SK63998A3 - Quinoline derivatives, method for the preparation thereof, pharmaceutical composition containing same, and their use - Google Patents

Abstract

8-(Benzo[c]thiadiazolyl, benzo[c]furazanyl, or 2-methyl-2H-benzo[d]triazolyl)-quinolines, in free or N-oxide or acid addition or ammonium salt form, are novel and found to be useful as pharmaceuticals, e.g., as PDEIV inhibitors, for example in the treatment of asthma. Novel methods of treatment using the compounds, processes for making the compounds, and pharmaceutical compositions comprising the compounds are also provided. For example, compounds of formula (1), wherein X is -O-, -S-, or -N(CH3)-, R1 is hydrogen or (C1-4)alkyl, and R2 is (C1-4)alkyl or pyridyl, in free or N-oxide or pharmaceutically acceptable acid addition or ammonium salt form.

Description

Described are 8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] thiazolyl) quinolines of formula (I) wherein X is -O-, -S- or -N (CH ₃ ) -, R ¹ is hydrogen or (C 1-4) alkyl, R ² is (C 1-4) alkyl or pyridyl, in free form, in the form of an N -oxide or acid addition salt, or an ammonium salt ; processes for the preparation of these compounds, pharmaceutical compositions containing them and their use as PDE IV inhibitors or for the treatment of asthma.

C31 - $

Quinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and their use

Technical field

The invention relates to novel quinoline derivatives, processes for their preparation, their use as medicaments and pharmaceutical compositions containing them.

SUMMARY OF THE INVENTION

Quinoline derivatives substituted at the 8-position by benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl residues (which form a completely new group of compounds) have been found to have very desirable and useful properties, as described below, in particular good oral efficacy, improved side-effect profile and significant selective PDE IV inhibitory activity.

In its broadest aspect, the invention provides 8- (benzo- (c) thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) quinoline in free form, in the form of an N-oxide, acid addition salt or ammonium salt. The 8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) quinoline is optionally substituted on the quinoline nucleus, for example at the 3 and / or 6 positions. 3 includes an alkyl group having 1 to 4 carbon atoms, for example a methyl group in the presence of 3-alkyl-8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) quinoline C 1 -C 4 alkyl. The substituents at the 6-position are preferably attached via a carbon atom, i. it is 8- (benzo- [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) -6-carboquinoline or 8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) -3-alkyl-6-carboquinoline having 1 to 4 carbon atoms in the alkyl moiety. A particularly preferred substituent at the 6-position is pyridylmethyl, for example pyridin-4-ylmethyl. Preferred compounds include, for example

8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) -6- (pyridylmethyl) quinolines or 8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) -3-alkyl-6- (pyridylmethyl) quinolines having 1 to 4 carbon atoms in the alkyl moiety, in free form, in the form of an N-oxide, acid addition salt or ammonium salt .

The benzo [c] thiadiazolyl residue is a radical of the following formula:

The benzo [c] furazanyl residue is a residue of the following formula:

The 2-methyl-2H-benzo [d] triazolyl residue is a radical of the following formula:

The 8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) quinoline of the invention is preferably a compound of formula I

N-X (I) wherein

X represents an oxygen atom, a sulfur atom or a group

-N (CH ₃ ) - (preferably oxygen or sulfur),

R ^x represents a hydrogen atom or a C 1 -C 4 alkyl group (preferably a methyl group or a hydrogen atom), and

R ² represents a C 1 -C 4 alkyl group or a pyridyl group (preferably a 4-pyridyl group), in free form or in the form of an N-oxide or in the form of a pharmaceutically acceptable acid addition salt or ammonium salt.

For example, the invention includes compounds of formula I wherein X is O or S, R ^x is hydrogen or C 1 -C 4 alkyl, and R ² is C 1 -C 4 alkyl or pyridyl in the form of the free base or an acid addition salt thereof.

The 8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) quinoline of the invention is preferably

8-benzo [c] thiadiazolyl-3- or -4-yl) - or 8- (benzo [c] furazan-3- or 4-yl) - or 8- (2-methyl-2H-benzo [d] triazole -4 or -5-yl) quinoline, preferably 8- (benzo [c] thiadiazol-4-yl) - or 8- (benzo [c] furazan-4-yl) - or 8- (2-methyl-2H) -benzo [d] -triazol-4-5-yl) quinoline, for example a compound of formula la:

(Ia) wherein X, R ¹ and R ^{2 are} as defined above, in free form or in the form of an N-oxide or in the form of a pharmaceutically acceptable acid addition salt or ammonium salt.

