EP0873338A1 - Derives quinolines en tant qu'inhibiteurs des phosphodiesterases de type iv - Google Patents

Derives quinolines en tant qu'inhibiteurs des phosphodiesterases de type iv

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Publication number
EP0873338A1
EP0873338A1 EP96938196A EP96938196A EP0873338A1 EP 0873338 A1 EP0873338 A1 EP 0873338A1 EP 96938196 A EP96938196 A EP 96938196A EP 96938196 A EP96938196 A EP 96938196A EP 0873338 A1 EP0873338 A1 EP 0873338A1
Authority
EP
European Patent Office
Prior art keywords
benzo
quinoline
methyl
disease
treatment
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP96938196A
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German (de)
English (en)
Inventor
Rainer LÜÖND
Esteban Pombo Villar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma GmbH
Novartis AG
Original Assignee
Novartis Erfindungen Verwaltungs GmbH
Ciba Geigy AG
Novartis AG
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 Novartis Erfindungen Verwaltungs GmbH, Ciba Geigy AG, Novartis AG filed Critical Novartis Erfindungen Verwaltungs GmbH
Publication of EP0873338A1 publication Critical patent/EP0873338A1/fr
Withdrawn legal-status Critical Current

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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
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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 present invention relates to novel quinoline derivatives, processes for their production, their use as pharmaceuticals and pharmaceutical compositions containing them.
  • the present invention provides an 8-(benzo[c]thiadiazolyl, benzo[c]furazanyl, or 2-methyl-2H-benzo[(/Jtriazolyl)-quinoline, in free, N-oxide, or acid addition or ammonium salt form.
  • the 8-(benzo[c]thiadiazolyl, benzo[c]furazanyl, or 2- methyl-2H-benzo[ ⁇ /]triazolyl)-quinoline is optionally substituted on the quinoline nucleus, e.g.. at the 3- and/or 6-positions. Suitable substituents at the 3-position include C alkyl, e.g.. methv l.
  • Substituents at the 6-position are preferably linked via a carbon atom, i.e., to provide a 8-(benzo[c]thiadiazolyl, benzo[c]furazanyl, or 2-methyI-2H-benzo[J]triazolyl)-6-carbo-quinoline or a 8-(benzo[c]thiadiazolyl, benzo[c]furazanyl, or 2-methyl-2H-benzo[ ⁇ ]triazolyl)-3-(C M alkyl)-6-carbo-quinoline.
  • Particularly preferred at the 6-position is pyridylmethyl, e.g., pyridin-4-yl-methyl.
  • Preferred compounds thus include, for example, 8-(benzo[c]thiadiazolyl, benzo[c]furazanyl, or 2-methyl-2H-benzo[c/
  • 2-methyl-2H-benzo[t/]triazolyl is meant a radical of the following structure:
  • the 8-(benzo[c]thiadiazolyl. benzo[c]furazanyl, or 2-methyI-2H-benzo[c/]triazoly])- quinoline of the invention is preferably a compound of formula I:
  • X is -0-. -S-. or -N(CH 3 )- (preferably -O- or -S-),
  • R is hydrogen or (C )alkyl (preferably methyl or hydrogen), and
  • R is (C,. )alkyl or pyridyl (preferably 4-pyridyl) in free or N-oxide or pharmaceutically acceptable acid addition or ammonium salt form.
  • the invention includes compounds of formula I wherein X is O or S, R, is hydrogen or (C ,. 4 )alkyl, and R : is (C M )alkyl or pyridyl. in free base or acid addition salt form.
  • the 8-(benzo[c]thiadiazolyl, benzo[c]furazanyl, or 2-methyl-2H-bewzo[d]triazolyl)- quinoline of the invention is 8-(benzo[c]thiadiazol-3- or -4-yl)- or 8-(benzo[c]furazan-3- or -4-yl)- or 8-(2-methyl-2H-benzo[-7]triazol-4- or -5-yl)- -quinoline, preferably 8- (benzo[c]thiadiazol-4-yl)- or 8-(benzo[e]furazan-4-yl)- or 8-(2-methyl-2H-benzo[c/]triazol- 5-yl)-quinoline e.g., a compound of formula Ia:
  • Alkyl groups may be branched or straight chain, preferably straight chain, methyl being preferred.
  • the compounds may be in free form or may be associated with an acid to form an acid addition salt or with an alkyl halide to form an ammonium salt, or N-oxidated, and these different forms of the molecule are considered to be pharmaceutically useful.
  • Suitable pharmaceutically acceptable acid addition salts for use in accordance with the present invention include salts of inorganic acids, for example the hydrochloride from hydrochloric acid, and salts of organic acids, for example the hydrogen maleinate from maleic acid or the oxalate from oxalic acid.
