WO1999032466A1 - Derives de benzenesulfonamide substitues et leur utilisation pharmaceutique - Google Patents

Derives de benzenesulfonamide substitues et leur utilisation pharmaceutique Download PDF

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Publication number
WO1999032466A1
WO1999032466A1 PCT/EP1998/008333 EP9808333W WO9932466A1 WO 1999032466 A1 WO1999032466 A1 WO 1999032466A1 EP 9808333 W EP9808333 W EP 9808333W WO 9932466 A1 WO9932466 A1 WO 9932466A1
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Prior art keywords
substituted
dalkyl
alkyl
dalkoxy
formula
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PCT/EP1998/008333
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English (en)
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Peter Buehlmayer
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Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft M.B.H.
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Priority to AU24152/99A priority Critical patent/AU2415299A/en
Publication of WO1999032466A1 publication Critical patent/WO1999032466A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention relates to a compound of formula (I)
  • X is S or NH, and Y and Z are each CH; or X is NH and one of variables Y and Z is N and the other is CH; R, and R 2 , independently of one another, represent hydrogen, C C 7 alkyl or d-dalkyl substituted by hydroxy, halogen, C C 7 alkoxy, carboxy, d-C 7 alkoxycarbonyl, carbamoyl, d- C 7 alkylcarbamoyl, di-C ⁇ -C 7 alkylcarbamoyl, C 3 -C ⁇ cycloalkyl or by C 3 -C 8 cycloalkyl which is substituted by d-C 7 alkoxy-carbonyl, or represent C 2 -C -alkanoyl; whereas at least one of variables R 1 and R 2 is different from hydrogen; or the group NR R 2 is linear C 2 -C 6 alkyleneamino that is unsubstituted or substituted by C C 7 alkyl
  • the compounds of formula (I) may be present in the form of salts, especially in the form of pharmaceutically acceptable salts.
  • Acid addition salts may be formed with the basic amino group.
  • acid component there come into consideration, for example, strong inorganic acids, such as mineral acids, for example hydrohalic acids, e.g. hydrochloric acid, or strong organic carboxylic acids, e.g. acetic acid or trifluoroacetic acid, or organic sulfonic acids, e.g. methanesulfonic acid or p-toluenesulfonic acid.
  • salts that are not suitable for therapeutic use which can be used, for example, in the isolation and purification of free compounds of formula (I) or their pharmaceutically acceptable salts. Only the pharmaceutically acceptable, non-toxic salts are used therapeutically and they are therefore preferred.
  • the compounds according to the invention may accordingly be in the form of stereoisomers, mixtures of stereoisomers or in the form of the (substantially) pure diastereoisomers.
  • Corresponding compounds having one optically active carbon atom are in the form of racemates, especially in the form of (substantially pure) enantiomers.
  • Corresponding stereoisomers are likewise covered by the present invention.
  • d-dAlkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or a corresponding pentyl, hexyl or heptyl radical. Preference is given to C rdalkyl, especially methyl.
  • d-dAlkoxy is e.g.
  • d-dAlkoxy is preferred. Methoxy is especially preferred.
  • d-C 7 Alkoxy-d-C alkyl is especially d-C 4 alkoxy-C ⁇ -C 4 alkyl, such as methoxymethyl, methoxyethyl, 2-ethoxyethyl, 2-n-propyloxyethyl or ethoxymethyl. Methoxymethyl, ethoxymethyl and 1 -methyl-2-methoxyethyl are preferred.
  • C ⁇ -C 7 Alkoxy-d-C 7 alkoxy-C ⁇ -C 7 alkyl is especially d-dalkoxy-d-dalkoxy-C.-dalkyl, such as methoxymethoxymethyl, ethoxymethoxymethyl, 2-m ethoxy ethoxymethyl, 2-ethoxy-2- ethoxy-methyl, 2-n-propyloxyethoxy-methyl or ethoxymethyl. 2-Methoxy-ethoxymethyl or 2- ethoxyethoxymethyl are preferred.
  • Cycloalkyl is especially C 4 -C 7 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclohexyl or cycloheptyl.
  • Carboxy-C ⁇ -C 7 alkyl is especially carboxy-d-C 4 alkyl, such as carboxy methyl, 2-carboxyethyl or 3-carboxypropyl.
  • C ⁇ -C 7 Alkoxycarbonyl is especially d-C 4 alkoxycarbonyl, such as methoxy-, ethoxy-, n- propyloxy- or n-butyloxy-carbonyl.
  • d-dAlkyl-carbamoyl is especially C ⁇ -C 4 -alkyl-carbamoyl, such as methyl-, ethyl-, n-propyl-, or n-butyl-carbamoyl.
  • Di-d-C 7 alkyl-carbamoyl is especially di-C ⁇ -C 4 -alkyl-carbamoyl, such as dimethyl-, methyl- ethyl-, diethyl-, di-n-propyl-, or di-n-butyl-carbamoyl.
  • C ⁇ -C 7 Alkoxycarbonyl-d-C alkyl is especially d-dalkoxycarbonyl-d-daikyl, such as methoxy-, ethoxy-, n-propyioxy- or n-butyloxy-carbonyl-methyl or -ethyl.
  • Preferred examples are 1 -methoxy carbonylethyl, 1 -methoxycarbonyl-2-methylethyl and 1- methoxycarbonyl-2-methylpropyl.
  • Aminocarbonyl-C ⁇ -C 7 alkyl is especially aminocarbonyl-CrC alkyl, such as aminocarbonyl- methyl, -ethyl or -n-propyl.
  • d-C Alkylaminocarbonyl-C ⁇ -C 7 alkyl is especially C 1 -C 4 alkylaminocarbonyl-C ⁇ -C 4 alkyi, such as methyl-, ethyl- or n-propyl-aminocarbonylmethyl.
  • a preferred example is 1 -methyl amino- 2-methylpropyl.
  • Di-C ⁇ -C 7 alkylaminocarbonyl-C ⁇ -C 7 alkyl is especially di-d-C 4 alkylaminocarbonyl-C ⁇ -C 5 alkyl, such as dimethyl-, diethyl- or di-n-propyl-aminocarbonylmethyl.
