WO2000017170A2 - Composes chimiques viii - Google Patents

Composes chimiques viii Download PDF

Info

Publication number
WO2000017170A2
WO2000017170A2 PCT/GB1999/003187 GB9903187W WO0017170A2 WO 2000017170 A2 WO2000017170 A2 WO 2000017170A2 GB 9903187 W GB9903187 W GB 9903187W WO 0017170 A2 WO0017170 A2 WO 0017170A2
Authority
WO
WIPO (PCT)
Prior art keywords
disorders
compound
formula
hydrogen
alkyl
Prior art date
Application number
PCT/GB1999/003187
Other languages
English (en)
Other versions
WO2000017170A3 (fr
Inventor
David Reginald Adams
Jonathan Mark Bentley
Jonathan Richard Anthony Roffey
Matthew Alexander James Duncton
Original Assignee
Vernalis Research Limited
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 Vernalis Research Limited filed Critical Vernalis Research Limited
Priority to AU61045/99A priority Critical patent/AU6104599A/en
Publication of WO2000017170A2 publication Critical patent/WO2000017170A2/fr
Publication of WO2000017170A3 publication Critical patent/WO2000017170A3/fr

Links

Classifications

    • 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

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
  • rrf height squared
  • 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).
  • both products were withdrawn after reports of preliminary evidence of heart valve abnormalities associated with their use.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 C agonists for the treatment of CNS diseases and appetite regulation disorders. It is an object of this invention to provide selective, directly acting 5HT receptor ligands for use in therapy and particularly for use as anti-obesity agents.
  • Ri to R 3 are independently selected from hydrogen and alkyl:
  • R 5 is selected from alkylthio. arylthio. alkylsulfoxyl, arylsulfoxyl. alkylsulfonyl and arylsulfonyl; , R ⁇ . and R 7 are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, alkoxy, aryloxy. alkylthio, arylthio, arylsulfoxyl, alkylsulfoxyl, alkylsulfonyl, arylsulfonyl, amino, monoalkylamino. dialkylamino, nitro. cyano.
  • alkylcarbonyl alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl. alkoxycarbonylamino, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino and dialkylaminocarbonylamino, 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
  • the alkyl group is preferably C t to Cio, 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
  • amides e.g. aminocarbonyl. mono- or di- alkylaminocarbonyl. aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl, ary laminocarbony 1
  • carbamates e.g. alkoxycarbonylamino, aryloxvcarbonvlamino. 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. nitriles (e.g. cyano, cyanoalkyl), nitro: sulfur-containing groups such as thiols. thioethers, sulfoxides and sulfones
  • thienyl furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, .
  • 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.
  • acids include acetic, benzenesulfonic. benzoic. camphorsulfonic. citric, ethenesulfonic. dichloroacetic. formic, fumaric. gluconic, glutamic. hippuric, hydrobromic. hydrochloric, isethionic, lactic, maleic. malic, mandelic,
  • oxalic, p-toluenesulfonic and the like Particularly preferred are fumaric, hydrochloric, hydrobromic, phosphoric, succinic. sulfuric and methanesulfonic acids.
  • Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
  • the compounds of formula (I) are selected from compounds in which
  • Ri is the same as R 2 .
  • Ri and R 2 are both hydrogen.
  • Ri is hydrogen and R 2 is alkyl, preferably lower alkyl, preferably methyl.
  • Ri is hydrogen and R 2 is arylalkyl, preferably arylmethyl. Where R 2 is arylalkyl. it is preferred that said aryl substituent is a substituted or unsubstituted phenyl or thienyl group.
  • the compounds of formula (I) are selected from compounds in which R 3 is alkyl, preferably lower alkyl, preferably methyl. Where R 3 is alkyl. 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)-conf ⁇ guration, wherein the stereochemical assignment is defined with respect to a compound wherein R 3 is an unsubstituted alkyl group.
