MXPA97004136A - Compounds for inhibition of gastr acid secretion - Google Patents
Compounds for inhibition of gastr acid secretionInfo
- Publication number
- MXPA97004136A MXPA97004136A MXPA/A/1997/004136A MX9704136A MXPA97004136A MX PA97004136 A MXPA97004136 A MX PA97004136A MX 9704136 A MX9704136 A MX 9704136A MX PA97004136 A MXPA97004136 A MX PA97004136A
- Authority
- MX
- Mexico
- Prior art keywords
- treatment
- salt
- salt according
- inhibition
- acid secretion
- Prior art date
Links
- 230000002401 inhibitory effect Effects 0.000 title claims description 22
- 150000001875 compounds Chemical class 0.000 title abstract description 21
- 230000028327 secretion Effects 0.000 title abstract description 15
- QPFYXYFORQJZEC-FOCLMDBBSA-N Phenazopyridine Chemical compound NC1=NC(N)=CC=C1\N=N\C1=CC=CC=C1 QPFYXYFORQJZEC-FOCLMDBBSA-N 0.000 title 1
- 229960001181 Phenazopyridine Drugs 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 239000011780 sodium chloride Substances 0.000 claims abstract description 46
- 230000002496 gastric Effects 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 200000000018 inflammatory disease Diseases 0.000 claims description 10
- 241000282414 Homo sapiens Species 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 9
- 230000027119 gastric acid secretion Effects 0.000 claims description 9
- 210000001156 Gastric Mucosa Anatomy 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000004599 antimicrobial Substances 0.000 claims description 7
- 230000000069 prophylaxis Effects 0.000 claims description 7
- 201000009910 diseases by infectious agent Diseases 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 229940037467 Helicobacter pylori Drugs 0.000 claims description 4
- 241000282412 Homo Species 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 206010019375 Helicobacter infection Diseases 0.000 claims 1
- XNTVAQRDRZKWDH-UHFFFAOYSA-N 1-[4-(2-methylanilino)-8-(2-methylsulfinylethoxy)quinolin-3-yl]butan-1-one Chemical compound CCCC(=O)C1=CN=C2C(OCCS(C)=O)=CC=CC2=C1NC1=CC=CC=C1C XNTVAQRDRZKWDH-UHFFFAOYSA-N 0.000 abstract description 13
- 210000004211 Gastric Acid Anatomy 0.000 abstract description 7
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- 208000008665 Gastrointestinal Disease Diseases 0.000 abstract description 2
- 230000002757 inflammatory Effects 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
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- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical class CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 5
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- 231100000673 dose–response relationship Toxicity 0.000 description 4
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- 235000011152 sodium sulphate Nutrition 0.000 description 4
- FEWJPZIEWOKRBE-LWMBPPNESA-N (-)-tartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 3
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- 238000004458 analytical method Methods 0.000 description 2
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
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- HWSISDHAHRVNMT-UHFFFAOYSA-N Bismuth subnitrate Chemical compound O[NH+]([O-])O[Bi](O[N+]([O-])=O)O[N+]([O-])=O HWSISDHAHRVNMT-UHFFFAOYSA-N 0.000 description 1
- ZREIPSZUJIFJNP-UHFFFAOYSA-K Bismuth subsalicylate Chemical compound C1=CC=C2O[Bi](O)OC(=O)C2=C1 ZREIPSZUJIFJNP-UHFFFAOYSA-K 0.000 description 1
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- 229960005361 Cefaclor Drugs 0.000 description 1
- XIURVHNZVLADCM-IUODEOHRSA-N Cefalotin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CC1=CC=CS1 XIURVHNZVLADCM-IUODEOHRSA-N 0.000 description 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N Cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
- 229940106195 Cephalothin Drugs 0.000 description 1
- 229960005091 Chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N Chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- MYSWGUAQZAJSOK-UHFFFAOYSA-N Ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 1
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- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
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- 210000004731 Jugular Veins Anatomy 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N Kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
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- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
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- NXFQHRVNIOXGAQ-YCRREMRBSA-N Nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N Norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
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- ANRIQLNBZQLTFV-DZUOILHNSA-N Pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 description 1
- 108010079943 Pentagastrin Proteins 0.000 description 1
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- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000001262 anti-secretory Effects 0.000 description 1
