WO2003070723A1 - Indoles a substitution 5-heteroaryle - Google Patents

Indoles a substitution 5-heteroaryle Download PDF

Info

Publication number
WO2003070723A1
WO2003070723A1 PCT/DK2003/000105 DK0300105W WO03070723A1 WO 2003070723 A1 WO2003070723 A1 WO 2003070723A1 DK 0300105 W DK0300105 W DK 0300105W WO 03070723 A1 WO03070723 A1 WO 03070723A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
fluoro
methyl
piperidin
triazol
Prior art date
Application number
PCT/DK2003/000105
Other languages
English (en)
Inventor
Thomas Balle
Kim Andersen
Original Assignee
H. Lundbeck A/S
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 H. Lundbeck A/S filed Critical H. Lundbeck A/S
Priority to KR10-2004-7013026A priority Critical patent/KR20040085215A/ko
Priority to MXPA04008190A priority patent/MXPA04008190A/es
Priority to AU2003214018A priority patent/AU2003214018A1/en
Priority to CA002477074A priority patent/CA2477074A1/fr
Priority to EP03709663A priority patent/EP1478643A1/fr
Priority to IL16363803A priority patent/IL163638A0/xx
Priority to BR0307814-0A priority patent/BR0307814A/pt
Publication of WO2003070723A1 publication Critical patent/WO2003070723A1/fr
Priority to IS7390A priority patent/IS7390A/is

