WO2000026208A1 - N-oxydes de composes heterocycliques avec activite inhibitrice de tnf et pde-iv - Google Patents

N-oxydes de composes heterocycliques avec activite inhibitrice de tnf et pde-iv Download PDF

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Publication number
WO2000026208A1
WO2000026208A1 PCT/GB1999/003628 GB9903628W WO0026208A1 WO 2000026208 A1 WO2000026208 A1 WO 2000026208A1 GB 9903628 W GB9903628 W GB 9903628W WO 0026208 A1 WO0026208 A1 WO 0026208A1
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Prior art keywords
amide
carboxylic acid
oxypyridin
trifluoromethylquinoline
disease
Prior art date
Application number
PCT/GB1999/003628
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English (en)
Inventor
Hazel Joan Dyke
John Gary Montana
Original Assignee
Darwin Discovery Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP99954132A priority Critical patent/EP1045845A1/fr
Application filed by Darwin Discovery Limited filed Critical Darwin Discovery Limited
Priority to CA002312430A priority patent/CA2312430A1/fr
Priority to KR1020007007402A priority patent/KR20010033842A/ko
Priority to NZ504933A priority patent/NZ504933A/en
Priority to JP2000579596A priority patent/JP2002528541A/ja
Priority to HU0100570A priority patent/HUP0100570A3/hu
Priority to SK1008-2000A priority patent/SK10082000A3/sk
Priority to BR9906719-6A priority patent/BR9906719A/pt
Priority to PL99341732A priority patent/PL341732A1/xx
Priority to IL13639899A priority patent/IL136398A0/xx
Priority to AU10571/00A priority patent/AU735574B2/en
Publication of WO2000026208A1 publication Critical patent/WO2000026208A1/fr
Priority to NO20003439A priority patent/NO20003439D0/no

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    • 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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to novel heterocyclic compounds and to their formulation and use as pharmaceuticals.
  • EP-A-0498722 describes quinoline derivatives as angiotensin A 2 and endothelin inhibitors.
  • This invention provides novel compounds having therapeutic utility, in particular for the treatment of disease states associated with proteins which mediate cellular activity, for example by inhibiting TNF and/or PDE IV.
  • the compounds are of formula (i):
  • R is CH 3 , CH 2 F, CHF 2 or CF 3
  • R 2 is CH 3 or CF ;
  • R 3 is F, Cl, Br, CN or CH 3 ;
  • R 4 is H, F, Cl, Br, CN or CH 3 ; or a pharmaceutically-acceptable salt thereof.
  • the compounds of the invention are N-oxides of the corresponding free bases which are disclosed, some specifically, in WO-A-9744036.
  • the novel compounds have superior solubility, improved metabolic stability, and an improved pharmacokinetic profile.
  • the compound of Example 8 is particularly preferred.
  • This invention provides also a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (i) or a pharmaceutically- acceptable salt thereof.
  • a compound of Formula (i) or a pharmaceutically- acceptable salt thereof comprises administering to said mammal an effective amount of a compound of Formula (i) or a pharmaceutically- acceptable salt thereof.
  • acid addition salts include pharmaceutically-acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide, and pharmaceutically-acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphate, ⁇ -ketoglutarate, ⁇ -glycerophosphate and glucose- 1 -phosphate.
  • the pharmaceutically-acceptable salts of the compounds of formula (i) are prepared using conventional procedures. Compounds of the invention may be prepared by N-oxidation of the corresponding free base. The free bases are known, or can be prepared by the processes disclosed in
  • a compound of formula (i) may be prepared by treating the free base with peracetic acid in acetic acid in an appropriate solvent such as chloroform, or with hydrogen peroxide in acetic acid.
  • the invention includes the prevention and treatment of TNF mediated disease or disease states, by which is meant any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6.
  • TNF- ⁇ also known as lymphotoxin
  • TNF- ⁇ also known as cachectin
  • PDE IV inhibitors are useful in the treatment of a variety of allergic and inflammatoiy diseases, including: asthma, chronic bronchitis, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, psoriasis, Bechet's disease, erythematosis, anaphylactoid purpura nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome.
  • asthma chronic bronchitis
  • PDE IV inhibitors are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease, depression and multi-infarct dementia. PDE IV inhibitors are also useful in conditions ameliorated by neuroprotectant activity, such as cardiac arrest, stroke and intermittent claudication. Additionally, PDE IV inhibitors could have utility as gastroprotectants.
  • a special embodiment of the therapeutic methods of the present invention is the treatment of asthma.
  • the viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (i).
  • viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.
  • CMV cytomegalovirus
  • influenza influenza
  • adenovirus adenovirus
  • Herpes group of viruses such as, but not limited to, Herpes zoster and Herpes simplex.
  • This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (i) or a pharmaceutically-acceptable salt thereof.
  • HAV human immunodeficiency virus
  • TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • viruses include, but are not limited to feline immunodeficiency virus (FIV) or other retroviral infection such as equine infectious anaemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
  • FMV feline immunodeficiency virus
  • retroviral infection such as equine infectious anaemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
  • the compounds of this invention are also useful in treating parasite, yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production /// vivo.
  • a preferred disease state for treatment is fungal meningitis.
  • the compounds of formula (i) are preferably in pharmaceutically-acceptable form.
  • pharmaceutically-acceptable form is meant, inter alia, a pharmaceutically-acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a pharmaceutically- acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95%.
  • pharmaceutically-acceptable encompasses materials suitable for both human and veterinary use.
  • a compound of formula (i) or where appropriate a pharmaceutically-acceptable salt thereof and/or a pharmaceutically-acceptable solvate thereof may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically- acceptable carrier. Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (i) or where appropriate a pharmaceutically-acceptable salt thereof and/or a pharmaceutically-acceptable solvate thereof, and a pharmaceutically- acceptable carrier.
  • the active compound may be formulated for administration by any suitable route, the preferred route depending upon the disorder for which treatment is required, 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 administration or through the respiratory tract. Preparations may be designed to give slow release of the active ingredient.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc.
  • the compounds of the invention are effective in the treatment of humans.
  • compositions of the invention may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions. Topical formulations are also envisaged where appropriate.
  • a composition of the invention is in the form of a unit dose.
  • Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example microcrystalline cellulose, lactose, sugar, maize- starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically-acceptable wetting agents such as sodium lauryl sulphate.
  • Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Oral liquid preparations 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 preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia, non- aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose,
  • compositions may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebuliser, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of active compound suitably have diameters of less than 50 ⁇ m, such as from 0J to 50 ⁇ m, preferably less than 10 ⁇ m, for example from 1 to 10 ⁇ m, 1 to 5 ⁇ m or from 2 to 5 ⁇ m.
  • small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
  • sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine
  • corticosteroids such as prednisolone
  • adrenal stimulants such as ACTH
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% to 99% by weight, preferably from 10- 60% by weight, of the active material, depending on the method of administration.
  • Compounds of formula (i), or if appropriate a pharmaceutically-acceptable salt thereof and/or a pharmaceutically-acceptable solvate thereof, may also be administered as a topical formulation in combination with conventional topical excipients.
  • Topical formulations may be presented as, for instance, ointments, creams or lotions, impregnated dressings, gels, gel sticks, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Suitable cream, lotion, gel, stick, ointment, spray or aerosol formulations that may be used for compounds of formula (i) or if appropriate a pharmaceutically-acceptable salt thereof, are conventional formulations well known in the art, for example, as described in standard text books such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the British and US Pharmacopoeias.
  • the compound of formula (i), or if appropriate a pharmaceutically- acceptable salt thereof will compromise from about 0.5 to 20% by weight of the formulation, favourably from about 1 to 10%, for example 2 to 5%.
  • suitable unit doses may be 0.1 to 1000 mg, such as 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg, for example 0.5, 1, 2, 3, 4 or 5 mg; and such unit doses may be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total daily dosage for a 70 kg adult is in the range of about 0.1 to 1000 mg, that is in the range of about 0.001 to 20 mg/kg/day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5 mg/kg/day, for example 0.01 , 0.02, 0.04, 0.05, 0.06, 0.08, 0J or 0.2 mg/kg day, and such therapy may extend for a number of weeks or months.
  • Assay Methods may be 0.1 to 1000 mg, such as 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg, for example 0.5, 1, 2, 3, 4 or 5 mg; and such unit doses may be administered
  • the assays used to confirm the phosphodiesterase IV inhibitory activity of compounds of formula (1) are standard assay procedures as disclosed by Schilling et al, Anal. Biochem. 216: 154 (1994), Thompson and Strada, Adv. Cycl. Nucl. Res. 8:119 (1979) and Gristwood and Owen, Br. J. Pharmacol. 87:91P (1986).
  • PMBC peripheral blood mononuclear cells
  • the pharmacokinetic profile of the compounds of the invention is determined in rats cannulated in the right carotid artery for blood collection.
  • the compound is prepared in a suitable formulation, for example 10% v/v DMSO, 50% v/v PEG 400 in water, and dosing is carried out by cannulation of the left jugular vein. Samples are collected at 5min, 0.5, 1, 2, 4, 6 and 8 hours post-dosing.
  • the compound is prepared in a suitable formulation such as 0.4% w/v methylcellulose in water. Samples are collected at 0.5, 1, 2, 4, 6 and 8 hours post-dosing. In some cases, samples are also collected at 12 hours post-dosing. Plasma is obtained by centrifiigation of the each blood sample and drug concentration is then determined using standard methods, such as liquid chromatography-mass spectrometry following protein precipitation.
  • Results are tabulated below, and are also shown in the accompanying drawing.
  • the drawing is a graph of PK data following oral dosing in the rat; PC (plasma concentration; ng/ml) is plotted against t (time; hours).
  • ⁇ represents the compound of Example 8, and • the free base. The superiority of the novel compound is evident.
  • Example 2 8-Difluoromethoxy-2-trifluoro ⁇ nethyIquinoline-5-carboxylic acid (3-chloro-l-oxypyridin-4-yl)a ⁇ nide Prepared from 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3- chloropyridin-4-yl)amide (261 mg) to give the product (223 mg) as a cream solid.
  • TLC R f 0.4 ethyl acetate
  • Example 8 8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5- dichloro-l-oxypyridin-4-yl)amide 8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dichloropyridin-4- yl)amide (200mg) was stirred in the presence of peracetic acid (36-40% in acetic acid, OJml) in chloroform at 50°C for 5 days. Additional peracetic acid (0.1ml) was added and the reaction heated for a further 2 days. Purification by column chromatography eluting with 10% methanol in ethyl acetate gave the product (123mg) as a white solid. TLC R r 0J 7 ( 10% methanol in ethyl acetate) mp 280-281°C
  • Example 9 8-Difluoromethoxy-2-trifluoromethylquinoline-5-carboxyIic acid (3,5-dichloro-l-oxypyridin-4-yl)an ⁇ ide Prepared from 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dichloropyridin-4-yl)amide (415mg) in a similar manner to 8-methoxy-2- trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro- l-oxy-pyridin-4-yl)-amide.
  • Example 10 8-Difluoromethoxy-2-methyIquinoIine-5-carboxyiic acid (3- methyl-l-oxypyridin-4-yI)amide Sodium hydride (60% dispersion in oil, 0.1 lg) was added to a stirred solution of

Abstract

La présente invention concerne des N-oxydes représentés par la formule (i) dans laquelle R1 est CH3, CH2F, CHF2 ou CF3; R2 est CH3 ou CF3; R3 est F, Cl, Br, CN ou CH3; et R4 est H, F, Cl, Br, CN or CH3; ainsi que des sels desdits composés acceptables au plans pharmaceutique, qui sont utiles comme agents thérapeutiques, notamment pour le traitement de maladies inflammatoires.
PCT/GB1999/003628 1998-11-04 1999-11-02 N-oxydes de composes heterocycliques avec activite inhibitrice de tnf et pde-iv WO2000026208A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
HU0100570A HUP0100570A3 (en) 1998-11-04 1999-11-02 N-oxides of heterocyclic compounds with tnf and pde-iv inhibiting activity and their pharmaceutical use
CA002312430A CA2312430A1 (fr) 1998-11-04 1999-11-02 N-oxydes de composes heterocycliques avec activite inhibitrice de tnf et pde-iv
KR1020007007402A KR20010033842A (ko) 1998-11-04 1999-11-02 티엔에프 및 피디이-ⅳ 억제 활성을 갖는 헤테로시클릭화합물의 엔-옥사이드
NZ504933A NZ504933A (en) 1998-11-04 1999-11-02 Substituted quinoline-carboxylic acid (pyridinyl)amides and use as inhibitors of tumour necrosis factor and phosphodiesterase-IV
JP2000579596A JP2002528541A (ja) 1998-11-04 1999-11-02 Ｔｎｆおよびｐｄｅ−ｉｖ阻害活性を有する複素環式化合物のｎ−オキシド
EP99954132A EP1045845A1 (fr) 1998-11-04 1999-11-02 N-oxydes de composes heterocycliques avec activite inhibitrice de tnf et pde-iv
SK1008-2000A SK10082000A3 (sk) 1998-11-04 1999-11-02 Zlúčeniny heterocyklických n-oxidov
IL13639899A IL136398A0 (en) 1998-11-04 1999-11-02 N-oxides of heterocyclic compounds with tnf and pde-iv inhibiting activity
PL99341732A PL341732A1 (en) 1998-11-04 1999-11-02 N-oxides of heterocyclic compounds capable to inhibit thf and pde-iv
BR9906719-6A BR9906719A (pt) 1998-11-04 1999-11-02 "n-óxidos de compostos heterocìclicos com atividade inibidora de tnf e de pde-iv"
AU10571/00A AU735574B2 (en) 1998-11-04 1999-11-02 N-oxides of heterocyclic compounds with TNF and PDE-IV inhibiting activity
NO20003439A NO20003439D0 (no) 1998-11-04 2000-07-03 N-oksyder av heterocykliske forbindelser med TNF og PDE-IV inhibiterende aktivitet

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9824160.7 1998-11-04
GBGB9824160.7A GB9824160D0 (en) 1998-11-04 1998-11-04 Heterocyclic compounds and their therapeutic use

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001056988A1 (fr) * 2000-02-01 2001-08-09 Kirin Beer Kabushiki Kaisha Composes contenant de l'azote et possedant une activite d'inhibition des kinases, et medicaments comprenant ces composes
WO2007045979A1 (fr) 2005-10-19 2007-04-26 Ranbaxy Laboratories Limited Compositions pharmaceutiques d'antagonistes du recepteur muscarinique
US7947705B2 (en) 2003-04-24 2011-05-24 Biotie Therapies Gmbh 7-azaindoles and the use thereof as therapeutic agents
WO2017089347A1 (fr) 2015-11-25 2017-06-01 Inserm (Institut National De La Sante Et De La Recherche Medicale) Procédés et compositions pharmaceutiques pour le traitement de mélanomes résistant aux inhibiteurs de braf

Families Citing this family (2)

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MXPA06002917A (es) * 2003-09-15 2006-05-31 Schering Corp Sintesis de quinolina 5-carboxamidas utiles para la preparacion de inhibidores de fosfodiesterasa iv.
US20070048389A1 (en) * 2005-08-26 2007-03-01 Fu-Pao Tsao Stabilized and preserved ketotifen ophthalmic compositions

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WO1997044036A1 (fr) * 1996-05-20 1997-11-27 Darwin Discovery Limited Carboxamides de quinoline en tant qu'inhibiteurs de tnf et inhibiteurs de la photodiesterase-iv
WO1997048697A1 (fr) * 1996-06-19 1997-12-24 Rhone-Poulenc Rorer Limited Composes azabicycliques substitues et leur utilisation en tant qu'inhibiteurs de la production de tnf et de la photodiesterase cyclique d'amp

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WO1997044036A1 (fr) * 1996-05-20 1997-11-27 Darwin Discovery Limited Carboxamides de quinoline en tant qu'inhibiteurs de tnf et inhibiteurs de la photodiesterase-iv
WO1997048697A1 (fr) * 1996-06-19 1997-12-24 Rhone-Poulenc Rorer Limited Composes azabicycliques substitues et leur utilisation en tant qu'inhibiteurs de la production de tnf et de la photodiesterase cyclique d'amp

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REGAN J ET AL: "2-substituted-4-methoxybenzimidazole-based PDE4 inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,GB,OXFORD, vol. 8, no. 19, 6 October 1998 (1998-10-06), pages 2737 - 2742, XP004139611, ISSN: 0960-894X *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001056988A1 (fr) * 2000-02-01 2001-08-09 Kirin Beer Kabushiki Kaisha Composes contenant de l'azote et possedant une activite d'inhibition des kinases, et medicaments comprenant ces composes
US7217722B2 (en) 2000-02-01 2007-05-15 Kirin Beer Kabushiki Kaisha Nitrogen-containing compounds having kinase inhibitory activity and drugs containing the same
US7947705B2 (en) 2003-04-24 2011-05-24 Biotie Therapies Gmbh 7-azaindoles and the use thereof as therapeutic agents
WO2007045979A1 (fr) 2005-10-19 2007-04-26 Ranbaxy Laboratories Limited Compositions pharmaceutiques d'antagonistes du recepteur muscarinique
WO2017089347A1 (fr) 2015-11-25 2017-06-01 Inserm (Institut National De La Sante Et De La Recherche Medicale) Procédés et compositions pharmaceutiques pour le traitement de mélanomes résistant aux inhibiteurs de braf

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KR20010033842A (ko) 2001-04-25
CO5160316A1 (es) 2002-05-30
AR021094A1 (es) 2002-06-12
IL136398A0 (en) 2001-06-14
GB9824160D0 (en) 1998-12-30
JP2002528541A (ja) 2002-09-03
RU2205830C2 (ru) 2003-06-10
ZA200002604B (en) 2001-05-28
HUP0100570A2 (hu) 2001-10-28
CN1287555A (zh) 2001-03-14
PE20001232A1 (es) 2000-11-28
CA2312430A1 (fr) 2000-05-11
AU735574B2 (en) 2001-07-12
HUP0100570A3 (en) 2002-12-28
EP1045845A1 (fr) 2000-10-25
NO20003439L (no) 2000-07-03
NZ504933A (en) 2001-10-26
SK10082000A3 (sk) 2001-01-18
NO20003439D0 (no) 2000-07-03
TR200001941T1 (tr) 2001-01-22
BR9906719A (pt) 2000-10-17
AU1057100A (en) 2000-05-22
TW546296B (en) 2003-08-11

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