CA2484473A1 - 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salt - Google Patents
1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salt Download PDFInfo
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- CA2484473A1 CA2484473A1 CA 2484473 CA2484473A CA2484473A1 CA 2484473 A1 CA2484473 A1 CA 2484473A1 CA 2484473 CA2484473 CA 2484473 CA 2484473 A CA2484473 A CA 2484473A CA 2484473 A1 CA2484473 A1 CA 2484473A1
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- hydroxy
- methyl
- piperidin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)ethyl]-3-(2-methyl-quinolin-4-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 or formulations of said 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea as a crystalline salt in the preparation of pharmaceutical compositions. The invention also relates to the use of such salts in formulations as neurohormonal antagonists.
Description
01/10 2004 17:32 FAX ~ 003/032 Actelion 73IU8 i-[2-(4-BENZYL-4-HYDROXY-PIPERIDIN-1-YL~ETHYL]-3-(2-METHYL
QUINOLIN-4-YL)-UREA SALT
The prosent Invention rotates to 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea as a crystalline salt or a non defined salt hydrate thereof and a process for its preparation. Further, the present Invention rotates to the use of said 1-[2-(4-benryl~-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-[Z-(4-benryl-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-uroa as a crystalline sah and inert carrier material which are useful as urotensln-li antagonist.
1-[2-(4-Benryl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-qulnolin-4-yl~urea of formula I as well as the process for its preparation as free base is known from WO-2004026838. 1-[2-(4-Benzyl~-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 [Marline Clozel et al. in J. Pharmcol. Exp. Ther. 2004, 311, 204-212].
I HO
O
Nw/''.N~N w H H .4 I
,', .
1-[2-(4-i3enryi-4-hydroxy-piperidln-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 chang~s at higher temperature and higher humidity, and it agglomerates to a substance cake under these conditions. 1-[2-(d-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 {comparo F~cample 9). The said compound of formula I as free base was shown to have a low bioavailabillty after oral dosing in the rat (comparo 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 proparations. In addition, large scale production and storage of the 01!10 2004 17:32 FAX ~ 004/032 said compound of formula I causes problems due to the properties mentioned above.
The subject of the prosent 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 prepatations, production In large scale, and atorape.
The present invention relates to 1-[2-(4-benZyi-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-uroa of formula I as a sulfate or non defined sulfate hydrate. A sulfate sail of 1-[2-(4-benryl-4-hydroxy-piperldin-1-yl)-ethylr3-(2-methyl-quinolin-4-yl~-urea of formula I is described by [Martins Clozei et.
al., J
Pharmacol i:xp Ther. X004; 001:10.11241jpet.104.088320] but no procedure for its preparation has been disolosed.
The present invention in addition also relates to 1-[2-(4-benryl-4-hydroxy-piperldin-1-yl)-ethylJ-3-(2-methyl-quinolin-4-yl)-unsa of formula 1 as a malate or non defined malate hydrate.
Further the present invention also relates to 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.
The present invention also rotates 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 a) mixing 1-[2-(4-benzyl-4-hydroxy-plperidin-1-yl)-ethyl]-3-(2-methyl-quinoiin-yl)-urea of formula I with an organic solvent and adding an acid, a solution of an acid in water, a solution of an acid in an organic solvent, or a solution of an acid in a mixture of water and an organic solvent, and st(rring the mixture; or b) mixing 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)~thyl]-3-(2-methyl-quinolin~-yl)-urea of tormuta I wfth a mixture of an organic solvent and water and adding an acid, a solution of an acid in water, a solution of an acid in an 01/10 2004 17:33 FAX ~ 005/032 organic solvent, or a solution of an acid in a mixture of water and an organic solvent, and stiMng the mixturo; or c) adding 1-[2-(4-benryl~4-hydroxy-piperldin-1-yl)-ethyl]-3-(2-methyl-quinoiin-4-yl)-urea of formula I as s solid, or dissolved in a mixture of an organic solvent and water to an acid, to a solution of an acid in water, to a solution of an acid in an organic solvent, or to a solution of an acid in a mixture of water with an organic solvent, and stirring the mixture; or d) adding 1-[2-(4-benryl-4-hydroxy-piperidin-1-yl)-amyl]-3-(2-methyl-quinoiin-~-yl)-urea of formula 1 as a solid, or dissolved in an organic solvent to an acid, to a solution of an acid in water, to a solution of an acid in eon organic solvent, or to a solution of an acid in a mixturo of water with an organic solvent, and stirring the mixture.
The acids used in the above process are sulfuric acid, malic acid, and citric acid (compare also Facamples 1 to B).
16 Further, the present invention rotates to 1-[2-(4~benzyl-4-hydraxy-piperidin-1-yi)~
ethylJ-3-(2-methyl-quinolin-4-yl)-uroa salts obtainable by the process mentioned above.
Further, the present invent'ron rotates to pharmaceutical compositions comprising 1-[2-(4-benryl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-qulnolin-4-yl)-urea salts as mentioned above and inert carrier material.
Further, the present invention relates to 1-[2-(4-benzyl-4-hydroxy-plperidln-1-yi)-ethyl]-3-(2-methyl~uinolin-4-yl)-urea salts as mentioned above end their use as medicaments, Because of their ability to inhibit the actions of urotensin II, 1-[2-(4-benryl-4-hydroxy-piperidin-1-yl)-ethyl]-3-{2-methyl-quinolln~i-yl)-urea salts as described above can be used for treatment of diseases which are associated with an incroase in vasoconstriction, proliferation or other disease states associated with the actions of urotensin II. F~camples of such diseases aro hypertension, atherosclerosis, ang)na or myocardial ischemia, congestive heart (allure, cardiac insufficiency, cardiac arrhythmias, ronat Ischemia, chronic kidney disease, renal 01/10 2004 17:33 FAX ~ 006/032 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, prastatic hypertrophy, en3ctile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sidle cell anemia, sickle cell acute chest syndrome, glomerulonaphrttis, renal oolic, glaucoma, therapy and prophylaxie of diabetic Complications, complications of vascular or cardiac surgery or after organ transplantat'ron, complications of cyclosporin treatment, pain, addic~tiona, schizophrenia, Alzheimer's disease, anxiety, obsessive-compulsive behavior, epileptic seizures, stress, depression, demsntlas, neuromuscular disorders, neurodegenerative diseases, as well as other diseases related to a dyeregulation of urotensin II or urootensin II receptors.