  • Ammonium and N-oxide forms are provided particularly when R, is pyridyl such that the nitrogen in the pyridyl ring is alkylated or oxidized, e.g.
  • ammonium salts include N-alkylated (e.g., N-methylated) pyridinium salts and N-oxides include compounds of formula I or Ia wherein R 2 is N-oxo-pyridyl, e.g., l -oxo-pyridin-4-yl.
  • the present invention provides a process for the production of an 8- (benzo[c]thiadiazolyl, benzo[c]furazanyl, or 2-methyl-2H-benzo[-f
  • Q and Q' are halogen (e.g., bromine) or trifiuoromethanesulfonyl
  • the other is suitably a metallic or organometallic leaving group (e.g., B(OH) 2 -,
  • N-alkylating e.g. reacting with an alkyl halide, e.g., Mel
  • N-ozidizing e.g. reacting with an alkyl halide, e.g., Mel
  • the reaction is suitably carried out in the presence of a palladium or nickel catalyst with or without the addition of further metals such as copper, for example in analogy to known aryl coupling reactions, e.g. a Stille, Suzuki, Negishi or Heck reaction, for example as described in Example 1 .
  • aryl coupling reactions e.g. a Stille, Suzuki, Negishi or Heck reaction, for example as described in Example 1 .
  • Recovery and purification of the 8-(benzo[c]thiadiazolyl, benzo[c]furazanyl, or 2-methyl-2H-benzo[*/]triazolyl)-quinoline thus obtained may be accomplished using standard procedures, e.g., by chromatography or crystallization.
  • R, and R are as defined above and Y is (C,. 4 )alkyl, with a benzo[c]thiadiazole, benzo[c]furazan, or 2-methyl-2H-benzo[ ⁇ /)triazole of formula III
  • Y is preferably butyl, e.g., n-butyl.
  • Z is preferably bromine.
  • the starting compounds of formula II may be produced from the compounds of formula IV
  • R, and R 2 are as defined above, according to known methods.
  • the compounds of formula V can be obtained using 2-R r acrolein in the presence of an acid.
  • Ri is hydrogen
  • acroiein can be prepared in situ (quinoline synthesis according to Skraup).
  • the compounds of formulae III and IV are known or may be produced by known methods.
  • the compound of formula IV wherein R 2 is pyridin-4-yl, for example, may be prepared as described in the international patent application WO 94/22852.
  • the compound is obtained by Skraup quinoline synthesis as described in Manske R.H.F.. Organic Reactions, 7, 59 ( 1953), using 2-bromo-4-(pyridin-4-yl-methyl)- phenylamine (compound of formula IV).
  • Rf Silica gel, hexane - ethyl acetate - ethanol 65:35 : 1 0: 0.25; melting point: 96-99°C.
  • the combined aqueous extracts are made alkaline with aq. Na 2 C0 3 , and extracted with ethyl acetate.
  • the organic extracts are dried (Na 2 SO 4 ) to give a brown oil from which the title compound crystallizes. Melting point 154- 157°C; MS (FAB): 339 (MH+).
  • 2-Methyl-2H-benzo[d]triazole-5-boronic acid (240mg, 1 .36 mmol) and 8-bromo-6-(4-methylpyridyl)quinoline (470 mg, 1 .56 mmol) are kept at 90°C in 40 m l of toluene in the presence of Pd(OAc)2 ( 12 mg), P(o-tolyl)3 ( 17 mg), 2M Na2C03 solution ( 1.8 ml) and ethanol (0.5 ml) for 20 h. The cold reaction mixture is filtered, diluted with brine (80 ml) and extracted with ethyl acetate (3x50ml), dried over sodium sulfate, filtered and evaporated.
  • AGENTS OF THE INVENTION are selective inhibitors of the Type IV cAMP phosphodiesterase isoenzyme family, and have relatively little effect on the phosphodiesterase isoenzymes of Types I,II,III and V. As such AGENTS OF THE INVENTION can be used in conditions where elevation of cAMP levels through the selective inhibition of Type IV phosphodiesterase isoenzymes is useful. Since elevation of cAMP levels in inflammatory cells such as eosinophils inhibits their activation, AGENTS OF THE INVENTION are useful in inflammatory conditions in which eosinophil activation plays a role.
  • AGENTS OF THE INVENTION by virtue of their inhibition of Type IV phosphodiesterase in human eosinophils, are useful in the treatment of atopic and non- atopic asthma, as supported by the models of PDE inhibition, inhibition of eosinophil activation and bronchodilator models described below .
  • Type III and IV preparations are obtained taking advantage of the predominance of type III isoenzymes in platelets and type IV isoenzymes in neutrophils applying the following techniques: Citrated human blood is collected and neutrophils separated by dextran sedimentation, density gradient centrifugation on a mixture of Histopaque 1077 and 1 1 19 with a final density of 1 .089g/l and hypotonic lysis of erythrocytes. Human platelets from the same source are washed with PBS (NaCl 140 mM, KCl 2.7 mM, KH 2 P0 4 1 .5 mM. Na 2 HP0 4 8.1 M, pH 7.4).