  • R 4 , R ⁇ and R 7 are independently selected from hydrogen, halogen, hydroxy, alkyl (including cvcloalkyl. halo-alkyl (such as trifluoromethyl) and arylalkyl), aryl, alkoxy (including arylalkoxy), aryloxy, alkylthio. arylthio. alkylsulfoxyl. arylsulfoxyl, alkylsulfonyl, arylsulfonyl, amino, monoalkylamino. dialkylamino. nitro, cyano, carboxaldehyde. alkylcarbonyl, arylcarbonyl, aminocarbonyl.
  • monoalkylaminocarbonyl dialkylaminocarbonyl, alkoxycarbonylamino. aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino and dialkylaminocarbonylamino.
  • R ⁇ R réelle and R 7 are independently selected from hydrogen, halogen, hydroxy. alkyl (including cvcloalkyl. halo-alkyl (such as trifluoromethyl) and arylalkyl). aryl, alkoxy (including arylalkoxy), aryloxy, alkylthio. arylthio. alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl and arylsulfonyl.
  • the compounds of formula (I) are selected from compounds in which one or both of R 4 and R7 is/are hydrogen.
  • the compounds of formula (I) are selected from compounds in which R6 is selected from halogen (preferably fluoro and chloro) and hydrogen.
  • the compounds of formula (I) are selected from compounds in which
  • R 5 is selected from alkylthio, arylthio and alkylsulfoxyl, preferably alkylthio and arylthio, preferably alkylthio. and more preferably lower alkylthio.
  • the compounds of formula (I) are selected from l-(6-methylthioindazol-l-yl)-2-propylamine and l-(6-phenylthioindazol-l- yl)-2-propylamine. and particularly the (S)-enantiomers thereof. Where the compounds of formula (I) are in salt form, the fumarate salt is preferred.
  • the compounds of the invention 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 of the racemates or by asymmetric synthesis.
  • a compound of formula (I) is in the form of its (S)-enantiomer, substantially free of its (i?)-enantiomer.
  • the term “substantially free of its (J?)-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 (/?)-enantiomer of the compound of formula (I).
  • the term “substantially free of its (7?)-enantiomer " is substantially free of its (S)-enantiomer, substantially free of its (i?)-enantiomer.
  • the composition contains at least 90 % by weight of the (S)-enantiomer and 10 % by weight or less of the (i?)-enantiomer.
  • the term "substantially free of its (i.)-enantiomer” means that the composition contains at least 99 % by weight of the (S)-enantiomer and 1 % or less of the (i?)-enantiomer.
  • the term "substantially free of its (J?)-enantiomer” means that the composition contains 100 % by weight of the (S)-enantiomer. The above percentages are based on the total amount of a compound of formula (I) present in the composition.
  • the compounds of formula (I) may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT 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
  • 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.
  • 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.
  • a compound of formula (I) in the manufacture of a medicament for the treatment (including prophylaxis) of the above-mentioned disorders.
  • a compound of formula (I) in the manufacture of a medicament for the treatment (including prophylaxis) of obesity.
  • a method of treatment (including prophylaxis) of a disorder selected from the group consisting of the 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 (indazolyl)-alkylethanol (III) may be prepared by reaction of the indazole (II) with an alkylene oxide in the presence of a strong base such as sodium hydride in a solvent such as tetrahydrofuran.
  • the corresponding azido derivative (V) can be formed in a two step procedure from the derivative (III) by formation of the mesylate (IV), obtained by reaction of (III) with methanesulfonyl chloride in the presence of a base such as triethylamine. and subsequent treatment of the mesylate (IV) with sodium azide in a solvent such as dimethyl formamide.