These oompositlons may be adminiaten3d in enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, sofutlons or suspensions, In nasal form ltke sprays and aerosols, or rectally in form of suppositories. 1-[2-(4-Benryl~-hydroxy-piperidin-1-yl)-ethylJ-3-(2-methyl-quinolin-4-yl)-uroa salts as mentioned above may also be administered in intramuscular, parenteral or intravenous form, e.a. in torte of in)ectable solutions.
These pharmaceutical compositions may contain 1-[2-(4-benzyM~-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salts as mentioned above in combination with inorganic andlor organic exapients, which are usual in the pharmaceutical industry, like lactose, maize or derivatives thereof, talcum, stearic acid or salts of these matcrlals, For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquid polyols etc.
may be used. For the proparatlon of solutions and slrups e.g. water, polyols, sacchaross, glucose stc. ere used. Injectables are prepared by using e.g.
water, pvlyols, alcohols, glycerin, vegetable oils, lecithin, lipoaomes stc.
Suppositories 01/10 2004 11:33 FAX ~ 0071032 are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats ), liquid or half-liquki polyols etc.
The compositions may contain in addition preservatives, stabilisation improving substances, viscosity improving or r~equlating substances, solubility improving 5 substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, anti-oxidants etc.
1-j2-(4-6enzyl-4-hydroxy-piperidin-1-yl)ethyl]-3-(2-methyl-quinoiin-4-yl)-urea salts as mantioned above may also be used in combination with one or more other therapeutically useful substances e.g. with a- and ~i-bk~ckers like phen6olamine, phenoxybenzamine, atenolot, propranolol, timolol, metoprolol, car~olal, carvedilol, etc.; with vasodilators Ilke hydralazlne, minoxidil, diszoxide, flosequlnan, stc.; with calcium-antagonists like diltiazem, nicardipine, nimodlpfne, verapamil, nifedipine, etc.; with angiotensin converting enzyme-inhibkora like cllazapril, captopril, enalapril, Ilsinopril etc.; with potassium channel activators like plnacidll, chromakalim, etc.; with angiotensin receptor antagonists like losartan, valsarten, candeaartan, irbesartan, eprosartan, teimisartan, and tasosartan, etc.; with diuretics like hydrochlorothiazide, chlorothiazlde, acetolamide, bumetanide, furosemide, metolazone, chlortalidone, etc.; with syrnpatholytics like methyldopa, clonidine, guanabenz, reserpine, etc.; with endothelin roceptor antagonists like bosentan, tezosentan, clazosentan, darusentan, atrasentan, enrasentan, or sitaxser~tan, etc.; with anti-hyperlipidemic agents like lovastatln, pravastatin, tluvastatin, atorvastatin, cerivaatatin, simvaatatin, etc.; and other th4rapeutics 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 apee~tc 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 weigh per day. As usual children should receive lower doses which are adapted to body weight and age.
QUINOLIN-4-YL)-UREA SALT
The prosent Invention rotates to 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea as a crystalline salt or a non defined salt hydrate thereof and a process for its preparation. Further, the present Invention rotates to the use of said 1-[2-(4-benryl~-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-[Z-(4-benryl-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-uroa as a crystalline sah and inert carrier material which are useful as urotensln-li antagonist.
1-[2-(4-Benryl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-qulnolin-4-yl~urea of formula I as well as the process for its preparation as free base is known from WO-2004026838. 1-[2-(4-Benzyl~-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 [Marline Clozel et al. in J. Pharmcol. Exp. Ther. 2004, 311, 204-212].
I HO
O
Nw/''.N~N w H H .4 I
,', .
1-[2-(4-i3enryi-4-hydroxy-piperidln-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 chang~s at higher temperature and higher humidity, and it agglomerates to a substance cake under these conditions. 1-[2-(d-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 {comparo F~cample 9). The said compound of formula I as free base was shown to have a low bioavailabillty after oral dosing in the rat (comparo 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 proparations. In addition, large scale production and storage of the 01!10 2004 17:32 FAX ~ 004/032 said compound of formula I causes problems due to the properties mentioned above.
The subject of the prosent 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 prepatations, production In large scale, and atorape.
The present invention relates to 1-[2-(4-benZyi-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-uroa of formula I as a sulfate or non defined sulfate hydrate. A sulfate sail of 1-[2-(4-benryl-4-hydroxy-piperldin-1-yl)-ethylr3-(2-methyl-quinolin-4-yl~-urea of formula I is described by [Martins Clozei et.
al., J
Pharmacol i:xp Ther. X004; 001:10.11241jpet.104.088320] but no procedure for its preparation has been disolosed.
The present invention in addition also relates to 1-[2-(4-benryl-4-hydroxy-piperldin-1-yl)-ethylJ-3-(2-methyl-quinolin-4-yl)-unsa of formula 1 as a malate or non defined malate hydrate.
Further the present invention also relates to 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.
The present invention also rotates 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 a) mixing 1-[2-(4-benzyl-4-hydroxy-plperidin-1-yl)-ethyl]-3-(2-methyl-quinoiin-yl)-urea of formula I with an organic solvent and adding an acid, a solution of an acid in water, a solution of an acid in an organic solvent, or a solution of an acid in a mixture of water and an organic solvent, and st(rring the mixture; or b) mixing 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)~thyl]-3-(2-methyl-quinolin~-yl)-urea of tormuta I wfth a mixture of an organic solvent and water and adding an acid, a solution of an acid in water, a solution of an acid in an 01/10 2004 17:33 FAX ~ 005/032 organic solvent, or a solution of an acid in a mixture of water and an organic solvent, and stiMng the mixturo; or c) adding 1-[2-(4-benryl~4-hydroxy-piperldin-1-yl)-ethyl]-3-(2-methyl-quinoiin-4-yl)-urea of formula I as s solid, or dissolved in a mixture of an organic solvent and water to an acid, to a solution of an acid in water, to a solution of an acid in an organic solvent, or to a solution of an acid in a mixture of water with an organic solvent, and stirring the mixture; or d) adding 1-[2-(4-benryl-4-hydroxy-piperidin-1-yl)-amyl]-3-(2-methyl-quinoiin-~-yl)-urea of formula 1 as a solid, or dissolved in an organic solvent to an acid, to a solution of an acid in water, to a solution of an acid in eon organic solvent, or to a solution of an acid in a mixturo of water with an organic solvent, and stirring the mixture.
The acids used in the above process are sulfuric acid, malic acid, and citric acid (compare also Facamples 1 to B).
16 Further, the present invention rotates to 1-[2-(4~benzyl-4-hydraxy-piperidin-1-yi)~
ethylJ-3-(2-methyl-quinolin-4-yl)-uroa salts obtainable by the process mentioned above.