- 229940027991 antiseptics and disinfectants Quinoline derivatives Drugs 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 150000001621 bismuth Chemical class 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- MGLUJXPJRXTKJM-UHFFFAOYSA-L bismuth subcarbonate Chemical compound O=[Bi]OC(=O)O[Bi]=O MGLUJXPJRXTKJM-UHFFFAOYSA-L 0.000 description 1
- 229940036358 bismuth subcarbonate Drugs 0.000 description 1
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- 229960001482 bismuth subnitrate Drugs 0.000 description 1
- 229960000782 bismuth subsalicylate Drugs 0.000 description 1
- ZQUAVILLCXTKTF-UHFFFAOYSA-H bismuth;tripotassium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [K+].[K+].[K+].[Bi+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O ZQUAVILLCXTKTF-UHFFFAOYSA-H 0.000 description 1
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
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- 238000000034 method Methods 0.000 description 1
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Abstract
The present invention relates to certain salts of the compound 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinyl ethoxy) quinoline, which exogenously or endogenously inhibit the stimulated secretion of gastric acid, and thus may be used in the prevention and treatment of inflammatory gastrointestinal diseases
Description
COMPOUNDS FOR INHIBITION OF THE SECTION OF GASTRIC ACID TECHNICAL FIELD The present invention relates to certain salts of a quinoline compound, which exogenously or endogenously inhibit the stimulated secretion of gastric acid, and can thus be used in the prevention and treatment of gastrointestinal inflammatory diseases. In additional aspects, the invention relates to salts of the invention for use in therapy; to pharmaceutical compositions containing at least one salt of the invention as an active ingredient, and to the use of the salts in the manufacture of medicaments for the medical use indicated above. BACKGROUND TECHNIQUES Substituted quinoline derivatives that inhibit gastric acid secretion are known in the art, for example EP-A1-259, 174 and EP-A1-330, 485. See also Pope, A. J. & Parsons, M.E. (1993) Trends in Pharmacological Sciences 14, 323-325. The salts of 4-amino-3-acyl-quinoline derivatives are known from WO 92/12969. REF: 24817
The compound 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline is described in WO 94/29274 (publication date December 22, 1994).
DESCRIPTION OF THE INVENTION The salts according to the invention are proposed to improve the dissolution in water of the compound 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline, and thus improve the bioavailability in vivo of the compound. Accordingly, the invention provides the compound 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfi-nylethoxy) quinoline in the form of a hydrochloride salt, a methanesulfonic salt or a tartaric salt.
Included in the invention are the racemates, as well as the optical isomers of the salts according to the invention. Accordingly, another aspect of the invention is the (+) form, as well as the (-) form of the compound 3-butyryl-4- (2-methylphenylamino) -8- (2-methyl-sulfinylethoxy) quinoline in the form of a hydrochloride salt, a methanesulfonic salt or a tartaric salt. The salts according to the invention can be prepared by known methods, such as those described in Swedish Patent Application SE 9302005-5, corresponding to published International Application WO 94/29274. The salts according to the invention are effective as inhibitors of gastric acid secretion, and exert this effect by inhibiting gastrointestinal H +, K + -ATPase. In a more general sense, the salts of the invention can be used for the prevention and treatment of gastrointestinal inflammatory diseases, and diseases related to gastric acid in mammals, including man, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Ellison syndrome.
Additionally, the salts can be used for the treatment of other gastrointestinal disorders where the antisecretory effect is desirable, for example in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding. They can also be used in patients in intensive care situations, and pre- and post-operatively, to prevent acid aspiration and stress ulceration. A further aspect of the invention is consequently a salt according to the invention, for use in therapy, or more specifically for use in the inhibition of gastric acid secretion and / or for the treatment of gastrointestinal inflammatory diseases. Still a further aspect of the invention is a pharmaceutical formulation comprising a salt according to the invention as an active ingredient. For clinical use, the salts according to the invention can be formulated into pharmaceutical formulations for oral, rectal, parenteral or other administration, as described for example in WO 94/29274.