  • ketone (VI) may be obtained via reaction of indazole (II) with a 1 -halo-2-oxoalkane in the presence of a strong base such as potassium hydroxide in a solvent such as methyl sulfoxide. Reduction of the ketone (VI) with a reducing agent such as sodium borohydride or Baker ' s yeast may give the (indazolyl)-alkylethanol (III). Conversion of the (indazolyl)-alkylethanol (III) to compounds of formula (I) may be achieved using methods described in Reaction Scheme 1.
  • the carbamate (VII) may be formed by reaction of the indazole (II) with a 2-carbamylethylsulfonate in the presence of a strong base such as potassium hydroxide in a solvent such as methyl sulfoxide.
  • the substituent group R-i, R 5 , R$ or R 7 may be converted to the desired substituent by known methods.
  • the substituents R 4 , R 5 , R 6 or R 7 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 the invention in the form of a free base or as an acid addition salt. If the compound of the 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 of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral
  • 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 hydroxypropylmethylcellulose): 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 hydroxypropylmethylcellulose
  • 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
  • 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.
  • the active compounds of the invention 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 the invention 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 the invention 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 of the invention and a suitable powder base such as lactose or starch.
  • a proposed dose of the active compounds of the invention 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.
  • the affinity of the compounds for human 5-HT 2B receptors in a CHO cell line was determined according to the procedure of K. Schmuck, C. Ullmer, P. Engels and H. Lubbert, FEBS Lett., 1994, 342, 85-90.
  • the drug (dissolved in 50 ⁇ L of the assay buffer) was added at a rate of 70 ⁇ L/sec to each well of the FLIPR 96 well plate during fluorescence measurements. The measurements were taken at 1 sec intervals and the maximum fluorescent signal was measured (approx 10- 15 sees after drug addition) and compared with the response produced by 10 ⁇ M 5-HT (defined as 100%) to which it was expressed as a percentage response (relative efficacy). Dose response curves were constructed using Graphpad Prism (Graph Software Inc.).
  • the 5-HT 2 c syndrome is a rapid screening method to assess the in vivo efficacy of 5-HT 2 c agonists through their ability to induce three specific behaviours in rats.
  • the animals were dosed with either a positive control (mCPP), test compound or vehicle, either s.c. or p.o..
  • mCPP positive control
  • test compound test compound
  • vehicle either s.c. or p.o.
  • the animals were then observed on an open bench, typically 30, 60 and 180 minutes after treatment and the degree of syndrome assessed on a scale of 0-3 depending on the presence and severity of splayed limbs, hunched posture and retropulsion. the three specific behaviours which constitute the syndrome.
  • Data were analysed using Kruskal-Wallis Analysis of Variance followed with appropriate post-hoc tests. All statistical analysis were conducted using Excel version 7.0 (Microsoft Corp.) and Statistica version 5.0 (Statsoft. Inc.).
  • Examples 1 and 3 indicate that after a dose of 1 mg/kg s.c. the compounds maintain significant pharmacological efficacy for at least 180 minutes.
  • the anorectic drug d-fenfluramine normally serves as a positive control.
  • the route of drug administration, drug volume and injection-test-interval are dependent upon the compounds used.
  • a palatable wet mash made by adding powdered lab chow and water in a ratio of 1 :2 and mixing to a smooth consistency, is presented in 120 mL glass jars for 60 minutes each day. Intake is measured by weighing before and after each session. Care is taken to collect all spillage. Animals are allowed to habituate to the wet mash meal for 10 days. After drug administration, animals are allowed to consume the wet mash. Food consumption is assayed at pre-determined time points (typically 1. 2 and 4 hours after administration).