  • Hydroxy-C ⁇ -C 7 alkyl is especially hydroxy-C 1 -C 4 alkvi, such as hydroxy methyl, 2-hydroxy ethyl or 3-hydroxypropyl.
  • a preferred example is hydroxymethyl.
  • C 2 -C 6 Alkyleneamino is cyclobutylene-, cyclopentylene- or cyclohexylene-amino (pyrrolidino, piperidino or azepino). Cyclobutylene- and cyclohexylene-amino are preferred.
  • d-dAlkylthio-d-dalkyl is especially d-C 4 alkylthio-C ⁇ -C 4 alkyl, such as methylthiomethyl, 2-methylthio-ethyl, ethylthiomethyl or 2-ethylthio-ethyl.
  • d-C 7 Alkanesulphinyl-C ⁇ -C 7 alkyl is especially d-C 4 alkanesulphinyl-d-C 4 alkyl, such as methanesuiphinylmethyl, 2-methanesulphinyl-ethyl, ethanesulphinyimethyl or 2- ethanesulphinyl-ethyl.
  • Alkanesulphonyl-C ⁇ -C alkyl is especially d-C 4 alkanesulphonyl-C ⁇ -C 4 alkyl, such as methanesulphonylmethyl, 2-methanesulphonyl-ethyl, ethanesulphonylmethyl or 2- ethanesulphonyl-ethyl.
  • Hydroxylimino-C ⁇ -C 7 -alkyl is especially hydroxylimino-d-C 4 -alkyl, such as hydroxylimino- methyl.
  • Amino-d-C 7 alkyl is especially amino-C ⁇ -C 4 alkyl, such as aminomethyl, 2-aminoethyl, 3- aminopropyl or 4- aminobutyl. - o -
  • C ⁇ -C 7 Alkyl-amino-C ⁇ -C 7 alkyl is especially d-dalkyl-amino-d-dalkyl, such as methylaminomethyl, ethylaminomethyl or 2-ethylamino-ethyl.
  • Di-d-C 7 alkyl-amino-C ⁇ -C 7 alkyi is especially di-C ⁇ -C alkyl-amino-C ⁇ -C 4 alkyl, such as dimethylaminomethyl, diethylaminomethyl or 2-di-ethylamino-ethyl.
  • Pyrrolyl is especially 2- or 3- pyrrolyl.
  • Furyl is 2- or 3-furyl.
  • Thienyl is 2- or 3-thienyl.
  • Pyridyl is 2-, 3- or 4-pyridyl.
  • Alkylamino is especially d-dalkylamino, such as methyl-, ethyl-, n-propyl-, isopropyl- or n-butyl-amino. Methylamino is preferred.
  • Di-d-C 7 alkylamino is especially di-C ⁇ -C 4 alkylamino, such as dimethyl-, diethyl- or diisopropyl-amino.
  • C ⁇ -C 7 Alkoxy-C ⁇ -C 7 alkoxy is especially d-C 4 alkoxy-C ⁇ -C 4 alkoxy, such as methoxyethoxy, 2- ethoxyethoxy, 2-n-propyloxyethoxy or ethoxymethoxy.
  • C ⁇ -C 7 Alkanoyl is especially C 2 -C 5 alkanoyl, such as formyl, acetyl, propionyl or pivaloyl.
  • C 2 -C 7 Alkanoyloxy is especially C 2 -C 5 alkanoyloxy, such as acetyloxy, propionyloxy or pivaloyloxy.
  • Halogen is especially halogen having an atomic number of up to and including 35, that is to say fluorine, chlorine or bromine, and also includes iodine. Chlorine is preferred.
  • Halo-C ⁇ -C 7 alkyl is especially halo-C ⁇ -C 4 alkyl, such as fluoromethyl, fluoroethyl, chloromethyl, trifluoromethyl, trichloromethyl, chloroethyl or 1 ,1 ,1-difluorochloroethyl.
  • Halo-C C 7 alkoxy is especially halo-C C 4 alkoxy, such as fluoromethoxy, fluoroethoxy, chloromethoxy, trifluoromethoxy, trichloromethoxy, chloroethoxy or 1 ,1 ,1- difluorochloroethoxy.
  • C ⁇ -C Alkyleneoxy-d-C alkylene is especially d-d-alkyleneoxy-d-C ⁇ alkylene, such as methyleneoxymethylene.
  • Hetero-Aryl radicals for example, ring A or corresponding radicals attached to ring B, may be substituted one or more times, e.g. twice or three times.
  • Preferred C 2 -C 6 alkyleneamino [-N(R ⁇ )(R 2 )] is pyrrolidino, piperidino or azepino.
  • Preferred substituted C 2 -C 6 alkyieneamino is pyrrolidino which is especially mono-substituted.
  • Preferred substituents of pyrrolidino are C rC 4 alkoxy-d-C alkyl, especially methoxymethyl or ethoxymethyl, C ⁇ -C 4 alkanesulphonyl-C ⁇ C 4 alkyl, especially methanesulphonylmethyl, C dalkyl, especially methyl, ethyl or propyl, hydroxy-d-dalkyl, especially hydroxy methyl, cyano, or d-dalkoxycarbonyl, especially methoxycarbonyl, all of which are preferably located in position 2, or is mono-substituted by C rdalkoxy, especially methoxy, which is preferably located in position 3, of the pyrrolidino ring.
  • Obesity is a widespread phenomenon that is responsible for a whole series of pathological symptoms and has an adverse effect on health generally.
  • obesity is associated with considerable socio-economic costs and constitutes a serious financial burden on the healthcare system.
  • eating behaviour can be regulated by modulation of the neuropeptide Y(NPY) receptor subtype Y5.