Further, the present invent'ron rotates to pharmaceutical compositions comprising 1-[2-(4-benryl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-qulnolin-4-yl)-urea salts as mentioned above and inert carrier material.
Further, the present invention relates to 1-[2-(4-benzyl-4-hydroxy-plperidln-1-yi)-ethyl]-3-(2-methyl~uinolin-4-yl)-urea salts as mentioned above end their use as medicaments, Because of their ability to inhibit the actions of urotensin II, 1-[2-(4-benryl-4-hydroxy-piperidin-1-yl)-ethyl]-3-{2-methyl-quinolln~i-yl)-urea salts as described above can be used for treatment of diseases which are associated with an incroase in vasoconstriction, proliferation or other disease states associated with the actions of urotensin II. F~camples of such diseases aro hypertension, atherosclerosis, ang)na or myocardial ischemia, congestive heart (allure, cardiac insufficiency, cardiac arrhythmias, ronat Ischemia, chronic kidney disease, renal 01/10 2004 17:33 FAX ~ 006/032 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, prastatic hypertrophy, en3ctile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sidle cell anemia, sickle cell acute chest syndrome, glomerulonaphrttis, renal oolic, glaucoma, therapy and prophylaxie of diabetic Complications, complications of vascular or cardiac surgery or after organ transplantat'ron, complications of cyclosporin treatment, pain, addic~tiona, schizophrenia, Alzheimer's disease, anxiety, obsessive-compulsive behavior, epileptic seizures, stress, depression, demsntlas, neuromuscular disorders, neurodegenerative diseases, as well as other diseases related to a dyeregulation of urotensin II or urootensin II receptors.
These oompositlons may be adminiaten3d in enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, sofutlons or suspensions, In nasal form ltke sprays and aerosols, or rectally in form of suppositories. 1-[2-(4-Benryl~-hydroxy-piperidin-1-yl)-ethylJ-3-(2-methyl-quinolin-4-yl)-uroa salts as mentioned above may also be administered in intramuscular, parenteral or intravenous form, e.a. in torte of in)ectable solutions.
These pharmaceutical compositions may contain 1-[2-(4-benzyM~-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salts as mentioned above in combination with inorganic andlor organic exapients, which are usual in the pharmaceutical industry, like lactose, maize or derivatives thereof, talcum, stearic acid or salts of these matcrlals, For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquid polyols etc.
may be used. For the proparatlon of solutions and slrups e.g. water, polyols, sacchaross, glucose stc. ere used. Injectables are prepared by using e.g.
water, pvlyols, alcohols, glycerin, vegetable oils, lecithin, lipoaomes stc.
Suppositories 01/10 2004 11:33 FAX ~ 0071032 are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats ), liquid or half-liquki polyols etc.
The compositions may contain in addition preservatives, stabilisation improving substances, viscosity improving or r~equlating substances, solubility improving 5 substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, anti-oxidants etc.
1-j2-(4-6enzyl-4-hydroxy-piperidin-1-yl)ethyl]-3-(2-methyl-quinoiin-4-yl)-urea salts as mantioned above may also be used in combination with one or more other therapeutically useful substances e.g. with a- and ~i-bk~ckers like phen6olamine, phenoxybenzamine, atenolot, propranolol, timolol, metoprolol, car~olal, carvedilol, etc.; with vasodilators Ilke hydralazlne, minoxidil, diszoxide, flosequlnan, stc.; with calcium-antagonists like diltiazem, nicardipine, nimodlpfne, verapamil, nifedipine, etc.; with angiotensin converting enzyme-inhibkora like cllazapril, captopril, enalapril, Ilsinopril etc.; with potassium channel activators like plnacidll, chromakalim, etc.; with angiotensin receptor antagonists like losartan, valsarten, candeaartan, irbesartan, eprosartan, teimisartan, and tasosartan, etc.; with diuretics like hydrochlorothiazide, chlorothiazlde, acetolamide, bumetanide, furosemide, metolazone, chlortalidone, etc.; with syrnpatholytics like methyldopa, clonidine, guanabenz, reserpine, etc.; with endothelin roceptor antagonists like bosentan, tezosentan, clazosentan, darusentan, atrasentan, enrasentan, or sitaxser~tan, etc.; with anti-hyperlipidemic agents like lovastatln, pravastatin, tluvastatin, atorvastatin, cerivaatatin, simvaatatin, etc.; and other th4rapeutics 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 apee~tc 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 weigh 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-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 of all of the water molecules can be bound to 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.
6a The term "acid", as used with4rt the present anve~on, means acids, such as sulfuric add, malic acid, and dtric acid. Matic acid like all optically active acids can be used as a racemate, as optically pure enantiomer, and mixtures of enantiomers. Especlatly preferred acids are sulfuric acid, and malic add. Most prefen~ed 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:
Pn~ferably, 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 C~.,-alkanol (CH30H, CsHsOH, n-CaHzOH, i-C~H~OH, n-C~HoOH, i-C4H~OH, t-C,H90H), ketoses (acetone, ethylmethylketone, methylisobuiylketone), ethers (diethylether, tetrahydrofurane, 1,4~ioxane, methyl_ tart. butylether) or acatonttrile. Preferred "organic solvents" are CH'OH, CZH~OH, n-C3H~OH, i-CsHrOH and acetone. Most preferred "organic solvents" are CH30H, C2H30H, i-C~H~OH 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 tn the concentration range of 0.01 to 10 moUl., more preferred in the concentration range of 0.1 to 5 moUL, most preferred in the concentration range of 0.6 to 2 moIIL.
01/10 2004 17:34 FAX ~ 0091032 The foregoing general description of the invention will now be further illustrated with a number of non-limiting examples.
El(AAIIPLES OF THE INVENTION
lis~r of ABeaevanoNa:
aq. aqueous AUC area under the curve DM80 dimethylsulfoxide HV high vacuum conditions J coupling constant in NMR
min minutes MHz megahertz MP melting point NMR nuclear magnetic resonance ppm part per million RH relative humidity r.t. room temperature XRD X-ray powder diffraction NMR spectra were roc~rded 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-K,,ph~ (1.6418 A) source, a 40kV - 30mA
generator, in a range of 3 et 40 (2theta).
Stress test studies were done by exposing samples In open and dosed glass bottles to the following conditions: 60CI80 % RH (8 weeks) and 80CIRH
not controlled (48 h).