  • PBS NaCl 140 mM, KCl 2.7 mM, KH 2 P0 4 1 .5 mM. Na 2 HP0 4 8.1 M, pH 7.4
  • Neutrophils and platelets are suspended in 10ml of buffer (0.24 M sucrose, 1 mM EDTA, I mM dithiothreitol, l OmM tris HCl, pH 7.4) containing the following protease inhibitor solutions: 5 ⁇ l/ml of phenylmethylsulphonylfluoride (7 mg/ml in 2-propanol), 1 ⁇ l/ml leupeptin and pepstatin A ( 1 mg/ml each, in ethanol). After sonication ( 15 sec at 4°C) using a probe sonicator, homogenates are centrifuged (2200g). The pellet is resuspended in 10ml of buffer and the sonication repeated. Pooled supernatants are stored at -20°C.
  • isoenzymes are partially purified employing chromatographic methods as described in the art (Types I and V from human lung, and type II from human platelets). PDE activity is assayed in the presence and absence of test substance at varying concentration using the ion-exchange column method described by Thompson et al., Nucleotide Res., J_0, 69-92 ( 1979). with l ⁇ M [ 3 H]-cyclic AMP as substrate (Types III and IV) or 0.5 ⁇ M calcium, 0.
  • AGENTS OF THE INVENTION predominantly inhibit PDE isoenzymes of the type IV, having relatively little effect in relation to types I, II, III and V.
  • the AGENTS OF THE INVENTION are further characterized as having selectivity against the PDE IV D, with the compound of example 2. for example, inhibiting PDE IV D at subnanomolar levels.
  • Blood samples (50ml) are collected from non-atopic laboratory staff with eosinophil numbers ranging between 0.06 and 0.47 x I O 9 L “1 (Microcellcounter F300, Sysmex). Venous blood is collected into centrifuge tubes containing 5 ml trisodium citrate (3.8%. pH 7.4. Sigma).
  • the anticoagulated blood is diluted ( 1 : 1 , v:v) with phosphate-buffered saline (PBS, containing neither calcium nor magnesium, Gibco) and is layered onto 15 ml isotonic Percoll (density 1 .082 - 1 .085 g/ml, pH 7.4, Pharmacia), in a 50ml centrifuge tube (Falcon). Following centrifugation (30 min, 1000 x g, 20°C), mononuclear cells at the plasma/Percoll interface are aspirated carefully and discarded.
  • PBS phosphate-buffered saline
  • the neutrophil/eosinophil/erythrocyte pellet (circa 5 ml by volume) is gently resuspended in 35 ml of isotonic ammonium chloride solution (NH 4 C1, 155mM; KHC0 3 , l OmM; EDTA. O. l mM ; 0-4°C). After 15 min, cells are washed twice ( 10 min, 400 x g, 4°C) in PBS containing foetal calf serum (2%, FCS, Gibco).
  • a magnetic cell separation system (Miltenyi Biotec) is used to separate eosinophils and neutrophils. This system is developed to separate cells in suspension according to surface markers, and comprises a permanent magnet, into which is placed a column that includes a magnetizable steel matrix. Prior to use, the column was equilibrated with PBS/FCS for 1 hr and then flushed with ice-cold PBS/FCS retrogradely via a 20ml syringe. A 21 G hypodermic needle is attached to the base of the column and 1 -2 mis of ice cold buffer allowed to efflux through the needle.
  • Non-labelled eosinophils are collected in a 50ml centrifuge tube and washed ( 10 min, 400 x g, 4°C). The resulting pellet is resuspended in 5 ml Hank's balanced salt solution (HBSS) so that cell numbers and purity can be assessed prior to use.
  • HBSS Hank's balanced salt solution
  • the separation column is removed from the magnet and the neutrophil fraction eluted. The column is then washed with PBS (50ml) and ethanol (absolute), and stored at 4°C.
  • Eosinophils are diluted in HBSS and pipetted into 96 well microtitreplates (MTP) at 1 - 10 x 10 1 cells/well. Each well contains a 200 ⁇ l sample comprising:
  • the samples are incubated with test compound or vehicle for 10 min prior to addition of an activation stimulus fMLP ( 10 ⁇ M) dissolved in dimethylsulphoxide and thereafter diluted in buffer, such that the highest solvent concentration used is 1 % (at 100 ⁇ M test compound).
  • MTPs are agitated (Titertek MTP mixer, Flow) to facilitate mixing of the cells and medium, and the MTP placed into a Hamamatsu luminometer. Total chemiluminescence and the temporal profile of each well is measured simultaneously over 20 min and the results expressed as arbitrary units, or as a percentage of fMLP-induced che iluminescence in the absence of test compound. Results are fitted to the Hill equation and IC 50 values calculated automatically.
