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WO1996002509A1 - Derives de quinoline utilises comme antagonistes de la neurokinine 3 (nk3) - Google Patents

Derives de quinoline utilises comme antagonistes de la neurokinine 3 (nk3) Download PDF

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Publication number
WO1996002509A1
WO1996002509A1 PCT/EP1995/002638 EP9502638W WO9602509A1 WO 1996002509 A1 WO1996002509 A1 WO 1996002509A1 EP 9502638 W EP9502638 W EP 9502638W WO 9602509 A1 WO9602509 A1 WO 9602509A1
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WO
WIPO (PCT)
Prior art keywords
disorders
alkyl
compound
hydrogen
formula
Prior art date
Application number
PCT/EP1995/002638
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English (en)
Inventor
Carlo Farina
Giuseppe Arnaldo Maria Giardina
Mario Grugni
Luca Francesco Raveglia
Original Assignee
Smithkline Beecham Farmaceutici S.P.A.
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 Smithkline Beecham Farmaceutici S.P.A. filed Critical Smithkline Beecham Farmaceutici S.P.A.
Publication of WO1996002509A1 publication Critical patent/WO1996002509A1/fr

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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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2

Definitions

  • the present invention relates to the use of certain quinoline derivatives in medicine.
  • the mammalian peptide Neurokinin B belongs to the Tachykinin (TK) peptide family which also include Substance P (SP) and Neurokinin A (NKA).
  • TK Tachykinin
  • SP Substance P
  • NKB Neurokinin A
  • NK3 receptor antagonists are known (Drapeau, 1990 Regul. Pept., 31, 125-135), and findings with peptidic NK3 receptor agonists suggest that NKB, by activating the NK3 receptor, has a key role in the modulation of neural input in airways, skin, spinal cord and nigro-striatal pathways (Myers and Undem, 1993, J. Phisiol, 470, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429;
  • a class of quinoline derivatives are active as selective, non-peptide NK3 antagonists and are far more stable from a metabolic point of view than the known peptidic NK3 receptor antagonists.
  • These derivatives are of potential therapeutic utility in treating pulmonary disorders (asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough), skin disorders and itch (for example, atopic dermatitis and cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinson's disease, movement disorders, anxiety, psychosis).
  • pulmonary disorders asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough
  • skin disorders and itch for example, atopic dermatitis and cutaneous wheal and flare
  • neurogenic inflammation and CNS disorders Parkinsoninson's disease, movement disorders, anxiety, psychosis.
  • the derivatives are also of potential therapeutic utility in treating convulsive disorders (for example epilepsy), renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders (for example Alzheimer's disease), psoriasis, Huntington's disease, and depression (hereinafter referred to as the Secondary Disorders).
  • convulsive disorders for example epilepsy
  • renal disorders urinary incontinence
  • ocular inflammation inflammatory pain
  • eating disorders food intake inhibition
  • allergic rhinitis neurodegenerative disorders
  • neurodegenerative disorders for example Alzheimer's disease
  • psoriasis Huntington's disease
  • depression hereinafter referred to as the Secondary Disorders.
  • Ar is an optionally substituted phenyl or naphthvl group or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;
  • R is an optionally substituted phenyl, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;
  • R is a group CH-R4R5, in which R4 is hydrogen, linear or branched Ci _g alkyl, C3.7 cycloalkyl, C4.7 cycloalkylalkyl, optionally substituted phenyl or phenyl C ⁇ g alkyl, optionally substituted five- membered heteroaromatic rings comprising up to four heteroatom selected from O and N, hydroxy Ci.g alkyl, amino Cj. ⁇ alkyl, Ci.g alkylaminoalkyl, di Ci .g alkylaminoalkyl, C ⁇ _6 acylaminoalkyl, Ci .g alkoxyalkyl, C ⁇ . alkylcarbonyl, carboxy, C ⁇ .