The salts according to the invention can also be used in formulations together with other active ingredients, for example for the treatment or prophylaxis of conditions involving an infection by Helicobacter pylori of the human gastric mucosa. Such other active ingredients may be antimicrobial agents, especially: β-lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefaclor or cefixime; . macrolides such as erythromycin, or clarithromycin; tetracyclines such as tetracycline or doxycycline; aminoglycosides such as genta icine, kanamycin or amikacin; quinolones such as norfloxacin, ciprofloxacin or enaxacin; others such as metronidazole, nitrofurantoin or chloramphenicol, or preparations containing bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgalate.
Therefore also included in the invention is the use of a salt according to the invention, for the manufacture of a medicament for (i) inhibiting the secretion of gastric acid, (ii) the treatment of gastrointestinal inflammatory diseases, or (iii) the treatment or prophylaxis of conditions that involve an infection by Helicobacter pylori of the human gastric mucosa. In case (iii), the salt is adapted to be administered in combination with at least one antimicrobial agent. Also included in the invention is a method for (i) inhibiting the secretion of gastric acid, (ii) the treatment of gastrointestinal inflammatory diseases, or (iii) the treatment or prophylaxis of conditions involving an infection by Helicobacter pylori of the gastric mucosa. human, which comprises administering to a mammal, including humans, in need of such inhibition, an effective amount of a salt according to the invention. In case (iii), the salt is administered in combination with at least one antimicrobial agent.
Yet a further aspect of the invention is a pharmaceutical formulation for use in (i) the inhibition of gastric acid secretion, (ii) the treatment of gastrointestinal inflammatory diseases, or (iii) the treatment or prophylaxis of conditions involving an infection by Helicojacter pylori of the human gastric mucosa, wherein the active ingredient is a salt according to the invention. In case (iii), the salt is in combination with at least one antimicrobial agent.
EXAMPLES Example 1 Preparation of 3-butyryl-4- (2-methylphenylamino) -8- (2-methyl-sulfinylethoxy) quinoline 3-Butyryl-4- (2-methylphenylamino) -8- (2-methylthioethoxy) quinoline was dissolved ( 0.15 g, 0.38 mmol) in methylene chloride (3 mL), and cooled to -20 ° C. A 71% solution of m-CPBA (0.089 g, 0.36 mmol) in 1 mL of chloride was added dropwise. of methylene. The temperature was allowed to rise to room temperature, and after that the
The solution was stirred for 15 minutes at room temperature. The reaction mixture was washed with a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, and evaporated. Chromatography with methylene chloride: methanol 10: 1 as the eluant gave 0.064 g (41%) of the desired product. NMR of XH (300 MHz, CDC13): 1.04, (t, 3 H), 1.82 (m, 2 H), 2.34 (s, 3 H), 2.80 (s, 3 H), 3.08 (t, 2 H) , 3.21 (m, 1 H), 3.44 (m, 1 H), 4.62 (m, 2 H), 6.89 (d, 1 H), 6.94-7.16 (m, 5 H), 7.28 (d, 1 H) , 9.20 (s, 1 H), 11.82 (s, 1 H) Example 2 Resolution of 3-butyryl-4- (2-methylphenylamino) -8- (2-methyl-sulfinylethoxy) quinoline A mixture of 3-butyryl-4 - (2-Methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline (9.3 g, 0.023 mmole) and D- (-) - tartaric acid (3.45 g, 0.023 mmole) in methanol (180 ml) was heated to reflux. The solution was allowed to cool to room temperature and was stirred for 60 hours. The precipitate was separated by filtration, and washed with a total amount of 20 ml of methanol, giving 6.1 g of the tartaric salt (the filtrate was used in example 3). The recrystallization of methanol was repeated 3 times,