  • Food intake data are subjected to oneway analysis of variance (ANOVA) with drug as a between-subjects factor.
  • a significant main effect is followed up by the performance of Dunnett's test in order to assess which treatment mean(s) are significantly different from the control mean. All statistical analyses were performed using Statistica Software, Version 5.0 (Statsoft Inc.) and Microsoft Excel 7.0 (Microsoft Corp.).
  • Examples 1 and 3 The thus determined activity of Examples 1 and 3 indicates that the compounds maintain significant hypophagia 4 hours after a dose of 1 mg/kg s.c.
  • 6-Iodo-lH-indazole (15 g, 62 mmol) was added portionwise over 40 min to a stirred suspension of sodium hydride (60%, 2.95 g, 73.8 mmol) in tetrahydrofuran (200 mL) at 0 °C under Ar. The mixture was stirred at 0 °C for a further 1 h then ( ⁇ S)-propylene oxide (21.5 mL. 308 mmol) was added in one portion. The mixture was allowed to warm to room temperature and stirred for 24 h then heated to 50 °C and stirred at this temperature for a further 24 h. Sodium hydride (60%.
  • Methanesulfonyl chloride (0.81 mL. 10 mmol) was added in one portion to a stirred solution of (ftS l-(6-iodoindazol-l-yl)-2-propanol (3.1 g, 10 mmol) and triethylamine (1.43 mL. 10.3 mmol) in dichloromethane (100 mL) at 0 °C under Ar. The mixture was stirred at 0 °C for a further 1 h. concentrated in vacuo and partitioned between water (150 mL) and ethyl acetate (80 mL).
  • 1,3-Propanedithiol (65 ⁇ L. 0.64 mmol) was added to a stirred solution of (RS)- ⁇ -(2- azidopropyl)-6-iodoindazole (2.1 g, 6.4 mmol). triethylamine (1.80 mL, 1.28 mmol) and sodium borohydride (0.39 g, 9.6 mmol) in 2-propanol (60 mL) at room temperature. The mixture was stirred at room temperature for 2 h then a further aliquot of 1,3- propanedithiol (200 ⁇ L, 2 mmol) was added.
  • Triphenylphosphine (0.035 g, 0.13 mmol) was added in one portion to a stirred solution of palladium (II) acetate (0.008 mg, 0.04 mmol) in tetrahydrofuran (3 mL) at room temperature under Ar. The mixture was stirred for 15 min then a solution of (RS)-2-(6- iodo-indazol-l-yl)-l-methylethylamine (0.20 g, 0.65 mmol) in THF (1 mL) was added in one portion.
  • 6-Iodo-lH- indazole (9.3 , 38 mmol) was added over 2 min to a stirred suspension of powdered potassium hydroxide (85%, 5.0g, 76 mmol) in methyl sulfoxide (100 mL) at room temperature. The mixture was stirred at room temperature for 45 min then cooled to 10 °C and chloroacetone (15.2 mL. 190 mmol) was added in one portion. The mixture was allowed to warm to room temperature and stirred for 1 h then poured into water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with brine (200 mL).
  • (S)-Methanesulfonic acid l-(6-iodoindazol-l-yl)-2-propyl ester was prepared according to the method described in Example 1. using (S)-l-(6-iodoindazol-l-yl)-2-propanol to give the product (0.9 g, 80%) as a white solid: IR v max (Nujoiycm "1 2924, 2855, 2227, 1737. 1694, 1604. 1562. 1465. 1436. 1415, 1378, 1353. 1332. 1309. 1294, 1203, 1175, 1162. 1138, 1126. 1118, 1068, 1042. 1021, 988, 978. 951.
  • 6-Iodo-lH-indazole (1.2 g, 5 mmol) was added in one portion to a stirred suspension of powdered potassium hydroxide (85%, 1.15 g, 17.5 mmol) in methyl sulfoxide (20 mL) at room temperature. The mixture was heated to 40 °C and stirred for 1 h then a solution of (S)-2-[(tert-butoxycarbonyl)amino]propyl methanesulfonate (3.2 g, 13 mmol) in methyl sulfoxide (15 mL) was added dropwise over 45 min.
  • 6-Iodo-lH-indazole (1.2 g, 5 mmol), copper iodide (1.43 g, 7.5 mmol) and methanesulfinic acid sodium salt (0.96 g, 8 mmol) in dimethylformamide (15 mL) were heated to 110 °C under Ar and stirred for 3 h. After allowing to cool to room temperature the mixture was poured into water (50 mL) and ethyl acetate (50 mL) then filtered through celite ® . The filtrate was partitioned and the aqueous layer was extracted with ethyl acetate (50 mL).

