WO2000012482A2 - Composes chimiques iii - Google Patents

Composes chimiques iii Download PDF

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Publication number
WO2000012482A2
WO2000012482A2 PCT/GB1999/002883 GB9902883W WO0012482A2 WO 2000012482 A2 WO2000012482 A2 WO 2000012482A2 GB 9902883 W GB9902883 W GB 9902883W WO 0012482 A2 WO0012482 A2 WO 0012482A2
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Prior art keywords
disorders
hydrogen
formula
compound
alkyl
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PCT/GB1999/002883
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English (en)
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WO2000012482A3 (fr
Inventor
David Reginald Adams
Jonathan Richard Anthony Roffey
Claire Elizabeth Dawson
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Vernalis Research Limited
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Publication date
Application filed by Vernalis Research Limited filed Critical Vernalis Research Limited
Priority to AU56374/99A priority Critical patent/AU5637499A/en
Publication of WO2000012482A2 publication Critical patent/WO2000012482A2/fr
Publication of WO2000012482A3 publication Critical patent/WO2000012482A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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

Definitions

  • the present invention relates to indazole derivatives, to processes and intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use.
  • the active compounds of the present invention are useful in treating obesity and other disorders.
  • BMI body mass index
  • m 2 body weight index
  • Overweight is defined as a BMI in the range 25-30 kg/m
  • obesity is a BMI greater than 30 kg/m 2 .
  • body fat content is also be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively.
  • Compounds marketed as anti-obesity agents include Orlistat (Reductil ® ) and
  • Sibutramine a lipase inhibitor
  • Orlistat a lipase inhibitor
  • Sibutramine a mixed 5-HT/noradrenaline reuptake inhibitor
  • the serotonin releaser/reuptake inhibitors fenfluramine (Pondimin ® ) and dexfenfluramine (ReduxTM) have been reported to decrease food intake and body weight over a prolonged period (greater than 6 months). However, both products were withdrawn after reports of preliminary evidence of heart valve abnormalities associated with their use. There is therefore a need for the development of a safer anti-obesity agent.
  • mCPP m- chlorophenylpiperazine
  • TFMPP trifluoromethylphenylpiperazine
  • CA-2132887 and CA-2153937 disclose that tricyclic 1 -aminoethylpyrrole derivatives and tricyclic 1-aminoethyl pyrazole derivatives bind to 5-HT 2 c receptors and may be used in the treatment of obesity.
  • WO-A-98/30548 discloses aminoalkylindazole compounds as 5-HT 2 c agonists for the treatment of CNS diseases and appetite regulation disorders.
  • EP-A-0494774 discloses 5-[(oxadiazolyl)alkyl]- and 5- [(thiadiazolyl)alkyl]-lH-indazole-3-ethanamines and their use as 5-HT ⁇ receptor agonists (selective vasoconstrictors).
  • the synthesis and radioprotective activity of ⁇ -(3- indazolyl)ethylamine derivatives have been disclosed by E. Rao et al. Yaoxue Xuebao, 1987, 22(6), 426).
  • JP-A-08/ 165276 discloses 2-[2-(indazol-3-yl)-ethyl]amino-l- phenylethanol derivatives as ⁇ 3 receptor ligands.
  • Ri and R are independently selected from hydrogen and alkyl; R 3 is alkyl;
  • R 7 are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, amino, monoalkylamino, dialkylamino, alkoxy, aryloxy, alkylthio, arylthio, arylsulfoxyl, arysulfonyl, alkylsulfoxyl, alkylsulfonyl, nitro, cyano, carboxaldehyde, alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino and dialkylaminocarbonylamino, wherein at least one of R 4 to R is a substituent group other than hydrogen; and R 8 is selected from hydrogen and alkyl, and pharmaceutically acceptable salts and prodrugs thereof,
  • alkyl means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical.
  • the alkyl group is preferably C 3 to C ⁇ 2 , more preferably C 5 to C 10 , more preferably C 5 , C 6 or C 7 .
  • the alkyl group is preferably Ci to C 10 , more preferably Ci to C 6 , more preferably methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary butyl), more preferably methyl.
  • lower alkyl means methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary butyl).
  • aryl means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more, preferably one, heteratom, such as pyridyl, pyrrolyl, furanyl and thienyl.
  • alkyl and aryl groups may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent.
  • Substituents may include: carbon-containing groups such as alkyl, aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloalkyl (e.g. trifluoromethyl); oxygen-containing groups such as alcohols (e.g. hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl), ethers (e.g.
  • alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl
  • aldehydes e.g. carboxaldehyde
  • ketones e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl
  • acids e.g. carboxy, carboxyalkyl
  • acid derivatives such as esters
  • alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl
  • amides e.g. aminocarbonyl, mono- or di- alkylaminocarbonyl, aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl, arylaminocarbonyl