  • alkoxyxcarbonyl Cj-6 alkoxycarbonyl C ⁇ .(. alkyl, aminocarbonyl, C ⁇ _6 alkylaminocarbonyl, di C ⁇ alkylaminocarbonyl, halogeno C ⁇ . alkyl;
  • R5 is a linear or branched Ci . ⁇ alkyl or a group (C b Ar j , where n is 0, 1, 2 or 3 and Ari has the same meaning as Ar:
  • Ri is hydrogen or linear or branched Cj.g alkyl
  • R2 and R3 which may be the same or different, are independently hydrogen, linear or branched Ci .g alkyl, C2-6 alkenyl, aryl, carboxamido, sulphonamido, Cj.g alkoxy, hydroxy, halogen, nitro, cyano.
  • X is O. S, H 2 or N-C ⁇ N: for use as an active therapeutic substance.
  • Ar, R or Arl are phenyl, optionally substituted by one or more Cj.g alkoxy, Cj.g alkoxycarbonyl or one or more trifluoromethyl groups.
  • An example of Cj.g alkoxy is methoxy and an example of Cj.g alkoxycarbonyl is methoxycarbonyl .
  • Examples of Ar, R or Aq as a heterocyclic group are py ⁇ dyl.
  • R is a group CH-R4R5
  • examples of R4 are hydrogen and methoxycarbonyl.
  • R5 examples are i-propyl and when it is a group (CH2)n-Ar ⁇ , typically n is O or 1.
  • R2 and R3 are hydrogen, hydroxy, Cj.g alkyl, preferably methyl and Ci.g alkoxy, preferably methoxy.
  • a preferred group of compounds of formula (I) are those in which: Ar is phenyl, R is a group CH-R4R5, Ri is hydrogen, R2 is hydrogen, Ci.g alkoxy or hydroxy, R3 is hydrogen or Ci _g alkyl and X is oxygen.
  • a further preferred group of compounds of formula (I) are those in which: Ar is phenyl,
  • R is a group CH2Ar ⁇
  • R] is hydrogen
  • R2 is hydrogen, methoxy or hydroxy
  • R3 is methyl, and X is oxygen.
  • the compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceuncally acceptable form is meant, inter alia, of a pharmaceutically acceptable level of punty excluding normal pharmaceutical additives such as diluents and earners, and including no material considered toxic at normal dosage levels.
  • a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • Examples of pharmaceutically acceptable salts of a compound of formula (I) include the acid addition salts with the conventional pharmaceutical acids, for example maleic, hydrochloric, hydrobromic. phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric. succinic, benzoic, ascorbic, and methanesulphonic.
  • Examples of pharmaceutically acceptable solvates of a compound of formula (I) include hydrates.
  • the compounds of formula (I) may have one or more asymmetric centres and therefore may exist in more than one stereoisomeric form.
  • the invention extends to all such forms and to mixtures thereof, including racemates.
  • the compounds of formula (I) are either known compounds or can be made from known compounds by known methods.
  • Compounds of formula (I), and methods for their manufacture, are disclosed in the following publications:
  • the present invention also provides the use of a Compound, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Primary and Secondary Disorders (hereinafter referred to as the 'Conditions').
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a Compound, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • a medicament, and a composition of this invention may be prepared by admixture of a Compound with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner. These conventional excipients may be employed for example as in the preparation of compositions of known agents for treating the Conditions.
  • a pharmaceutical composition is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of the Conditions.
  • the suitable dosage range for the Compounds depends on the Compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
  • the Compounds or compositions may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • compositions may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyirolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like.
  • compositions may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • the composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.
  • compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose.
  • emulsifying agents for example lecithin, sorbitan monooleate, or acacia
  • aqueous or non-aqueous vehicles which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal
  • compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • a pharmaceutically acceptable liquid e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • the liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives.
  • Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
  • the Compounds may also be administered by inhalation, via the nasal or oral routes. Such administration can be carried out with a spray formulation comprising a Compound and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.
  • Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended panicles.
  • the compound panicle size is from about 2 to 10 microns.
  • a further mode of administration of the Compounds comprises transdermal delivery utilising a skin-patch formulation.
  • a preferred formulation comprises a Compound dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient.
  • pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.
  • the effective dose of Compound depends on the particular Compound employed, the condition of the patient and on the frequency and route of administration.
  • a unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in pa ⁇ icular 50, 100, 150, 200, 250. 300, 350, 400, 450, or 500 mg.
  • composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg.
  • unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
  • the present invention also provides a method for the treatment and/or prophylaxis of the Primary and Secondary Disorders in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and or prophylaxis an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • NK3 ligands The activity of the Compounds, as NK3 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK3 ligands, [ 125 I]-[Me-Phe 7 ]-NKB or [ ⁇ HJ-Senktide, to guinea-pig and human NK3 receptors (Renzetti et al, 1991, Neuropeptide, 18, 104-1 14; Buell et al, 1992, FEBS, 299(1), 90-95: Chung et al, 1994, Biochem. Biophys. Res. Com un., 198(3), 967-972).
  • binding assays allow the determination of the concentration of the individual compound required to reduce by 50% the [ ⁇ 5 .[Me-Phe ⁇ ]-NKB and [3H]-Senktide specific binding to NK3 receptor in equilibrium conditions (IC50). Binding assays provide for each Compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate.
  • the most potent Compounds show IC50 values in the range 100-2000 nM; in particular, in guinea-pig conex membranes by displacement of [125 _[M e _ph e 7].
  • the NK3-antagonist activity of the Compounds is determined by their ability to inhibit senktide-induced contraction of the guinea-pig ileum (Maggi et al, 1990, Br. J. Pharmacol., 101, 996- 1000) and rabbit isolated iris sphincter muscle (Hall et al., 1991, Eur. J. Pharmacol., 199, 9-14) and human NK3 receptors mediated Ca “1 " 1 " mobilization (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658).
  • Guinea-pig and rabbit in-vitro functional assays provide for each Compound tested a mean Kg value of 3-8 separate experiments, where Kjj is the concentration of the individual Compound required to produce a 2-fold rightward shift in the concentration-response curve of senktide.
  • Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca" 1-1" mobilization induced by the agonist NKB. In this assay, the Compounds behave as antagonists.
  • the therapeutic potential of the Compounds in treating the Conditions can be assessed using rodent disease models.
  • the following Descriptions illustrate the preparation of the intermediates, whereas the Examples illustrate the preparation of the Compounds.
  • the Compounds of the Examples are summarised in the Table.
  • reaction mixture was ice-cooled and quenched with 150 ml of H2O; the solvent was evaporated in-vacuo, 100 ml of CH2CI2 were added and the mixture was filtered over celite. The organic layer was separated, dried over N 2SO4, filtered and evaporated in-vacuo to dryness to yield 6.0 g of the title compound.
  • reaction mixture was evaporated in-vacuo to dryness to yield 1.5 g of the title compound, used without further purification.
  • the precipitated dicyclohexylurea was filtered off and the solution evaporated in- vacuo to dryness.
  • the residue was dissolved in CH2CI2 and washed with H2O, sat. sol. NaHCO3, 5% citric acid, sat. sol. NaHCO3 an ⁇ ⁇ sa so1 - NaCl.
  • reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in EtOAc and washed twice with a sat. sol. of NaHCO3.
  • the organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to dryness.
  • the crude product was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/ethyl acetate 3:2 containing 0.5% NH4OH.
  • the purified solid was dissolved in Et2 ⁇ and acidified with HCl/Et2 ⁇ ; the precipitate was collected by filtration and triturated with a mixture of -PrOH/z ' -PnO 1 : 1 to yield 0.1 g of the title compound.
  • N,N'-carbonyldiimidazole were added and the reaction mixture was kept at room temperature for 3 hours.
  • 0.65 ml (5.9 mmol) of benzylamine, dissolved in 5 ml of dry CT Cb, were added dropwise and the solution was kept at room temperature for 6 days and then evaporated in-vacuo to dryness.
  • the crude product was washed with warm CTbCb and MeOH and the residue was collected by filtration.
  • the reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in EtOAc and washed twice with a sat. sol. of NaHCO3-
  • the organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to dryness.
  • the residual oil was flash chromatographed on 230-400 mesh silica gel. eluting with ethyl acetate.
  • the purified solid obtained was triturated with /-PoO, filtered, washed and dried to yield 1.8 g of the title compound as a white solid.
  • thermospray interface eluent water/ acetonirrile 50 : 50.