providing 3.05 g, 1.30 g and finally 1.05 g of the tartaric salt of Example 3. The salt was neutralized with a saturated solution of sodium bicarbonate in methylene chloride and water. The organic layer was dried over sodium sulfate, and the solvent was evaporated. Trituration with isopropyl ether gave 0.7 g of the pure (+) enantiomer. Example 3 Resolution of 3-butyryl-4- (2-methylphenylamino) -8- (2-methyl-sulfinylethoxy) quinoline The filtrate of the first crystallization was evaporated in Example 2. The salt was neutralized with a saturated solution of sodium bicarbonate. sodium in methylene chloride and water. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The solid residue (4.6 g, 0.011 mol) and L- (+) - tartaric acid (1.68 g, 0.011 mol) were dissolved in hot methanol (110 ml). The solution was allowed to cool to room temperature, and was stirred for 72 hours. The precipitate was separated by filtration, and washed with a total amount of 11 ml of methanol, giving 1.5 g of the tartaric salt. Recrystallization from methanol gave 1.05 g of the tartaric salt of Example 57. The salt was neutralized with a saturated solution of sodium bicarbonate in
methylene chloride and water. The organic layer was dried over sodium sulfate, and the solvent was evaporated. Trituration with isopropyl ether gave 0.7 g of the pure (-) enantiomer. The enantiomers were separated on a Chiralpak AD 250 x 4.6 mm d.i. (Daciel, Japan), using the following parameters: n-hexane: 2-propanol: acetonitrile: diethyl amine (82: 18: 2: 0.1); temperature: + 35 ° C; Flow rate: 0.8 ml / minute. Retention times: Example 2: 14.5 minutes, Example 3: 18.4 minutes. Example 2: (XH NMR, 300 MHz, DMSO-d6): 0.95 (t, 3 H), 1.55-1.8 (m, 2 H), 2.3 (s, 3 H), 2.75 (s, 3 H), 3.05-3.25 (m, 3 H), 3.33-3.5 (m, 1 H), 4.3 (s, 2 H), 4.45-4.65 (m, 2 H), 6.85 (d, 1 H), 7.05-7.25 ( m, 4 H), 7.3 (d, 1 H), 7.35 (d, 1 H), 9.15 (s, 1 H). Example 3: (XH NMR, 300 MHz, DMSO-d6): 0.95 (t, 3 H), 1.55-1.7 (m, 2 H), 2.3 (s, 3 H), 2.75 (s, 3 H), 3.05-3.2 (m, 3 H), 3.35-3.5 (m, 1 H), 4.3 (s, 2 H), 4.45-4.6 (m, 2 H), 6.85 (d, 1 H), 7.05-7.2 ( m, 4 H), 7.25 (dd, 1 H), 7.35 (d, 1 H), 9.15 (s, 1 H).
Example 4 Preparation of the hydrochloride salt of 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline 3-Butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) was dissolved quinoline (10.2 g, 24.8 mmol) in methylene chloride (80 ml). A solution of hydrogen chloride in isopropanol was added until a pH value was obtained below 3. The solvent was evaporated, and the residue was treated with ethyl acetate (100 ml). The product was filtered, and washed with ethyl acetate. Yield 9.6 g (86%). X H NMR (300 MHz, CDC13): 1.03 (t, 3 H), 1.80 (m, 2 H), 2.25 (s, 3 H), 2.87 (s, 3 H), 3.12-3.25 (m, 3 H) ), 4.08 (m, 1 H), 4.68 (m, 2 H), 6.90-7.39 (m, 7 H), 9.34 (s, 1 H), 13.35 (s, 1 H). Example 5 Preparation of the ethanesulfonic acid salt of 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline Methanesulfonic acid (0.145 g, 1.51 mmol) was added to 3-butyryl-4- (2 -methylphenylamino) -8- (2-methylsulfinylethoxy) -quinoline (0.62 g, 1.51 mmole) in ethanol (10 ml). He
solvent was evaporated. Trituration with ethyl acetate gave 0.4 g (52%) of the desired product. NMR from XH (300 MHz, CDC13): 1.05 (t, 3 H), 1.75 (m, 2 H), 2.25 (s, 3 H), 2.75 (s, 3 H), 2.90 (s, 3 H), 3.10-3.20 (m, 3 H), 3.85 (m, 1 H), 4".70 (m, 2 H), 6.95 (d, 1 H), 7.10-7.45 (m, 6 H), 9.90 (s) , 1 H), 13.35 (s, 1 H).