  • the compounds according to the present invention and their pharmaceutically acceptable salts have been shown to have a marked and selective affinity for the receptor subtype Y5 (demonstrated in Y5-binding studies) and exhibit antagonistic properties in vitro and in vivo. Those properties are manifested in vitro by the ability of the compounds to inhibit the NPY- induced increase in calcium in stably transfected cells that express the Y5 receptor. In vivo the antagonistic effect is manifested by the ability to inhibit in conscious rats the intake of food induced by intraventricular administration of NPY or by withdrawal of food for 24 hours.
  • Y5 receptor has been demonstrated in a Y5-binding assay on LM(tk-)-hY5-7 eel Is, which provide long-term expression of the human NPY5 receptor, and on HEK-293 cells, which provide long-term expression of the NPY5 receptor of rats.
  • buffer 1 homoogenisation buffer, pH 7.7 at 4°C
  • buffer 2 saliva buffer, pH 7.4 at room temperature
  • HEPES N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid
  • the cells are washed in phosphate-buffered saline solution and collected using a rubber blade. Homogenisation of the cells is carried out using a Polytron homogeniser (3 pulses of 8 seconds) in ice-cooled hypotonic buffer solution (buffer 1 , pH 7.7 at 4°C). The homogenate is centrifuged for 20 minutes at 32 000 g and 4°C. The sediment is resuspended in the same buffer and again centrifuged. The resulting sediment is suspended in buffer 2. The protein concentration is determined using the Coomassie Blue method [Pierce, Socochim, Lausanne, CH]. Bovine serum albumin is used as standard. The crude membrane suspension is divided into aliquots, frozen in liquid nitrogen and stored at -80°C. Before use, 0.1% (1 mg/ml) bovine serum albumin is added. 25 l-[Pro 34 ]hPYY (60 pM final concentration, Anawa, Wangen, Switzerland], dissolved in buffer 3, is used as radio ligand.
  • the following substances are introduced by pipette into each sample well: 60 microl of buffer 3, 20 microl of 125 l-[Pro 3 ]hPYY (600 pM), 20 microl of test compound (or binding buffer plus 10 % DMSO for the controls), 100 microl of crude membrane suspension (about 10 microg of protein). Incubation is carried out at room temperature for two hours. Binding that is still present in the presence of 1 microM [Pro ⁇ JhPYY [BACHEM, Bubendorf, Switzerland] is defined as non-specific binding. The incubation is terminated by rapid filtration and washing four times with 300 microl of phosphate-buffered saline solution. The filters are removed from the wells of the plate, inserted into plastics test tubes and examined for their radioactivity in a gamma counter [Gammamaster, WALLAC, Finland].
  • IC50 values of the compounds (according to the present invention) at the human Y5 receptor lie predominantly between about 0.1 nM and about 10 microM.
  • IC 50 binding data
  • stably transfected LM(tk-)-hY5-7 cells are used in which an NPY-induced increase in calcium has been measured as follows: the cells are collected in a medium containing EDTA (0.5 mM) and phosphate-buffered saline solution (PBS).
  • EDTA 0.5 mM
  • PBS phosphate-buffered saline solution
  • the cells are then washed in phosphate-buffered saline solution and incubated for 90 minutes at room temperature and pH 7.4 with 10 microM FLUO-AM (fluoro-3-acetoxymethyl ester supplemented by pluronic acid, as suggested by the manufacturer, Molecular Probes Inc., Eugene, Oregon, USA) in a cell culture buffer of the following composition: (NaC1 120 mM, MgCI 2 1 mM, KCI 5.4 mM, NaH 4 P0 4 0.33 mM, glucose 11 mM, taurine 5 mM, pyruvate 2 mM, glutamine 1.5 mM, HEPES 10 mM, insulin 10 U/litre, BSA 0.1 %). After centrifugation, the cells are resuspended in the cell culture buffer in a concentration of 3 -4 million cells/ml, and 200 ⁇ M sulfinpyrazone are added.
  • FLUO-AM fluoro-3-acetoxymethyl ester supplement
  • the increase in calcium is measured at room temperature in a millititre plate using a Cytofluor 2350 (Millipore) at wavelengths of 485 nm (excitation) and 530 n (emission). 180 microl of the cell suspension are incubated for 5 minutes in the presence of different amounts of the compounds, which have been dissolved in 2 microl of DMSO (each x 3 ) (or in 2 microl of DMSO for the controls). Then NPY is added in a final concentration of 100 nM. The concentrations of the compounds that result in 50% inhibition of the maximum increase in calcium are calculated.
  • the ability of the compounds and their pharmaceutically acceptable salts to inhibit the NPY- induced increase in intracellular calcium provides evidence of their antagonistic properties.
  • the IC50 values lie predominantly between about 0.1 nM and about 10 microM.
  • NPY-induced food intake in conscious rats Furthermore, this antagonism to the Y5 receptor subtype is also observed in vivo in conscious rats in which the NPY-induced intake of food can be inhibited.
  • the food intake of satiated rats after cerebroventricular administration (i.c.v.) of neuropeptide Y [BACHEM, Feinchemikalien, Bubendorf, Switzerland] with and without additional administration of the compounds (according to the present invention) was determined. All tests were carried out using male Sprague-Dawley rats weighing between 180 and 220 g. The animals were kept individually in Makrolon cages with a light/darkness rhythm of 11 :13 hours (dark from 18.00) at controlled temperatures (21-23°C).
  • the position of the cannula was checked post-operatively two days before the actual tests by testing the feeding behaviour of all rats after a cerebroventricular (i.c.v.) injection of 300 pmol NPY.
  • a cerebroventricular (i.c.v.) injection of 300 pmol NPY To determine NPY-induced food intake, only rats that had consumed at least 2 g of food within a period of 2 hours after the NPY injection were used. The injections were carried out in the morning, two hours after the start of the light phase.
  • the peptides were administered in 5-10 ⁇ l of artificial cerebrospinal fluid (ACSF) [FLUKA, Buchs, Switzerland].
  • ACSF artificial cerebrospinal fluid
  • ACSF contains NaCI 124mM, KCI 3.75mM, CaCI 2 2.5mM, MgS0 4 2.0mM, KH 4 P0 4 0.22mM, NaHC0 3 26mM and glucose 10mM.