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to novel 5-heteroaryl substituted indoles having high affinity for ⁇ adrenoceptors. Accordingly, the compounds of the invention are considered useful for the treatment of diseases or disorders responsive to ⁇ . ⁇ -adrenoceptor antagonists. Further, as some of the compounds are selective ⁇ . ⁇ -adrenoceptor ligands they may be particularly useful as PET or SPECT ligands.
  • the compounds may be substituted in position 5 with a substituent selected from halogen, lower alkyl, lower al oxy, hydroxy, cyano, nitro, lower alkylthio, CF 3 , lower alkylsulphonyl, amino, lower alkyla ino and lower di-alkyamino.
  • a substituent selected from halogen, lower alkyl, lower al oxy, hydroxy, cyano, nitro, lower alkylthio, CF 3 , lower alkylsulphonyl, amino, lower alkyla ino and lower di-alkyamino.
  • This type of compounds has also been shown to be useful for the treatment of a range of other disorders including anxiety (WO 92/00070), cognitive disorders (WO 92/15303), abuse (WO 92/15302) and hypertension (WO 92/15301).
  • WO 92/15301 discloses compounds having affinity for the ⁇ i-adrenoceptor, however, the compounds disclosed herein are not selective for the ⁇ i-adrenoceptor.
  • WO 99/46259 and WO 01/21614 relate to ⁇ i-adrenoceptor antagonists related to the compounds ofthe invention which, however, have very different substituents on the piperazine, piperidine and tetrahydropyridine ring.
  • the compounds of WO 01/21614 are not substituted in position 5 of the indole ring with a heteroaryl group.
  • Prazosin is the prototype of an ⁇ i-adrenoceptor antagonist which has very potent peripherally effects. Prazosin has also in some animal models indicated effects in the central nervous system, although prazosin is considered to have poor CNS penetration.
  • Centrally acting ⁇ i-adrenoceptor antagonists may also have effect against Post Traumatic Stress Disorder (Raskind, M.A.; Dobie, D.J.; Kanter, E.D.; Petrie, E.G.; Thompson, C.E.; Peskind, E.R., J. Clin. Psychiatry, 2000, 61, 129-133 and Taylor, F.; Raskind, M.A., J. Clin Psychopharmacol. 2002, 22, 82-85)
  • Post Traumatic Stress Disorder Raskind, M.A.; Dobie, D.J.; Kanter, E.D.; Petrie, E.G.; Thompson, C.E.; Peskind, E.R., J. Clin. Psychiatry, 2000, 61, 129-133 and Taylor, F.; Raskind, M.A., J. Clin Psychopharmacol. 2002, 22, 82-85
  • Labelled compounds of the present invention are considered to be valuable PET (positron emission tomography) ligands and SPECT ligands due to their selectivity for cti-adrenoceptors.
  • PET positron emission tomography
  • SPECT positron emission tomography
  • Het is a five- or six-membered aromatic, heterocyclic ring containing at least one nitrogen atom as a ring member, and optionally substituted with C ⁇ -6 -alkyl;
  • n 0 or 1
  • G is N, C or CH; the dotted line meaning a bond when G is C, and the dotted line meaning no bond when G is CH or N;
  • Ar is phenyl optionally substituted with one or more substituents independently selected from halogen, C 1-6 -alkyl, C ⁇ -6 -alkoxy, hydroxy, trifluoromethyl and cyano, or Ar is 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
  • R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, C ⁇ . 6 -alkyl, C ⁇ -6 -alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, amino, C ⁇ -6 -alkylammo and C ⁇ -6 -dialkylarnino;
  • n 1, 2 or 3;
  • X is a bond, -CH 2 -, -O-, -S-, -NH-, -NHCO- or -CONH-; and T DK03/00105
  • Y is cyano, C ⁇ . 6 -alkyloxy, C ⁇ -6 -alkyl substituted with hydroxy, C ⁇ . 6 -alkoxy, or C 1-6 - alkylcarbonyloxy or Y is phenyl which may optionally be substituted one or more times with substituents selected from halogen, C ⁇ .
  • Y is an aromatic mono- or bicyclic heterocyclic ring containing only one heteroatom which may optionally be substituted one or more times with substituents selected from halogen, C ⁇ -6 -alkyl, trifluoromethyl, hydroxy, C ⁇ -6 -alkoxy, C ⁇ -6 -all ylcarbonyloxy, nitro, cyano, amino, C ⁇ -6 -all ylamino and C ⁇ -6 -diallylamino; provided Y is not cyano when X is O, S, NH, NHCO or CONH; and Y is not C 1-6 -alkoxy when X is O, S or NH
