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WO2002020521A1 - Utilisation de derives indoliques pour traiter des troubles du systeme nerveux central - Google Patents

Utilisation de derives indoliques pour traiter des troubles du systeme nerveux central Download PDF

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Publication number
WO2002020521A1
WO2002020521A1 PCT/EP2001/010443 EP0110443W WO0220521A1 WO 2002020521 A1 WO2002020521 A1 WO 2002020521A1 EP 0110443 W EP0110443 W EP 0110443W WO 0220521 A1 WO0220521 A1 WO 0220521A1
Authority
WO
WIPO (PCT)
Prior art keywords
quinuclidine
indolyl
groups
alkyl
carbamoyl
Prior art date
Application number
PCT/EP2001/010443
Other languages
German (de)
English (en)
Inventor
Günter Hölzemann
Kai Schiemann
Henning Böttcher
Joachim Leibrock
Original Assignee
Merck Patent Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to AU2002212226A priority Critical patent/AU2002212226A1/en
Publication of WO2002020521A1 publication Critical patent/WO2002020521A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to substances which are used for the treatment of diseases in which stimulation of the nicotinic acetylcholine receptors leads to an improvement in the clinical picture.
  • the substances used according to the invention contain an optionally substituted 3-indolyl group which is linked to quinuclidinyl or dehydroquinuclidinyl units.
  • Some members of the well-characterized class of acetylcholine receptors are held responsible for certain clinical pictures of the central nervous system.
  • Known active ingredients that can interact with the class of acetylcholine receptors are, for example, pilocarpine, nicotine, lobeline and epibatidine.
  • the object of the present invention is to provide compounds with which these clinical pictures can be treated. This object is achieved by using substances of the general formula (I)
  • R 1 to R 5 are independently selected from the group consisting of hydrogen, branched and unbranched C 1 -C 4 alkyl groups, branched and unbranched dC alkoxy groups, branched and unbranched C 1 -C 4 alkoxy groups, trifluoromethyl groups, C 6 -C ⁇ o Aryloxy groups, C 7 -Cn aralkyloxy groups, CrC 5 acyloxy groups, C 6 -C 10 aroyloxy groups, CrC 4 alkylsulfonyloxy groups, C 6 -C 10 arylsulfonyloxy groups, linear and branched dC alkoxycarbonyl groups, amino, mono (CrC 5 alkyl) amino and di (C 1 -C 5 alkyl) amino groups, carbamoyl, N-mono (CrC 5 -alkyl) carbamoyl and N- di (CrC 5 -alkyl) carbamoyl group, methylenedioxy
  • R is selected from the group consisting of hydrogen and linear and branched alkyl groups, and (Chin.) Means a 3-quinuclidinyl or a 2,3-dehydro-3-quinuclidinyl group for the manufacture of a medicament for diseases in which an excitation of the nicotinic acetylcholine receptors leads to improvement of the clinical picture.
  • the substances to be used according to the invention are known. They are disclosed in the applicant's EP-B-450345 and are used according to this invention for the treatment of diseases which are characterized by an excess of circulating serotonin or by a serotonergic hyperfunction. These include in particular psychoses, nausea and vomiting (which occur, for example, in the chemo- or radiotherapeutic treatment of cancer), dementia or other cognitive disorders, migraines and addictions. Furthermore, the use as an anxiolytic, antiaggressive, antidepressant and analgesic also belongs to the indications according to this invention.
  • the compounds antagonize the action of serotonin at 5-HT 3 receptors, such as, for example, the von Bezold-Jarisch reflex caused by serotonin (methodology see J.Pharm. Pharmacol. 40 (1988), 301-302 and Nature 316 ( 1985), 126-131).
  • these compounds displace the substance 3 H-GR65630 known as selective 5-HT 3 ligand from homogenized tissue from the endorhinal cortex of the rat (see European J. Pharmacol. 159 (1989), 157-164).
  • the substances of the formula (I) can, in addition to the indication disclosed in EP-B-450 375, also be used specifically for the treatment of diseases in which stimulation of the nicotinic acetylcholine receptors to improve the Disease picture leads.