  • NPY 300 pmol was administered cerebroventricularly 10 to 60 minutes after the administration of the com pounds or of the respective vehicle DMSO/water (10% v/v), Cremophor/water (20% v/v) [SIGMA, Buchs, Switzerland] or Tween 80/water (10% v/v) [FLUKA, Buchs, Switzerland].
  • the food intake was determined by placing a preweighed amount of feed pellets in the cages at the time of the NPY injection. At each of the time points indicated the pellets were removed from the cages and replaced by fresh preweighed pellets.
  • NPY- induced food intake in rats predominantly between about 0.01 and about 100 mg/kg.
  • Determination of food intake in rats after withdrawal of food for 24 hours On the basis of the observation that withdrawal of food induces a rise in the NPY level in the hypothalamus, it is assumed that NPY is responsible for food intake induced by hunger.
  • the compounds (according to the filed invention) were therefore also tested in rats after withdrawal of food for 24 hours. These tests were carried out with male Sprague-Dawley rats weighing between 180 and 250 g.
  • the animals were kept in individual cages for the duration of the test and (with the exception of the withdrawal of food for 24 hours) received food and tap water ad libitum.
  • the animals were kept at 22 ⁇ 2°C and in controlled humidity with a light/darkness rhythm of 12:12 hours (light from 6.00 to 18.00).
  • the rats were given two weeks to become accustomed to their new environment and to the powdered food or feed pellets [NAFAG, Gossau, Switzerland] (acclimatisation phase). At the end of that phase, the animals were given no food for 24 hours (beginning 8.00 a.m.).
  • either the compounds according to the present invention or an equal volume of the respective vehicle DMSO/water (10%, v/v), Cremophor/water (20%, v/v) or Tween 80/water (10%, v/v) were administered to the animals intraperitoneally, intra enously or orally. 10 to 60 minutes later the animals were given food again. During the subsequent 24 hours, the food intake was measured at various time points. The inhibition of food intake brought about by the compounds according to the present invention was given as a percentage of the food intake of the control animals treated with the vehicle.
  • the compounds according to the present invention administered orally, intraperitoneally, subcutaneously or intravenously, brought about an inhibition of food intake; the ED50 lay between 0.01 and about 100 mg/kg.
  • the anti-obesity activity of the compounds according to the present invention was also demonstrated in obese sugar rats, which are a known animal model for obesity.
  • the studies were carried out using male obese Zucker rats (fa/fa) [HARLAN CPB, Austerlitz, NL] weighing between 480 and 500 g.
  • the animals were kept individually in metabolism cages for the duration of the study and received food in powder form and tap water ad libitum.
  • the animals were kept in a room with a light/darkness rhythm of 12:12 hours (light from 8.00 to 20.00) at a temperature of 24°C and with controlled humidity. After being placed in the metabolism cages, the rats were given six days to become accustomed to their new environment and to the powdered food (acclimatisation phase).
  • the food consumption during the light and darkness phases was determined.
  • the animals were treated with the compounds according to the present invention or with the DMSO/water (10% v/v), Cremophor/water (20% v/v) [SIGMA, Buchs, Switzerland] or Tween 80/water(10% v/v) [FLUKA, Buchs, Switzerland].
  • the compounds according to the present invention administered orally, intraperitoneally, subcutaneously or intravenously, brought about an inhibition of food intake in obese sugar rats, predominantly between about 0.01 and about 100 mg/kg.
  • mice The anti-obesity activity of the compounds according to the present invention was also demonstrated in genetically obese mice.
  • the tests were carried out using male and/or female mice having the ob/ob mutation (The Jackson Laboratory, Bar Harbor, ME) (C57BL/61-ob) weighing between 30 and 80 grams.
  • the mice were kept individually in Makrolon or metabolism cages and received food in powder form and tap water ad libitum.
  • the mice were kept at 24 °C and with a light/darkness rhythm of 12:12 hours (light from 8.00 to 20.00). After being placed in the cages, the mice were given six days to become accustomed to their new environment (acclimatisation phase).
  • mice were treated with the compounds according to the filed invention or with the DMSO/water (10% v/v), Cremophor/water (20% v/v) [SIGMA, Buchs, Switzerland] or Tween 80/water (10% v/v) [FLUKA, Buchs, Switzerland].
  • the compounds according to the present invention administered orally, intraperitoneally, subcutaneously or intravenously, brought about an inhibition of the food intake in obese ob/ob mice, predominantly in a range between about 0.01 and about 100 mg/kg.
  • the compounds according to the present invention are capable of inhibiting food intake induced either by cerebroventricular administration of NPY or by withdrawal of food as well as being capable of inhibiting the spontaneous intake of food in obese sugar rats and ob/ob mice. Accordingly, the compounds (according to the filed invention) act against the binding of the neuropeptide Y (NPY) to the Y5 receptor subtype (NPY -antagonism) and could be used especially in the treatment and prevention of disorders or diseases that are associated with the Y5 receptor subtype, that is to say in which the NPY Y5 receptor subtype is involved. They could especially be used in the treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dyslipidaemia and hypertonia.
  • NPY neuropeptide Y
  • NPY -antagonism Y5 receptor subtype
  • the invention relates to a method of treating diseases and disorders associated with the NPY Y5 receptor subtype, which could be used especially in the prophylaxis and treatment of disorders and diseases in which the NPY Y5 receptor subtype is involved, and especially in the treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dyslipidaemia and hypertonia. Furthermore, they could be used in the treatment of loss of memory, epileptic convulsions, migraine, sleep disorders and pain, and additionally in the treatment of sexual disorders, depression, anxiety states, cerebral haemorrhages, shock, decompensated cardiac insufficiency, nasal congestion and diarrhoea.
  • the method comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt of such a compound, to warm-blooded animals, including human beings, that require such treatment.
  • the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt of such a compound, as has been described hereinabove and as will be described hereinbelow also for the preparation of a medicament for the prophylaxis and treatment of corresponding diseases or disorders.