BIOLOGICAL TESTS In vitro experiments The inhibitory effect on in vitro acid secretion in isolated gastric glands of rabbit was measured as described by Berglindh et al., (1976), Acta
Physiol. Scand. 97, 401-414. Bioavailability Bioavailability was determined by calculating the quotient between the area under the blood / plasma concentration curve (AUC) following (i) intraduodenal (i.d.) or oral (p.o.) and (ii) intravenous administration
(i.v.) of the rat or dog, respectively. Potency for the inhibition of acid secretion Potency for the inhibition of acid secretion is measured in the rat or dog intravenously, intraduodenally or orally. Inhibitory effect on acid secretion in female rats Female rats of the Sprague-Dawly strain were used. They were equipped with cannulated fistulas in the stomach (lumen) and in the upper part of the duodenum, for the collection of
gastric secretions and the administration of test substances, respectively. A resuscitation period of 14 days after surgery was allowed before the test began. Before the secretory tests, the animals were deprived of food but not of water for 20 hours. The stomach was repeatedly washed through the gastric cannula with running water (37 ° C), and 6 ml of Ringer-Glucose given subcutaneously. The secretion of acid was stimulated with an infusion for 3 hours (1.2 ml / hour, subcutaneously) of pentagastrin and carbacol (20 and 110 nmol / kg hour, respectively), and during this time the gastric secretions were collected in fractions of 30 minutes . The test substances or the vehicles were given intravenously or intraduodenally 60 minutes after initiating the stimulation, in a volume of 1.0 ml / kg. Samples of gastric juice were titrated at pH 7.0 with NaOH, 0.1 M, and the acid production was calculated as the product of the volume and concentration of titrant. Additional calculations were based on average group responses of 4-5 rats. The production of acid during the periods after the administration of
test substances or vehicle were expressed as fractional responses, fixing the acid production in the period of 30 minutes preceding the administration at 1.0. Percent inhibition was calculated from the fractional responses produced by the test compound and the vehicle. ED50 values were obtained from the graphical interpolation on dose-response log curves, or were estimated from single-dose experiments, assuming a similar slope for all dose-response curves. After the administration i.d. of 6 μmol / kg, the compound according to Example 4 gave an 85% inhibition of acid secretion.
Rat bioavailability Adult rats of the Sprague-Dawley strain were used. One to three days before the experiments, all rats were prepared by cannulation of the left carotid artery under anesthesia. The rats used for the intravenous experiments were also cannulated in the jugular vein (Popovic (1960), J. Appl. Physiol. 15, 727-728). The cannulas were exteriorized at the nape of the neck. Blood samples (0.1-0.4 g) were taken repeatedly from the carotid artery, at intervals up to 5.5 hours after a given dose. The samples were frozen until the analysis of the test compound. The area under the blood concentration curve vs. time, AUC, was determined by the trapezoidal log / linear rule, and extrapolated to infinity by dividing the last blood concentration determined by the constant elimination rate in the terminal phase. The systemic bioavailability (F%) following intraduodenal or oral administration was calculated as: F ("%) = (AUC (po or id) / AUC (iv)) x 100 Inhibition of gastric acid secretion and bioavailability in the conscious dog
Dogs of either sex Retriever or Harrier were used. They were equipped with a duodenal fistula for the administration of the test compounds or the vehicle, and a cannulated gastric fistula or a Heidenhaim bag for the collection of gastric secretion. Before the secretory tests, the animals were fasted for about 18 hours, but they were allowed free access to water. The secretion of gastric acid was stimulated by infusion for up to 6.5 hours of histamine dihydrochloride (12 ml / hour) at a dose that produced about 80% of the individual maximum secretory response, and the gastric juice was collected in consecutive fractions of 30 minutes. The test substance or vehicle was given orally, i. d. or i. v. , 1 or 1.5 hours after initiating the histamine infusion, in a volume of 0.5 ml / kg of body weight. In the case of oral administration, it should be noted that the test compound is administered to the main stomach which is secreting the dog's acid with Heidenham's pouch. The acidity of the gastric juice samples was determined by titration at pH 7.0, and acid production was calculated. The production of acid in the periods
After the administration of the test substance or the vehicle, they were expressed as fractional responses, fixing the acid production in the fraction that preceded the administration at 1.0. Percent inhibition was calculated from the fractional responses produced by the test compound and the vehicle. ED50 values by graphical interpolation over dose-response log curves, or were estimated under the same slope assumption of the dose-response curve for all test compounds. All results are based on acid production during the period from 1.5 to 2 hours after dose administration. Blood samples were taken for analysis of the concentration of the test compound in plasma at intervals up to 4 hours after dose administration. The plasma was separated and frozen within 30 minutes after collection, and analyzed later. Systemic bioavailability (F%) after oral administration or i. d. it was calculated as described above, in the rat model.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, property is claimed as contained in the following:
CLAIMS 1. The compound 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline, characterized in that it is in the form of a hydrochloride salt or an ethanesulfonic salt. 2. The compound according to claim 1, characterized in that it is in the form of a hydrochloride salt. 3. The compound according to claim 1, characterized in that it is in the form of a methanesulfonic salt. 4. The compound (+) - 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline, characterized in that it is in the form of a hydrochloride salt or a methanesulfonic salt. 5. The compound (-) - 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline, characterized in that it is in the form of a hydrochloride salt or a methanesulfonic salt.