  • diseases in which stimulation of the nicotinic acetylcholine receptors to improve the Disease picture leads.
  • Examples are known to the person skilled in the art and include schizophrenia, dementia, and in particular Alzheimer's disease, neurodegenerative diseases, Parkinson's disease and Tourette's syndrome.
  • R is preferably hydrogen. It is then preferred if all of the groups R 1 to R 5 in the substances of the formula (I) are hydrogen. In a further embodiment, it is preferred if in the substances of the formula (I) one or two groups R 1 to R 5 have a meaning other than hydrogen, these groups then preferably being in 5, 6 and / or 7-position of the indyl group. In a further embodiment of the invention, preference is also given to substances of the formula (I) in which R is an alkyl group; here too, the radicals R 1 to R 5 preferably have the meaning which was defined above as the preferred embodiment.
  • Preferred radicals R 1 to R 5 are selected from the group consisting of hydrogen, methyl, hydroxy, methoxy, formyloxy, acetyloxy, propanoyloxy, and butanoyloxy, i-butanoyloxy and pivaloyloxy, methanesulfonyloxy, phenoxy, benzyloxy, benzoyloxy, methylenedioxy , Hydroxymethyl, amino and carbamoyl.
  • the compounds of formula (I) is generally carried out according to known methods such as, 3 rd edition in the literature (eg J. March, Advanced Organic Chemistry, John Wiley & Sons, New York or Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions as they are known and suitable for the reactions mentioned. You can also fall back on variants which are known per se and are not mentioned in more detail below.
  • the compounds of the formula (I) which contain a 3-quinuclidinyl radical have at least one asymmetric carbon atom. They can therefore be present in various optically active forms or as a racemate or racemate mixture.
  • a base of the formula (I) can be converted into the associated acid addition salt using an acid.
  • Acids which provide physiologically acceptable salts are preferably suitable for this reaction.
  • inorganic acids can be used, for example sulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulphuric acid. famincicre.
  • organic acids for example aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid .
  • Acid addition salts which are not physiologically safe (picrates) can be suitable for the isolation and purification of the bases of the formula (I).
  • a base of the formula (I) can also be liberated from one of its salts with strong bases such as sodium or potassium hydroxide, sodium or potassium carbonate.
  • the compounds (I) set out above are used for the production of medicaments which are used for the treatment of diseases which are based on a dysfunction of nicotinic acetylcholine receptors.
  • nicotinic acetylcholine receptors can be divided into two principal classes, depending on the locations where they occur.
  • neuromuscular receptors there are the neuromuscular receptors. These are further divided into ( ⁇ i ⁇ iß ⁇ ) and (o. ⁇ ß ⁇ ) receptors.
  • neuronal nicotinic acetylcholine receptors that are found in the ganglia.
  • ( ⁇ 2- ⁇ ) receptors and the (0: 2 -0: 9) receptors, see also “Basic Neurochemistry”, Ed. Siegel et. Al., Raven Press, New York 1993.
  • the substances of the formula (I) are able to interact with each of these receptors more or less well, for example depending on the structure of the molecule used in each case.
  • Receptor can, for example, be analogous to JM Ward et al., FEBS 1990, 270, 45-48 or DRE Macallan, FEB 1998, 226, 357-363.
  • Diseases that can be treated with the substances according to formula (I) include schizophrenia, dementia, in particular Alzheimer's disease, neurodegenerative diseases, Parkinson's disease, Tourette's syndrome, age-related memory loss, relief of withdrawal symptoms, and also due to the neuroprotective effect Stroke and brain damage from toxic compounds.
  • Another object of the present invention are pharmaceutical preparations containing one or more compounds corresponding to formula (I) and / or their physiologically active salts.
  • these can be brought into a suitable dosage form together with at least one carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
  • Suitable carrier substances are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds. Examples include water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly.
  • Tablets, coated tablets, capsules, syrups, juices, drops or suppositories are used in particular for enteral administration, and solutions, preferably for parenteral administration oily or aqueous solutions, also suspensions, emulsions or implants, for topical applications, ointments, creams, plasters or powders.