  • Het is optionally substituted triazolyl, pyrazolyl, pyrimidyl, pyridinyl or imidazolyl.
  • Het is l-methyl-lH-l,2,4-triazol-3-yl, 2-methyl-2H-l,2,4-triazol-3-yl, 3-methyl-3H-l,2,3-triazol-4-yl, l-methyl-lH-pyrazol-4-yl, 2-methyl-2H-pyrazol-3-yl, l-methyl-lH-imidazol-2-yl, pyrimidin-2-yl or pyridin-3-yl.
  • the invention relates to compounds of formula (I) wherein Y is cyano, C ⁇ . 6 -alkyl substituted with hydroxy, C ⁇ -6 -alkoxy, or C ⁇ -6 -alkylcarbonyloxy or Y is optionally substituted phenyl, in particular the group of compounds wherein Y is C ⁇ . 6 -alkyl substituted with hydroxy, C ⁇ _ 6 -alkoxy, or C ⁇ . 6 -alkylcarbonyloxy or Y is optionally substituted phenyl
  • X is a bond , -C ⁇ 2 -, O or S, preferably O or S.
  • Y is an optionally substituted, aromatic bicyclic heterocyclic ring containing only one heteroatom, such as for example optionally substituted indolyl, benzofuranyl or dihydro-l,4-benzodioxinyl.
  • X is -NHCO- or -CONH-.
  • Y is optionally substituted phenyl.
  • the invention relates to compounds wherein Y is C 1-6 -alkyl substituted with hydroxy, C ⁇ -6 -alkoxy or C ⁇ -6 -alkylcarbonyloxy
  • the invention relates to the group of compounds wherein Y is cyano.
  • the compounds of the invention are potent 0 -adrenoceptor antagonists and the compounds are therefore useful for the treatment of disorders or diseases responsive to antagonism of the ⁇ i- adrenoceptor.
  • Some of the compounds of the invention have stronger affinity to the ⁇ la -adrenoceptor than the ⁇ , ⁇ b -adrenoceptor and the ⁇ d -adrenoceptor.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof and optionally a second pharmaceutically active ingredient in combination with one or more pharmaceutically acceptable carriers or diluents.
  • the present invention relates to the use of a compound of formula I as defined above or an acid addition salt thereof and optionally a second pharmaceutically active ingredient for the manufacture of a pharmaceutical medicament for the treatment of a disorder or disease responsive to antagonism of ⁇ i-adrenoceptor.
  • the present invention relates to the use of a compound of formula I as above and optionally a second agent having antipsychotic activity for the preparation of a medicament for the treatment of psychosis.
  • cci-adrenoceptors Diseases and disorders responsive to antagonism of cci-adrenoceptors includes psychosis, mania, benign prostatic hyperplacia, hypertension, post traumatic stress disorder and cardiac arrhytmias. Antagonists of ⁇ , ⁇ -adrenoceptors are also useful for the reduction of intra ocular pressure.
  • the invention relates to a method for the treatment of a disorder or disease responsive to antagonism of cq-adrenoceptors in a mammal comprising administering a compound of formula I as above and optionally a second pharmaceutically active ingredient to said mammal.
  • the present invention relates to a method for the treatment of psychosis in a mammal comprising administering a compound of formula I as above and optionally a second agent having antipsychotic activity to said mammal.
  • the above mentioned second pharmaceutically active ingredient may be another agent having antipsychotic activity, for example an agent having dopamine D 2 antagonistic effect.
  • an agent having dopamine D 2 antagonistic effect for example an agent having dopamine D 2 antagonistic effect.
  • the present invention relates to radio-labelled compounds of formula I and the use thereof in various biological assays and PET- or SPECT studies.
  • halogen means fluoro, chloro, bromo or iodo.
  • C ⁇ _ 6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including groups such as methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2-butyl, 2- methyl-2-propyl and 2-methyl-l-propyl.
  • C 1-6 -alkoxy, C ⁇ -6 -alkylamino, C ⁇ . 6 -dialkylamino etc. designate such groups in which C ⁇ _ 6 alkyl is as defined above.