01/10 2004 17:34 FAX ~ 010/032 1-I2-(4-Benzvl-4-hvdroxv-niuoridin-1-YIL~thvll~3-(~ mr~ui~l~olin-4.v11-urea suH(~
To a suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-y!)-ethyl]-3-(2-methyl-quinolin-4-yirurea of formula 1 (9.70 g, 0.22$ mol) In CH~OH (260 mL, 0.9 M
solution of compound I) is added aqueous HzSO4 (11.4 mL, 2 M, 0.228 rnol). The clear solution Is stirrod at 4°C for 15 h. The formed preclpit8te Is filtered, washed with CH3OH (2 x 10 mL) and dried in HV to provide the title compound as white crystalline powder in 83 % yield.
AnalytlCs MP: 239-242 °C (deGOmpositlon).
Ha0 oontent:1.41 %, Elemental Analysis for CZeHszN40sS (0.41 H20): % found (calculated):
C: 57.20 (57.30); H 8.37 (8,31); N 10.73 (10.89); S 6.14 (6.12).
'H-NMR (d8-DMSO): 8.28 (d, J = 8.5, 1 H); 8.09 (s, 1 H); 7.83 (d, J ~ 8.2, 1 H): 7.70 (t, J = 7.8, 1 H); 7,51 (t, J = 7.8, 1 H); 7.43 (br. s, 1 H); 7.27-7.15 (m, 5H); 4.77 (br. s, 1 H); 3.54-3.53 (m, 2H); 3.36-3.31 (m, 2H); 3.20-3.08 (m, 5H); 2.70 (s, 2H);
2,58 (s, 3H); 1.83-1.75 (m, 2H); 1.69-1.54 (m, 2H).
~'~. 20 if2d4~Benzvl.4-hYdroxv-olnerldin-9-vl)-eth 11.3-(2~ethvl-auinolin~vl~na su~,f,8to.
To a suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-ylrurea of formula I (4.3 kg) In CH3OH (88 L) is added aqueous HzS04 (8.5 L, 9.91%) durin0 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 (-5°C, 2 X 9 L) and dried under a stream of nitrogen to provide the title compound as white crystalline powder in i38% yield.
Analytlcs MP: ca. 200°C (decomposition).
Hz0 content: 0.38 %.
01/10 2004 17:35 FAX ~ 011/032 Examo~e 3~
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 of all of the water molecules can be bound to 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.
6a The term "acid", as used with4rt the present anve~on, means acids, such as sulfuric add, malic acid, and dtric acid. Matic acid like all optically active acids can be used as a racemate, as optically pure enantiomer, and mixtures of enantiomers. Especlatly preferred acids are sulfuric acid, and malic add. Most prefen~ed 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:
Pn~ferably, 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 C~.,-alkanol (CH30H, CsHsOH, n-CaHzOH, i-C~H~OH, n-C~HoOH, i-C4H~OH, t-C,H90H), ketoses (acetone, ethylmethylketone, methylisobuiylketone), ethers (diethylether, tetrahydrofurane, 1,4~ioxane, methyl_ tart. butylether) or acatonttrile. Preferred "organic solvents" are CH'OH, CZH~OH, n-C3H~OH, i-CsHrOH and acetone. Most preferred "organic solvents" are CH30H, C2H30H, i-C~H~OH 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 tn the concentration range of 0.01 to 10 moUl., more preferred in the concentration range of 0.1 to 5 moUL, most preferred in the concentration range of 0.6 to 2 moIIL.
01/10 2004 17:34 FAX ~ 0091032 The foregoing general description of the invention will now be further illustrated with a number of non-limiting examples.
El(AAIIPLES OF THE INVENTION
lis~r of ABeaevanoNa:
aq. aqueous AUC area under the curve DM80 dimethylsulfoxide HV high vacuum conditions J coupling constant in NMR
min minutes MHz megahertz MP melting point NMR nuclear magnetic resonance ppm part per million RH relative humidity r.t. room temperature XRD X-ray powder diffraction NMR spectra were roc~rded 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-K,,ph~ (1.6418 A) source, a 40kV - 30mA
generator, in a range of 3 et 40 (2theta).
Stress test studies were done by exposing samples In open and dosed glass bottles to the following conditions: 60CI80 % RH (8 weeks) and 80CIRH
not controlled (48 h).
01/10 2004 17:34 FAX ~ 010/032 1-I2-(4-Benzvl-4-hvdroxv-niuoridin-1-YIL~thvll~3-(~ mr~ui~l~olin-4.v11-urea suH(~
To a suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-y!)-ethyl]-3-(2-methyl-quinolin-4-yirurea of formula 1 (9.70 g, 0.22$ mol) In CH~OH (260 mL, 0.9 M
solution of compound I) is added aqueous HzSO4 (11.4 mL, 2 M, 0.228 rnol). The clear solution Is stirrod at 4°C for 15 h. The formed preclpit8te Is filtered, washed with CH3OH (2 x 10 mL) and dried in HV to provide the title compound as white crystalline powder in 83 % yield.
AnalytlCs MP: 239-242 °C (deGOmpositlon).
Ha0 oontent:1.41 %, Elemental Analysis for CZeHszN40sS (0.41 H20): % found (calculated):
C: 57.20 (57.30); H 8.37 (8,31); N 10.73 (10.89); S 6.14 (6.12).
'H-NMR (d8-DMSO): 8.28 (d, J = 8.5, 1 H); 8.09 (s, 1 H); 7.83 (d, J ~ 8.2, 1 H): 7.70 (t, J = 7.8, 1 H); 7,51 (t, J = 7.8, 1 H); 7.43 (br. s, 1 H); 7.27-7.15 (m, 5H); 4.77 (br. s, 1 H); 3.54-3.53 (m, 2H); 3.36-3.31 (m, 2H); 3.20-3.08 (m, 5H); 2.70 (s, 2H);
2,58 (s, 3H); 1.83-1.75 (m, 2H); 1.69-1.54 (m, 2H).
~'~. 20 if2d4~Benzvl.4-hYdroxv-olnerldin-9-vl)-eth 11.3-(2~ethvl-auinolin~vl~na su~,f,8to.
To a suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-ylrurea of formula I (4.3 kg) In CH3OH (88 L) is added aqueous HzS04 (8.5 L, 9.91%) durin0 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 (-5°C, 2 X 9 L) and dried under a stream of nitrogen to provide the title compound as white crystalline powder in i38% yield.
Analytlcs MP: ca. 200°C (decomposition).
Hz0 content: 0.38 %.