  • carbamates e.g. alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, arylaminocarbonyloxy
  • ureas e.g.
  • amines e.g. amino, mono- or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl
  • azides e.g. cyano, cyanoalkyl
  • sulfur-containing groups such as thiols, thioethers, sulfoxides and sulfones
  • alkoxy means alkyl-O- and "alkoyl” means alkyl- CO-.
  • Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by one or more alkyl groups.
  • halogen means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical.
  • prodrug means any pharmaceutically acceptable prodrug of the compound of formula (I).
  • salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydro
  • Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
  • Ri and R are independently selected from hydrogen and lower alkyl.
  • the compounds of formula (I) are selected from compounds in which Ri is the same as R .
  • Ri and R 2 are both hydrogen.
  • Ri is hydrogen and R 2 is alkyl, preferably lower alkyl, preferably methyl.
  • the compounds of formula (I) are selected from compounds in which R 3 is selected from alkyl other than ethyl. Most preferably R 3 is methyl.
  • the carbon atom to which R 3 is attached is an asymmetric carbon atom. It is preferred that this asymmetric carbon atom is in the (S)-configuration, wherein the stereochemical assignment is defined with respect to a compound wherein R 3 is an unsubstituted alkyl group.
  • R 7 are independently selected from hydrogen, halogen, hydroxy, alkyl
  • R 4 to R 7 is a substituent group other than hydrogen.
  • R» to R 7 are independently selected from hydrogen, halogen, hydroxy, alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl) and arylalkyl), aryl, alkoxy (including arylalkoxy), aryloxy, alkylthio, alkylsulfoxyl and alkylsulfonyl, wherein at least one of R 4 to R is a substituent group other than hydrogen.
  • the compounds of formula (I) are selected from compounds in which two or three of Rj, R 5 , R 6 and R 7 are hydrogen.
  • R Preferably, one or both of R» and R are hydrogen.
  • R 5 and R preferably at least R 5 , is selected from alkyl (preferably lower alkyl and preferably trifluoromethyl), alkoxy (preferably lower alkoxy and more preferably methoxy), halogen and alkylthio (preferably lower alkylthio).
  • Re is selected from hydrogen and halogen, and preferably from hydrogen and fluoro.
  • R 5 is selected from alkyl (preferably lower alkyl and preferably trifluoromethyl), alkoxy (preferably lower alkoxy and more preferably methoxy), halogen (preferably chloro and bromo) and alkylthio (preferably lower alkylthio).
  • Rs is selected from alkyl
  • R is selected from lower alkyl, preferably methyl.
  • Rs is hydrogen.
  • the compounds of formula (I) are selected from l-(5- chloroindazol-3-yl)-2-propylamine, l-(5-chloro-l-methylindazol-3-yl)-2-propylamine, l-(5-chloro-l-isopropylindazol-3-yl)-2-propylamine, l-(5-methoxyindazol-3-yl)-2- propylamine, l-(5-methoxy-l-methylindazol-3-yl)-2-propylamine and l-(5- bromoindazol-3-yl)-2-propylamine, preferably the (S)-enantiomers thereof.
  • the compounds of formula (I) are in the form of a salt, the fumarate salt is preferred.
  • the compounds of formula (I) are selected from
  • the compounds of formula (I) may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • the compounds can be, for example, racemates or optically active forms.
  • the optically active forms can be obtained by resolution ofthe racemates or by asymmetric synthesis.
  • a compound of formula (I) is in the form of its (S)-enantiomer, substantially free of its (R)-enantiomer.
  • the term "substantially free of its (R)-enantiomer” means that a composition comprising a compound of formula (I) contains a greater proportion of the (S)-enantiomer of the compound of formula (I) in relation to the (R)-enantiomer of the compound of formula (I).
  • the term "substantially free of its (R)-enantiomer”, as used herein, means that the composition contains at least 90 % by weight ofthe (S)-enantiomer and 10 % by weight or less of the (R)-enantiomer. In a further preferred embodiment, the term “substantially free of its (R)-enantiomer” means that the composition contains at least 99 % by weight of the (S)-enantiomer and 1 % or less of the (R)-enantiomer. In another preferred embodiment, the term “substantially free of its (R)-enantiomer” means that the composition contains 100 % by weight ofthe (S)-enantiomer. The above percentages are based on the total amount of a compound of formula (I) present in the composition.
  • a novel compound of formula ( ⁇ ),per se there is provided a novel compound of formula ( ⁇ ),per se.
  • a compound of formula (I), per se wherein at least one of R 4 to R 8; preferably at least one of R 5 and R ⁇ , is a substituent other than alkyl, preferably other than methyl.
  • a compound of formula (I), per se wherein at least one of R 4 to R , preferably at least one of R 5 and R ⁇ is a substituent other than halogen, preferably other than chloro, or a substituent other than alkoxy, preferably other than methoxy.
  • Ri to R 7 are selected from hydrogen, fluorine, bromine, hydroxy, aryl, amino, monoalkylamino, dialkylamino, aryloxy, alkylthio, arylthio arylsulfoxyl, arylsulfonyl, alkylsulfoxyl, alkylsulfonyl, nitro, cyano, carboxaldehyde, alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino and dialkylaminocarbonylamino, wherein at least one of R 4 to R 7 is a substituent other than hydrogen.