  • the residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with hexane/ethyl acetate 50:50.
  • the purified solid obtained was triturated with -Pr2 ⁇ , filtered, washed and dried to yield 0.4 g of the title compound as a yellow solid.
  • the residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with hexane/ethyl acetate 80:20 containing 0.5% NH4OH.
  • the purified solid obtained was crystallized from toluene, filtered, washed and dried to yield 2.3 g of the title compound as a white solid.
  • the precipitated dicyclohexylurea was filtered off and the solution evaporated in- vacuo to dryness.
  • the residue was dissolved in CT Cb and washed with H2O, sat. sol. NaHCO3, 5% citric acid.
  • sat. sol. NaHCO3 ancl sat - so1 - Na Cl-
  • the organic layer was separated, dried over Na2 ⁇ 4 and evaporated in-vacuo to dryness; the residue was dissolved in 20 ml of CH2CI2 and left overnight.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Des antagonistes du récepteur de NK3 de la formule (I) conviennent au traitement de troubles pulmonaires et du système nerveux central.
PCT/EP1995/002638 1994-07-14 1995-07-06 Derives de quinoline utilises comme antagonistes de la neurokinine 3 (nk3) WO1996002509A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI941466A IT1270615B (it) 1994-07-14 1994-07-14 Uso di derivati di chinolina
ITMI94A001466 1994-07-14

Publications (1)

Publication Number Publication Date
WO1996002509A1 true WO1996002509A1 (fr) 1996-02-01

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Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019926A1 (fr) * 1995-11-24 1997-06-05 Smithkline Beecham S.P.A. Nouveaux derives de quinoline-4-carboxamide, leur preparation et leur utilisation en tant qu'antagonistes des recepteurs des neurokinines 3 (nk-3) et des neurokinines 2 (nk-2)
WO1997019927A1 (fr) * 1995-11-24 1997-06-05 Smithkline Beecham S.P.A. Derives de quinoline utilises en tant qu'antagonistes des neurokinines 3
WO1997021680A1 (fr) * 1995-11-24 1997-06-19 Smithkline Beecham S.P.A. Derives de quinoline
EP0983243A1 (fr) * 1997-03-14 2000-03-08 Smithkline Beecham Corporation Nouveaux quinoline- et naphthalenecarboxamides, compositions pharmaceutiques et procedes d'inhibition de la calpaine
WO2000013681A2 (fr) * 1998-09-04 2000-03-16 Vernalis Research Limited Derives de 4-quinolinemethanol utilises comme antagonistes (i) du recepteur de purine
WO2000031038A1 (fr) * 1998-11-20 2000-06-02 Smithkline Beecham S.P.A. Derives de quinoline utilises comme ligands des recepteurs nk-2 et nk-3
WO2000043008A1 (fr) * 1999-01-25 2000-07-27 Smithkline Beecham Corporation Anti-androgenes et procedes de traitement
WO2000058303A1 (fr) * 1999-03-29 2000-10-05 Neurogen Corporation Derives de quinoline 4-substitues comme ligands de recepteurs de nk-3 et/ou de gaba¿a?