01/10 2004 17:35 FAX ~ 011/032 Examo~e 3~
1-fZ-l4-Benzvl~4~hyyoxv-oiosridin-1-yll.ethv11~8-IZ.~thvl.aui~olin~.i f11~
sulfate.
To a suspension of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-ylrethylj-3~2-methyl-qulnolln-4-yl)-urea of formula I {21.38 kg) in GH30H (178 L) is added aqueous H2S0,, (8 L, 9.91 °~) during 10 min. The clear solution i8 filtered and further aqueous IizS04 (33.A L, 1.07 M) is added during 45 min. The aolutlon is cooled to -2°C during 1.5 h and stirnsd at -5 to~9'C for 1 h. The fanned precipitate is filtered, washed with cooled CNaOH (- 5'C, 54 L) and dried under a stream of nitrogen to provide the title compound as white crystalline powder in 84 °~ yield.
AnalytJcs Hx0 content: 0.84 %.
Eautmols 4~
1-I2-t4-Benzvl~~hvdroxv~py~rldin~1 ~vll.ethvll.3-IZ-methvl~auinoll_n-4-vlHrrsa isu fate.
To a suspension of 1-(2-(4-t~er~zyl-4-hydroxy-piperidn-1-yl)-etr,yl]-3-(2-methyt-quin0lin-4-yl~urea of formula I (68.29 mol) in CH30H (285 L, 0.24 M solution of compound I) is added aqueous HzS04 (11 L, 9.91 %) during i0 min. The clear solution is hl~red and further aqucous HzS04 (39.5 L, 9.91 %, 1.07 M) Is added _ 20 during 30 min. Ths 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 {- 4°C, 41 L) and dried under a stream of nitrogen to provide the title compound as white crystalline powder in 83 % yield.
Analytics 26 Hz0 content: o.5a %.
'H-NMR (DSO): 7.97 {d, J = 8.5, 1 H); 7,75 (s, 1 H); 7.65 (t, J = 7.4, 1 H);
7.53 (d, J =
8.2, 1 H); 7.45 (t, J ~ 7.7, 1 H); 7.21-7.07 (m, 5H); 3.82 (t, ~ 5.7, 2H);
3.41-3.45 (m, 2H); 3.27 (t, J a 5.7, 2H); 3.08-3.18 (m, 2H); 2.88 (s, 2H); 2.54 (s, 3H);
1.88-1.93 (m, 2H); 1.87-1.71 (m, 2H).
01/10 2004 17:35 FAX ~ 012/032 -(4-Beipnl.4-hvdroxv-oloarld_in-~.y11-ethvll-3-(2-methpvl-auinalin-4-v11-uroa malate.
A suspension of 1-[2-(4-benzyi-4-hydroxy-piperldin-1-yl)-ethyl]-3-{2-methyl-5 qulnolin-4-ylrurea of formula I (2,09 g, 0.005 mol) In acetone (50 mL) is heated at 50'C arM an aqueous solution of L-(-~mallc 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.
sulfate.
To a suspension of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-ylrethylj-3~2-methyl-qulnolln-4-yl)-urea of formula I {21.38 kg) in GH30H (178 L) is added aqueous H2S0,, (8 L, 9.91 °~) during 10 min. The clear solution i8 filtered and further aqueous IizS04 (33.A L, 1.07 M) is added during 45 min. The aolutlon is cooled to -2°C during 1.5 h and stirnsd at -5 to~9'C for 1 h. The fanned precipitate is filtered, washed with cooled CNaOH (- 5'C, 54 L) and dried under a stream of nitrogen to provide the title compound as white crystalline powder in 84 °~ yield.
AnalytJcs Hx0 content: 0.84 %.
Eautmols 4~
1-I2-t4-Benzvl~~hvdroxv~py~rldin~1 ~vll.ethvll.3-IZ-methvl~auinoll_n-4-vlHrrsa isu fate.
To a suspension of 1-(2-(4-t~er~zyl-4-hydroxy-piperidn-1-yl)-etr,yl]-3-(2-methyt-quin0lin-4-yl~urea of formula I (68.29 mol) in CH30H (285 L, 0.24 M solution of compound I) is added aqueous HzS04 (11 L, 9.91 %) during i0 min. The clear solution is hl~red and further aqucous HzS04 (39.5 L, 9.91 %, 1.07 M) Is added _ 20 during 30 min. Ths 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 {- 4°C, 41 L) and dried under a stream of nitrogen to provide the title compound as white crystalline powder in 83 % yield.
Analytics 26 Hz0 content: o.5a %.
'H-NMR (DSO): 7.97 {d, J = 8.5, 1 H); 7,75 (s, 1 H); 7.65 (t, J = 7.4, 1 H);
7.53 (d, J =
8.2, 1 H); 7.45 (t, J ~ 7.7, 1 H); 7.21-7.07 (m, 5H); 3.82 (t, ~ 5.7, 2H);
3.41-3.45 (m, 2H); 3.27 (t, J a 5.7, 2H); 3.08-3.18 (m, 2H); 2.88 (s, 2H); 2.54 (s, 3H);
1.88-1.93 (m, 2H); 1.87-1.71 (m, 2H).
01/10 2004 17:35 FAX ~ 012/032 -(4-Beipnl.4-hvdroxv-oloarld_in-~.y11-ethvll-3-(2-methpvl-auinalin-4-v11-uroa malate.
A suspension of 1-[2-(4-benzyi-4-hydroxy-piperldin-1-yl)-ethyl]-3-{2-methyl-5 qulnolin-4-ylrurea of formula I (2,09 g, 0.005 mol) In acetone (50 mL) is heated at 50'C arM an aqueous solution of L-(-~mallc 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.
10 Analytic:
MP: 143-148°C (decomposition).
H20 oorltent: 1.92 96.
Elemental Analysis for CzAH~sN40~ (0.80 H20): % found (calculated):
C: 81.53 (81.82); H 8.80 (8.85); N 9.87 (9,94).