  • the new compounds can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavors and / or flavorings. If appropriate, they can also contain one or more further active ingredients which do not correspond to the formula (I), for example one or more vitamins.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavors and / or flavorings.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavors and / or flavorings.
  • they can also contain one or more further active ingredients which do not correspond to the formula (I), for
  • the substances according to the invention are generally administered in analogy to known, commercially available preparations (for example tacrin), preferably in doses between about 5 mg and 100 mg, in particular between 10 and 40 mg per dosage unit.
  • the daily dosage is preferably between about 0.5 and 1 mg / kg body weight.
  • the specific dose for each individual patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and Severity of the respective disease to which the therapy applies.
  • Preferred substances are:
  • Example B coated tablets Analogously to Example A, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • a solution of 1 kg of 3- (5-hydroxy-3-indolyl) -quinuclidine hydrochloride in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.
  • Tablets dragees, capsules and ampoules which contain another compound of the formula I and / or one or more physiologically acceptable acid addition salts of a compound of the formula (I) are obtainable analogously.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne l'utilisation de composés, de formule générale (I), ou de sels physiologiquement tolérables de ces composés pour préparer un médicament destiné à traiter des troubles pour lesquels une stimulation des récepteurs nicotiniques à l'acétylcholine conduit à une amélioration du tableau clinique. Dans ladite formule (I), R1 à R5 sont sélectionnés indépendamment dans le groupe constitué par hydrogène, des groupes alkyle C¿1?-C4 ramifiés ou non, des groupes alcoxy C1-C4 ramifiés ou non, des groupes alkythio C1-C4 ramifiés ou non, des groupes trifluorométhyle, des groupes aryloxy C6-C10, des groupes aralkyloxy C7-C11, des groupes acyloxy C1-C5, des groupes aroyloxy C6-C10, des groupes alkylsulfonyloxy C1-C4, des groupes arylsulfonyloxy C6-C10, des groupes alcoxycarbonyle C1-C4 linéaires et ramifiés, des groupes amino, mono(C1-C5-alkyl)amino et di(C1-C5-alkyl)amino, des groupes carbamoyle, N-mono(C1-C5-alkyl)carbamoyle et N-di(C1-C5-alkyl)carbamoyle, des groupes méthylènedioxy, des groupes hydroxy, des groupes hydroxyméthyle, ainsi que fluor et chlore ; R est sélectionné dans le groupe constitué par hydrogène et des groupes alkyle linéaires et ramifiés et (Chin) représente un groupe 3-quinuclidinyle ou 2,3-déshydro-3-quinuclidinyle.
PCT/EP2001/010443 2000-09-11 2001-09-10 Utilisation de derives indoliques pour traiter des troubles du systeme nerveux central WO2002020521A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002212226A AU2002212226A1 (en) 2000-09-11 2001-09-10 Use of indole derivatives for treating illnesses of the central nervous system

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10045112.8 2000-09-11
DE10045112A DE10045112A1 (de) 2000-09-11 2000-09-11 Verwendung von Indolderivaten zur Behandlung von Erkrankungen des zentralen Nervensystems

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WO2002020521A1 true WO2002020521A1 (fr) 2002-03-14

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DE (1) DE10045112A1 (fr)