  • AGENTS OF THE INVENTION are active in the above test method at concentrations of the order of from 0.0001 to 0.5 ⁇ M, generally on the order of about 1 nM for the exemplified compounds.
  • the compound of example 2 has an IC 50 in this assay of 1 .9 nM. while the compound of example 4 has an IC 50 of 0.71 nM.
  • Samples of human lungs dissected during surgery for cancer are obtained within 3 days after removal.
  • FCS foetal calf serum
  • DMSO dimethyl sulphoxide
  • sucrose sucrose
  • the ampoules are transferred into liquid nitrogen (- 196°C) where they are stored until use. Before use the tissues are exposed for 30-60 min to -70°C before being thawed within 2.5 min by placing the ampoules in a 37°C water bath. Thereafter the bronchial segments are rinsed by placing in a dish containing Krebs-Henseleit solution (composition mM : NaCl 1 1 8. KCl 4.7. MgS0 4 1 .2. CaCl 2 1 .2, KH 2 P0 4 1.2, NaHCO, 25, glucose 1 1 , EDTA 0.03) at 37°C.
  • composition mM NaCl 1 1 8. KCl 4.7. MgS0 4 1 .2
  • CaCl 2 1 .2, KH 2 P0 4 1.2, NaHCO, 25, glucose 1 1 , EDTA 0.03 at 37°C.
  • Concentration-response curves are produced by cumulative additions, each concentration being added when the maximum effect has been produced by the previous concentration.
  • Papaverine 300 ⁇ M is added at the end of the concentration- response curve to induce complete relaxation of the bronchial rings. This effect is taken as 100% relaxation.
  • AGENTS OF THE INVENTION produce concentration-related relaxation of human bronchus ring preparations at concentrations of from 0.001 to 1 .0 ⁇ M.
  • Ventilation is monitored at the trachea by a pneumotachograph (Fleisch, type 0000) connected to a differential pressure transducer (MP 4514871 , Validyne, USA) in line with the respiratory pump. Pressure changes within the thorax are monitored directly via an intrathoracic cannula, using a differential pressure transducer (MP 4524, Validyne) so that the pressure difference between the trachea and thorax can be measured and displayed. From these measurements of air-flow and transpulmonary pressure, both airway resistance (R, . cmH.O/1's) and compliance (C d n ) are calculated with a digital electronic respiratory analyzer ( PM S 300. M umed Ltd., UK) for each respiratory cycle. Blood pressure and heart rate are recorded from the carotid artery using a pressure transducer (P23Dd, Gould. USA).
  • Test compounds are administered when the response to bombesin was maximal and stable (ca. 2 min after start of bombesin infusion). Reversal of bronchoconstriction is assessed over 1 hour following either intratracheal or intraduodenal instillation or intravenous bolus injection. Bronchospasmolytic activity is expressed as % inhibition of the initial, maximal resistance (R L ) following the infusion of bombesin.
  • ED 50 values are given which represent the dose which caused 50% reduction of the increase in resistance induced by bombesin. Duration of action is defined as the time in min where bronchoconstriction is reduced by 50%) or more. Effects on blood pressure (BP) and heart rate (HR) are characterized by ED 20 values; i.e. the doses which reduced BP or HR by 20% (5 min after administration).
  • Test compounds are administered either as solutions or, in the case of intratracheal or intraduodenal instillation, also as aqueous suspensions containing 0.5 % tragacanth in case of insoluble compounds. Suspensions are sonicated for 5 min to achieve a small particle size prior to administration.
  • AGENTS OF THE INVENTION exhibit marked bronchodilator activity at dosages of the order of from 0.001 to 0.1 mg/kg i.v. or 0.1 to 5.0mg/kg i.d..
  • AGENTS OF THE INVENTION are useful for the treatment of inflammatory or obstructive airways disease or other conditions involving airways obstruction. In particular they are useful for the treatment of bronchial asthma.
  • AGENTS OF THE INVENTION are useful for the treatment, in particular prophylactic treatment, of obstructive or inflammatory airways disease.
  • AGENTS OF THE INVENTION are useful in providing advance protection against recurrence of bronchoconstrictor or other symptomatic attack consequential to obstructive or inflammatory airways disease or for the control, amelioration or reversal of basal status of such disease.
  • AGENTS OF THE INVENTION are useful as bronchodilators, e.g. for the treatment of chronic or acute broncho-constriction, e.g. for the symptomatic treatment of obstructive or inflammatory airways disease.
  • treatment and “treating” as used throughout the present specification and claims in relation to obstructive or inflammatory airways disease are to be understood accordingly as embracing both prophylactic and symptomatic modes of therapy.
