. The sulfate of 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea of general formula I is represented by [Martine Clozel et. Al., J Pharmacol Exp Ther. 2004; DOI: 10.1 124 / jpet. 104.068320], but its production method is not disclosed.

  The present invention also provides 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- of general formula I as maleate or amorphous maleate hydrate. Relates to (2-methyl-quinolin-4-yl) -urea.

  Furthermore, the present invention also provides 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- of general formula I as citrate or amorphous citrate hydrate. Relates to (2-methyl-quinolin-4-yl) -urea.

The present invention also provides the preparation of the above salts of 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea Regarding a method, the method comprises:
a. 1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea of general formula I mixed with organic solvent Adding an acid, a solution containing an acid in water, a solution containing an acid in an organic solvent, or a solution containing an acid in a mixture of water and an organic solvent, and stirring the mixture; or b. 1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea in a mixture of organic solvent and water Mixing, adding an acid, a solution containing an acid in water, a solution containing an acid in an organic solvent, or a solution containing an acid in a mixture of water and an organic solvent, and stirring the mixture; or c. 1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea of I as a solid or an organic solvent and water Dissolved in a liquid mixture containing acid and water. Adding to a solution containing an acid in an organic solvent, or a solution containing an acid in a mixture of water and an organic solvent, and stirring the mixture; or d. 1- [2- (4- Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea as a solid or dissolved in an organic solvent to contain acid in water and water Adding to a solution, a solution containing an acid in an organic solvent, or a solution containing an acid in a mixture of water and an organic solvent, and stirring the mixture;
Consists of.

  The acids used in the above method are sulfuric acid, malic acid, and citric acid (see Examples 1 to 6).

  Furthermore, the present invention provides 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea obtained by the above method Regarding salt.

  Furthermore, the present invention provides an inert compound with the 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea salt described above. It relates to a pharmaceutical composition comprising a carrier substance.

  Furthermore, the present invention provides the above 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea salt and a pharmaceutical product Relating to their use.

  1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea as described above, because it can inhibit the action of urotensin II Salts can be used to treat vasoconstriction associated with the action of urotensin II, diseases associated with increased proliferation, and other disease states. Examples of such diseases are hypertension, atherosclerosis, angina or myocardial ischemia, congestive heart failure, heart failure, cardiac arrhythmia, renal ischemia, chronic kidney disease, renal failure, stroke, cerebral vasospasm, cerebral ischemia, dementia, Migraine, subarachnoid hemorrhage, diabetes, diabetic arteropathy, diabetic nephropathy, connective tissue disease, cirrhosis, asthma, chronic obstructive pulmonary disease, high altitude pulmonary edema, Raynaud's syndrome, portal hypertension, thyroid dysfunction, lung Edema, pulmonary hypertension, pulmonary fibrosis. They are prevention of restenosis after balloon or stent angioplasty, cancer, enlarged prostate, erectile dysfunction, hearing loss, cataract, chronic bronchitis, asthma, Gram-negative bacterial sepsis, shock, sickle cell anemia, sickle cell Treatment of acute chest syndrome, glomerulonephritis, renal colic, glaucoma, treatment and prevention of diabetic complications, complications after vascular or cardiac surgery, or organ transplantation, complications of cyclosporine treatment, pain, addiction, mental Treatment and prevention of schizophrenia, Alzheimer's disease, anxiety, obsessive-compulsive behavior, epileptic seizures, stress, depression, dementia, neuromuscular abnormalities, neurodegenerative diseases and other disorders related to urotensin II or urothein II receptor dysregulation Can also be used.

 These compositions are administered enterally or orally, for example as tablets, dragees, gelatin capsules, emulsions, solutions or suspensions, nasally such as sprays, or rectally such as suppositories. it can. The above 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea salt is intramuscular, parenteral Alternatively, it may be administered in an intravenous dosage form, for example, in the form of an injection solution.

  These pharmaceutical compositions comprise the above 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea salt It can be contained in combination with inorganic and / or organic excipients common in the pharmaceutical industry, such as lactose, corn (starch) or derivatives thereof, talc, stearic acid or salts of these substances.

  For gelatin capsules, vegetable oils, waxes, fats, liquid or semi-liquid polyols and the like can be used. For the preparation of solutions and syrups, for example, water, polyols, saccharose (sucrose), glucose and the like are used. The injection is prepared using, for example, water, polyols, alcohols, glycerin, vegetable oil, lecithin, liposomes and the like. Suppositories are prepared using natural oils or hardened oils, waxes, fatty acids (fats), liquid or semi-liquid polyols, and the like.