Claims (1)
- 6. A salt according to any of claims 1-5, characterized in that it is for use in therapy. 7. A salt according to any of claims 1-5, characterized in that it is for use in the inhibition of gastric acid secretion and / or for the treatment of gastrointestinal inflammatory diseases. 8. A pharmaceutical formulation, characterized in that it comprises a salt according to any of claims 1-5 as an active ingredient. 9. The use of a salt according to any of claims 1-5, characterized in that it is for the manufacture of a medicament for the inhibition of gastric acid secretion. 10. The use of a salt according to any of claims 1-5, characterized in that it is for the manufacture of a medicament for the treatment of gastrointestinal inflammatory diseases. 11. The use of a salt according to any of claims 1-5, for the manufacture of a medicament for the treatment or prophylaxis of conditions which involve an infection by Helicobacter pylori of the human gastric mucosa, the use is characterized in that the salt is adapted to be administered in combination with at least one antimicrobial agent. 12. A method for inhibiting gastric acid secretion, characterized in that it comprises administering to a mammal, including humans, in need of such inhibition an effective amount of a salt according to any of claims 1-5. 13. A method for the treatment of gastrointestinal inflammatory diseases, characterized in that it comprises administering to a mammal, including humans in need of such treatment, an effective amount of a salt according to any of claims 1-5. 14. A method for the treatment or prophylaxis of conditions involving an infection by the human gastric pylori of the human gastric mucosa, which comprises administering to a mammal, including humans in need of such treatment, an effective amount of a salt in accordance with any of claims 1-5, the method is characterized in that the salt is administered in combination with at least one antimicrobial agent. 15. A pharmaceutical formulation for use in the inhibition of gastric acid secretion, characterized in that the active ingredient is a salt according to any of claims 1-5. 16. A pharmaceutical formulation for use in the treatment of gastrointestinal inflammatory diseases, characterized in that the active ingredient is a salt according to any of claims 1-5. 17. A pharmaceutical formulation for use in the treatment or prophylaxis of conditions involving a Helicobacter pylori infection of human gastric mucosa, characterized in that the active ingredient is a salt according to any of claims 1-5 in combination with at least an antimicrobial agent.