  • the present invention further provides
  • Obstructive or inflammatory airways diseases to which the present invention applies include asthma, pneumoconiosis, chronic obstructive airways or pulmonary disease (COAD or COPD) and adult respiratory distress syndrome (ARDS), as well as exacerbation of airways hyperreactivity consequent to other drug therapy, e.g. aspirin or ⁇ - agonist therapy.
  • COAD or COPD chronic obstructive airways or pulmonary disease
  • ARDS adult respiratory distress syndrome
  • the present invention is applicable to the treatment of asthma of whatever type or genesis, including intrinsic and, especially, extrinsic asthma. It is applicable to the treatment of allergic (atopic/IgE-mediated) asthma. It is also applicable to the treatment of non-atopic asthma, including e.g. bronchitic, exercise induced and occupational asthma, asthma induced following bacterial infection and other non-allergic asthmas. It is further applicable to the treatment of whez infant syndrome (infant, incipient asthma).
  • the invention is applicable to the treatment of pneumoconiosis of whatever type or genesis including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tobacoosis and byssinosis.
  • the invention is applicable to the treatment of COPD or COAD including chronic bronchitis, pulmonary emphysaema or dyspnea associated therewith.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g. acute, arachidic, catarrhal, chronic, croupus or phthinoid bronchitis etc..
  • AGENTS OF THE INVENTION are also useful for the down-regulation or inhibition of TNF- ⁇ release. e.g. for the treatment of diseases or conditions in which TNF- ⁇ release is implicated or plays a mediating role. e.g. diseases or conditions having an aetiology involving or comprising morbid, for example undesirable, excessive or unregulated TNF- ⁇ release, in particular for the treatment of cachexia or endotoxin shock and in treatment of AIDS.
  • the method of the invention is applicable to the treatment of cachexia associated with morbid TNF- ⁇ release or TNF- ⁇ blood-serum levels of whatever origin, including cachexia consequential to, e.g. bacterial, viral or parasitic, infection or to deprivation or deterioration of humoral or other organic, e.g. renal function. It is for example applicable to the treatment of cancerous, malarial and vermal cachexia. cachexia resulting from dysfunction of the pituitary, thyroid or thymus glands as well as uremic cachexia. It is in particular applicable to the treatment of AIDS-related cachexia, i.e. cachexia consequential to or associated with to HIV infection.
  • the method of the invention is also applicable to the treatment of septic shock, e.g., shock conditions resulting from bacterial infection.
  • septic shock e.g., shock conditions resulting from bacterial infection.
  • the present invention provides a method for the treatment of septic shock as such as well as of conditions consequential to or symptomatic of septic or shock, for example ARDS (adult respiratory distress syndrome).
  • ARDS adult respiratory distress syndrome
  • the method of the invention is further applicable to the treatment of disease consequential to HIV infection, e.g. AIDS, e.g. to the amelioration or control of the advance of such disease.
  • AGENTS OF THE INVENTION are also useful as immunosuppressive agents, e.g. for the treatment of autoimmune diseases, in particular for the treatment of autoimmune diseases in which inflammatory processes are implicated or which have an inflammatory component or aetiology, or as anti-inflammatory agents for the treatment of inflammatory disease in particular for the treatment of inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or aetiology.
  • autoimmune hematological disorders e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus polychondritis, scleroderma.
  • Wegener granulomatosis dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease) endocrine ophthalmopathy.
  • idiopathic nephrotic syndrome or minimal change nephropathy including idiopathic nephrotic syndrome or minimal change nephropathy), as well as inflammatory and/or hyperproliferative skin diseases such as psoriasis atopic dermatitis, pemphigus and, in particular, contact dermatitis, e.g. allergic contact dermatitis.
  • AGENTS OF THE INVENTION are in particular useful for the treatment of arthritis, and other rheumatic or inflammatory disease, especially for the treatment of rheumatoid arthritis.
  • immunosuppressants AGENTS OF THE INVENTION are further indicated for use in the prevention of graft rejection, e.g. for the maintenance of allogenic organ transplants or the like, e.g. in relation to kidney, liver, lung, heart, heart-lung, bowel, bone-marrow, skin, or corneal transplant.
  • AGENTS OF THE INVENTION are also useful for the treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related disorders of the airways (e.g. involving morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil-related disorders of the airways consequential or concomitant to L ⁇ ffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoal) infestation (including tropical eosinophilia).
  • eosinophil related disorders e.g. eosinophilia
  • eosinophil related disorders of the airways e.g. involving morbid eosinophilic infiltration of pulmonary tissues
  • hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil
  • bronchopulmonary aspergillosis including Churg-Strauss syndrome
  • polyarteritis nodosa including Churg-Strauss syndrome
  • eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.