  These compositions further include preservatives, stabilization enhancing substances, viscosity enhancing or regulating substances, solubility enhancing substances, sweeteners, pigments, taste-improving compounds, salts that alter osmotic pressure, buffers, antioxidants, etc. Can be contained.

  The above 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea salt may be one or more other Therapeutically useful substances such as α- and β-blockers such as phentolamine, phenoxybenzamine, atenolol, propranolol, timolol, metoprolol, carteolol, carvedilol; vasodilators such as hydralazine, minoxidil, diazoxide, flosequinan; Calcium antagonists such as diltiazem, nicardipine, nimodipine, verapamil, nifedipine, angiotensin converting enzyme inhibitors such as cilazapril, captopril, enalapril, lizinopril; potassium channel activators such as pinacidil, cromakalim; losartan, valsartan, candesartan, irbesartan Angiotensin receptor antagonists such as eprosartan, telmisartan, and tasosartan; diuretics such as hydrochlorothiazide, chlorothiazide, acetamide, bumetanide, furosemide, metolazone, chlorthalidone; sympathetic blockers such as methyldopa, clonidine, guanabenz, reserpine; bosentan And endothelin receptor antagonists such as tezosentan, clazosentan, darsentan, atrasentan, enlasentan, sitaxsentan; antihyperlipidemic agents such as lovastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, simvastatin; and hypertension, vascular disease or above It may be used in combination with other therapeutic agents useful for the treatment of other listed diseases.

  The dose can vary within wide limits but should be adapted to the particular situation. In general, the daily dosage in oral form should be between about 3 mg to about 3 g, preferably between about 5 mg to about 1 g, particularly preferably between 10 mg to 300 mg per adult weighing about 70 kg. . The dose is preferably administered in 1 to 3 equal doses per day. As usual, children should take lower doses that are compatible with their weight and age.

  The present invention also provides an amorphous form of the above 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea salt It relates to a composition comprising a part.

  The terms “crystallinity” or “crystalline” are used to describe a crystalline material compared to an amorphous (amorphous) material, for example, line shape and background intensity in an X-ray diffraction pattern. Evaluated by (background intensity).

  According to this method, a crystallinity of 90% to 100% is evaluated. In a more preferred embodiment, the crystallinity is in the range of 92% to 100%. In the most preferred embodiment, the crystallinity is in the range of 95% to 100%.

  The term “amorphous salt hydrate” is used to describe a salt that contains variable amounts of water. Some or all of the water molecules can bind to the crystal lattice. The term “amorphous salt hydrate” is also used to describe a salt containing water that is not bound to the crystal lattice. The amount of water contained in the “non-crystalline salt hydrate” is 0 to 20%, preferably 0 to 10%.

  The term “amorphous sulfate hydrate” includes 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2) containing the variable amounts of water described above. Used to describe -methyl-quinolin-4-yl) -urea sulfate.

  The term “amorphous malate hydrate” includes 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- () containing a variable amount of water as described above. Used to describe 2-methyl-quinolin-4-yl) -urea malate.

  The term “amorphous citrate hydrate” includes 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- () containing a variable amount of water as described above. Used to describe 2-methyl-quinolin-4-yl) -urea citrate.

  The term “acid” means acids, such as sulfuric acid, malic acid, and citric acid, as used within the present invention. Acids that are all optically active, such as malic acid, can be used as racemates, optically pure enantiomers, and mixtures of enantiomers. Particularly preferred acids are sulfuric acid and malic acid. The most preferred acid is sulfuric acid. The acid can be used without a solvent, or dissolved in an organic solvent, a mixed solution of an organic solvent and water, or water. Preferably, the acid is dissolved in a mixture of an organic solvent and water, or water.

The term “organic solvent” as used within the present invention refers to a solvent or mixture of solvents, such as C _1-4 -alkanols (CH ₃ OH, C ₂ H ₅ OH, n— C ₃ H ₇ OH, i-C ₃ H ₇ OH, n-C ₄ H ₉ OH, i-C ₄ H ₉ OH, t-C ₄ H ₉ OH), ketones (acetone, ethyl methyl ketone, methyl isobutyl) Ketone), ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, methyl-tert. Butyl ether) or acetonitrile. Preferred “organic solvents” are CH ₃ OH, C ₂ H ₅ OH, n-C ₃ H ₇ OH, i-C ₃ H ₇ OH and acetone. The most preferred “organic solvents” are CH ₃ OH, C ₂ H ₅ OH, i-C ₃ H ₇ OH and acetone.