  • Het meaning a five-membered aromatic heterocyclic ring containing at least one nitrogen as a ring member includes, but are not limited to, heterocyclic rings selected from pyrrol- 1-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,2,3-triazol-l-yl, l,2,3-triazol-2-yl, l,2,3-triazol-4-yl, 1,2,4-triazol-l-yl, l,2,4-triazol-3-yl, 1,2,4- triazol-5-yl, tetrazol-1-yl, tetrazol-2-yl, tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxa
  • Het meaning a six-membered aromatic heterocyclic ring containing at least one nitrogen as a ring member includes, but are not limited to, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl.
  • Y meaning an aromatic mono- or bicyclic heterocyclic ring containing only one heteroatom includes, but are not limited to, rings such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, furan-2-yl, furan-3-yl, 2-thienyl, 3-thienyl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, indol-1-yl, indol-2-yl, indol-
  • the acid addition salts of the compounds of the invention are pharmaceutically acceptable salts formed with non-toxic acids.
  • organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline.
  • inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids.
  • the selectivity of the compounds of the invention for the ⁇ i-adrenoceptor makes them particularly useful for the development of radiolabelled ligands useful in various biological assays and in PET and SPECT studies.
  • the compounds ofthe invention "can be labelled by reacting the unlabelled precursor molecules with [ n C] methyl iodide, [ U C] methyl triflate, or other [ n C] labelled reagents derived from [ ⁇ C] carbon dioxide.
  • the compounds may also be labelled with 18 F, 123 I or 125 I.
  • Radiolabeling of compounds ofthe present invention may be performed according to radiolabeling methods known and used in the prior art.
  • compounds can be labelled by reaction ofthe appropriate precursors with radiolabelled reagents, including n C-labelled reagents such as [ ⁇ C]methyl iodide and [ ⁇ C]methyl triflate.
  • Compounds ofthe present invention radiolabelled with 18 F may be prepared by aromatic nucleophilic substitution of a precursor molecule containing an appropriate leaving group (such as nitro, bro o, iodo or triflate) by reaction with [ 18 F]F ⁇
  • compounds ofthe present invention may be radiolabelled with 1S F in the 4-position ofthe phenyl group attached to the indole N-l .
  • the compounds may be prepared by aromatic nucleophilic substitution of a precursor molecule containing an appropriate leaving group (such as nitro, bromo, iodo or triflate) by reaction with [ 18 F]F-.
  • the formyl groups may easily be removed after radioflourination by reaction with Wilkinson's catalyst in dioxane at elevated temperature (Sobrio, F.; Amokhtari, M.; Gourand, F.; Dhilly, M.; Dauphin, F.; Barre, L., Bioorg. Med. Chem. 2000, 8, 2511-2518).
  • Radiolabelling with 125 I or 123 I may be performed by halodemetalation ofthe corresponding tin substituted (organotin) precursors, for example by treatment of an ethanolic solution of the organotin precursor with Na 123 I or Na 125 I in the presence of chloramine-T and aqueous hydrochloric acid analogously to the procedure described by Foged et al (Foged, C; Halldin, C; Hiltunen, J.; Braestrup, C; Thomsen, C; Hansen, H.C.; Suhara, T.; Pauli, S.; Swahn, C.-G.; Karlsson, P.; Larsson, S. and Farde, L., Nucl. Med. Biol. 1996, 23, 201-209).
  • the organotin precursors ofthe compounds ofthe invention can be readily prepared from l-(4- bromophenyl) or l-(4-iodophenyl) substituted 5 -heteroaryl-indoles by reaction with n- butyllithium or tert-butyllithium in THF at low temperature, followed by reaction with a trialkyltin halide such as trimethyltin chloride or tributyltin chloride.
  • a trialkyltin halide such as trimethyltin chloride or tributyltin chloride.
  • Magnesium metalated intermediates may also be used in place of lithium.
  • palladium catalyzed reaction with hexaalkyldistannanes may also give the corresponding organotin precursors.