  • the invention relates to a medicament comprising a compound of formula (I) or a pharmaceutically acceptable salt of such a compound, as has been described hereinabove and as will be described hereinbelow also for the treatment of corresponding diseases or disorders.
  • the invention relates especially to a compound of formula (I) wherein
  • X is S or NH, and Y and Z are each CH; or
  • X is NH and one of variables Y and Z is N and the other is CH;
  • Ri is d-dalkyl or d-dalkyl substituted by hydroxy, halogen, C C 7 alkoxy, carboxy, C C 7 - alkoxycarbonyl, carbamoyl, d-C 7 alkylcarbamoyl, di-d-dalkylcarbamoyl, , C 3 -C 8 cycloalkyl or by C 3 -C 8 cycloalkyl which is substituted by d-C 7 alkoxycarbonyl; whereas at least one of variables R 1 and R 2 is different from hydrogen;
  • R 2 is hydrogen, d-C alkyl or hydroxy-C ⁇ -C alkyl; or a salt thereof, especially a pharmaceutically acceptable salt thereof.
  • the invention relates especially to a compound of formula (I')
  • Ri is d-C 7 alkyl, d-C alkoxy-d-C 7 alkyl, carboxy-C ⁇ -C 7 alkyl, C ⁇ -C 7 alkoxycarbonyl-d-C 7 alkyl, aminocarbonyl-d-C 7 alkyl, C ⁇ -C 7 alkylaminocarbonyl-C ⁇ -C 7 alkyl or di-C ⁇ -C 7 aIkylamino- carbonyl-d-dalkyl; and R 2 is hydrogen or d-C 7 alkyl; or the group NR,R 2 is C 4 -C 6 alkyleneamino that is unsubstituted or substituted by C rdalkoxy, hydroxy-d-dalkyl, C ⁇ -C 7 alkoxy-d-C 7 alkyl or by d-C 7 alkoxycarbonyl, or is morpholino, thiomorpholino or d-dalkoxycarbonyl-substituted 2,3-dihydro
  • the invention relates especially to a compound of formula (I') wherein
  • Rt is d-dalkyl, C ⁇ -C alkoxy-d-C alkyl, C ⁇ -C 4 alkoxycarbonyl-C C 4 alkyl or d-dalkyl- aminocarbonyl-d-dalkyl;
  • R 2 is hydrogen or C ⁇ -C 4 alkyl; or the group NR ⁇ R 2 is C 4 -C 6 alkyleneamino that is unsubstituted or substituted by C rdalkoxy, hydroxy-C ⁇ -C 4 alkyl, C ⁇ -C 4 alkoxy-d-C alkyl or by d-C 4 alkoxycarbonyl, or is morpholino, thiomorpholino or d-C 4 alkoxycarbonyl-substituted 2,3-dihydro-indol-1-yl;
  • X is -S- or -NH-; and wherein the ring A, apart from being substituted by -SO ⁇ R ⁇ and -NH-, is unsubstituted or substituted one or more times by a substituent selected from the group consisting of C C 4 - alkyl, d-dalkoxy, d-C 4 alkoxy-C ⁇ -C 4 alkoxy, hydroxy, halogen and CF 3 ; and wherein the ring B is substituted once or twice by a substituent selected from the group consisting of
  • C ⁇ -C 4 alkyl furyl and pyridyl, and phenyl that is unsubstituted or substituted one or more times by a substituent selected from the group consisting of halogen, C ⁇ -C 4 alkoxy, amino, d-dalkylamino and di-d-C 4 alkylamino; or a salt thereof.
  • the invention relates especially to a compound of formula (I) wherein
  • X is S and Y and Z are each CH;
  • X is NH and Y and Z are each CH;
  • X is NH and one of variables Y and Z is N and the other is CH;
  • Rt is d-C alkyl or d-dalkyl substituted by halogen, C rdalkoxy, d-dalkoxycarbonyl, or by d-dalkyicarbamoyl;
  • R 2 is hydrogen or d-dalkyl; or the group NR ⁇ R 2 is linear C 2 -C 6 alkyleneamino, pyrrolidino that is unsubstituted or substituted by d-dalkyl, hydroxy-d-dalkyl, d-dalkoxy, d-dalkoxy-d-dalkyl, d- dalkanesulfonyl-Crdalkyl, cyano, or by d-dalkoxycarbonyl, or is morpholino, or C dalkoxycarbonyl-substituted dihydroindol-1-yl or is a group of formula and wherein the ring A, apart from being substituted by -SO aNR ⁇ and -NH-, is unsubstituted or substituted one or more times by a substituent selected from the group consisting of C dalkyl, d-dalkoxy, d-dalkoxy-d-d
  • R 3 is furyl, thienyl, pyridyl, phenyl, phenyl substituted one or more times by a substituent selected from the group consisting of halogen, C rdalkyl, d-dalkoxy, and di-d-d- alkylamino, or is phenyl di-substituted by methyleneoxymethylene; and
  • R 4 is hydrogen, halogen.C rdalkyl, d-C 7 alkoxy, or phenyl; or a pharmaceutically acceptable salt thereof.
  • the invention relates especially to a compound of formula (I A)
  • Ri is d-dalkyl, Crdalkoxy-d-dalkyl, CrC 4 alkoxycarbonyl-d-C 4 alkyl or d-dalkyl- aminocarbonyl-d-dalkyl; and R 2 is hydrogen or d-dalkyl; or the group NR ⁇ R 2 is pyrrolidino or piperidino, each unsubstituted or substituted by d-dalkoxy, hydroxy-C rdalkyl, d-dalkoxy-d-dalkyl or by d-dalkoxycarbonyl, or is morpholino, thiomorpholino or C rdalkoxycarbonyl-substituted 2,3-dihydro-indol-1 -yl; R 3 and R 4 are each independently of the other hydrogen, C rdalkyl, furyl, pyridyl, or phenyl that is unsubstituted or substituted by halogen, C
  • the invention relates especially to a compound of formula (I A) wherein Ri is d-dalkyl, such as methyl ethyl or n-propyl; R 2 is hydrogen or d-dalkyl, such as ethyl; or the group NR 1 R 2 is pyrrolidino that is unsubstituted or substituted, especially in position 2 of the pyrrolidino ring, by hydroxy-C rdalkyl, d-C 4 alkoxy-CrC 4 alkyl or d-dalkanesulfonyl- d-dalkyl or substituted, especially in position 3 of the pyyrolidino ring, by C rdalkoxy, such as methoxy;
  • R 3 is thienyl, pyridyl, phenyl, or phenyl substituted one or more times by a substituent selected from the group consisting of halogen and C rdalkoxy; and R 4 is hydrogen, halogen, d-dalkoxy or phenyl; or a pharmaceutically acceptable salt thereof.