  The term “acid solution” as used within the present invention means the acid solution mentioned above, preferably an aqueous solution. The acid solution has a concentration range of 0.01 to 10 mol / L, more preferably a concentration range of 0.1 to 5 mol / L, more preferably a concentration range of 0.5 to 2 mol / L.

  Although more specific examples will be described with respect to the above-described general description of the present invention, the present invention is not limited to these examples.

List of Example Abbreviations for Invention:
aq. Water-soluble AUC Area under the curve DMSO Dimethyl sulfoxide HV High vacuum condition J NMR coupling constant min min MHz Megahertz MP Melting point NMR Nuclear magnetic resonance ppm parts per million
RH Relative humidity rt Room temperature XRD Powder X-ray diffraction NMR spectra were recorded on a 300VX nuclear magnetic resonance apparatus manufactured by Varian Mercury. The spectrum was referenced to tetramethylsilane as an external standard. X-ray diffraction patterns (XRD) were recorded with a Bruker D5000 in the range of 3et40 ° (2θ) using a Cu-Kα (1.5418Å) source and a 40 kV-30 mA generator. The load test was performed by exposing samples in open and sealed glass bottles to the following conditions: 60 ° C./80% RH (8 weeks) and 80 ° C./RH unregulated (48 hours).

Example 1
1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea sulfate

1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinoline of general formula I in CH ₃ OH (250 mL, 0.9 M of compound I) To a suspension containing -4-yl) -urea (9.70 g, 0.228 mol), an aqueous solution of H ₂ SO ₄ (11.4 mL, 2M, 0.228 mol) is added. The clear solution is stirred at 4 ° C. for 15 hours. The resulting precipitate is filtered, washed with CH ₃ OH (2 × 10 mL) and dried under high vacuum to give a white crystalline powder of the indicated compound in 83% yield.

Analytical melting point: 239-242 ° C (decomposition)
H ₂ O content: 1.41%
Elemental analysis of C ₂₅ H ₃₂ N ₄ O ₆ S (0.41 H 2 O):% actual value (calculated value):

Example 2
1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea sulfate

1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea of the general formula I in CH ₃ OH (86 L) H ₂ SO ₄ (8.5 L, 9.91%) aqueous solution is added to the suspension containing (4.3 kg) for 15 minutes. The solution is cooled to −8 ° C. and then stirred at this temperature for 1 hour. The formed precipitate is filtered, washed with chilled CH ₃ OH (−5 ° C., 2 × 9 L) and dried under a stream of nitrogen to give 68% yield of the title compound as a white crystalline powder.

Analytical melting point: ca. 200 ° C. (decomposition)
H ₂ O content: 0.38%

Example 3
1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea sulfate

1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea of the general formula I in CH ₃ OH (178 L) H ₂ SO ₄ (6 L, 9.91%) aqueous solution is added to the suspension containing (21.36 kg) for 10 minutes. The clear solution is filtered and more H ₂ SO ₄ (33.8 L, 1.07 M) aqueous solution is added for 45 minutes. The solution is cooled to −2 ° C. for 1.5 hours and stirred at −5 to −9 ° C. for 1 hour. The resulting precipitate is filtered, washed with chilled CH ₃ OH (−5 ° C., 54 L), and dried under a stream of nitrogen to give the display compound as a white crystalline powder in 84% yield.

Analytical H2O content: 0.84%

Example 4
1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea sulfate

1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl- of formula I was added to CH ₃ OH (285 L, 0.24 M solution of compound I). To a suspension containing quinolin-4-yl) -urea (68.29 mol), an aqueous solution of H ₂ SO ₄ (11 L, 9.91%) is added for 10 minutes. The clear solution is filtered and more H ₂ SO ₄ (59.5 L, 9.91%, 1.07 M) aqueous solution is added for 30 minutes. The solution is cooled to −7 ° C. for 2 hours and stirred at this temperature for 1 hour. The resulting precipitate is filtered, washed with chilled CH ₃ OH (−4 ° C., 41 L), and dried under a stream of nitrogen to give the display compound as a white crystalline powder in a yield of 83%.

analysis

Example 5
1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea malate

1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea (2) of general formula I in acetone (50 mL) 0.09 g, 0.005 mol) is heated at 50 ° C. and an aqueous L-(−)-malic acid solution (738 mg in 10 L) is added. The clear solution is cooled at 4 ° C. for 15 hours. The resulting precipitate is filtered, washed with acetone (20 mL), and dried at 50 ° C. under high vacuum to obtain a white crystalline powder of the indicated compound with a yield of 71%.