  • 4-[ 18 F]fiouroiodobenzene may be prepared as described in the literature (Shah, A.; Widdowson, D. A.; Pike, V. W., J.Labelled Compd.Radiopharm. 1997, 40, 65-67), and reacted with N-unsubstituted indole to give the final radiolabelled compounds.
  • the compounds ofthe present invention can be prepared according to the procedures described below:
  • R , R , R , R , Ar, Het and n are as defined above, with a 4-piperidone ofthe formula
  • A is an oxygen atom or a -0-(CH 2 ) q -0- chain, wherein q is 2 or 3;
  • R , R , R , R , m, X, Y, Ar, Het and n are as defined above;
  • R 2 , R 3 , R 4 , R 5 , G, the dotted line, Ar, Het and n are as defined above, with a reagent of formula L-(CH 2 ) m -X-Y wherein m, X, and Y are defined above and L is halogen, mesylate or tosylate
  • R 2 , R 3 , R 4 , R 5 , G, the dotted line, Ar, Het and n are as defined above and R 8 is (CH 2 ) (m- i ) -X-Y, wherein m, X, and Y are defined above
  • R 2 , R 3 , R 4 , Ar, Het and n are as defined above, followed by reaction with a piperazine of the formula wherein m, X and Y is as defined above;
  • an alkylating reagent such as C ⁇ -6 -alkyl-L, wherein L is chloro, bromo, iodo, mesylate or tosylate.
  • Method g) may accordingly be used to introduce radiolabelled alkyl groups, such as [ u C]methyl iodide, [ ⁇ C]methyl triflate, etc.
  • Starting materials wherein the group Het is tetrazol-5-yl may be prepared by reacting the corresponding 5-cyano-indole with azide.
  • Starting materials wherein the group Het-(CH 2 ) n - is tetrazol-5-ylmethyl may likewise be prepared from the corresponding indole containing a 5-cyanomethyl group by reaction with azide.
  • the 5- cyanomethyl-indoles may be prepared by hydrolysis of the corresponding 5-cyano-indole, reduction of the carboxylic acid functionality obtained to hydroxymethyl, reaction with methanesulphonyl chloride to form the corresponding 5-chloromethyl-indoles followed by reaction with a cyanide to form the 5-cyanomethyl-indole.
  • N-Boc-protected 5-bromo-l-Ar-3-piperidinyl-lH-indole is prepared in three steps from 5-bromo- 1-Ar-lH-indole.
  • reaction with boc-anhydride affords the desired starting material.
  • Method A the N-boc-protected 5-bromo-l-Ar-3-piperidinyl-lH-indole is treated with n- butyllithium followed by transmetalation to the corresponding zinc chloride.
  • Addition of the appropriate heteroaryl halide and 5 mol% tetral is(triphenylphosphine)palladium(0) affords the corresponding heteroaryl substituted intermediates
  • the reaction is performed under strong acidic conditions by heating.
  • Trifluoroacetic acid or ⁇ C1 in ethanol are preferred as acidic catalysts.
  • the reduction is preferably carried out at low hydrogen pressures (3 Ato.) in the presence of platinum or palladium on carbon black.
  • the arylation is preferably carried out at about 160-210 °C in aprotic polar solvents such as ⁇ -methyl-2-pyrrolodine or hexamethylphosphoric triamide with K 2 C0 3 as base and copper as a catalyst.
  • aprotic polar solvents such as ⁇ -methyl-2-pyrrolodine or hexamethylphosphoric triamide with K 2 C0 3 as base and copper as a catalyst.
  • the all iations are performed in a an aprotic solvent such as dimethylformamide or acetonitrile using an appropriate base such as potassium carbonate or diisopropyl ethyl amine at elevated temperatures (50-120 °C).
  • aprotic solvent such as dimethylformamide or acetonitrile
  • an appropriate base such as potassium carbonate or diisopropyl ethyl amine at elevated temperatures (50-120 °C).
  • the reduction is preferably carried out with LiALH 4 in THF or diethylether or with diborane in THF.
  • Method f is a two step procedure in which compound VIII is first decarboxylated in the presence of an inorganic salt as e.g. LiCl or MgCl 2 in a polar solvent as e.g. diglyme, hexamethylphosphoric triamide or N-methyl-2-pyrolidone at elevated temperatures (120-150 °C). Finally, the appropriate piperazine is added and the temperature raised to about 200 °C and kept there until the corresponding indoxyle has disappeared according to TCL analysis.