'N-NMR (d8-DMSO): 9.12 (br, s, 1 H); 8.12 (d, J = 8.3, 1 H); 8.07 (s, 1 H);
7.82 (d, J
= 8.8, 1 H); 7.85 (t, J - 7.2, 1 H); 7.49 (t, J = 7.1, 1 H); 7.27-7.15 (m, 5H); 7.08 (br. t, J = 4.8, 1 H); 4.49 (br. s, 1 H); 4.05 (dd, J = 5.9, 7.3, 1 H); 3.38 {m, 2H);
2.96 (m, 2N); 2.81 (m, 2H); 2.70 (m, 4H); 2.55 (dd, J = 7.5, 15.5, 1 H); 2.54 (s, 3H);
2.36 (dd, J = 5.9, 15.8, 1 H); 1.89-1.81 (m, 2H); 1.61-1.47 (m, 2H).
nl~ B.
i t2.f4-Benzvl-4-hvdroxv-niosridin-1 vl1-tthvll-3.(Z-mdhvl-auinolin-4 v11-urea A solution of citric acid (1.05 ~) in C2HeOH {400 mL) is heated at 85°C
and 1~[2-(4-benxyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-uroa of formula I
(2.09 g, 0.006 mol) is added portion wise as a solid. The mixture is stirred at 4°C
for 15 h. The formed precipitate is fliterod and dried in HV at 50°C to provide the tide compound as white crystalline powder in 72 % yield.
Analytics MP: 152-15T°C (decomposition).
01/10 2004 17:35 FAX ~ 013/032 Hz0 content; 1.08 %.
Elemental Analysis for C3~H3aNa~~ (0.37 H20): % found {calculated):
C: 80.51 (60.31 ); H 8.31 (d,33); N 8.97 (9,08).
'H-NMR (CD~OD): 8.48 (d, 8.5, 1 H); 8.18 (s, 1 H); 7.83 (d, J ~ 7,9, 1 H);
7.72 (t, J
7.4, 1 H); 7.57 (t, J ' 7,3, 1 H); 7.28-7.15 {m, 5H); 3.88 (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), 2.87 (s, 3H); 2,07 (m, 2H); 1.8B (m, 2H).
The following examples serve to aid the understanding of the present invention.
Figure 1 shows the XRD-diffraction pattern of the compound described in Example 2. Table 1 summarizes the peaks and their intensity. It has to be understood that due to small changes in the experimental details, small deviations in the 2-Theta values of the characteristic peaks in the X-ray powder diffraction patterns may occur.
Figuro 1: X-ray dH'fradion pattern (XRD) of the compound da:crlbed in Example ,a 90 ~0 Z-Theta - Scab 01/10 2004 17:35 FAX ~ 01d/032 Facampla 2 Type : 2ThlTh locked - Stwt : 3.000' - End : 40.000- - Slep :
0,020' - Step time : 1 s -Temp. : 30~G - Tlme Started : 3 s - 2-Theta : 3.00 DIF-Y:87.92%dxby:l.WL:1.5403l3-0-Table 1: 2-Theta Andes and them intensities of the X-ray diffraction pattern (XRD) of the compound described In Example 2 Z Theta Angled valve ht~nslty tnbnslty C1 fM4~~1 tCount] . I%1 7.988 11.062 21125 12.8 9.016 9.8 15544 9.4 9.46 9.341 88555 41.6 ~' ~~.-9.749 9.085 72939 44.3 9.974 8.881 184812 100 10. i 98 8.887 128740 ~ 78.2 10.838 8.158 25110 15.3 -11.236 7.888 150862 91.5 12.582 7.041 18342 9.9 12.738 8.945 31888 19.4 13.217 8.893 5979 3.8 13.43 8.587 12358 7.5 14.339 8.172 8568 5,8 14.541 8.087 30690 18.8 15.538 5.898 19530 11.9 18.012 5.53 21922 13.3 18.289 5.437 32286 19.6 18.541 5.355 45039 2~.4 18.979 5.218 41452 25.2 17.18 5.183 86491 62.6 17.874 5.014 45438 27.8 ... 17.807 4.977 24313 14.8 -_ --18.8A7 4.744 75729 48 19.037 4.858 158840 95.2 19.429 4.565 85388 39.7 19.983 4.44 43445 28,4 21.284 4.171 31487 19.1 -22.431 3.98 ~ 48828 z9.s 22.641 3.924 124'764 73.8 23.121 3.844 39080 23.7 23.812 3.734 19132 11.8 23.946 3.713 33082 20.1 ~
25.033 3.564 38283 23.2 25.209 3.53 29893 18.2 25.841 3.471 44242 28.9 01/10 2004 17:36 FAX ~ 015/032 25.804 3,46 72541 44.1 26.081 3.414 62213 31.7 27.27 3.268 19132 ~ 11.6 28.438 3.136 10762 8.5 28.758 3.102 21125 12,8 ~
29.023 3.074 18342 9.8 30.028 2,973 7174 4.4 30.824 2.898 10363 8.3 31.509 2.837 17537 10.7 33.925 2.84 13153 8 34.236 2,817 7673 4.6 34.803 2.578 9984 6.1 35.838 2.517 111 fi0 8.8 36.094 2.488 7174 4.4 36.825 2.452 7174 4.4 37.882 2.373 __ 3.8 39.827 2.272 13652 8.2 Ny~rosoopicity was evaluated using the stag method acconiing to European Pharmacoposla Technical 4uide. Welght increase of the compound was observed when stored In a humidfty cabinet at RT I 79% RH for 24 h. The rosults are shown 6 in Table 2.
Table 2. Increase in webht ( M1) after exposure to 79% Rhl for 24 h f:xampk em [Xl Compound I 8 os ire beep s 6 s 2 Example 9: Solubillhr In water and at nH 7 Solubility was measured in water and aqueous phosphate buffer (pH = 7, 100 mM). Results aro exprossed as mg dissolved compound per mL
solvent. The results are summarized in Tablo 3.
01/10 2004 17:36 FAX ~ 016/032 Table 3: Solubility in water and phosphate buffer Sxampls Solubhity Bufhr pH 7 wabr (phosphstr.100 mM) (mp I mL) (mp I mL) Compound 0.8 0.31 Z 11.3 27 8 ~ 101 -6 17.8 -Examols 10; Pl~amm~t>at(c usnsmant of 1-f2-(4-banzvl-4-hvdroxv-niooridin-1-vl[~pthy~~~0p~,i~nolin~ vli-unaa compounds The pharmaookinedc parameter8 after oral (pavage) administration of 10 mg per kg of 1-[2-(4-benzyl-4-hydroxy-plperldin-1-yl~ethylj-3-(2-methyl-quinolin-4-yl)-uroa given as free base or sulfate salt have been determined in male Wlstar rata.