Abstract

L'invention concerne un composé chimique de formule (I), dans laquelle R1 à R3 sont indépendamment choisis entre hydrogène et alkyle; R5 est choisi parmi alkylthio, arylthio, alkylsulfoxyle, arylsulfoxyle, alkylsulfonyle et arylsulfonyle; R4, R6, et R7 sont indépendamment choisis parmi hydrogène, halogène, hydroxy, alkyle, aryle, alkoxy, aryloxy, alkylthio, arylthio, arylsulfoxyle, alkylsulfoxyle, alkylsulfonyle, arylsulfonyle, amino, monoalkylamino, dialkylamino, nitro, cyano, carboxaldéhyde, alkylcarbonyle, arylcarbonyle, aminocarbonyle, monoalkylaminocarbonyle, dialkylaminocarbonyle, alkoxycarbonylamino, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino et dialkylaminocarbonylamino, et les sels pharmaceutiquement acceptables et les promédicaments de ceux-ci. Cette invention concerne également l'utilisation de ce composé en thérapie, en particulier pour traiter les troubles du système nerveux central, les lésions à ce système, ainsi que les troubles cardio-vasculaires, gastro-intestinaux, le diabète insipide, l'apnée du sommeil, et plus particulièrement l'obésité.
PCT/GB1999/003187 1998-09-23 1999-09-23 Composes chimiques viii WO2000017170A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61045/99A AU6104599A (en) 1998-09-23 1999-09-23 Chemical compounds viii

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9820767.3A GB9820767D0 (en) 1998-09-23 1998-09-23 Chemical compounds VIII
GB9820767.3 1998-09-23

Publications (2)

Publication Number Publication Date
WO2000017170A2 true WO2000017170A2 (fr) 2000-03-30
WO2000017170A3 WO2000017170A3 (fr) 2000-08-03

Family

ID=10839365

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1999/003187 WO2000017170A2 (fr) 1998-09-23 1999-09-23 Composes chimiques viii

Country Status (3)

Country Link
AU (1) AU6104599A (fr)
GB (1) GB9820767D0 (fr)
WO (1) WO2000017170A2 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001070702A1 (fr) * 2000-03-17 2001-09-27 Alcon, Inc. Derives de 6-hydroxy-indazole destines au traitement du glaucome
WO2002040457A1 (fr) 2000-11-20 2002-05-23 Biovitrum Ab Composes de piperazinylpyrazines utilises comme antagonistes du recepteur de la serotonine 5-ht2
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
US6956036B1 (en) 2000-03-17 2005-10-18 Alcon, Inc. 6-hydroxy-indazole derivatives for treating glaucoma
EP1606283A2 (fr) * 2003-03-03 2005-12-21 Array Biopharma, Inc. Inhibiteurs de la p 38 et leurs procedes d'utilisation
US7208494B2 (en) 2003-06-26 2007-04-24 Hoffmann-La Roche Inc. 5HT2c receptor agonists
WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
WO2009063992A1 (fr) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
US7799782B2 (en) 2003-03-03 2010-09-21 Array Biopharma Inc. P38 inhibitors and methods of use thereof
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
US8039639B2 (en) 2006-01-31 2011-10-18 Array Biopharma Inc. Kinase inhibitors and methods of use thereof
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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0700905A1 (fr) * 1994-08-12 1996-03-13 F. Hoffmann-La Roche Ag Dérivés tricycliques de pyrazole
WO1998030548A1 (fr) * 1997-01-13 1998-07-16 Yamanouchi Pharmaceutical Co., Ltd. AGONISTES DU RECEPTEUR 5-HT2c ET DERIVES D'AMINOALKYLINDAZOLE
WO2000012481A2 (fr) * 1998-09-01 2000-03-09 Vernalis Research Limited Composes chimiques iv