  • AGENTS OF THE INVENTION are also useful as co- therapeutic agents for use in conjunction with such drugs, e.g. as potentiators of therapeutic activity of such drugs or as means of reducing required dosaging or potential side effects of such drugs.
  • Drug substances with which AGENTS OF THE INVENTION may suitably be co-administered include, e.g. cyclopeptide, cyclopeptolide or macrolide immunosuppressive or anti-inflammatory drug substances, for examples drugs belonging to the cyclosporin class, e.g. cyclosporins A or G, the drug substances tacrolimus (also known as FK 506).
  • diseases to which such co-therapy may be applied include e.g. any disease or condition requiring immunosuppressive or anti- inflammatory drug therapy, e.g. as hereinbefore set forth.
  • AGENTS OF THE INVENTION are suitable for use in co-therapy as aforesaid, e.g. for the purposes of immunosuppressive, anti-inflammatory or anti-asthmatic treatment, e.g. to achieve cyclosporin, e.g. cyclosporin A-, macrolide- or steroid-sparing effect.
  • AGENTS OF THE INVENTION are further useful as type IV PDE inhibitors, for example for the treatment of disease involving tissue calcium depletion, in particular degenerative diseases of the bone and joint involving calcium depletion, especially osteoporosis.
  • they are further useful for the treatment of allergic inflammatory diseases such as rhinitis, conjunctivitis, atopic dermatitis, urticaria and gastro-intestinai allergies; as vasodilators, e.g.
  • the neuropathology of Parkinson's disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Elevation of cAMP levels in dopaminergic neurons improves their survival in culture and protects them from the effects of neurotoxic agents.
  • the Type IV phosphodiesterase inhibitors of the invention reduce MPTP- induced dopamine depletion in the striatum of C57BL/6 mice. Furthermore, the reduction in the number of tyrosine-hydroxylase-positive neurons caused by the toxin is partly prevented by the inhibitors.
  • Dopamine or MPP * uptake is measured using tritiated dopamine or MPP * at concentrations of 50 nM (spec. act. 45 Ci/mmol, New England Nuclear) or 1 ⁇ M (spec, activity 80 Ci/mmol, New England Nuclear), respectively.
  • the survival of dopaminergic neurons in the culture is assayed by counting tyrosine hydroxylase positive (TH * ) neurons previously stained with a mouse anti-TH antibody (Boehringer Mannheim).
  • C57BL/6 mice are subcutaneously injected with MPTP or saline.
  • a second and in some experiments third injection of MPTP follows two and four hours later.
  • At 0, 2, and 4 hours, are orally dosed with test compound in saline or same volume of saline alone.
  • Seven days later the animals are sacrificed by decapitation and the monoamines are determined by HPLC [Schneider et al., Science 256. 843-846 ( 1992)] or the brains processed for tyrosine hydroxylase (TH) immunocytochemistry.
  • the mice are intracardially perfused with 4% paraformaldehyde and whole brains further fixed in cold 4% paraformaldehyde overnight.
  • Cryosections (40 ⁇ m) are cut in the midbrain region, blocked for endogenous peroxidases with 0.3% peroxide in methanol for 15 minutes and digested with 0.1 % trypsin in PBS for 10 minutes.
  • AGENTS OF THE INVENTION are active in this assay.
  • MPTP-injected mice receiving the compound of example 2 at a dosage of 4 mg/kg p.o. at 0, 2, and 4 hours show dopamine levels 25% higher than those seen in untreated controls. Therefore AGENTS OF THE INVENTION are useful to inhibit dopamine depletion and enhance dopamine levels, and are thus useful, e.g., in the treatment of Parkinson's disease.
  • AGENTS OF THE INVENTION promote the survival of noradrenergic as well as serotoninergic neurons in culture. Therefore AGENTS OF THE INVENTION are useful in the treatment of neurodegenerative diseases.
  • Such neurodegenerative diseases include primary degenerative dementia, e.g. senile dementia, particularly senile dementia of the Alzheimer type, as well as senile mental decline, e.g. senile cognitive decline, and confusional conditions in the elderly.
  • primary degenerative dementia e.g. senile dementia, particularly senile dementia of the Alzheimer type, as well as senile mental decline, e.g. senile cognitive decline, and confusional conditions in the elderly.
  • AGENTS OF THE INVENTION improve the survival of motor neurons and sensory neurons in culture and suppress the expression of Tumor Necrosis Factors.
  • AGENTS OF THE INVENTION are useful in the treatment of multiple sclerosis, amyotrophic lateral sclerosis and other motor neuron or autoimmune diseases.
  • DOPAC/dopamine as well as 5-HIAA/serotonin ratios in the striatum are elevated by a factor of 2 and 1.5 respectively. Therefore AGENTS OF THE INVENTION are useful in the treatment of depression.