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US08351852 | 1994-12-08 | ||
US08/351,852 US5556863A (en) | 1993-06-11 | 1994-12-08 | Compound for gastric acid secretion inhibition |
PCT/SE1995/001369 WO1996017830A1 (en) | 1994-12-08 | 1995-11-17 | Compounds for inhibition of gastric acid secretion |
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MXPA97004136A true MXPA97004136A (en) | 1998-02-01 |
MX9704136A MX9704136A (en) | 1998-02-28 |
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MX9704136A MX9704136A (en) | 1994-12-08 | 1995-11-17 | Compounds for inhibition of gastric acid secretion. |
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US (1) | US5556863A (en) |
EP (1) | EP0796249A1 (en) |
JP (1) | JPH10510259A (en) |
CN (1) | CN1169142A (en) |
AR (1) | AR001996A1 (en) |
BR (1) | BR9509888A (en) |
CA (1) | CA2205896A1 (en) |
EE (1) | EE9700131A (en) |
FI (1) | FI972410A0 (en) |
HU (1) | HUT77949A (en) |
IL (1) | IL116285A0 (en) |
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MX (1) | MX9704136A (en) |
NO (1) | NO972529L (en) |
NZ (1) | NZ297566A (en) |
PL (1) | PL320754A1 (en) |
SK (1) | SK63797A3 (en) |
TR (1) | TR199501536A2 (en) |
WO (1) | WO1996017830A1 (en) |
ZA (1) | ZA9510066B (en) |
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UA80393C2 (en) | 2000-12-07 | 2007-09-25 | Алтана Фарма Аг | Pharmaceutical preparation comprising an pde inhibitor dispersed on a matrix |
MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
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US4042702A (en) * | 1973-08-16 | 1977-08-16 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Halogen pyrazole derivatives, a method for producing these halogen pyrazole derivatives, medicaments containing and methods of using them |
LU69428A1 (en) * | 1974-02-20 | 1975-12-09 | ||
US4120972A (en) * | 1975-02-03 | 1978-10-17 | Smith Kline & French Laboratories Limited | Imidazolylmethylthio-ethyl isothiourea compounds |
NO760996L (en) * | 1975-03-25 | 1976-09-28 | Byk Gulden Lomberg Chem Fab | |
FR2367750A1 (en) * | 1976-10-14 | 1978-05-12 | Byk Gulden Lomberg Chem Fab | ACID |
LU78804A1 (en) * | 1977-12-30 | 1979-07-20 | Byk Gulden Lomberg Chem Fab | N-SUBSTITUTED W-AMINOALKANOYL-W-AMINOALKANIC ACIDS, THEIR USE AND METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
US4243678A (en) * | 1977-12-30 | 1981-01-06 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Acylhydrocarbylaminoalkanoic acids, compositions and uses |
YU118379A (en) * | 1978-05-24 | 1983-02-28 | Byk Gulden Lomberg Chemischefa | Process for preparing phenylaminothiophene acetic acid |
US4343804A (en) * | 1979-03-26 | 1982-08-10 | A. H. Robins Company, Inc. | 4-Amino-3-quinolinecarboxylic acids and esters-antisecretory anti-ulcer compounds |
NO802326L (en) * | 1979-08-03 | 1981-02-04 | Byk Gulden Lomberg Chem Fab | PROCEDURE FOR THE PREPARATION OF SUBSTITUTED TETRAZA TRIACLES |
EP0024638A1 (en) * | 1979-08-30 | 1981-03-11 | Byk Gulden Lomberg Chemische Fabrik GmbH | Substituted quinolinone-alkanecarboxylic acids, their preparation, and medicaments containing them |
DE3063144D1 (en) * | 1979-09-07 | 1983-06-16 | Byk Gulden Lomberg Chem Fab | Substituted oxirane carboxylic acids, process for their preparation, their use and medicines containing them |
ES8202780A1 (en) * | 1979-10-31 | 1982-03-01 | Byk Gulden Lomberg Chem Fab | Substituted oxocarboxylic acids, process for their preparation, their use and medicines containing them. |
US4381301A (en) * | 1980-05-07 | 1983-04-26 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Substituted tricyclic thieno compounds, their synthesis, their use, their compositions and their medicaments |
US4337267A (en) * | 1980-08-25 | 1982-06-29 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Phenalkoxyalkyl- and phenoxyalkyl-substituted oxiranecarboxylic acids, their use and medicaments containing them |