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0700905A1 (fr) * 1994-08-12 1996-03-13 F. Hoffmann-La Roche Ag Dérivés tricycliques de pyrazole
WO1998030548A1 (fr) * 1997-01-13 1998-07-16 Yamanouchi Pharmaceutical Co., Ltd. AGONISTES DU RECEPTEUR 5-HT2c ET DERIVES D'AMINOALKYLINDAZOLE
WO2000012481A2 (fr) * 1998-09-01 2000-03-09 Vernalis Research Limited Composes chimiques iv

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6956036B1 (en) 2000-03-17 2005-10-18 Alcon, Inc. 6-hydroxy-indazole derivatives for treating glaucoma
WO2001070702A1 (fr) * 2000-03-17 2001-09-27 Alcon, Inc. Derives de 6-hydroxy-indazole destines au traitement du glaucome
US7247633B2 (en) 2000-11-20 2007-07-24 Biovitrum Ab Pyrimidine compounds and their use
WO2002040457A1 (fr) 2000-11-20 2002-05-23 Biovitrum Ab Composes de piperazinylpyrazines utilises comme antagonistes du recepteur de la serotonine 5-ht2
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
US8017641B2 (en) 2003-03-03 2011-09-13 Array Biopharma Inc. P38 inhibitors and methods of use thereof
EP1606283A2 (fr) * 2003-03-03 2005-12-21 Array Biopharma, Inc. Inhibiteurs de la p 38 et leurs procedes d'utilisation
US8518983B2 (en) 2003-03-03 2013-08-27 Array Biopharma Inc. P38 inhibitors and methods of use thereof
EP1606283A4 (fr) * 2003-03-03 2007-05-23 Array Biopharma Inc Inhibiteurs de la p 38 et leurs procedes d'utilisation
US7799782B2 (en) 2003-03-03 2010-09-21 Array Biopharma Inc. P38 inhibitors and methods of use thereof
EP2277513A2 (fr) 2003-04-25 2011-01-26 Pfizer Inc. Traitement de l'incontinence avec des 5ht2c agonistes
US7208494B2 (en) 2003-06-26 2007-04-24 Hoffmann-La Roche Inc. 5HT2c receptor agonists
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
US8039639B2 (en) 2006-01-31 2011-10-18 Array Biopharma Inc. Kinase inhibitors and methods of use thereof
US8044083B2 (en) 2006-01-31 2011-10-25 Array Biopharma Inc. Kinase inhibitors and methods of use thereof
WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
EP2727585A1 (fr) 2006-05-16 2014-05-07 Takeda Pharmaceutical Company Limited Méthode de dépistage in-vivo
WO2009063992A1 (fr) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
EP2789338A2 (fr) 2007-11-15 2014-10-15 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
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

Also Published As

Publication number Publication date
AU6104599A (en) 2000-04-10
WO2000017170A3 (fr) 2000-08-03
GB9820767D0 (en) 1998-11-18

Similar Documents

Publication Publication Date Title
US7145009B2 (en) Pirazino(aza)indole derivatives
EP1109809B1 (fr) Pyrrololoquinolines destinees au traitement de l'obesite
EP1202965B1 (fr) Derives d'indole, procede de leur preparation, compositions pharmaceutiques renfermant ceux-ci et leur application medicinale
US6433175B1 (en) Pyrroloindoles, pyridoindoles and azepinoindoles as 5-ht2c agonists
EP1328515B1 (fr) Derives d'indoline et leur utilisation en tant que ligands de recepteur 5-ht2
WO2000012475A1 (fr) Derives d'indoline utilises comme ligands des recepteurs 5-ht2b et/ou 5-ht2c
US6583134B2 (en) Aza- indolyl derivatives for treating obesity
US6552062B1 (en) Indazole derivatives with 5-HT2 receptor activity
WO2000017170A2 (fr) Composes chimiques viii
AU2002221670A1 (en) Indoline derivatives and their use as 5-HT2 receptor ligands
WO2000012482A2 (fr) Composes chimiques iii

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase