WO2016130043A1 - Inhibiteurs de réplication du virus de l'hépatite b à base de benzo[1,2,4]thiadiazine et compositions pharmaceutiques pour traiter l'hépatite b - Google Patents

Inhibiteurs de réplication du virus de l'hépatite b à base de benzo[1,2,4]thiadiazine et compositions pharmaceutiques pour traiter l'hépatite b Download PDF

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Publication number
WO2016130043A1
WO2016130043A1 PCT/RU2015/000856 RU2015000856W WO2016130043A1 WO 2016130043 A1 WO2016130043 A1 WO 2016130043A1 RU 2015000856 W RU2015000856 W RU 2015000856W WO 2016130043 A1 WO2016130043 A1 WO 2016130043A1
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WIPO (PCT)
Prior art keywords
hepatitis
general formula
pharmaceutically acceptable
virus
pharmaceutical composition
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Ceased
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PCT/RU2015/000856
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English (en)
Russian (ru)
Inventor
Александ Васильевич ИВАЩЕНКО
Андрей Александрович ИВАЩЕНКО
Николай Филиппович САВЧУК
Вадим Васильевич БЫЧКО
Александр Викторович ХВАТ
Борис РОГОВОЙ
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Alla Chem LLC
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Alla Chem LLC
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Priority claimed from RU2015104887/04A external-priority patent/RU2574397C1/ru
Application filed by Alla Chem LLC filed Critical Alla Chem LLC
Publication of WO2016130043A1 publication Critical patent/WO2016130043A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom

Definitions

  • This invention relates to new hepatitis B virus replication inhibitors (HBV), a new pharmaceutical composition for the treatment of hepatitis B, a method for their preparation and use.
  • HBV hepatitis B virus replication inhibitors
  • Hepatitis B is a liver infection that is potentially life threatening due to HBV. He presents one of the main problems of the global
  • Hepatitis B can lead to the development of chronic liver disease and create a high risk of death from cirrhosis and liver cancer.
  • hepatitis B virus infection The likelihood that a hepatitis B virus infection will become chronic depends on the age at which the person acquires the infection. Chronic infections develop in 80-90% of children infected during the first year of life and in 30-50% of children infected before the age of six. Among adults, chronic infections develop in ⁇ 5% of infected, otherwise healthy people. 5–25% of adults who become chronically infected in childhood die from hepatitis B-related cancer or cirrhosis.
  • hepatitis B More than 240 million people have chronic (long-term) liver infections. About 780,000 people die each year from the acute or chronic effects of hepatitis B. A hepatitis B vaccine has been available since 1982. This vaccine is 95% effective in preventing infection and its chronic effects and is the first vaccine against one of the main types of human cancer.
  • Treatment can slow the progression of cirrhosis, reduce the incidence of hepatocellular carcinoma, and improve long-term survival.
  • non-nucleoside heterocyclic compounds that inhibit the replication of hepatitis B virus [US 6436943, US 2013/0071354, WO 2013/102655], including: methyl (R) -4- (2-chloro-4-fluorophenyl) - 2- (3,5-difluoro-2-pyridinyl) - 6-methyl-l, 4-dihydro-pyrimidine-5-carboxylate (BAY 41-4109) [O. Weber et al. Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model. Antiviral Res.
  • HBV human hepatitis B virus
  • Derivatives of 1, 1-dioxo-2H-1, 2,4-benzothiadiazin-3 (4H) -one are known, which have shown high activity as antagonists of the orexin-2 receptor and are claimed for the treatment and prevention of drug dependence, motor disorders, sleep disorders, neurological diseases associated with depression, cognitive disorders, Alzheimer's disease.
  • a method for their preparation by the interaction of 2-nitrobenzene sulfonyl chloride and substituted aniline is also described, followed by reduction of the nitro group in the presence of tin dichloride and cyclization in the presence of triphosgene [WO 2014006402].
  • Alkyl means an aliphatic hydrocarbon linear or branched group with 1 to 12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl” substituents.
  • Alkyl may have one or more, same or different substituents, including halo, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbnyl, alkylthio, heteroarylthio, aralkyl alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl,
  • R k a R k + i a NS0 2 - where R k a and R k + i a are independently “amino substituents”, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or Rk a and RH-I 3 together with the N atom to which they are bonded form through R k a and R k + i a 4 - 7 membered heterocyclyl or heterocyclenyl.
  • Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylcarbonyl and pyridylmethyloxycarbonylmethyl.
  • Alkoxy or “alkyloxy” means an alkyl-O— group in which alkyl is defined in this section. Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy.
  • Aryl means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms.
  • Aryl may contain one or more “cyclic system substituents”, which may be the same or different.
  • Representative aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl.
  • Aryl can be annelated with a non-aromatic ring system or heterocycle.
  • Halogen means fluoro, chloro, bromo and iodo. Fluorine, chlorine and iodine are preferred.
  • Heterocyclyl means an aromatic or non-aromatic saturated monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 5 to 6 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur.
  • the prefix "aza”, “oxa” or “thia” before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • Heterocyclyl may have one or more “cyclic system substituents,” which may be the same or different.
  • the nitrogen and sulfur atoms in the heterocyclyl can be oxidized to ⁇ -oxide, S-oxide or S-dioxide.
  • heterocyclyl are piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, thiazolidine, 1, 4-dioxane, tetrahydrofuran, tetrahydrothiophene, etc.
  • Hydrate means a stoichiometric or non-stoichiometric composition of a compound or its salt with water.
  • “Urea carbamoyl” means a substituent attached to a carbamoyl group, the meaning of which is defined in this section.
  • the carbamoyl substituent is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R k a R k + i a N-, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl.
  • “Substituent cyclic system” means a substituent attached to an aromatic or non-aromatic cyclic system, including hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, aryloxy, acyl, aroyl, halogen , nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, arylalkyloxyalkyl, heterocyclylalkyl-hydroxyalkyl, alkylsulfonyl, arylsulfonyl, heterocylalkyl lfinil, arylsulfinyl, geterotsiklilsulfinil, alkylthio, aryl
  • Medical substance drug substance, drug substance
  • drug substance means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of a pharmaceutical composition used for the manufacture and manufacture of a drug drug (funds).
  • Medical product (preparation) a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules of injections, ointments and other finished forms, intended to restore, correct or alter the physiological functions in humans and animals, as well as for the treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology and more.
  • “Lower alkyl” means a linear or branched alkyl with 1 to 4 carbon atoms.
  • a “therapeutic cocktail” is a simultaneously administered combination of two or more drugs with a different mechanism of pharmacological action and aimed at different biological targets involved in the pathogenesis of the disease.
  • “Pharmaceutical composition” means a composition comprising a compound of formula 1 and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving agents, agents delivery, such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage.
  • suspending agents examples include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, such as parabens, chlorobutanol, sorbic acid and the like.
  • the composition may also include isotonic agents, for example, sugars, sodium chloride and the like.
  • the prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin.
  • suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate).
  • excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like.
  • grinders and distributors are starch, alginic acid and its salts, silicates.
  • lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.
  • the pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form in the form of a mixture with traditional pharmaceutical carriers.
  • Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
  • “Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid.
  • salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (Detailed description of the properties of such salts is given in Berge SM, et al., "Pharmaceutical Salts" J.
  • Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized.
  • Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts.
  • Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide.
  • amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity).
  • amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like.
  • tetraalkylammonium hydroxides for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation.
  • amino acids the main amino acids can be used - lysine, ornithine and arginine.
  • the subject of this invention is new inhibitors of hepatitis B virus replication, which are 1, 1-dioxo-1, 4-dihydro-2H-benzo [1, 2,4] thiadiazin-3-ones of general formula 1, their pharmaceutically acceptable salts and / or hydrates.
  • Ar 1 and Ar 2 are optionally the same aryl, including phenyl, optionally substituted with one, two or three substituents selected from C
  • preferred inhibitors of the general formula 1 are 1, 1-dioxo-1, 4-dihydro-2H-benzo [1, 2,4] thiadiazin-3-ones 1.1-1.15
  • Hepatitis B virus replication inhibitors of general formula 1 are commercially available compounds from a number of companies, including ChemDiv, Inc.
  • the "e” antigen (HBeAg) in a culture of HBV-infected HepG2 NTCP cells) was determined by ELISA according to the protocol described below in Example 1, and their cytotoxicity was determined by the protocol described below in Example 2.
  • new inhibitors of the general formula 1 are a drug for preparing a pharmaceutical composition and formulations for the prevention and treatment of HBV in warm-blooded animals and humans.
  • the subject of this invention is a pharmaceutical composition in the form of tablets, capsules or injections in a pharmaceutically acceptable package for the treatment of hepatitis B in humans and warm-blooded animals, comprising a therapeutically effective amount of an HBV replication inhibitor of general formula 1.
  • compositions may include pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field.
  • the pharmaceutical composition along with the inhibitor of the general formula 1 or their pharmaceutically acceptable salt and / or hydrate of the present invention may include other active substances, provided that they do not cause undesirable effects. If necessary, the use of the pharmaceutical composition of the present invention in clinical practice, it can be mixed with traditional pharmaceutical carriers.
  • the carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical industry to obtain common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless are used agents, flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.
  • the subject of this invention is a method for preparing a pharmaceutical composition by mixing with an inert excipient and / or solvent of at least one inhibitor of general formula 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount.
  • the subject of the present invention is also therapeutic cocktails for treating influenza, comprising, as one of the components, a new drug or a new pharmaceutical composition containing, as an active component, at least one compound of general formula 1 or a pharmaceutically acceptable salt and / or hydrate thereof.
  • a therapeutic cocktail for treating HBV may include other known drugs for treating hepatitis B virus, or drugs that enhance the patient’s immune system.
  • a method for the prevention and treatment of hepatitis B in animals and humans consists in introducing to the patient a new pharmaceutical composition or a new therapeutic cocktail.
  • Medicines may be administered via an inhaler, orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically).
  • the clinical dosage of an agent of general formula 1 in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as depending on the age, sex and stage of the patient’s disease, while the daily dose in adults is usually 10 ⁇ 500 mg. Therefore, when preparing the inhibitor of the present invention in the form of dosage units from the pharmaceutical composition, the above effective dosage must be taken into account, with each dosage unit containing 10-500 mg of the inhibitor of general formula 1. In accordance with the instructions of a doctor or pharmacist, these drugs may be taken times during certain periods of time.
  • the subject of this invention is also a method of inhibiting the activity of HBV in vivo, comprising the step of contacting an inhibitor of general formula 1 and HBV.
  • the invention is illustrated, but not limited to the following examples.
  • Example 1 Determination of the antiviral activity of a pharmaceutical composition containing one of the inhibitors of general formula 1 as an active substance against hepatitis B viruses (HBV) in a human hepatoma cell culture (HepG2 NTCP) infected with HBV in vitro (Elife 2012 Nov 13; 1 : e00049. doi:
  • HBV "e” antigen HBV "e” antigen
  • the HepG2 NTCP cell culture used in this experiment is capable of being able to support the full cycle of viral replication, being infected with the HBV virus.
  • the HBV preparation used in this experiment for infection of HepG2 / NTCP cells was obtained from supernatants of cell cultures of the AD38 line,
  • HepG2 NTCP cells were plated in 96-well plates (3.0 x 10 cells per well) in Huh-7 medium (50 ⁇ l per well). For each test compound
  • the reaction was stopped by adding 100 ⁇ l of 2N H 2 S0 4 to each well, after which absorbance was measured at a wavelength of 490 nm.
  • the value of EC 5 about which is the concentration of the test compound at which the virus replication is halved, was determined for each test compound using the Xlfit program.
  • EC 5 0 values are presented for some representatives of inhibitors of general formula 1 with respect to HBV.
  • HepG2 / NTCP cells were seeded in a black microplate with a transparent bottom (96 cells, 3.0 x 10 3 cells per well). Three independent repeats were used for each inhibitor. Test inhibitors were added after 18 hours, after which the cells were incubated with substances for 7 days.
  • the CC50 value which is the concentration of the test compound at which the cell viability is reduced by half, was determined for each
  • Example 3 Obtaining a drug in the form of tablets. 1600 mg of starch, 1600 mg of crushed lactose, 400 mg of talc and 1000 mg of inhibitor 1.13 are mixed and pressed into a block. The resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The granules obtained are tabletted into a suitable tablet form weighing 560 mg each.
  • Example 4 Obtaining a drug in the form of capsules. Thoroughly mix the 1.13 inhibitor with lactose powder in a ratio of 2: 1. The resulting the powder mixture is packaged in 600 mg in a suitable size gelatin capsule.
  • Example 5 Obtaining a medicinal product in the form of injection compositions for intramuscular, intraperitoneal or subcutaneous injection.
  • 500 mg of inhibitor 1.13 are mixed with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection water.
  • the resulting solution is filtered and placed in 1 ml ampoules, which are sealed.
  • the invention can be used in medicine and veterinary medicine.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'objet de la présente invention sont de nouveaux inhibiteurs de réplication du virus de l'hépatite B qui sont des 1,1-dioxo-1,4-dihydro-2N-benzo[1,2,4]thiadiazin-3-ones ayant la formule générale 1 et leurs sels ou hydrates pharmaceutiquement acceptables. (1) dans laquelle Ar1 и Ar2 sont des aryles éventuellement identiques, y compris phényle éventuellement substitué par deux ou trois substituants sélectionnés parmi alkyle C1-C4, méthoxyle, halogène, carboxyle, carbamyle et carbonitryle éventuellement substitué.
PCT/RU2015/000856 2015-02-13 2015-12-08 Inhibiteurs de réplication du virus de l'hépatite b à base de benzo[1,2,4]thiadiazine et compositions pharmaceutiques pour traiter l'hépatite b Ceased WO2016130043A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2015104887 2015-02-13
RU2015104887/04A RU2574397C1 (ru) 2015-02-13 Бензо[1,2,4]тиадиазиновые ингибиторы репликации вируса гепатита в и фармацевтическая композиция для лечения гепатита в

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WO2016130043A1 true WO2016130043A1 (fr) 2016-08-18

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PCT/RU2015/000856 Ceased WO2016130043A1 (fr) 2015-02-13 2015-12-08 Inhibiteurs de réplication du virus de l'hépatite b à base de benzo[1,2,4]thiadiazine et compositions pharmaceutiques pour traiter l'hépatite b

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107417641A (zh) * 2017-08-17 2017-12-01 山东大学 苯并噻二嗪类衍生物及其制备方法与应用
RU2662161C1 (ru) * 2017-08-11 2018-07-24 Васильевич Иващенко Александр Ингибитор входа вируса гепатита и фармацевтическая композиция для лечения гепатита

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008124450A1 (fr) * 2007-04-03 2008-10-16 Anadys Pharmaceuticals, Inc. Composés de 5,6-dihydro-1h-pyridine-2-un
WO2012064667A2 (fr) * 2010-11-08 2012-05-18 Omeros Corporation Traitement d'addiction et de troubles de contrôle des impulsions au moyen d'inhibiteurs de la pde7
WO2014006402A1 (fr) * 2012-07-03 2014-01-09 Heptares Therapeutics Limited Antagonistes du récepteur de l'orexine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008124450A1 (fr) * 2007-04-03 2008-10-16 Anadys Pharmaceuticals, Inc. Composés de 5,6-dihydro-1h-pyridine-2-un
WO2012064667A2 (fr) * 2010-11-08 2012-05-18 Omeros Corporation Traitement d'addiction et de troubles de contrôle des impulsions au moyen d'inhibiteurs de la pde7
WO2014006402A1 (fr) * 2012-07-03 2014-01-09 Heptares Therapeutics Limited Antagonistes du récepteur de l'orexine

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DATABASE CAS [O] retrieved from STN Database accession no. 121 :86193 *
DATABASE REGISTRY [O] Database accession no. RN483362-17-0 *
DATABASE Registry [O] retrieved from STN Database accession no. RN483362-16-9P *
MAKINO SHINGO ET AL.: "Efficient Synthesis of 2, 4- Disubstituted 1, 2, 4 -Benzothiadiazin-3-one 1, 1-Dioxides on Solid Support.", JOURNAL OF COMBINATORIAL CHEMISTRY, vol. 5, no. 1, 2003, pages 73 - 78 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2662161C1 (ru) * 2017-08-11 2018-07-24 Васильевич Иващенко Александр Ингибитор входа вируса гепатита и фармацевтическая композиция для лечения гепатита
CN107417641A (zh) * 2017-08-17 2017-12-01 山东大学 苯并噻二嗪类衍生物及其制备方法与应用

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