EP0046961B1 (en) * | 1980-08-29 | 1985-02-13 | Byk Gulden Lomberg Chemische Fabrik GmbH | Epoxy-cycloalkylalkanecarboxylic acids, process for their preparation, their use and medicaments containing them |
DE3262922D1 (en) * | 1981-02-02 | 1985-05-15 | Byk Gulden Lomberg Chem Fab | Tricyclic pyrrols, process for their preparation, their use and compositions containing them |
US4578381A (en) * | 1982-07-05 | 1986-03-25 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
EP0187977B1 (en) * | 1984-12-18 | 1990-08-29 | Otsuka Pharmaceutical Co., Ltd. | Tetrahydroquinoline derivatives, process for preparing the same and anti-peptic ulcer compositions containg the same |
US5250527A (en) * | 1985-10-24 | 1993-10-05 | Smithkline & French Laboratories Limited | Pyridyl containing benzimidazoles, compositions and use |
GB8621425D0 (en) * | 1986-09-05 | 1986-10-15 | Smith Kline French Lab | Compounds |
GB8717644D0 (en) * | 1987-07-24 | 1987-09-03 | Smithkline Beckman Intercredit | Compounds |
GB8804444D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
GB8804443D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
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GB8804447D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
US5049567A (en) * | 1988-02-25 | 1991-09-17 | Smithkline Beckman Intercredit B.V. | Substituted 4-aminoquinazoline derivatives and method of use |
GB8804445D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
GB8804448D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
CA2011086A1 (en) * | 1989-03-17 | 1990-09-17 | Karl-Heinz Geiss | 2-alkyl-4-arylmethylaminoquinolines, the use thereof and drugs prepared therefrom |
GB8908229D0 (en) * | 1989-04-12 | 1989-05-24 | Smithkline Beckman Intercredit | Compounds |
GB8910722D0 (en) * | 1989-05-10 | 1989-06-28 | Smithkline Beckman Intercredit | Compounds |
DE3917233A1 (en) * | 1989-05-26 | 1990-11-29 | Basf Ag | 8-SUBSTITUTED 4- (HETEROCYCLYLMETHYLAMINO) -INCHINOLINES, THEIR USE AND DRUGS DERIVED THEREFROM |
GB8918265D0 (en) * | 1989-08-10 | 1989-09-20 | Smithkline Beckman Intercredit | Compounds |
WO1991014677A1 (en) * | 1990-03-28 | 1991-10-03 | Otsuka Pharmaceutical Co., Ltd. | Quinoline derivative, antiulcer drug containing the same, and production of said derivative |
HUT67609A (en) * | 1991-01-29 | 1995-04-28 | Smithkline Beecham Intercredit | Salts of a 4-amino-3-acyl-quinoline derivative, their preparation and pharmaceutical compositions comprising them |
GB9126438D0 (en) * | 1991-12-12 | 1992-02-12 | Smithkline Beecham Intercredit | New quinoline derivatives |
IS4164A (en) * | 1993-06-11 | 1994-12-12 | Ab Astra | Compounds that inhibit gastric acid flow |
-
1994
- 1994-12-08 US US08/351,852 patent/US5556863A/en not_active Expired - Fee Related
-
1995
- 1995-11-08 AR ARP950100099A patent/AR001996A1/en unknown
- 1995-11-17 EE EE9700131A patent/EE9700131A/en unknown
- 1995-11-17 PL PL95320754A patent/PL320754A1/en unknown
- 1995-11-17 WO PCT/SE1995/001369 patent/WO1996017830A1/en not_active Application Discontinuation
- 1995-11-17 JP JP8517523A patent/JPH10510259A/en active Pending
- 1995-11-17 NZ NZ297566A patent/NZ297566A/en unknown
- 1995-11-17 MX MX9704136A patent/MX9704136A/en unknown
- 1995-11-17 SK SK637-97A patent/SK63797A3/en unknown
- 1995-11-17 BR BR9509888A patent/BR9509888A/en not_active Application Discontinuation
- 1995-11-17 CN CN95196698A patent/CN1169142A/en active Pending
- 1995-11-17 EP EP95941272A patent/EP0796249A1/en not_active Ceased
- 1995-11-17 CA CA002205896A patent/CA2205896A1/en not_active Abandoned
- 1995-11-17 HU HU9800175A patent/HUT77949A/en unknown
- 1995-11-27 ZA ZA9510066A patent/ZA9510066B/en unknown
- 1995-12-05 TR TR95/01536A patent/TR199501536A2/en unknown
- 1995-12-07 IL IL11628595A patent/IL116285A0/en unknown
-
1997
- 1997-05-22 IS IS4485A patent/IS4485A/en unknown
- 1997-06-03 NO NO972529A patent/NO972529L/en unknown
- 1997-06-06 FI FI972410A patent/FI972410A0/en unknown
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