  • the invention relates especially to a compound of formula (I A) wherein
  • Ri is d-dalkyl, such as methyl; and R 2 is hydrogen or d-dalkyl, such as methyl; or the group NRtR 2 is pyrrolidino or piperidino, each unsubstituted or substituted by C rdalkoxy, hydroxy-d-dalkyl, d-dalkoxy-d-dalkyl or by d-dalkoxycarbonyl; R 3 and R 4 are each independently of the other phenyl that is unsubstituted or substituted by halogen, such as fluorine or chlorine; or a salt thereof.
  • halogen such as fluorine or chlorine
  • the invention relates especially to a compound of formula (I A) wherein R ⁇ is d-C 4 alkyl, such as methyl; R 2 is hydrogen; or the group NR ⁇ is 2-(CrC 4 alkoxy-d-C 4 alkyl)- pyrrolidino, such as 2-methoxymethylpyrrolidino; R 3 is phenyl or halo-substituted phenyl, such as 4-chloro- or 4-fluoro-phenyl; and R 4 is hydrogen; or a pharmaceutically acceptable salt thereof.
  • the invention relates especially to a compound of formula (I A) wherein the group NR,R 2 is 2-(CrC2alkoxy-Crdalkyl)-pyrrolidino, such as 2-methoxymethylpyrrolidino; R 3 is phenyl or phenyl substituted in the 4-position by halogen, such as 4-chloro- or 4-fluoro-phenyl; and R is hydrogen; or a pharmaceutically acceptable salt thereof.
  • the invention relates especially to a compound of formula (I A) wherein
  • Ri is d-dalkyl, such as methyl; and R 2 is hydrogen; R 3 is phenyl and R 4 is hydrogen; or a pharmaceutically acceptable salt thereof.
  • the invention relates especially to a compound of formula (I B)
  • R ⁇ and R 2 independently of one another, are C rdalkyl, such as ethyl; or the group NR ⁇ is 2-(CrC 2 alkoxy-CrC 2 alkyl)-pyrrolidino, such as 2-methoxymethyl- pyrrolidino;
  • R 3 is phenyl
  • R 4 is hydrogen; or a pharmaceutically acceptable salt thereof.
  • the invention relates especially to a compound of formula (I C)
  • group NR ⁇ R is 2-(CrC2alkoxy-CrC 2 alkyl)-pyrrolidino, such as 2-methoxy- methylpyrrolidino;
  • R 3 is phenyl; or a pharmaceutically acceptable salt thereof.
  • the invention relates also to processes for the preparation of the compounds according to the invention. These processes are, for example, as follows: for the preparation of a compound of formula (I) wherein X is -S- and Y and Z are CH, or a compound of formula (I A) or a salt thereof, a compound of formula (II A)
  • the thio group is alkylated, for example with a C rdalkyl iodide, such as methyl iodide, and the resulting compound is then reacted in the presence of a base with a compound of formula (R 3 )-CO-C(FL»)-Hal (II B) wherein Hal is halogen, especially bromine.
  • the reactions described hereinabove and hereinbelow are carried out in a manner known perse, for example in the absence or, usually, in the presence of a suitable solvent or diluent or a mixture thereof, the operation being carried out as necessary with cooling, at room temperature or with heating, for example in a temperature range of approximately from -80°C to the boiling temperature of the reaction medium, especially from about -10 ° to about +200°C, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.
  • the reaction is preferably carried out in the presence of an organic base.
  • a base there come into consideration, for example, a tri-lower alkylamine, such as triethylamine, and also a tri-lower alkylamine having bulky radicals, e.g. ethyldiisopropylamine, or a heterocyclic base, e.g. pyridine, 4-dimethyiaminopyridine or N-methylmorphoiine.
  • the invention is especially illustrated by the Examples and relates also to the novel compounds mentioned in the Examples and also to their use and to processes for their preparation.
  • the starting material of formula (II A) can be obtained, for example, by reaction of a compound of formula
  • Hal is halogen, such as chlorine, with a compound of formula H-N(R ! )(R 2 ) (II D) in the presence of a base, e.g. ethyldiisopropylamine.
  • a base e.g. ethyldiisopropylamine.
  • Salts of compounds of formulae (I) and (I A) can be prepared in a manner known perse.
  • acid addition salts of compounds of formulae (I) and (I A) are obtained by treatment with an acid or a suitable ion ex change reagent.
  • Acid addition salts can be converted into the free compounds in customary manner, e.g. by treatment with a suitable basic agent.
  • Resulting acid addition salts can be converted into other salts in a manner known perse, for example by treatment with a suitable metal salt, such as a sodium, barium or silver salt, of a different acid in a suitable solvent in which an inorganic salt formed is insoluble and is therefore eliminated from the reaction equilibrium.
  • a suitable metal salt such as a sodium, barium or silver salt
  • the compounds of formulae (I) and (I A), including their salts, may also be obtained in the form of hydrates or may include the solvent used for crystallisation (solvates).
  • any reference to the free compounds and their salts is to be understood as including also the corresponding salts and free compounds, respectively, as appropriate and expedient.
  • the resulting compound of working example 104 may be used as starting material, e.g. for the manufacture of corresponding acylated or alkylated derivatives thereof.
  • Said compound can also be used for the treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dyslipidaemia and hypertonia.