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Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003101987A1 (fr) * 2002-05-30 2003-12-11 Neurosearch A/S Quinuclidines 3-substitutees et leur utilisation
WO2005100351A1 (fr) * 2004-04-14 2005-10-27 Astrazeneca Ab Nouveaux ligands de derives 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydro-isoindol-l-one/5,6-dihydro-furo[2,3-c]pyrrol-4one pour le recepteur nicotinique de l'acetylcholine alpha 7
US7001914B2 (en) 2000-02-18 2006-02-21 Astrazeneca Ab Compounds
US7750022B2 (en) 2003-08-13 2010-07-06 Neurosearch A/S Quinuclidine derivatives and their pharmaceutical use
WO2012131539A1 (fr) 2011-03-31 2012-10-04 Pfizer Inc. Nouvelles pyridones bicycliques
WO2012172449A1 (fr) 2011-06-13 2012-12-20 Pfizer Inc. Lactames convenant comme inhibiteurs des bêta-sécrétases
WO2013030713A1 (fr) 2011-08-31 2013-03-07 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazine-2-amines
WO2014045156A1 (fr) 2012-09-21 2014-03-27 Pfizer Inc. Nouvelles pyridinones bicycliques
US8697722B2 (en) 2007-11-02 2014-04-15 Sri International Nicotinic acetylcholine receptor modulators
WO2014128585A1 (fr) 2013-02-19 2014-08-28 Pfizer Inc. Composés d'azabenzimidazole en tant qu'inhibiteurs d'isozymes pde4 pour le traitement de troubles du snc et d'autres affections
US8822456B2 (en) 2012-12-11 2014-09-02 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US8865706B2 (en) 2013-02-13 2014-10-21 Pfizer Inc. Heteroaryl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US8962616B2 (en) 2012-05-04 2015-02-24 Pfizer Inc. Heterocyclic substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
WO2015049616A1 (fr) 2013-10-04 2015-04-09 Pfizer Inc. Nouvelles pyridinones bicycliques utilisées comme modulateurs de gamma-sécrétase
US9062042B2 (en) 2010-01-11 2015-06-23 Astraea Therapeutics, Llc Nicotinic acetylcholine receptor modulators
WO2015150957A1 (fr) 2014-04-01 2015-10-08 Pfizer Inc. Chromène et 1,1a,2,7b-tétrahydrocyclopropa[c]chromène pyridopyrazinediones comme modulateurs de gamma-sécrétase
US9233981B1 (en) 2013-02-15 2016-01-12 Pfizer Inc. Substituted phenyl hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
WO2016012896A1 (fr) 2014-07-24 2016-01-28 Pfizer Inc. Composés de pyrazolopyrimidine
WO2016020786A1 (fr) 2014-08-06 2016-02-11 Pfizer Inc. Composés d'imidazopyridazine
US9260455B2 (en) 2012-09-20 2016-02-16 Pfizer Inc. Alkyl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9315520B2 (en) 2014-04-10 2016-04-19 Pfizer Inc. 2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
US9403846B2 (en) 2012-12-19 2016-08-02 Pfizer Inc. Carbocyclic- and heterocyclic-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
WO2016125048A1 (fr) 2015-02-03 2016-08-11 Pfizer Inc. Nouveaux pyridopyrazinediones cyclopropabenzofuranyl
WO2016203347A1 (fr) 2015-06-17 2016-12-22 Pfizer Inc. Composés tricycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase
US9611264B1 (en) 2015-09-24 2017-04-04 Pfizer Inc. N-[2-(3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl)-1,3-thiazol-4-yl] amides
WO2017145013A1 (fr) 2016-02-23 2017-08-31 Pfizer Inc. Composés 6,7-dihydro-5 h-pyrazolo [5,1-b] [1,3]oxazine-2-carboxamide
US9751895B2 (en) 2015-09-24 2017-09-05 Pfizer Inc. N-[2-(2-amino-6,6-disubstituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl)-1,3-thiazol-4-yl]amides
US9771379B2 (en) 2015-09-24 2017-09-26 Pfizer Inc. N-(2-(2-amino-6-substituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]OXAZIN-8a(8H)-yl)-thiazol-4-yl) amides
WO2018002760A1 (fr) 2016-07-01 2018-01-04 Pfizer Inc. Dérivés de 5,7-dihydro-pyrrolo-pyridine pour le traitement de maladies neurologiques et neurodégénératives