  • R to R 7 are selected from hydrogen, hydroxy, aryl, amino, monoalkylamino, dialkylamino, aryloxy, alkylthio, arylthio, arylsulfoxyl, arylsulfonyl, alkylsulfoxyl, alkylsulfonyl, nitro, cyano, carboxaldehyde, alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino and dialkylaminocarbonylamino, wherein at least one of R 4 to R is a substituent other than hydrogen.
  • the compounds of formula (I) may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT 2 receptor function.
  • the compounds may act as receptor agonists or antagonists.
  • the compounds may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT 2B and/or 5-HT 2 c receptor function.
  • the compounds may be used in the treatment (including prophylactic treatment) of disorders where a 5-HT 2 c receptor agonist is required.
  • the compounds of formula (I) may be used in the treatment or prevention of central nervous disorders such as depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioural disorders, behavioural disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, anorexia nervosa or premenstrual tension; damage of the central nervous system such as by trauma, stroke, neurodegenerative diseases or toxic or infective CNS diseases such as encephalitis or meningitis; cardiovascular disorders such as thrombosis; gastrointestinal disorders such as dysfunction of gastrointestinal motility; diabetes insipidus; and sleep apnea.
  • central nervous disorders such as depression, atypical depression, bipolar disorders,
  • a method of treatment (including prophylaxis) of a disorder selected from the group consisting ofthe above-mentioned disorders comprising administering to a patient in need of such treatment an effective dose of a compound of formula (I).
  • a method of treatment (including prophylaxis) of obesity comprising administering to a patient in need of such treatment an effective dose of a compound of formula (I).
  • a pharmaceutical composition comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of formula (I) with a pharmaceutically acceptable carrier or excipient.
  • the indazole-3 -carboxaldehyde (III) may be prepared by reaction of indole (II) with acidic aqueous sodium nitrite solution.
  • the 1- (indazol-3-yl)-2-nitropropene (V) can be formed in a two step procedure from the aldehyde (III) by reaction with a nitro alkane in the presence of ammonium acetate, followed by protection at nitrogen.
  • a reducing agent such as sodium triacetoxyborohydride, formic acid or sodium cyanoborohydride.
  • the substituent group R t , R 5 , Re, R 7 or R 8 may be converted to the desired substituent by known methods.
  • the substituents R ⁇ R 5 , R , R or R 8 may also need protecting against the conditions under which the reaction is carried out. In such a case, the protecting group may be removed after the reaction has been completed.
  • a compound of formula (I) in the form of a free base or as an acid addition salt. If the compound ofthe invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from basic compounds.
  • compositions comprising a compound of formula (I) may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of formula (I) may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) transdermal or rectal administration or in a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylrnethylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulfate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylrnethylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium star
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p- hydroxybenzoates or sorbic acid).
  • suspending agents e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g. lecithin or acacia
  • non-aqueous vehicles e.g. almond oil, oily esters or ethyl alcohol
  • preservatives e.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the active compounds of formula (I) may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile pyrogen-free water
  • the active compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compounds of formula (I) are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound ofthe invention and a suitable powder base such as lactose or starch.
  • a proposed dose of the active compounds of formula (I) for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is 0.1 to 500 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • FLIPR Fmorimetric Imaging Plate reader
  • the reaction mixture was filtered through a pad of kieselguhr and the filtrate was concentrated in vacuo to yield a yellow- brown oil.
  • the oil (0.058 g, 0.28 mmol) was dissolved in ether (5 mL) and fumaric acid (0.033 g, 0.28 mmol) in 2-propanol (5 mL) was added.
  • a precipitate formed which was dissolved in 2-propanol at 50 °C
  • the solution was cooled to 0 °C and filtered.
  • the aqueous phase was basified to pH 10, extracted with dichloromethane (2 x 25 mL), washed with saturated brine (25 mL), dried (magnesium sulfate) and concentrated in vacuo.
  • the concentrate was dissolved in ether (5 mL) and a solution of fumaric acid (0.041 g, 0.35 mmol) in 2- propanol (5 mL) was added. A precipitate formed which was dissolved in 2-propanol at 50 °C The solution was cooled to 0 °C and filtered.