  • eating disorders such as obesity, bulimia nervosa, diabetes, dyslipidaemia and hypertonia.
  • they could be used in the treatment of loss of memory, epileptic convulsions, migraine, sleep disorders and pain, and additionally in the treatment of sexual disorders, depression, anxiety states, cerebral haemorrhages, shock, decompensated cardiac insufficiency, nasal congestion and diarrhoea.
  • the compound of example 103 and its use is also a subject matter of the present invention.
  • Resulting mixtures of diastereoisomers and mixtures of racemates can be separated into the pure diastereoisomers and enantiomers in known manner on the basis of the physico- chemical differences between the constituents, for example by means of chromatography and/or fractional crystallisation. _ ⁇ .
  • novel compounds of formula (I) can be used, for example, in the form of pharmaceutical compositions which contain a therapeutically effective amount of the active ingredient, as appropriate together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers that are suitable for enteral, e.g. oral, or parenteral administration.
  • the pharmaceutical compositions in question which, if desired, may contain further pharmacologically active substances, are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising procedures, and contain from approximately 0.1% to 100%, especially from approximately 1 % to approxi mately 50%, or in the case of lyophilisates up to approximately 100 %, active ingredient.
  • the invention relates also to the use of the compounds of formula (I), especially in the preparation of pharmaceutical compositions.
  • the dosage may depend upon various factors, such as the mode of administration, species, age and/or individual condition.
  • the daily doses to be administered are, in the case of oral administration, from about 0.25 to about 10 mg/kg and, for warm-blooded animals having a body weight of about 70 kg, especially from about 20 mg to about 500 mg.
  • the starting material can be prepared, for example, as follows:
  • R 3 is, for example, phenyl that is unsubstituted or substituted by halogen, d-dalkoxy, amino, d-dalkylamino or by di-d-dalkylamino:
  • ⁇ -bromoacetophenones that are not commercially available are obtained by treamtent of the corresponding acetophenones with one equivalent of bromine in acetic acid.
  • the starting material can be prepared, for example, as follows:
  • Product still present in the water is obtained by salting out the aqueous phase and extracting with tetrahydrofuran and is combined with the methylene chloride phase. Drying over sodium sulfate and concentration by evaporation are _ gg .
  • Example 106 r4-(2-Methoxymethyl-pyrrolidine-1-sulfonyl)-phenvn-(4-phenyl-1 H-imidazol-2-yl)-amine
  • the mixture is maintained under reflux for 3 hours and then, after a further 12, 6, 9 and 35 hours (always reflux), there are additionally added each time 0.3 equivalent of 2- amino-1-phenyl-ethanone hydrochloride and 0.4 equivalent of ethyldiisopropylamine.
  • the mixture is then concentrated, taken up in methylene chloride and washed with water, and the organic phase is dried over sodium sulfate.
  • the crude product is separated by means of flash chromatography (100 g of silica gel 60, eluant petroleum ether/ethyl acetate 3:8).
  • 5-Chlorophenylthiazole derivatives are obtained by treatment of the hydrochloride salts of the corresponding unsubstituted products with meta-chloroperbenzoic acid in methylene chloride (methanol may be added, depending upon the solubility of the reactants) or by
  • reaction mixture is stirred at room temperature for 4 hours, washed with 0.5N aqueous NaOH and once with water, dried and crystallised from ether/ethyl acetate, yielding [5-chloro-4-(3-fluoro-phenyl)-thiazol-2-yl]-[4-(2- methanesulfonylmethyl-pyrrolidine-1-sulfonyl)-phenyl]-amine.
  • Example 76 The starting material for Example 76 can be obtained, for example, as follows:
  • Example 70 or 71 is obtained by treatment of the tosylate of ⁇ 1 -[4-(4-phenyl- thiazol-2-ylamino)-benzenesulfonyl]-pyrrolidin-2-yl ⁇ -methanol (obtained by treatment of the alcohol with tosyl chloride in pyridine) with methylamine and dimethylamine, respectively.
  • Example 48 is obtained by reduction of the corresponding nitro derivative by means of hydrogenation (10 % Pd/carbon, THF or methanol). _ ⁇ _
  • Example 68 is obtained by formylation of the compound of example 48 with the mixed anhydride of formic acid and acetic acid and subsequent reduction with lithium aluminium hydride in tetrahydrofuran.
  • the amine of the sulfonamide from Example 68 is obtained by Wittig reaction (instant ylid) with the aldehyde of Z-proline and subsequent hydrogenation:
  • the amine of the sulfonamide from Example 103 is obtained by reaction of the acid chloride of Z-proline with methylmagnesium chloride at -78 °C and subsequent hydrogenation. See Example above.
  • the amine of the sulfonamide from Example 80 is obtained by treatment of the oxime of the aldehyde of Z-proiine with carbonyidiimidazole and subsequent hydrogenation:
  • Hard gelatin capsules comprising 100 mg of active ingredient, e.g. [4-(2-methoxymethyl-pyrrolidine-1-sulfonyl)-phenyl]-(4-phenyl-thiazol-2-yl)-amine or a salt, e.g. the hydrochloride, thereof, can be prepared, for example, as follows:
  • Composition for 1000 capsules
  • the sodium lauryl sulfate is added through a sieve of 0.2 mm mesh size to the lyophilised active ingredient.
  • the two components are mixed homogeneously together.
  • the lactose is added through a sieve of 0.6 mm mesh size and then the microcrystalline cellulose is added through a sieve of 0.9 mm mesh size.
  • the mixture is then mixed homogeneously again for 10 minutes.
  • magnesium stearate is added through a sieve of 0.8 mm mesh size. After being mixed for a further 3 minutes, the resulting formulation is introduced in 390 mg portions into size 0 hard gelatin capsules.

