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(12) Patent Application Publication (10) Pub. No.: US 2012/0329804 A1 LJUBCHANSKAYA Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2012/0329804 A1 LJUBCHANSKAYA Et Al US 20120329804A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0329804 A1 LJUBCHANSKAYA et al. (43) Pub. Date: Dec. 27, 2012 (54) PYRIDOPYRAZINDIONE DERIVATIVE AND (30) Foreign Application Priority Data ITS USE ASAN ANTULCER DRUG Mar. 5, 2010 (RU) ................................ 2010.107989 (75) Inventors: Valeriya Markovna LJUBCHANSKAYA, Moscow (RU); Publication Classification Valery Aleksandrovich PARSHIN, Moscow (RU); Marina Alekseevna (51) Int. Cl. KALINKINA, Moscow (RU); Vladimir A613 L/4985 (2006.01) Vladimirovich GRANK, Moscow A6IPI/00 (2006.01) (RU) C07D 47L/04 (2006.01) (73) Assignee: Innovative Pharmacology Research (52) U.S. Cl. ........................................ 514/249; 544/349 OOO, Tomsk (RU) (57) ABSTRACT (21) Appl. No.: 13/602,239 The invention relates to the fields of the chemical and phar maceutical industry and medicine and concerns a novel com (22) Filed: Sep. 3, 2012 pound which can be used as an antiulcer agent. The com O O pound is 9-(quinonyl-2)-2-p-ethoxyphenylethyl-4,5,6,7,8,9, Related U.S. Application Data 10, 11-octahydropyrido 1,2-alpyrazindione-1,4 of formula (63) Continuation of application No. PCT/RU2011/ (I), or pharmaceutically acceptable complex derivatives 000 103, filed on Feb. 28, 2011. thereof. The compound can be used as an antiulcer agent. US 2012/0329804 A1 Dec. 27, 2012 PYRIDOPYRAZINDONE DERVATIVE AND other drugs sometimes may be discovered only after exten ITS USEAS AN ANTULCER DRUG sive use hundreds of thousands uses may be required. How ever, even now adverse effects of PPI (mainly omeprazole) on RELATED APPLICATIONS liver are documented in children 1. Clinical use has also 0001. This application is a Continuation application of shown other adverse effects: diarrhea, nausea, abdominal International Application PCT/RU2011/0001.03, filedon Feb. colic, drowsiness, and headaches. 28, 2011, which in turn claims priority to Russian Patent 0010 Long-term use of omeprazole and other PPIs (as Applications No. RU 2010107989, filed Mar. 5, 2010, both of well as some other antisecretory drugs) may lead to a potent and prolonged inhibition of gastric secretion and sometimes which are incorporated herein by reference in their entirety. atrophy of gastric secretory cells, causing severe complica FIELD OF THE INVENTION tions (development of tumors like gastrinoma, adenocarci noma, Helicobacter Pylori infestation, intestinal infections, 0002 The present invention relates to the fields of the intestinal malabsorption of fats, minerals and vitamins). All chemical and pharmaceutical industry and medicine and con of these complications are described in the following litera cerns a novel compound which can be used as an antiulcer ture: 2. In addition, it should be taken into account that PPI agent. metabolism involves cytochrome P450 oxidase system, so long-term PPI use may cause tolerance to such drugs after this BACKGROUND OF THE INVENTION enzyme systems activity is exhausted 3. This may be con 0003 Gastrointestinal (GI) tract diseases were always nected to the known withdrawal syndrome relapse of the central to medical concern due to their high prevalence. Of disease after Some time (from 2 to 22 weeks, average 14 many diseases of this group gastric ulcers and duodenal ulcers weeks) of omeprazole cancellation 4. have special Social and medical significance, because their 0011. Other adverse and undesirable effects are known in prevalence exceeds the prevalence of all other GI tract drugs of this class, which are usually shown in indications for pathologies. use (headache, diarrhea, allergy, gynecomastia, etc). 0004 Medical treatment of peptic ulcer disease (PUD) 0012 PPIs are thus quite effective drugs, widely used in aims to reduce the damaging effects of gastric acid (antisecre PUD treatment, however they also have adverse effects and tory drugs) on gastric tissues, raise the resistance of affected negative consequences (the most dangerous of them, possibly tissues, foremost of all gastric mucosa (gastroprotective lethal, is infestation by Helicobacter pylori and tumor devel drugs), and combat Helicobacter Pylorimicroorganisms (an opment). Also, they are sometimes ineffective in treatment. timicrobial therapy). This makes the search for new antiulcer drugs important and 0005. The primary type of antiulcer treatment is periodic relevant. or Sustained therapy using antisecretory drugs: proton pump 0013 The most promising venue of new antiulcer drug inhibitors, histamine H-receptor antagonists, antacid drugs, development is synthesizing a drug with gastroprotective bismuth drugs (bismuth subsalicylate/subcitrate), sucralfate properties, as this does not cause "hard’ inhibition of