The alkyl groups may be branched or straight chain, preferably straight chain, with methyl being preferred.

The compounds of the invention may be in free form or may be associated with an acid to form an acid addition salt or an alkyl halide to form an ammonium salt, or may be N-oxidized, these various forms of the molecule being considered pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts for use herein include salts with inorganic acids, for example hydrochlorides (salts with hydrochloric acid), and salts with organic acids, for example, hydrogen maleate (salts with maleic acid), or oxalates (salts with oxalic acid) . The compounds of the invention are in the form of ammonium salts and N-oxides, in particular where R ² is a pyridyl group, the nitrogen atom of the pyridyl ring is alkylated or oxidized, so that ammonium salts include N-alkylated (e.g., N-methylated) pyridinium salts and the N-oxides of those compounds of formula I or Ia wherein ^R2 is N-oxo-pyridyl, e.g., 1-oxopyrrolidin pyrimidin-4-yl.

According to another embodiment, the invention provides a process for the preparation of 8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) quinoline, comprising (i) 3-Q- or 4-Q -benzo [c] thiadiazole, -benzo [c] furazan or -2-methyl-2H-benzo [d] triazole is reacted with 8-Q'-quinoline (e.g. optionally a C 1 -C 4 -alkyl substituted group and / or or 6-carbosubstituted), wherein Q and Q 'are leaving groups capable of participating in the cross-reaction (for example, if one of Q and Q' is a halogen atom (e.g. bromine) or a trifluoromethanesulfonyl group, the other is preferably a metal or an organometallic leaving group (e.g., B (OH) ₂ , (CH ₃ (CH ₂ ) ₃ ) ₃ Sn-, Li-, CIZn- or BrMg-), (ii) the product is optionally N-alkylated (e.g. by reaction with an alkyl halide , e.g., methyl iodide) or N-oxidized (e.g., by reaction with a peroxide reagent, e.g. m-chloroperbenzoic acid), the compound thus obtained is isolated in the free form, in the form of the N-oxide or in the form of a pharmaceutically acceptable acid addition salt or ammonium salt.

The reaction is conveniently carried out in the presence of a palladium or nickel catalyst, optionally with the addition of other metals, such as copper, for example in analogy to known reactions involving the coupling of aryl moieties, such as Still, Suzuki, Negishi or Heck reaction, e.g. is described in Example 1. The thus obtained 8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) quinoline can be isolated and purified by standard methods, for example by chromatography or crystallization procedures.

The compounds of formula I or Ia are preferably prepared, for example, by reaction of a quinoline of formula II

(II) in which they have symbols

R ¹ above to and R ² and Y represent an alkyl group with s. benzo [c] thiadiazole, benzo [c] furazan-benzo [d] triazole of the general formula III defined by the meaning, carbon atoms, or 2-methyl-2H-

(III) wherein X is as defined above and Z is bromine, iodine, or SO ₃ CF ₃ , and the compound thus obtained is isolated as the free base or as an acid addition salt.

In the compounds of formula II, Y preferably represents a butyl group, for example an n-butyl group. In the compounds of formula III, Z is preferably bromine.

The starting compounds of formula II can be prepared by known methods from compounds of formula IV

R ² (IV) wherein R ² is as defined above, or from compounds (V) of formula V

in which R ^x and R ² are as defined above. Compounds of formula V can be obtained using 2-R ^x -acrolein in the presence of an acid. When R ^x is hydrogen, acrolein can be prepared in situ (quinoline synthesis according to Skraup).

The compounds of formulas III and IV are known or can be prepared by known methods. For example, a compound of formula IV wherein R ² is pyridin-4-yl may be prepared as described in International Patent Application WO 94/22852.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the invention.

Example 1

8- (Benzo [c] furazan-4-yl) -6- (pyridin-4-ylmethyl) quinoline

I

a) 8-Bromo-6- (pyridin-4-ylmethyl) quinoline

The title compound is obtained by the Skraup synthesis of quinoline as described by Manske R. H. F., Organic Reactions, 7, 59 (1953) using 2-bromo-4- (pyridin-4-ylmethyl) phenylamine (as a compound of formula IV).