Blood samples were taken over a time period of 24 h after dosing and analysed wlth a spaclflc and sensklve Ilquld chromatogwaphy-mass-spectrometry (LC-MSIMS) methad. Phannacokinetic parameters were calculated using a non-compartmental method. The mean exposure of 1-[2-(4-benzyl-4-hydroxy-pipetidin-1-ylrethyQ-3-(2-methyl-quinolin-4-yl}~urea, expressed as area under the curve (AUCo-~ ), after administration of compound I as froe base was 194 ng"hlmL. The mean exposuro of 1-[2-(4-benzyl-4-hydroxy-piporidin-1-yl~.ethyl]-3-(2-methyl-puinolin~l-yl~urea expressed as area under the curve (AUCo-,~,,), after administration of the compound described in Example 1 was 396 ng~hlmL.
MP: 143-148°C (decomposition).
H20 oorltent: 1.92 96.
Elemental Analysis for CzAH~sN40~ (0.80 H20): % found (calculated):
C: 81.53 (81.82); H 8.80 (8.85); N 9.87 (9,94).
'N-NMR (d8-DMSO): 9.12 (br, s, 1 H); 8.12 (d, J = 8.3, 1 H); 8.07 (s, 1 H);
7.82 (d, J
= 8.8, 1 H); 7.85 (t, J - 7.2, 1 H); 7.49 (t, J = 7.1, 1 H); 7.27-7.15 (m, 5H); 7.08 (br. t, J = 4.8, 1 H); 4.49 (br. s, 1 H); 4.05 (dd, J = 5.9, 7.3, 1 H); 3.38 {m, 2H);
2.96 (m, 2N); 2.81 (m, 2H); 2.70 (m, 4H); 2.55 (dd, J = 7.5, 15.5, 1 H); 2.54 (s, 3H);
2.36 (dd, J = 5.9, 15.8, 1 H); 1.89-1.81 (m, 2H); 1.61-1.47 (m, 2H).
nl~ B.
i t2.f4-Benzvl-4-hvdroxv-niosridin-1 vl1-tthvll-3.(Z-mdhvl-auinolin-4 v11-urea A solution of citric acid (1.05 ~) in C2HeOH {400 mL) is heated at 85°C
and 1~[2-(4-benxyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-uroa of formula I
(2.09 g, 0.006 mol) is added portion wise as a solid. The mixture is stirred at 4°C
for 15 h. The formed precipitate is fliterod and dried in HV at 50°C to provide the tide compound as white crystalline powder in 72 % yield.
Analytics MP: 152-15T°C (decomposition).
01/10 2004 17:35 FAX ~ 013/032 Hz0 content; 1.08 %.
Elemental Analysis for C3~H3aNa~~ (0.37 H20): % found {calculated):
C: 80.51 (60.31 ); H 8.31 (d,33); N 8.97 (9,08).
'H-NMR (CD~OD): 8.48 (d, 8.5, 1 H); 8.18 (s, 1 H); 7.83 (d, J ~ 7,9, 1 H);
7.72 (t, J
7.4, 1 H); 7.57 (t, J ' 7,3, 1 H); 7.28-7.15 {m, 5H); 3.88 (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), 2.87 (s, 3H); 2,07 (m, 2H); 1.8B (m, 2H).
The following examples serve to aid the understanding of the present invention.
Figure 1 shows the XRD-diffraction pattern of the compound described in Example 2. Table 1 summarizes the peaks and their intensity. It has to be understood that due to small changes in the experimental details, small deviations in the 2-Theta values of the characteristic peaks in the X-ray powder diffraction patterns may occur.
Figuro 1: X-ray dH'fradion pattern (XRD) of the compound da:crlbed in Example ,a 90 ~0 Z-Theta - Scab 01/10 2004 17:35 FAX ~ 01d/032 Facampla 2 Type : 2ThlTh locked - Stwt : 3.000' - End : 40.000- - Slep :
0,020' - Step time : 1 s -Temp. : 30~G - Tlme Started : 3 s - 2-Theta : 3.00 DIF-Y:87.92%dxby:l.WL:1.5403l3-0-Table 1: 2-Theta Andes and them intensities of the X-ray diffraction pattern (XRD) of the compound described In Example 2 Z Theta Angled valve ht~nslty tnbnslty C1 fM4~~1 tCount] . I%1 7.988 11.062 21125 12.8 9.016 9.8 15544 9.4 9.46 9.341 88555 41.6 ~' ~~.-9.749 9.085 72939 44.3 9.974 8.881 184812 100 10. i 98 8.887 128740 ~ 78.2 10.838 8.158 25110 15.3 -11.236 7.888 150862 91.5 12.582 7.041 18342 9.9 12.738 8.945 31888 19.4 13.217 8.893 5979 3.8 13.43 8.587 12358 7.5 14.339 8.172 8568 5,8 14.541 8.087 30690 18.8 15.538 5.898 19530 11.9 18.012 5.53 21922 13.3 18.289 5.437 32286 19.6 18.541 5.355 45039 2~.4 18.979 5.218 41452 25.2 17.18 5.183 86491 62.6 17.874 5.014 45438 27.8 ... 17.807 4.977 24313 14.8 -_ --18.8A7 4.744 75729 48 19.037 4.858 158840 95.2 19.429 4.565 85388 39.7 19.983 4.44 43445 28,4 21.284 4.171 31487 19.1 -22.431 3.98 ~ 48828 z9.s 22.641 3.924 124'764 73.8 23.121 3.844 39080 23.7 23.812 3.734 19132 11.8 23.946 3.713 33082 20.1 ~
25.033 3.564 38283 23.2 25.209 3.53 29893 18.2 25.841 3.471 44242 28.9 01/10 2004 17:36 FAX ~ 015/032 25.804 3,46 72541 44.1 26.081 3.414 62213 31.7 27.27 3.268 19132 ~ 11.6 28.438 3.136 10762 8.5 28.758 3.102 21125 12,8 ~
29.023 3.074 18342 9.8 30.028 2,973 7174 4.4 30.824 2.898 10363 8.3 31.509 2.837 17537 10.7 33.925 2.84 13153 8 34.236 2,817 7673 4.6 34.803 2.578 9984 6.1 35.838 2.517 111 fi0 8.8 36.094 2.488 7174 4.4 36.825 2.452 7174 4.4 37.882 2.373 __ 3.8 39.827 2.272 13652 8.2 Ny~rosoopicity was evaluated using the stag method acconiing to European Pharmacoposla Technical 4uide. Welght increase of the compound was observed when stored In a humidfty cabinet at RT I 79% RH for 24 h. The rosults are shown 6 in Table 2.
Table 2. Increase in webht ( M1) after exposure to 79% Rhl for 24 h f:xampk em [Xl Compound I 8 os ire beep s 6 s 2 Example 9: Solubillhr In water and at nH 7 Solubility was measured in water and aqueous phosphate buffer (pH = 7, 100 mM). Results aro exprossed as mg dissolved compound per mL
solvent. The results are summarized in Tablo 3.