  • the present invention also provides:
  • a pharmaceutical composition comprising an AGENT OF THE INVENTION, optionally in combination or association with a pharmaceutically acceptable diluent or carrier therefor, e.g. for use in any method as hereinbefore set forth, e.g., as defined under A or B above, for example a pharmaceutical composition in inhalable form or in oral dosage form.
  • Dosages employed in practicing the present invention will of course vary depending, e.g. on the particular disease or condition to be treated, the particular agent of the invention used, the mode of administration and the therapy desired. In general, however, satisfactory results, e.g. for the treatment of obstructive or inflammatory disease, e.g. for asthma therapy are indicated to be obtained at dosages of the order from about 0.01 to 2.0 mg/kg/p.o.. In larger mammals, for example humans, an indicated daily dosage for oral administration, for treatment of airways hyperreactivity or for treatment of inflammatory events in obstructive or inflammatory airways disease will be in the range of from about 0.75 to 1 50 mg, conveniently administered 1 x or in divided doses 2 to 4x daily or in sustained release form.
  • Unit dosage forms for oral administration thus suitably comprise from about 0.2 to 75 or 1 50, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg AGENTS OF THE INVENTION, together with a pharmaceutically acceptable diluent or carrier therefor.
  • asthma AGENTS OF THE INVENTION may also be administered by the inhaled route.
  • dosages employed will vary, e.g. depending on the particular disease or condition, the particular AGENT OF THE INVENTION employed, the particular mode of administration (e.g. whether by dry powder inhalation or otherwise) and the effect desired.
  • an indicated inhaled daily dosage will be of the order of from about 2.5 to about 130.0 ⁇ g/kg/day e.g. from about 13.0 to about 60.0 ⁇ g/kg/day.
  • an indicated daily dosage for administration by inhalation e.g.
  • an appropriate dosage per administration will thus be of the order of from about 200 ⁇ g to about 3.3 mg, with administration up to 3 times daily, suitably administered from a dry powder inhalation delivery device in a series of 2 to 8 puffs at each administration.
  • an indicated daily dosage for oral administration, for treatment of said neurodegenerative diseases and depression will be in the range of from about 40 to 400 mg, conveniently administered 1 x or in divided doses 2 to 4x daily or in sustained release form.
  • Unit dosage forms for oral administration thus suitably comprise from about 10 to 200 or 400 mg AGENTS OF THE INVENTION, together with a pharmaceutically acceptable diluent or carrier therefor.
  • AGENTS OF THE INVENTION may also be administered by any other appropriate route, e.g. by infusion, for example for the treatment of septic shock; nasally, for example for the treatment of rhinitis; ocularly, for example for the treatment of autoimmune diseases of the eye; dermally, i.e. topically to the skin, for example for the treatment of dermatoses or psoriasis; or rectally, e.g. via enemation or suppository, for example for the treatment of inflammatory bowel disease.
  • Suitable dosages for application by such routes will generally be Iower, e.g., of the order of 10 to l OOx less, than those required for oral administration.
  • compositions comprising AGENTS OF THE INVENTION may be prepared using conventional diluents or excipients as known in the art and employing any of the techniques known in the galenic art.
  • oral dosage forms may include tablets, capsules and the like.
  • Compositions for inhalation may comprise aerosol or other atomisable formulations as well as inhalable dry powder formulations, with or without diluent, for administration by any appropriate dry powder inhalation system as known in the art.
  • Formulations for dermal administration may take the form of creams, ointments, gels, or transdermal delivery systems, e.g. patches and, in addition to inert diluents or carriers, may suitably contain skin penetration enhancing agents, again as known in the art.

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Abstract

Des quinolines substituées en position 8 par benzo(c)thiadiazolyle, benzo(c)furazanyle, ou 2-méthyl-2H-benzo(d)triazolyle, sous forme libre ou de N-oxyde ou d'un sel d'addition d'acide ou d'ammonium, sont nouvelles et se sont avérées utiles en tant que produits pharmaceutiques, par exemple en tant qu'inhibiteurs des phosphodiestérases de type IV, notamment dans le traitement de l'asthme. On décrit également des nouvelles méthodes de traitement dans lesquelles on utilise ces composés, des procédés de fabrication de ceux-ci et des compositions pharmaceutiques comprenant ces composés. A titre d'exemple, on décrit des composés répondant à la formule (1) dans laquelle X représente -O-, -S- ou -N(CH3)-, R1 représente hydrogène ou alkyle C1-4 et R2 représente alkyle C1-4 ou pyridyle, ces composés étant sous forme libre ou de N-oxyde ou d'un sel d'addition d'acide ou d'ammonium, acceptable sur le plan pharmacologique.
