Patent Application
20060079552
The present invention relates to 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin4-yl)-urea as a crystalline salt or a non-defined salt hydrate thereof and a process for its preparation. Further, the present invention relates to the use of said 1-[2-(4-benzyl-4-hydroxy-piperidin- 1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea as a crystalline salt alone or in combination with other compounds. The present invention also relates to compositions containing said 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea as a crystalline salt and inert carrier material which are useful as urotensin-II antagonist.
1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin4-yl)-urea of formula I as well as the process for its preparation as free base is known from WO-2004026836. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I has been shown to be a potent urotensin II receptor antagonist [Martine Clozel et al. in J. 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 formula I as free base has the disadvantages that it is hygroscopic, its colour changes at higher temperature and higher humidity, and it agglomerates to a substance cake under these conditions. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as free base is slightly soluble in water at pH 7 (compare Example 9). The said compound of formula I as free base was shown to have a low bioavailability after oral dosing in the rat (compare Example 10). Therefore, the said compound of formula I as free base is not suitable as a pharmaceutical product since it is not easy to handle in pharmaceutical preparations. In addition, large scale production and storage of the said compound of formula I causes problems due to the properties mentioned above.
The subject of the present invention is to provide 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I in crystalline forms which show improved properties suitable for a pharmaceutical product, pharmaceutical preparations, production in large scale, and storage.
The present invention relates to a compound, 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as a sulfate or non-defined sulfate hydrate as shown below.
A sulfate salt of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I is described by [Martine Clozel et. al., J Pharmacol Exp Ther. 2004; DOI:10.1124/jpet.104.068320] but no procedure for its preparation has been disclosed.
The present invention in addition also relates to a compound, 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as a malate or non-defined malate hydrate as shown below.
Further the present invention also relates to a compound, 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as a citrate or non-defined citrate hydrate as shown below.
The present invention also relates to a process for preparing the above mentioned salts of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea which process comprises
The acids used in the above process are sulfuric acid, malic acid, and citric acid (compare also Examples 1 to 6).
Further, the present invention relates to 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salts obtainable by the process mentioned above.
Further, the present invention relates to pharmaceutical compositions comprising 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl )-urea salts as mentioned above and inert carrier material.
Further, the present invention relates to 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salts as mentioned above and their use as medicaments.
Because of their ability to inhibit the actions of urotensin II, 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salts as described above can be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or other disease states associated with the actions of urotensin II. Examples of such diseases are hypertension, atherosclerosis, angina or myocardial ischemia, congestive heart failure, cardiac insufficiency, cardiac arrhythmias, renal ischemia, chronic kidney disease, renal failure, stroke, cerebral vasospasm, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, diabetes, diabetic arteriopathy, diabetic nephropathy, connective tissue diseases, cirrhosis, asthma, chronic obstructive pulmonary disease, high-altitude pulmonary edema, Raynaud's syndrome, portal hypertension, thyroid dysfunction, pulmonary edema, pulmonary hypertension, or pulmonary fibrosis. They can also be used for prevention of restenosis after balloon or stent angioplasty, for the treatment of cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, sickle cell acute chest syndrome, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, addictions, schizophrenia, Alzheimer's disease, anxiety, obsessive-compulsive behavior, epileptic seizures, stress, depression, dementias, neuromuscular disorders, neurodegenerative diseases, as well as other diseases related to a dysregulation of urotensin II or urotensin II receptors.
These compositions may be administered in enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays and aerosols, or rectally in form of suppositories. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salts as mentioned above may also be administered in intramuscular, parenteral or intravenous form, e.g. in form of injectable solutions.
These pharmaceutical compositions may contain 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salts as mentioned above in combination with inorganic and/or organic excipients, which are usual in the pharmaceutical industry, like lactose, maize or derivatives thereof, talcum, stearic acid or salts of these materials.
For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquid polyols etc. may be used. For the preparation of solutions and sirups e.g. water, polyols, saccharose, glucose etc. are used. Injectables are prepared by using e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes etc. Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats ), liquid or half-liquid polyols etc.
The compositions may contain in addition preservatives, stabilisation improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, anti-oxidants etc.