01/10 2004 17:36 FAX ~ 016/032 Table 3: Solubility in water and phosphate buffer Sxampls Solubhity Bufhr pH 7 wabr (phosphstr.100 mM) (mp I mL) (mp I mL) Compound 0.8 0.31 Z 11.3 27 8 ~ 101 -6 17.8 -Examols 10; Pl~amm~t>at(c usnsmant of 1-f2-(4-banzvl-4-hvdroxv-niooridin-1-vl[~pthy~~~0p~,i~nolin~ vli-unaa compounds The pharmaookinedc parameter8 after oral (pavage) administration of 10 mg per kg of 1-[2-(4-benzyl-4-hydroxy-plperldin-1-yl~ethylj-3-(2-methyl-quinolin-4-yl)-uroa given as free base or sulfate salt have been determined in male Wlstar rata.
Blood samples were taken over a time period of 24 h after dosing and analysed wlth a spaclflc and sensklve Ilquld chromatogwaphy-mass-spectrometry (LC-MSIMS) methad. Phannacokinetic parameters were calculated using a non-compartmental method. The mean exposure of 1-[2-(4-benzyl-4-hydroxy-pipetidin-1-ylrethyQ-3-(2-methyl-quinolin-4-yl}~urea, expressed as area under the curve (AUCo-~ ), after administration of compound I as froe base was 194 ng"hlmL. The mean exposuro of 1-[2-(4-benzyl-4-hydroxy-piporidin-1-yl~.ethyl]-3-(2-methyl-puinolin~l-yl~urea expressed as area under the curve (AUCo-,~,,), after administration of the compound described in Example 1 was 396 ng~hlmL.
Claims (16)
1. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as crystalline salt or non defined crystalline salt hydrate.
2. 1-[2-(4-Benzyl-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea according to claim 1, as a sulfate or a non-defined sulfate hydrate.
3. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)ethyl]-3-(2-methyl-quinolin-4-yl)-urea according to claim 1, as a malate or a non defined malate hydrate.
4. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea according to claim 1, as a citrate or a non defined citrate hydrate.
5. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as sulfate salt according to claim 1 and 2 having a corresponding X-ray powder diffraction pattern as depicted in Figure 1.
6. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as sulfate salt according to claim 1 and 2 which shows the peaks at the diffraction (2-theta) angles shown in the following table in its X-ray powder diffraction pattern.
7. The process for the preparation of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl-3-(2-methyl-quinolin-4-yl)-urea of formula I as a salt according to any one of claims 1 to 6 which process comprises a. mixing 1-[2-(4-benzyl-4-hydroxy piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I with an organic solvent and adding an acid, a solution of an acid in water, a solution of an acid in an organic solvent, or s solution of an acid in a mixture of water with an organic solvent, and stirring the mixture; or b. mixing 1-[2-(4-benzyl-4-hydroxy-piperidin-1-ylmethyl]-3-(2-methyl-quinolin-4-yl-urea of formula I with a mixtures of an organic solvent with water and adding an acid, a solution of an acid in water, a solution of an acid in an organic solvent, or a solution of an acid in a mixture of water with an organic solvent, and stirring the mixture; or c. adding 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-9-(2-methyl-quinolin-4-yl)-urea of formula 1 as a solid, or dissolved in a mixture of an organic solvent with water to an acid, to a solution of an add in water, to a solution of an acid in an organic solvent, or to a solution of an acid in a mixture of water with an organic solvent, and stirring the mixture; or d. adding 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as a solid, or dissolved in an organic solvent to an acid, to a solution of an acid in water, to a solution of an acid in an organic solvent, or to a solution of an acid in a mixture of water with an organic solvent, and stirring the mixture.
8. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as a salt obtainable by the process according to claim 7.
9. Compositions comprising 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as a salt according to any one of claims 1 to 6 or 8 and inert carrier material.
10. Pharmaceutical compositions containing a Compound of any one of claims 1 to 8 or 8 and usual inert carrier material and adjuvants for the treatment of disorders which are associated with a dysregulation of urotensin II or urotensin II receptors, or disorders associated with vascular or myocardial dysfunction, comprising 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.
11. Pharmaceutical compositions containing a compound of any one of claims 1 to 6 or 8 and usual inert carrier material and adjuvants for the treatment of disorders comprising restenosis after balloon or stent angioplasty, for 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, demential, neuromuscular disorders, or neurodegenerative diseases.
12. The use of one or more compounds of any one of claims 1 to 6 or 8 to 9 in combination with other pharmacologically active compounds for the treatment of hypertension, atheroaclerosis, 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, subarchnoidal 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, pulmonary fibrosis, restenosis after balloon or stent angioplasty, 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, addiction, schizophrenia, Alzheimer's disease, anxiety, obsessive-compulsive behavior, epileptic seizures, stress, depression, dementias, neuromuscular disorders, or neurodegenerative diseases.
13. The use of one or more compounds of any one of claims 1 to 6 or 8 to 9 in combination with other pharmacologically active compounds comprising ACE inhibitors, angiotensin II receptor antagonists endothelin receptor antagonists, vasopressin antagonists, beta-adrenergic antagonists, alpha-adrenergic antagonists, vasopressin antagonists, TNFalpha antagonists, or peroxisome proliferator activator receptor modulators.
14. The method of treating a patient suffering from a disorder given in any one of claims 10 to 12 by administering a pharmaceutical composition according to any one of claims 9 to 11.
15. Compositions containing crystalline parts of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as a salt according to any one of claims 1 to 6 and amorphous parts of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as a salt according to any one of claims 1 to 6, to sum up to 100%,
16. The invention as hereinbefore described.
Priority Applications (1)
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| CA 2484473 CA2484473A1 (en) | 2004-10-12 | 2004-10-12 | 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salt |
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| Application Number | Priority Date | Filing Date | Title |
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| CA 2484473 CA2484473A1 (en) | 2004-10-12 | 2004-10-12 | 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salt |
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| CA2484473A1 true CA2484473A1 (en) | 2006-04-12 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110285353A (en) * | 2019-07-06 | 2019-09-27 | 冯睿鸣 | A kind of LED light lamp |
-
2004
- 2004-10-12 CA CA 2484473 patent/CA2484473A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110285353A (en) * | 2019-07-06 | 2019-09-27 | 冯睿鸣 | A kind of LED light lamp |
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