Abstract

L'invention concerne un composé de la formule (I) destiné à s'utiliser pour un traitement. Dans la formule selon l'invention, R1 et R2 sont indépendamment sélectionnés dans le groupe formé par hydrogène et alkyle; R3 représente un alkyle; R4 à R7 sont indépendamment sélectionnés dans le groupe formé par hydrogène, halogène, hydroxy, alkyle, aryle, amino, monoalkylamino, dialkylamino, alcoxy, aryloxy, alkylthio, arylthio, arylsulfoxyle, arylsulfonyle, alkylsulfoxyle, alkylsulfonyle, nitro, cyano, carboxaldéhyde, alkylcarbonyle, arylcarbonyle, aminocarbonyle, monoalkylaminocarbonyle, dialkylaminocarbonyle, alcoxycarbonylamino, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino et dialkylaminocarbonylamino, au moins un des éléments de R4 à R7 représentant un substituant autre que l'hydrogène; et R8 est sélectionné dans le groupe formé par hydrogène et alkyle. L'invention concerne également des sels et promédicaments de ce composé acceptables du point de vue pharmaceutique, autres que les composés dans lesquels R1 représente un hydrogène et R2 représente -H2CH(OH)-Ar; et autres que les composés dans lesquels R2 représente H et R1 représente -H2CH(OH)-Ar, Ar désignant 3-halophényle ou 3-trifluorométhylphényle. L'invention concerne en outre l'utilisation de ces composés pour une thérapie, notamment pour le traitement de troubles du système nerveux central; de lésions du système nerveux central; de troubles cardiovasculaires; de troubles gastro-intestinaux; du diabète insipide et de l'apnée du sommeil et particulièrement pour le traitement de l'obésité. L'invention concerne enfin de nouveaux composés chimiques de la formule (I).
PCT/GB1999/002883 1998-09-01 1999-09-01 Composes chimiques iii WO2000012482A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56374/99A AU5637499A (en) 1998-09-01 1999-09-01 Chemical compounds iii

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GBGB9819020.0A GB9819020D0 (en) 1998-09-01 1998-09-01 Chemical compounds III
GB9819020.0 1998-09-01

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WO2001070701A1 (fr) * 2000-03-17 2001-09-27 Alcon, Inc. Derives d'indazole 5-hydroxy permettant de traiter le glaucome
WO2002040457A1 (fr) 2000-11-20 2002-05-23 Biovitrum Ab Composes de piperazinylpyrazines utilises comme antagonistes du recepteur de la serotonine 5-ht2
US6465467B1 (en) 1999-05-21 2002-10-15 Biovitrum Ab Certain aryl-aliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases
US6593330B2 (en) 2000-11-20 2003-07-15 Biovitrum Compounds and their use
WO2004000830A1 (fr) 2002-06-19 2003-12-31 Biovitrum Ab Nouveaux composes, leur utilisation et leur preparation
US6780862B2 (en) 2000-12-20 2004-08-24 Bristol-Myers Squibb Pharma Company Aryl and aminoaryl substituted serotonin receptor agonist and antagonist ligands
US7005443B1 (en) 2000-03-17 2006-02-28 Alcon, Inc. 5-Hydroxy indazole derivatives for treating glaucoma
US7208494B2 (en) 2003-06-26 2007-04-24 Hoffmann-La Roche Inc. 5HT2c receptor agonists
EP1799640A2 (fr) * 2004-09-27 2007-06-27 Organix, Inc. Composes indole convenant comme agents selectifs par rapport a la serotonine
WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
US7507732B2 (en) 2005-03-31 2009-03-24 Pfizer Inc. Cyclopentapyridine and tetrahydroquinoline derivatives
WO2009063992A1 (fr) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
EP2108649A1 (fr) 2008-04-10 2009-10-14 Korea Research Institute of Chemical Technology Nouveaux dérivés de bispyridyl carboxamide de l'acide carboxylique de l'indole comme antagonistes du récepteur 5-HT2c
EP2248524A2 (fr) 2004-08-25 2010-11-10 Takeda Pharmaceutical Company Limited Agents préventifs/remèdes pour l'incontinence de stress et procédé de séléction de ceux-ci
EP2277513A2 (fr) 2003-04-25 2011-01-26 Pfizer Inc. Traitement de l'incontinence avec des 5ht2c agonistes
WO2011071136A1 (fr) 2009-12-11 2011-06-16 アステラス製薬株式会社 Agent thérapeutique pour la fibromyalgie
WO2015066344A1 (fr) 2013-11-01 2015-05-07 Arena Pharmaceuticals, Inc. Agonistes du récepteur 5-ht2c et compositions et procédés d'utilisation
WO2019131902A1 (fr) 2017-12-27 2019-07-04 武田薬品工業株式会社 Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale

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US7655691B2 (en) 2004-09-27 2010-02-02 Sard Howard P Indole compounds useful as serotonin selective agents
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