gastric (a combination of aluminium hydroxide and Sucrose octasul secretion. The latter causes the main adverse effects—Heli fate). Histamine H-receptor antagonists, popular in the cobacter pylori infestation and tumor processes Inhibition 1980s, have largely been superseded by more effective anti may be undesirable, when secretion levels are normal or low, secretory drugs proton pump inhibitors. which is frequently encountered during PUD. In such case all 0006 Proton pump inhibitors (PPIs) were first synthe that is needed is to “protect gastric mucosa from irritation, so sized in 1976. The first PPIs were timoprazole and omepra that the damaged mucosa was not further damaged by acid, Zole. Timoprazole fell into obscurity, while omeprazole but instead protected from it. achieved widespread medical recognition. In 1988 Omepra 0014. Such drugs are usually based on prostaglandins. Zole was officially recommended for clinical use at the World Prostaglandins stimulate mucus secretion and activate pro Congress of Gastroenterology in Rome. One of the reasons tein kinase, which, by acting on cell membrane, can protect for Such recognition was the proof of its high efficacy in gastric mucosa from aggressive effects of acid and pepsin. On eliminating Helicobacter pylori (HP) bacteria, the discovery the other hand, prostaglandins can inhibit gastric acid secre of which in 1983 has forced the medical community to review tion. This combined action makes prostaglandins very prom the nature of gastro duodenal diseases. Helicobacter infec ising antiulcer drugs, however, there is little experience of tion received great attention because WHO experts recog their use, currently they are only at clinical trials stage 5. nized it as carcinogenic for humans after extensive research. 0015. Another promising venue is the development of gas That made the problem of HP eradication in gastric mucosa troprotective drugs NO donors. Nitric oxide acts as a mul (and providing optimal conditions for ulcer healing) tifunctional gastroprotective mediator, affecting some extremely important. aspects of GI tract action, including bile and bicarbonate 0007. Despite omeprazole's widespread recognition and secretion and blood flow in GI tract walls 6. NO also pos use as the first effective PPI, efforts to improve it continued. In sesses antimicrobial properties, in particular towards Helico 1992 specialists of Japanese firm Takeda have synthesized a bacter pylori bacteria 7. NO donors do not have direct new-generation PPI lansoprazole. After a few years next antisecretory effect, but bicarbonate, secreted under their generation PPIs have appeared: pantoprazole, rabeprazole, influence in stomach, interacts with gastric acid, neutralizing esomeprazole. it. 0008 Currently IPPs are the most widely used gas 0016 Other drugs are used to inhibit gastric acid secre troduodenal ulcer treatment drugs in the world. tion: H-receptor antagonists (famotidine, ranitidine, cimeti 0009 PPIs have been used for PUD treatment for over 15 dine) and proton pump inhibitors. H-receptor antagonists years, however, their safety is not fully established. Danger have significant drawbacks compared to PPIs: a) they block ous adverse effects or life threatening PPI interactions with only the signal created during histamine binding, b) their US 2012/0329804 A1 Dec. 27, 2012 action is reversible and they eliminate quickly from the 5,6,7,8,9,10,11-octahydropyrido 1,2-alpyrazindione-1,4 of bloodstream, forcing a patient to take several pills a day. Their formula (I) and its pharmaceutically useful complex deriva use also leads to intense histamine receptor synthesis, causing tives. "rebounds” of HCL secretion after their cancellation. 0017. The first proton pump inhibitor in the market was omeprazole (AstraZeneca), a Substituted benzimidazole which appeared in the 80s. PPIs currently present in the market are also substituted benzimidazoles. They are: nexium (S-enantiomer of omeprazole or esomeprazole, AstraZen eca), multiple omeprazole generics, pariet (rabeprazole, Jan ssen-Cillag) and controloc (pantoprazole, Byk Gulden, not sold in Russia). All these compounds are prodrugs. They are weak bases, and being exposed to the acidic environment of parietal vesicles they bind H and undergo molecular trans formation into the drug an active Sulfenamide interacting with SH-groups of H-ATPase in secretory vesicle. Sulfena mides form covalent bond with SH groups, so their action is irreversible. Their action stops only after the elimination of H-ATPase molecule, modified by an inhibitor, and half-life of DETAILED DESCRIPTION OF THE PREFERRED H.K-ATPase in humans is about 40 hours. This makes sec EMBODIMENTS ond-generation PPIs like pariet and nexium highly effective in treating acid-dependent diseases. PUD treatment using these inhibitors combined with antibiotics,
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