EP96938196A 1995-11-14 1996-11-13 Derives quinolines en tant qu'inhibiteurs des phosphodiesterases de type iv Withdrawn EP0873338A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9523267.4A GB9523267D0 (en) 1995-11-14 1995-11-14 Organic compounds
GB9523267 1995-11-14
PCT/EP1996/004978 WO1997018208A1 (fr) 1995-11-14 1996-11-13 Derives quinolines en tant qu'inhibiteurs des phosphodiesterases de type iv

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EP0873338A1 true EP0873338A1 (fr) 1998-10-28

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EP (1) EP0873338A1 (fr)
JP (1) JPH11515000A (fr)
KR (1) KR19990067574A (fr)
CN (1) CN1202170A (fr)
AU (1) AU7570996A (fr)
BR (1) BR9611504A (fr)
CA (1) CA2235126A1 (fr)
CO (1) CO4770973A1 (fr)
CZ (1) CZ149498A3 (fr)
GB (1) GB9523267D0 (fr)
HU (1) HUP9903492A3 (fr)
MX (1) MX9803839A (fr)
PE (1) PE17598A1 (fr)
PL (1) PL326636A1 (fr)
SK (1) SK63998A3 (fr)
TR (1) TR199800851T2 (fr)
WO (1) WO1997018208A1 (fr)

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DE60043318D1 (de) 1999-08-21 2010-01-14 Nycomed Gmbh Synergistische kombination von pumafentrine und salmeterol
US20040146561A1 (en) 2001-05-23 2004-07-29 Naoki Sakurai Compositions for promoting healing of bone fracture
CN1537018A (zh) 2001-05-23 2004-10-13 田边制药株式会社 一种用于软骨疾病再生治疗的组合物
TW200536851A (en) * 2004-01-23 2005-11-16 Amgen Inc Compounds and methods of use
JP2006347936A (ja) * 2005-06-15 2006-12-28 Bayer Cropscience Ag 殺虫性ベンズアニリド類
NZ603136A (en) 2010-05-10 2014-11-28 Gilead Sciences Inc Bifunctional quinoline derivatives
AR081377A1 (es) 2010-05-10 2012-08-29 Gilead Sciences Inc Compuestos de pirazolopiridina bifuncionales
AU2013331505A1 (en) 2012-10-16 2015-04-30 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of ROR-gamma-t
WO2014062655A1 (fr) 2012-10-16 2014-04-24 Janssen Pharmaceutica Nv Modulateurs de roryt de type quinolinyle à liaison hétéroaryle
CA2888210C (fr) 2012-10-16 2021-02-09 Janssen Pharmaceutica Nv Modulateurs de ror-gamma-t de type quinolinyle a liaison methylene
US9328095B2 (en) 2013-10-15 2016-05-03 Janssen Pharmaceutica Nv Heteroaryl linked quinolinyl modulators of RORgammat
JP6423423B2 (ja) 2013-10-15 2018-11-14 ヤンセン ファーマシューティカ エヌ．ベー． Ｒｏｒγｔのアルキル結合キノリニルモジュレーター
US9284308B2 (en) 2013-10-15 2016-03-15 Janssen Pharmaceutica Nv Methylene linked quinolinyl modulators of RORγt
EP3057422B1 (fr) 2013-10-15 2019-05-15 Janssen Pharmaceutica NV Modulateurs quinolinyl de ror(gamma)t
US10555941B2 (en) 2013-10-15 2020-02-11 Janssen Pharmaceutica Nv Alkyl linked quinolinyl modulators of RORγt
US9403816B2 (en) 2013-10-15 2016-08-02 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
US9221804B2 (en) 2013-10-15 2015-12-29 Janssen Pharmaceutica Nv Secondary alcohol quinolinyl modulators of RORγt
IL279410B2 (en) * 2018-06-24 2024-03-01 Adama Agan Ltd Process for preparing Quinmark

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GB9027055D0 (en) * 1990-12-13 1991-02-06 Sandoz Ltd Organic compounds
US5455252A (en) * 1993-03-31 1995-10-03 Syntex (U.S.A.) Inc. Optionally substituted 6,8-quinolines

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Title
See references of WO9718208A1 *

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HUP9903492A2 (en) 2000-07-28
GB9523267D0 (en) 1996-01-17
AU7570996A (en) 1997-06-05
CO4770973A1 (es) 1999-04-30
MX9803839A (es) 1998-09-30
CN1202170A (zh) 1998-12-16
PL326636A1 (en) 1998-10-12
SK63998A3 (en) 1998-10-07
CA2235126A1 (fr) 1997-05-22
JPH11515000A (ja) 1999-12-21
HUP9903492A3 (en) 2000-08-28
BR9611504A (pt) 1999-03-02
KR19990067574A (ko) 1999-08-25
TR199800851T2 (xx) 1998-08-21
WO1997018208A1 (fr) 1997-05-22
PE17598A1 (es) 1998-04-06
CZ149498A3 (cs) 1998-08-12

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