  • the compounds of Formula VIII are conveniently prepared according to the procedures reported by Unangst et al., J. Heterocyclic Chem. 1984, 21, 709.
  • the alkylation with alkyl iodides or bromides is performed by in aprotic solvents such as acetone or dimethylformamide using an appropriate base such as potassium carbonate or diisopropyl ethyl amine at elevated temperatures (40-90 °C).
  • aprotic solvents such as acetone or dimethylformamide
  • an appropriate base such as potassium carbonate or diisopropyl ethyl amine at elevated temperatures (40-90 °C).
  • the heteroaryl hahde (amount specified below) was added together with Pd(PPh 3 ) 4 (1.2 g, 5 mol %) and DMF (60 mL). The reaction mixture was stirred at 80 °C for 8 h. After cooling to room temperature, ⁇ 2 0 (300 mL) and EtOAc (500 mL) were added and the phases were separated. The organic phase was washed with H 2 0 (200 mL) and saturated aqueous CaCl 2 (3 x 100 mL), d ⁇ ed over MgS0 and the solvent was removed in vacuo. The crude product was purified by flash chromatography. The amount of reagents and solvents were scaled according to the actual amount of 1 used.
  • 3-Bromopyridine was lithiated as described by Furneaux et al. Tetrahedron 1997, 53, 2915. T ⁇ F (200 mL) was cooled to -100 °C (Et 2 0/liquid N 2 ) and ra-butyllithium (19 mL, 30.4 mmol) was added. 3-Bromopyridine (4.00 g, 25.3 mmol) was added during 2 minutes.
  • alkylating agents were used for the preparation of the examples listed below: 3- bromo-propionitrile, 3-(2-chloroethyl)-oxazolidin-2-one, 3-(2-chloroethyl)-lH-quinazoline-2,4- dione, 3-(2-chloroethyl)-l-methylpyrolidin-2-one, l-(2-Chloro-ethyl)-4-methoxy-benzene, l-(2- Bromo-ethoxy)-2-methoxy-ethane, 3-Bromo-N-(2,5-dimethoxy-phenyl)-propionamide, 3-Bromo- N-(2,5-dimethoxy-phenyl)-propionamide, 5-(3-Bromo-propoxy)-2,3-dihydro-benzo[l,4]dioxine, 1 -(2-Chloro-ethoxy)-propane, 2-(3 -Bromo-propy
  • the compounds of the invention have been tested using well-recognised and reliable methods. The tests are as follows:
  • the compounds of the invention showed high affinity for the a adrenoceptor. Most of the compounds having an IC 50 value below 30 nM in this test.
  • Cell lines Cell lines expressing the bovine ⁇ ia , rat ⁇ ld receptors and the hamster ⁇ i receptor were used in the assays.
  • In vitro binding assays Briefly, the cells were homogenised in ice-cold 50 rnM Tris, pH 7.7, using an Ultra-Turrax and the homogenates either kept on ice or stored at -80 °C until used.
  • the assay buffer subsequently used contained 50 rnM Tris, pH 7.7.
  • Non-specific displacer was WB- 4101 (1 ⁇ M) for the ⁇ a , ⁇ b , and ⁇ , d assays. All assays were incubated at 25 °C for 20 minutes. All assays were terminated by vacuum filtration on GF/B filters and counted in a scintillation counter (Wallac Trilux).
  • the radioligand used was [ 3 H]prazosin.
  • many of the compounds of the invention have much stronger affinity for the ⁇ . ⁇ - adrenoceptor compared to the D 2 and the 5-HT 2 receptor.
  • compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection.
  • suitable route for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection.
  • methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.
  • the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg.
  • the total daily dose is usually in the range of about 0.05 - 500 mg, and most preferably about 0.1 to 50 mg ofthe active compound ofthe invention.
  • the pharmaceutical formulations of the invention may be prepared by conventional methods in the art.
  • Tablets may for example be prepared by mixing the active ingredient with ordinary adjuvants, carriers and/or diluents and subsequently compressing the mixture in a conventional tabletting machine.
  • adjuvants, carriers or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.
  • Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilisation of the solution and filling in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.