1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salts as mentioned above may also be used in combination with one or more other therapeutically useful substances e.g. with α- and β-blockers like phentolamine, phenoxybenzamine, atenolol, propranolol, timolol, metoprolol, carteolol, carvedilol, etc.; with vasodilators like hydralazine, minoxidil, diazoxide, flosequinan, etc.; with calcium-antagonists like diltiazem, nicardipine, nimodipine, verapamil, nifedipine, etc.; with angiotensin converting enzyme-inhibitors like cilazapril, captopril, enalapril, lisinopril etc.; with potassium channel activators like pinacidil, chromakalim, etc.; with angiotensin receptor antagonists like losartan, valsartan, candesartan, irbesartan, eprosartan, telmisartan, and tasosartan, etc.; with diuretics like hydrochlorothiazide, chlorothiazide, acetolamide, bumetanide, furosemide, metolazone, chlortalidone, etc.; with sympatholytics like methyidopa, clonidine, guanabenz, reserpine, etc.; with endothelin receptor antagonists like bosentan, tezosentan, clazosentan, darusentan, atrasentan, enrasentan, or sitaxsentan, etc.; with anti-hyperlipidemic agents like lovastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, simvastatin, etc.; and other therapeutics which serve to treat high blood pressure, vascular disease or other disorders listed above.
The dosage may vary within wide limits but should be adapted to the specific situation. In general the dosage given daily in oral form should be between about 3 mg and about 3 g, preferably between about 5 mg and about 1 g, especially preferred between 10 mg and 300 mg, per adult with a body weight of about 70 kg. The dosage should be administered preferably in 1 to 3 doses of equal weight per day. As usual children should receive lower doses which are adapted to body weight and age.
The present invention also relates to compositions containing amorphous parts of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salts as mentioned above.
The term “crystallinity” or “crystalline” is used to describe the part of crystalline material compared to amorphous material and is estimated e.g. by the line shape and the background intensity in X-ray diffraction patterns.
According to these methods, a crystallinity of 90% to 100% is estimated. In a more preferred embodiment the crystallinity is within the range of 92% to 100%. In the most preferred embodiment the crystallinity is within the range of 95% to 100%.
The term “non-defined crystalline salt hydrate” is used to describe salts that contain variable amounts of water. A part or all of the water molecules can be bound the crystal lattice. The term “non-defined crystalline salt hydrate” also describes salts that contain water that is not bound to the crystal lattice. The amount of water contained in a “non-defined crystalline salt hydrate” is within a range of 0 to 20%, preferably within a range of 0 to 10%.
The term “non-defined sulfate hydrate” is used to describe 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl )-urea sulfate salts that contain variable amounts of water as described above.
The term “non-defined malate hydrate” is used to describe 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea malate salts that contain variable amounts of water as described above.
The term “non-defined citrate hydrate” is used to describe 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea citrate salts that contain variable amounts of water as described above.
The term “acid”, as used within the present invention, means acids, such as sulfuric acid, malic acid, and citric acid. Malic acid like all optically active acids can be used as a racemate, as optically pure enantiomer, and mixtures of enantiomers. Especially preferred acids are sulfuric acid, and malic acid. Most preferred acid is sulfuric acid. The acid may be used without solvent or dissolved either in organic solvents, mixtures of organic solvents and water, or water. Preferably, the acid is dissolved in mixtures of organic solvents and water, or in water.
The term “organic solvents”, as used within the present invention, means solvents or mixtures of solvents, such as C1-4-alkanol (CH3OH, C2H5OH, n-C3H7OH, i-C3H7OH, n-C4H9OH, i-C4H9OH, t-C4H9OH), ketones (acetone, ethylmethylketone, methylisobutylketone), ethers (diethylether, tetrahydrofurane, 1,4-dioxane, methyl-tert.butylether) or acetonitrile. Preferred “organic solvents” are CH3OH, C2H5OH, n-C3H7OH, i-C3H7OH and acetone. Most preferred “organic solvents” are CH3OH, C2H5OH, i-C3H7OH and acetone.
The term “solution of an acid” as used within the present invention, means solutions of an acid as described before, preferably aqueous solutions. Acid solutions are in the concentration range of 0.01 to 10 mol/L, more preferred in the concentration range of 0.1 to 5 mol/L, most preferred in the concentration range of 0.5 to 2 mol/L.
The foregoing general description of the invention will now be further illustrated with a number of non-limiting examples.
NMR spectra were recorded on a Varian Mercury 300VX NMR Spectrometer. The spectra are referenced to tetramethylsilane as external standard. X-ray diffraction patterns (XRD) were recorded on a Bruker D5000, using a CU-Kalpha (1.5418 Å) source, a 40 kV-30 mA generator, in a range of 3 et 40° (2theta). Stress test studies were done by exposing samples in open and closed glass bottles to the following conditions: 60° C./80% RH (8 weeks) and 80° C./RH not controlled (48 h).
To a suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I (9.70 g, 0.228 mol) in CH3OH (250 mL, 0.9 M solution of compound 1) is added aqueous H2SO4 (11.4 mL, 2 M, 0.228 mol). The clear solution is stirred at 4° C. for 15 h. The formed precipitate is filtered, washed with CH3OH (2×10 mL) and dried in HV to provide the title compound as white crystalline powder in 83% yield.
Analytics
MP: 239-242° C. (decomposition).
H2O content: 1.41%.
Elemental Analysis for C25H32N4O6S (0.41 H2O): % found (calculated): C: 57.20 (57.30); H 6.37 (6.31); N 10.73 (10.69); S 6.14 (6.12).
1H-NMR (d6-DMSO): 8.26 (d, J=8.5, 1H); 8.09 (s, 1H); 7.83 (d, J=8.2, 1H); 7.70 (t, J≈7.6, 1H); 7.51 (t, J≈7.6, 1H); 7.43 (br. s,1 H); 7.27-7.15 (m, 5H); 4.77 (br. s, 1 H); 3.54-3.53 (m, 2H); 3.35-3.31 (m, 2H); 3.20-3.06 (m, 5H); 2.70 (s, 2H); 2.58 (s, 3H); 1.83-1.75 (m, 2H); 1.59-1.54 (m, 2H).
To a suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I (4.3 kg) in CH3OH (86 L) is added aqueous H2SO4 (8.5 L, 9.91%) during 15 min. The solution is cooled to −8° C. and stirred at this temperature for 1 h. The formed precipitate is filtered, washed with cooled CH3OH (−5° C., 2×9 L) and dried under a stream of nitrogen to provide the title compound as white crystalline powder in 68% yield.
Analytics
MP: ca. 200° C. (decomposition).
H2O content: 0.38%.
To a suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I (21.36 kg) in CH3OH (178 L) is added aqueous H2SO4 (6 L, 9.91%) during 10 min. The clear solution is filtered and further aqueous H2SO4 (33.8 L, 1.07 M) is added during 45 min. The solution is cooled to −2° C. during 1.5 h and stirred at −5 to −9° C. for 1 h. The formed precipitate is filtered, washed with cooled CH3OH (−5° C., 54 L) and dried under a stream of nitrogen to provide the title compound as white crystalline powder in 84% yield.
Analytics
H2O content: 0.84%.
To a suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I (68.29 mol) in CH3OH (285 L, 0.24 M solution of compound 1) is added aqueous H2SO4 (11 L, 9.91%) during 10 min. The clear solution is filtered and further aqueous H2SO4 (59.5 L, 9.91%, 1.07 M) is added during 30 min. The solution is cooled to −7° C. during 2 h and stirred at this temperature for 1 h. The formed precipitate is filtered, washed with cooled CH3OH (−4° C., 41 L) and dried under a stream of nitrogen to provide the title compound as white crystalline powder in 83% yield.
Analytics
H2O content: 0.58%.
1H-NMR (D2O): 7.97 (d, J=8.5, 1H); 7.75 (s, 1H); 7.65 (t, J=7.4, 1H); 7.53 (d, J=8.2, 1H); 7.45 (t, J=7.7, 1H); 7.21-7.07 (m, 5H); 3.62 (t, =5.7, 2H); 3.41-3.45 (m, 2H); 3.27 (t, J=-5.7, 2H); 3.08-3.16 (m, 2H); 2.68 (s, 2H); 2.54 (s, 3H); 1.88-1.93 (m, 2H); 1.67-1.71 (m, 2H).
A suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I (2.09 g, 0.005 mol) in acetone (50 mL) is heated at 50° C. and an aqueous solution of L-(−)-malic acid (738 mg in 10 mL) is added. The clear solution is cooled at 4° C. for 15 h. The formed precipitate is filtered, washed with acetone (20 mL) and dried in HV at 50° C. to provide the title compound as white crystalline powder in 71% yield.
Analytics
MP: 143-146° C. (decomposition).
H2O content: 1.92%.
Elemental Analysis for C29H36N4O7 (0.60 H2O): % found (calculated): C: 61.53 (61.82); H 6.60 (6.65); N 9.87 (9.94).
1H-NMR (d6-DMSO): 9.12 (br. s, 1H); 8.12 (d, J=8.3, 1H); 8.07 (s, 1H); 7.82 (d, J=8.6, 1H); 7.65 (t, J≈7.2, 1H); 7.49 (t, J≈7.1, 1H); 7.27-7.15 (m, 5H); 7.08 (br. t, J≈4.6, 1 H); 4.49 (br. s, 1H); 4.05 (dd, J=5.9, 7.3, 1 H); 3.38 (m, 2H); 2.96 (m, 2H); 2.81 (m, 2H); 2.70 (m, 4H); 2.55 (dd, J=7.5, 15.5, 1H); 2.54 (s, 3H); 2.36 (dd, J=5.9, 15.6, 1H); 1.69-1.61 (m, 2H); 1.51-1.47 (m, 2H).
A solution of citric acid (1.05 g) in C2H5OH (400 mL) is heated at 65° C. and 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I (2.09 g, 0.005 mol) is added portion wise as a solid. The mixture is stirred at 4° C. for 15 h. The formed precipitate is filtered and dried in HV at 50° C. to provide the title compound as white crystalline powder in 72% yield.
Analytics
MP: 152-157° C. (decomposition).
H2O content: 1.08%.
Elemental Analysis for C31H38N4O9 (0.37 H2O): % found (calculated): C: 60.51 (60.31); H 6.31 (6.33); N 8.97 (9.08).
1H-NMR (CD3OD): 8.46 (d, 8.5, 1H); 8.18 (s, 1H); 7.83 (d, J=7.9, 1H); 7.72 (t, J≈7.4, 1H); 7.57 (t, J=7.3, 1H); 7.28-7.15 (m, 5H); 3.68 (m, 2H); 3.48 (m, 2H); 3.31 (m, 2H); 3.17 (m, 2H); 2.87 (d, J=15.2, 2H), 2.80 (s, 2H); 2.70 (d, J=15.5, 2H), 2.67 (s, 3H); 2.07 (m, 2H); 1.68 (m, 2H).
The following examples serve to aid the understanding of the present invention.
Example 2 Type: 2Th/Th locked—Start: 3.000°—End: 40.000°—Step: 0.020°—Step time: 1 s—Temp.: 30° C.—Time Started: 3 s—2-Theta: 3.00
DIF—Y: 97.92% d×by: 1.—WL: 1.54056—0—
Hygroscopicity was evaluated using the static method according to European Pharmacopoeia Technical Guide. Weight increase of the compound was observed when stored in a humidity cabinet at RT/79% RH for 24 h. The results are shown in Table 2.
Solubility was measured in water and aqueous phosphate buffer (pH=7, 100 mM). Results are expressed as mg dissolved compound per mL solvent. The results are summarized in Table 3.
The pharmacokinetic parameters after oral (gavage) administration of 10 mg per kg of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl )-ethyl]-3-(2-methyl-quinolin-4-yl )-urea given as free base or sulfate salt have been determined in male Wistar rats. Blood samples were taken over a time period of 24 h after dosing and analysed with a specific and sensitive liquid chromatography-mass-spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were calculated using a non-compartmental method. The mean exposure of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea, expressed as area under the curve (AUC0-inf.), after administration of compound I as free base was 194 ng*h/mL. The mean exposure of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl )-ethyl]-3-(2-methyl-quinolin-4-yl )-urea expressed as area under the curve (AUC0-inf.), after administration of the compound described in Example 1 was 396 ng*h/mL.