WO2018234953A1 (fr) 2017-06-22 2018-12-27 Pfizer Inc. Dérivés de dihydro-pyrrolo-pyridine
WO2019183636A1 (fr) 2018-03-23 2019-09-26 Pfizer Inc. Dérivés azaspiro de pipérazine
WO2024118524A1 (fr) 2022-11-28 2024-06-06 Cerevel Therapeutics, Llc Composés d'azaindole et leur utilisation en tant qu'inhibiteurs de phosphodiestérase
US12144815B2 (en) 2021-02-23 2024-11-19 Hoth Therapeutics, Inc. Use of aprepitant for treating Alzheimer's disease

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Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7214688B2 (en) 2000-02-18 2007-05-08 Astrazeneca Ab Compounds
US7491734B2 (en) 2000-02-18 2009-02-17 Astrazeneca Ab 2-(pyridine-4-yl)-N-(quinuclidin-2-yl)thiazole-4-carboxide nicotinic acetylcholine receptor ligands
US7001914B2 (en) 2000-02-18 2006-02-21 Astrazeneca Ab Compounds
WO2003101987A1 (fr) * 2002-05-30 2003-12-11 Neurosearch A/S Quinuclidines 3-substitutees et leur utilisation
US7332507B2 (en) 2002-05-30 2008-02-19 Neurosearch A/S 3-substituted quinuclidines and their use
US7750022B2 (en) 2003-08-13 2010-07-06 Neurosearch A/S Quinuclidine derivatives and their pharmaceutical use
WO2005100351A1 (fr) * 2004-04-14 2005-10-27 Astrazeneca Ab Nouveaux ligands de derives 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydro-isoindol-l-one/5,6-dihydro-furo[2,3-c]pyrrol-4one pour le recepteur nicotinique de l'acetylcholine alpha 7
US7566727B2 (en) 2004-04-14 2009-07-28 Astrazeneca Ab 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydro-isoindole-1-one/5,6-dihydro-furo[2,3-c] pyrrol-4-one derivative ligands for alpha 7 nicotinic acetylcholine receptor
RU2372350C2 (ru) * 2004-04-14 2009-11-10 Астразенека Аб НОВЫЕ ПРОИЗВОДНЫЕ 2-(1-АЗА-БИЦИКЛО[2.2.2]ОКТ-3-ИЛ)-2,3-ДИГИДРОИЗОИНДОЛ-1-ОНА/5,6-ДИГИДРО-ФУРО[2,3-c]ПИРРОЛ-4-ОНА В КАЧЕСТВЕ ЛИГАНДОВ К АЛЬФА 7 НИКОТИНОВОМУ АЦЕТИЛХОЛИНОВОМУ РЕЦЕПТОРУ
US8697722B2 (en) 2007-11-02 2014-04-15 Sri International Nicotinic acetylcholine receptor modulators
US9670198B2 (en) 2010-01-11 2017-06-06 Astraea Therapeutics, Llc Nicotinic acetylcholine receptor modulators
US9062042B2 (en) 2010-01-11 2015-06-23 Astraea Therapeutics, Llc Nicotinic acetylcholine receptor modulators
WO2012131539A1 (fr) 2011-03-31 2012-10-04 Pfizer Inc. Nouvelles pyridones bicycliques
WO2012172449A1 (fr) 2011-06-13 2012-12-20 Pfizer Inc. Lactames convenant comme inhibiteurs des bêta-sécrétases
WO2013030713A1 (fr) 2011-08-31 2013-03-07 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazine-2-amines
US8933221B2 (en) 2011-08-31 2015-01-13 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9550795B2 (en) 2011-08-31 2017-01-24 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US8962616B2 (en) 2012-05-04 2015-02-24 Pfizer Inc. Heterocyclic substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9260455B2 (en) 2012-09-20 2016-02-16 Pfizer Inc. Alkyl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
WO2014045156A1 (fr) 2012-09-21 2014-03-27 Pfizer Inc. Nouvelles pyridinones bicycliques
US9045498B2 (en) 2012-12-11 2015-06-02 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US8822456B2 (en) 2012-12-11 2014-09-02 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9198917B2 (en) 2012-12-11 2015-12-01 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9403846B2 (en) 2012-12-19 2016-08-02 Pfizer Inc. Carbocyclic- and heterocyclic-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US8865706B2 (en) 2013-02-13 2014-10-21 Pfizer Inc. Heteroaryl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9045499B2 (en) 2013-02-13 2015-06-02 Pfizer Inc. Heteroaryl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
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