Landscapes

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

Abstract

L'invention concerne des indoles à substitution 5-hétéroaryle possédant une affinité importante pour les récepteurs adrénergiques α1. De ce fait, ces composés sont considérés utiles pour traiter des troubles ou des maladies sensibles aux antagonistes du récepteur adrénergique α1. Etant donné, également, que quelques uns de ces composés sont des ligands sélectifs du récepteur adrénergique α1, ils peuvent être particulièrement utiles en tant que ligands de PET ou CPECT.
PCT/DK2003/000105 2002-02-22 2003-02-17 Indoles a substitution 5-heteroaryle WO2003070723A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
KR10-2004-7013026A KR20040085215A (ko) 2002-02-22 2003-02-17 5-헤테로아릴 치환 인돌
MXPA04008190A MXPA04008190A (es) 2002-02-22 2003-02-17 Indoles sustituidos con 5-hetoroarilo.
AU2003214018A AU2003214018A1 (en) 2002-02-22 2003-02-17 5-heteroaryl substituted indoles
CA002477074A CA2477074A1 (fr) 2002-02-22 2003-02-17 Indoles a substitution 5-heteroaryle
EP03709663A EP1478643A1 (fr) 2002-02-22 2003-02-17 Indoles a substitution 5-heteroaryle
IL16363803A IL163638A0 (en) 2002-02-22 2003-02-17 5-Heteroaryl substituted indoles
BR0307814-0A BR0307814A (pt) 2002-02-22 2003-02-17 Composto, composição farmacêutica, uso de um composto, e, métodos para o tratamento de um distúrbio ou de uma doença e para tratamento de psicose em um mamìfero
IS7390A IS7390A (is) 2002-02-22 2004-08-09 5-Heteróarýl setin indól

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US35900102P 2002-02-22 2002-02-22
DKPA200200287 2002-02-22
DKPA200200287 2002-02-22
US60/359,001 2002-02-22

Publications (1)

Publication Number Publication Date
WO2003070723A1 true WO2003070723A1 (fr) 2003-08-28

Family

ID=27758693

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2003/000105 WO2003070723A1 (fr) 2002-02-22 2003-02-17 Indoles a substitution 5-heteroaryle

Country Status (5)

Country Link
EP (1) EP1478643A1 (fr)
AU (1) AU2003214018A1 (fr)
CA (1) CA2477074A1 (fr)
MX (1) MXPA04008190A (fr)
WO (1) WO2003070723A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7074801B1 (en) * 2001-04-26 2006-07-11 Eisai Co., Ltd. Nitrogen-containing condensed cyclic compound having a pyrazolyl group as a substituent group and pharmaceutical composition thereof
US7759365B2 (en) * 2005-04-30 2010-07-20 Boehringer Ingelheim International Gmbh Piperidine-substituted indoles
JP2015531398A (ja) * 2012-10-05 2015-11-02 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． アルドステロンシンターゼインヒビター関連用途としてのインドリン化合物
US9598401B2 (en) 2013-07-29 2017-03-21 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4710500A (en) * 1985-04-10 1987-12-01 H. Lundbeck A/S 1-(4'-fluorophenyl)-3,5-substituted indoles useful in the treatment of psychic disorders and pharmaceutical compositions thereof
WO1992015301A1 (fr) * 1991-03-01 1992-09-17 H. Lundbeck A/S Traitement de l'hypertension et de maladies vasculaires peripheriques
WO1999046259A1 (fr) * 1998-03-09 1999-09-16 H. Lundbeck A/S Indoles a substitution 5-heteroaryle
WO2001021614A1 (fr) * 1999-09-09 2001-03-29 H. Lundbeck A/S Indoles substitues 5-aminoalkyle et 5-aminocarbonyle

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4710500A (en) * 1985-04-10 1987-12-01 H. Lundbeck A/S 1-(4'-fluorophenyl)-3,5-substituted indoles useful in the treatment of psychic disorders and pharmaceutical compositions thereof
WO1992015301A1 (fr) * 1991-03-01 1992-09-17 H. Lundbeck A/S Traitement de l'hypertension et de maladies vasculaires peripheriques
WO1999046259A1 (fr) * 1998-03-09 1999-09-16 H. Lundbeck A/S Indoles a substitution 5-heteroaryle
WO2001021614A1 (fr) * 1999-09-09 2001-03-29 H. Lundbeck A/S Indoles substitues 5-aminoalkyle et 5-aminocarbonyle