Analytical MP: 143-146 ° C (decomposition)
H ₂ O content: 1.92%

Example 6
1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea citrate

A solution of citric acid (1.05 g) in C2H5OH (400 mL) was heated at 65 ° C. to give 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl]- 3- (2-Methyl-quinolin-4-yl) -urea (2.09 g, 0.005 mol) is added dropwise as a solid. The mixture is stirred at 4 ° C. for 15 hours. The resulting precipitate is filtered and dried at 50 ° C. under high vacuum to obtain a white crystalline powdery display compound with a yield of 72%.

Analytical melting point: 152-157 ° C (decomposition)
H ₂ O content: 1.08%

Example 7: X-ray diffraction pattern (XRD)

FIG. 1 shows the XRD-diffraction pattern of the compound described in Example 2. Table 1 summarizes the peaks and the intensity of these compounds. It should be understood that due to small changes in experimental details, the deviation of 2-θ values of specific peaks in the powder X-ray diffraction pattern is small.

Example 8: Hygroscopicity

Hygroscopicity was evaluated using a static method according to the European Pharmacopoeia Technical Guide. An increase in the weight of the compound was observed when the compound was stored in a humidity cabinet for 24 hours at RH 79% at room temperature. The results are shown in Table 2.
Table 2: Weight gain (Δm) after 24 hours exposure at 79% RH

Example 9: Solubility in water and PH7

Solubility was measured with water and an aqueous phosphate buffer solution (pH = 7, 100 mM). Results are expressed as dissolved compound (mg) per solvent (mL). Table 3 summarizes these results.

Example 10: Pharmacokinetic evaluation of 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea compound

1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea as free base or sulfate per kg Pharmacokinetic parameters after oral administration of 10 mg were determined in male Wistar rats. Blood samples were collected 24 hours after administration and analyzed by specific sensitive liquid chromatography mass spectrometry (LC-MS / MS). Pharmacokinetic parameters were calculated using a non-compartmental method. The average exposure to 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea is as described in Example 1. After administration of the compound at 396 ng * h / mL, it is expressed as the area under the curve (AUC _0-inf.) .

FIG. 1 shows the X-ray diffraction (XRD) pattern of the compound described in Example 2.

Claims (16)

1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl of general formula I as crystalline or amorphous salt hydrate )-urea.
The 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinoline- of claim 1 as sulfate or amorphous sulfate hydrate. 4-yl) -urea.

1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-) according to claim 1 as malate or amorphous malate hydrate. Quinolin-4-yl) -urea.

1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-) according to claim 1 as citrate or amorphous citrate hydrate. Quinolin-4-yl) -urea.

1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl as a sulfate according to claim 1 and 2 having a corresponding powder X-ray diffraction pattern as in FIG. ] -3- (2-Methyl-quinolin-4-yl) -urea.
The powder X-ray diffraction pattern shows a peak at the diffraction (2-θ) angle shown in the following table, and 1- [2- (4-benzyl-4-hydroxy- Piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea.

1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl) of the general formula I as a salt according to any one of claims 1 to 6 -Quinolin-4-yl) -urea, the process comprising:
a. 1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea of general formula I mixed with organic solvent Adding an acid, a solution containing an acid in water, a solution containing an acid in an organic solvent, or a solution containing an acid in a mixture of water and an organic solvent, and stirring the mixture; or

b. 1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea of general formula I in an organic solvent and water Adding an acid, a solution containing an acid in water, a solution containing an acid in an organic solvent, or a solution containing an acid in a mixture of water and an organic solvent, and stirring the mixture; Or

c. 1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea of general formula I as a solid, or Dissolve in a mixture of organic solvent and water and add to acid, solution containing acid in water, solution containing acid in organic solvent, or solution containing acid in mixture of water and organic solvent, and mix Stirring the liquid; or

d. 1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea of general formula I as a solid, or Dissolving in an organic solvent and adding to an acid, a solution containing an acid in water, a solution containing an acid in an organic solvent, or a solution containing an acid in a mixture of water and organic solvent, and stirring the mixture;