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Abstract

Cette invention concerne un composé, ou l'un de ses sels, représenté par la formule (I). L'invention concerne plus particulièrement un sel pharmaceutiquement acceptable de ce composé. L'invention concerne également des procédés de préparation associés, des compositions pharmaceutiques et l'utilisation des composés de formule (I) ainsi que de leurs sels. Dans la formule (I), X est S ou NH, et Y et Z sont chacun CH. X peut également être NH, l'une des variables Y ou Z étant N l'autre étant CH. R1 et R2 sont indépendamment hydrogène, C1-C7 alkyle ou C1-C7 alkyle substitué par hydroxy, par halogène, par alcoxy C1-C7, par carboxy, par C1-C7 alcoxycarbonyle, par carbamoyle, par C1-C7 alkylcarbamoyle, par di-C1-C7 alkylcarbamoyle, par C3-C8 cycloalkyle ou par C3-C8 cycloalkyle lui-même substitué par C1-C7 alcoxy-carbonyle; R1 et R2 peuvent également être C2-C7 alcanoyle. Par contre, l'une au moins des variables R1 et R2 est différente d'hydrogène. Le groupe NR1R2 peut également être C2-C6 alkylèneamino linéaire non substitué ou C2-C6 alkylèneamino linéaire substitué. Le cycle A, sauf à être substitué par -SO2NR1R2 et -NH-, est non substitué ou substitué une ou plusieurs fois. Le cycle B est substitué une ou deux fois via un atome de carbone du cycle B.
PCT/EP1998/008333 1997-12-22 1998-12-18 Derives de benzenesulfonamide substitues et leur utilisation pharmaceutique WO1999032466A1 (fr)

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US6191160B1 (en) 1998-11-10 2001-02-20 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
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US6222040B1 (en) 1999-06-30 2001-04-24 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (tricyclics)
US6225330B1 (en) 1999-06-30 2001-05-01 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (tricyclics)
WO2001037826A1 (fr) * 1999-11-26 2001-05-31 Shionogi & Co., Ltd. Antagonistes npyy5
US6340683B1 (en) 1999-04-22 2002-01-22 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (triazines)
EP1183245A1 (fr) * 1999-04-22 2002-03-06 Synaptic Pharmaceutical Corporation Antagonistes selectifs npy (y5)
WO2002030923A1 (fr) * 2000-10-13 2002-04-18 Les Laboratoires Servier Nouveaux composes aminotriazolones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2003043985A1 (fr) * 2001-11-21 2003-05-30 Novartis Ag Composes heterocycliques et procedes d'utilisation
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EP1381360A1 (fr) * 2001-03-29 2004-01-21 SmithKline Beecham Corporation Composes et procedes pour inhiber la metap2 chez les mammiferes
WO2004092146A2 (fr) * 2003-04-14 2004-10-28 The Institutes For Pharmaceutical Discovery, Llc Acides phenylalcanoiques substitues
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US20160263125A1 (en) * 2013-10-01 2016-09-15 Ann Marie Schmidt Amino, amido and heterocyclic compounds as modulators of rage activity and uses thereof
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US6191160B1 (en) 1998-11-10 2001-02-20 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
US6638942B1 (en) 1998-11-10 2003-10-28 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
US6495559B2 (en) 1998-11-10 2002-12-17 Merck & Co., Inc. NPY Y5 receptor antagonists
US6313298B1 (en) 1998-11-10 2001-11-06 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
US6245916B1 (en) * 1999-04-15 2001-06-12 Adir Et Compagnie Aminotriazole compounds
EP1044970A1 (fr) * 1999-04-15 2000-10-18 Adir Et Compagnie Nouveaux composés aminotriazoles, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
US6340683B1 (en) 1999-04-22 2002-01-22 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (triazines)
EP1183245A4 (fr) * 1999-04-22 2002-10-02 Synaptic Pharma Corp Antagonistes selectifs npy (y5)
EP1816127A1 (fr) * 1999-04-22 2007-08-08 H. Lundbeck A/S Dérivés triazines utiles comme des antagonistes sélectifs du npy(y5)
US7189720B2 (en) 1999-04-22 2007-03-13 H. Lundbeck A/S Selective NPY (Y5) antagonists
EP1183245A1 (fr) * 1999-04-22 2002-03-06 Synaptic Pharmaceutical Corporation Antagonistes selectifs npy (y5)
US6989379B1 (en) 1999-04-22 2006-01-24 H. Lundbick A/S Selective NPY (Y5) antagonists
US6569856B2 (en) 1999-04-22 2003-05-27 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (triazines)
US6222040B1 (en) 1999-06-30 2001-04-24 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (tricyclics)
US7273880B2 (en) 1999-06-30 2007-09-25 H. Lunbeck A/S Selective NPY (Y5) antagonists
US6218408B1 (en) 1999-06-30 2001-04-17 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (bicyclics)
US6214853B1 (en) 1999-06-30 2001-04-10 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (bicyclics)
US6225330B1 (en) 1999-06-30 2001-05-01 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (tricyclics)
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EP2014285A1 (fr) * 1999-11-26 2009-01-14 Shionogi&Co., Ltd. Antagonistes NPYY5
US7781461B2 (en) 1999-11-26 2010-08-24 Yasuyuki Kawanishi NPY Y5 antagonist
US7265130B2 (en) 1999-11-26 2007-09-04 Shionogi & Co., Ltd. NPY Y5 antagonist
US6699891B1 (en) 1999-11-26 2004-03-02 Shionogi & Co., Ltd. Npyy5 antagonists
US8115027B2 (en) 1999-11-26 2012-02-14 Shionogi & Co., Ltd. NPY Y5 antagonist
WO2001037826A1 (fr) * 1999-11-26 2001-05-31 Shionogi & Co., Ltd. Antagonistes npyy5
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US7105550B2 (en) 2000-03-01 2006-09-12 Christopher Love 2,4-disubstituted thiazolyl derivatives
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FR2815346A1 (fr) * 2000-10-13 2002-04-19 Servier Lab Nouveaux composes aminotriazolones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
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AR014406A1 (es) 2001-02-28
ZA9811705B (en) 1999-09-07
AU2415299A (en) 1999-07-12
PE20000127A1 (es) 2000-03-14

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