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BALLE THOMAS ET AL: "Synthesis and structure- affinity relationship investigations of 5-heteroaryl-substituted analogues of the antipsychotic sertindole. A Nec class of highly selective a1 adrenoceptor antagonists", JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, December 2002 (2002-12-01), pages 265 - 283, XP002968230 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7074801B1 (en) * 2001-04-26 2006-07-11 Eisai Co., Ltd. Nitrogen-containing condensed cyclic compound having a pyrazolyl group as a substituent group and pharmaceutical composition thereof
US7759365B2 (en) * 2005-04-30 2010-07-20 Boehringer Ingelheim International Gmbh Piperidine-substituted indoles
JP2015531398A (ja) * 2012-10-05 2015-11-02 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． アルドステロンシンターゼインヒビター関連用途としてのインドリン化合物
US9598401B2 (en) 2013-07-29 2017-03-21 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use thereof

Also Published As

Publication number Publication date
EP1478643A1 (fr) 2004-11-24
CA2477074A1 (fr) 2003-08-28
MXPA04008190A (es) 2004-11-26
AU2003214018A1 (en) 2003-09-09

Similar Documents

Publication Publication Date Title
CA2478229C (fr) Pyridinoylpiperidines utilisees comme agonistes de 5-ht1f
EP1089993B1 (fr) Agonistes de 5-ht1f
JP4632544B2 (ja) アミノピラゾール誘導体
CA2482655C (fr) Indoles substitues
US20010039286A1 (en) 2-aryl indole derivatives and their use as therapeutic agents
KR19980703048A (ko) 5-치환-3-(1,2,3,6-테트라히드로피리딘-4-일)- 및 3-(피페리딘-4-일)-1ｈ-인돌: 신규한 5-ｈｔ1ｆ 아고니스트
TW201725203A (zh) 作為ａｐｊ受體促效劑之雜芳基羥基嘧啶酮
JP2013510125A (ja) ブロモドメイン阻害剤としてのテトラヒドロキノリン誘導体
EP2393802B1 (fr) Derives de dihydroquinolinone
CA2575560A1 (fr) Composes chimiques
JP2004518745A (ja) 新規な複素環式アミド誘導体およびドーパミンｄ３受容体リガンドとしてのその使用
SK50895A3 (en) 3-indolylpiperidine derivative, method of its preparation, its use for preparation of pharmaceutical composition and pharmaceutical composition containing them
JP2011225579A (ja) レニン阻害剤としての３，４−置換ピペリジン誘導体
BG106168A (bg) Индолилпиперидинови производни като антихистаминови и антиалергични средства
JP5564147B2 (ja) 新規なベンズアミド誘導体
WO2003070723A1 (fr) Indoles a substitution 5-heteroaryle
CA2470214A1 (fr) Inhibiteurs de kinase
KR20030022363A (ko) Ｃｎｓ 장애 치료에 유용한 4-, 5-, 6- 및 7- 인돌 유도체
US6602889B1 (en) 5-heteroaryl substituted indoles
US20070197603A1 (en) Substituted indole ligands for the orl-1 receptor
WO1993020066A1 (fr) Derives de l'imidazole, du triazole et du tetrazole
JP2004509871A (ja) 二重ヒスタミンｈ１およびｈ３のアゴニストまたはアンタゴニストとしての置換イミダゾール
KR20040085215A (ko) 5-헤테로아릴 치환 인돌
WO2000034266A1 (fr) Derives d'indoles et utilisation de ces derniers comme agonistes de 5-ht¿1f?
EP1214312B1 (fr) Indoles substitues 5-aminoalkyle et 5-aminocarbonyle

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC 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 MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ 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)
WWE Wipo information: entry into national phase

Ref document number: 534694

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2003709663

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 163638

Country of ref document: IL

Ref document number: 200406615

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2004/008190

Country of ref document: MX

Ref document number: 2003569630

Country of ref document: JP

Ref document number: 2477074

Country of ref document: CA

Ref document number: 1020047013026

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2003214018

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 1020047013026

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2003709663

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 2003709663

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 1-2004-501218

Country of ref document: PH

NENP Non-entry into the national phase

Ref country code: JP