Consists of.
1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl-quinoline-- of the general formula I as a salt obtained by the method according to claim 7 4-yl) -urea.
1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2) of the general formula I as a salt according to any one of claims 1 to 6 or 8 A composition comprising -methyl-quinolin-4-yl) -urea and an inert carrier material.
Diseases associated with dysregulation of urotensin II or urotensin II receptor, or hypertension, atherosclerosis, angina or myocardial ischemia, congestive heart failure, heart failure, cardiac arrhythmia, renal ischemia, chronic kidney disease, renal failure, stroke, Cerebral vasospasm, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, diabetes, diabetic arteropathy, diabetic nephropathy, connective tissue disease, cirrhosis, asthma, chronic obstructive pulmonary disease, high altitude pulmonary edema, Raynaud's syndrome, 9. A compound according to any one of claims 1 to 6 or 8 for the treatment of diseases associated with vascular or myocardial dysfunction such as portal hypertension, thyroid dysfunction, pulmonary edema, pulmonary hypertension, or pulmonary fibrosis and A pharmaceutical composition comprising conventional inert carrier materials and adjuvants.
Treatment of diseases including restenosis after balloon or stent angioplasty, cancer, enlarged prostate, erectile dysfunction, hearing loss, cataract, chronic bronchitis, asthma, Gram-negative bacterial sepsis, shock, sickle cell anemia, sickle cell Acute chest syndrome, glomerulonephritis, renal colic, glaucoma treatment, diabetes complications, complications after vascular or cardiac surgery, or organ transplantation, complications of cyclosporine treatment, pain, addiction, schizophrenia, Alzheimer 9. A compound according to any one of claims 1 to 6 or 8 and a conventional inert carrier for the treatment and prevention of disease, anxiety, obsessive-compulsive behavior, epileptic seizures, stress, depression, dementia, neuromuscular abnormalities, neurodegenerative diseases A pharmaceutical composition comprising a substance and an adjuvant.
Hypertension, atherosclerosis, angina or myocardial ischemia, congestive heart failure, heart failure, cardiac arrhythmia, renal ischemia, chronic kidney disease, renal failure, stroke, cerebral vasospasm, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage , Diabetes, diabetic arteropathy, diabetic nephropathy, connective tissue disease, cirrhosis, asthma, chronic obstructive pulmonary disease, high altitude pulmonary edema, Raynaud's syndrome, portal hypertension, thyroid dysfunction, pulmonary edema, pulmonary hypertension, lung Fibrosis, restenosis after balloon or stent angioplasty, cancer, enlarged prostate, erectile dysfunction, hearing loss, cataract, chronic bronchitis, asthma, gram-negative sepsis, shock, sickle cell anemia, sickle cell acute Chest syndrome, glomerulonephritis, renal colic, glaucoma treatment, diabetic complications, complications after vascular or cardiac surgery or organ transplantation, complications of cyclosporine treatment, pain, addiction, mental Claim 1 in combination with other pharmacologically active compounds for the treatment and prevention of fissure, Alzheimer's disease, anxiety, compulsive behavior, epileptic seizures, stress, depression, dementia, neuromuscular or neurodegenerative diseases Use of one or more compounds according to any one of 1 to 6 or 8 to 9.
Others such as ACE inhibitors, angiotensin II receptor antagonists, endothelin receptor antagonists, vasopressin antagonists, β-adrenergic antagonists, α-adrenergic antagonists, TNF alpha antagonists, or peroxisome proliferator-activated receptor modulators Use of one or more compounds according to any one of claims 1 to 6 or 8 to 9 in combination with a pharmacologically active compound.
A method for treating a patient suffering from the disease according to any one of claims 10 to 12 by administering the pharmaceutical composition according to any one of claims 9 to 11.
1- [2- (4-Benzyl-4-hydroxy-piperidin-1-yl) -ethyl] -3- (2-methyl) of the general formula I as salt according to any one of claims 1 to 6 1- [2- (4-Benzyl-4-hydroxy-piperidine-1 of the general formula I as a salt according to any one of claims 1 to 6) and a crystalline part of -quinolin-4-yl) -urea -Yl) -ethyl] -3- (2-methyl-quinolin-4-yl) -urea amorphous part and up to 100% in total.
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The invention described above.

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