WO2000064877A1 (fr) * 1999-04-26 2000-11-02 Neurogen Corporation 2-aminoquinolinecarboxamides: ligands de recepteurs de la neurokinine
WO2001034603A2 (fr) * 1999-11-12 2001-05-17 Neurogen Corporation Composes heteroaromatiques bicycliques et tricycliques
US6310212B1 (en) 2000-03-28 2001-10-30 Neurogen Corporation 4-substituted quinoline derivatives
WO2002013825A1 (fr) * 2000-08-11 2002-02-21 Smithkline Beecham P.L.C. Nouvelle utilisation pharmaceutique de dérivés quinnoliniques
US6432977B1 (en) * 1995-11-24 2002-08-13 Smithkline Beecham S.P.A. Salts of quinoline derivatives as NK3 antagonists
WO2002083645A1 (fr) * 2001-04-11 2002-10-24 Glaxosmithkline S.P.A. Nouveaux composes
US6521618B2 (en) 2000-03-28 2003-02-18 Wyeth 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors
WO2004072045A1 (fr) * 2003-02-11 2004-08-26 Merck Sharp & Dohme Limited Hydrazides d'acide carboxylique de 4-quinoleine substitues en tant que ligands du recepteur de nk-2/nk-3
US20060178514A1 (en) * 2004-12-31 2006-08-10 Anima Baruah Novel benzylamine derivatives as CETP inhibitors
WO2006130080A2 (fr) * 2005-06-03 2006-12-07 Astrazeneca Ab Derives de quinoline utilises comme antagonistes de nk3
WO2007012900A1 (fr) 2005-07-29 2007-02-01 Merck Sharp & Dohme Limited Dérivés de la quinoline en tant qu’antagonistes des récepteurs de la neurokinine
WO2007018465A1 (fr) * 2005-08-11 2007-02-15 Astrazeneca Ab Amide alkyl pyridiyl quinolines en tant que modulateurs du récepteur des nk3
WO2007018469A1 (fr) * 2005-08-11 2007-02-15 Astrazeneca Ab Modulateurs récépteurs nk3 en tant qu’amides de quinoléine oxopyridyl
US7217740B2 (en) 2004-08-27 2007-05-15 Merck Sharp And Dohme Diarylsulfones as 5-HT2A antagonists
EP1981882A1 (fr) * 2006-01-27 2008-10-22 AstraZeneca AB Quinoléines substituées par un amide
US7608628B2 (en) 2005-12-12 2009-10-27 Astrazeneca Ab Alkylsulphonamide quinolines
US7964733B2 (en) 2005-09-21 2011-06-21 Astrazeneca Ab Alkyl sulfoxide quinolines as NK-3 receptor ligands
US8357653B2 (en) 2000-11-16 2013-01-22 Maier Nathan C System and method for inhibiting cellular proliferation with tachykinins
WO2014004230A1 (fr) 2012-06-29 2014-01-03 Eli Lilly And Company Composés acide diméthyl-benzoïque
US9000007B2 (en) 2011-09-27 2015-04-07 Dr. Reddy's Laboratories Ltd. 5-benzylaminomethyl-6-aminopyrazolo [3, 4 -B] pyridine derivatives as cholesteryl ester-transfer protein (CETP) inhibitors useful for the treatment of atherosclerosis
WO2015094912A1 (fr) 2013-12-17 2015-06-25 Eli Lilly And Company Composés d'acide diméthylbenzoïque
US9199967B2 (en) 2011-08-18 2015-12-01 Dr. Reddy's Laboratories Ltd. Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (CETP) inhibitors
WO2016037954A1 (fr) 2014-09-09 2016-03-17 Bayer Pharma Aktiengesellschaft N,2-diarylquinoline-4-carboxamides substitués et utilisation desdits n,2-diarylquinoline-4-carboxamides substitués comme anti-inflammatoires
US9371289B2 (en) 2013-05-17 2016-06-21 Eli Lilly And Company Phenoxyethyl dihydro-1H-isoquinoline compounds
US9475773B2 (en) 2013-04-19 2016-10-25 Astrazeneca Ab NK3 receptor antagonist compound (NK3RA) for use in a method for the treatment of polycystic ovary syndrome (PCOS)
WO2017153235A1 (fr) 2016-03-09 2017-09-14 Bayer Pharma Aktiengesellschaft N-cyclo-3-aryl-1-naphthamides substitués et leur utilisation
WO2017153234A1 (fr) 2016-03-09 2017-09-14 Bayer Pharma Aktiengesellschaft N-cyclo-2-arylchinolin-4-carboxamides substitués et leur utilisation
WO2017153231A1 (fr) 2016-03-09 2017-09-14 Bayer Pharma Aktiengesellschaft N-cyclo-2-arylisochinolinon-4-carboxamides substitués et leur utilisation
WO2018189012A1 (fr) 2017-04-10 2018-10-18 Bayer Aktiengesellschaft N-aryléthyl-2-aminoquinoléine-4-carboxamides substitués et leur utilisation
WO2018189011A1 (fr) 2017-04-10 2018-10-18 Bayer Aktiengesellschaft N-aryléthyl-2-arylquinoléine-4-carboxamides substitués et leur utilisation
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