R _£ silica gel, hexane: ethyl acetate: ethanol = 35: 10): 0.25

Melting point: 96-99'C

b) 6- (pyridin-4-ylmethyl) -8-tributylstanylquinoline

2 » ⁵ 9 (8.36 mmol) of 8-bromo-6- (pyridin-4-ylmethyl) quinoline,

5.33 g (9.2 mmol) of hexabutyldistante and 485 mg (0.42 mmol) of tetrakis (triphenylphosphine) palladium are suspended in 40 ml of toluene, the mixture is refluxed under argon for 24 hours, and then The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was diluted with ethyl acetate, washed with aqueous sodium carbonate, dried over sodium sulfate and evaporated to give a yellow oil which was then chromatographed on silica gel using hexane / ethyl acetate (2: 1) as eluent to give the product in the form of a yellow oil.

_Rf (silica gel, hexane: ethyl acetate 2: 1): 0.18 MS (FAB neutral particles - fast atom bombardment (FAB)): 510 (MH +)

c) 8- (Benzo [c] furazan-4-yl) -6- (pyridin-4-ylmethyl) quinoline

A suspension of 420 mg (2.1 mmol) of 4-bromobenzo [c] furazane, 1.0 g (1.96 mmol) of 8-tributylstanyl-6- (pyridin-4-ylmethyl) quinoline and 20 mg (0.017 mmol) of tetrakis ( of triphenylphosphine) palladium in 15 ml of dimethylformamide was heated at reflux for 8 hours, then allowed to cool, diluted with ethyl acetate and extracted with aqueous hydrochloric acid. The combined aqueous extracts were basified with aqueous sodium carbonate, and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate to give a brown oil, from which the title compound crystallized.

Melting point 154-157 ° C.

Mass Spectrometry (FAB): 339 (MH < + >)

Example 2

8- (benzo [c] thiadiazol-4-yl) -6- (pyridin-4-ylmethyl) quinoline

The title compound is obtained in an analogous manner to that described in Example 1c) except that

4-bromo-benzo [c] thiadiazole. The hydrochloride of the product has a melting point of 150-155 ° C.

FAB-MS: 391 (MH < + >)

Example 3

6- (pyridin-4-ylmethyl) -8- (benzo [c] -furazan-3-yl) quinoline

The title compound is obtained in an analogous manner to that described in Example 1c except that 3-bromobenzo [c] furazan is used. Melting point 183-188'C.

Mass Spectrometry (FAB): 339 (MH < + >)

Example 4

8- (benzo [c] -furazan-4-yl) -3-methyl-6- (pyridin-4-ylmethyl) quinoline

a) 8-Bromo-3-methyl-6- (pyridin-4-ylmethyl) quinoline

A solution of 6.0 g (22.8 mmol) of 2-bromo-4- (pyridin-4-ylmethyl) phenylamine, 4.3 g (22.8 mmol) of p-toluenesulfonic acid and 20.0 ml (228 mmol) of methacrolein in 200 ml of toluene was heated to reflux in a Dean-Stark apparatus for 8 hours. The reaction mixture was allowed to cool overnight and the toluene was decanted off. The resin residue is stirred with 150 ml of dichloromethane and 80 ml of saturated aqueous potassium carbonate solution until dissolved. The organic phase is separated and washed with 50 ml of brine. The aqueous phase is extracted twice with 50 ml of dichloromethane each time. The combined organic extracts were dried over magnesium sulfate and evaporated to give a brown oil. The product was isolated by chromatographic alkyl gel chromatography using hexane, ethyl acetate and ethanol in a ratio of 65:35:10 as eluent, the product ^Rf 0.25. The product is obtained as a crystalline solid, m.p. 108-109 ° C.

MS (chemical ionization (Cl), C ₂ H _s): 313, 315 (100, MH +)

b) 3-methyl-6- (pyridin-4-ylmethyl) -8-tributylstanylquinoline

The title compound was prepared from 3-methyl-6- (pyridin-4-ylmethyl) -8-bromoquinoline in an analogous manner to that described in Example 1b. The product is a yellow oil.

R (silica gel, hexane / ethyl acetate / ethanol 65: 35: 10): 0.5.

Mass Spectrometry (FAB): 523 (M < + >)

c) 8- (Benzo [c] furazan-4-yl) -3-methyl-6- (pyridin-4-ylmethyl) quinoline

The title compound is obtained from 3-methyl-6- (pyridin-4-ylmethyl) -8-tributylstanylquinoline and 4-bromobenzo [c] furazan in an analogous manner to that described in Example 1c).

_Rf (silica gel, hexane: ethyl acetate: ethanol 65: 35: 10): 0.25

Electron impact (EI) mass spectrometry: 352 (MH +)

Melting point: 193-194 ° C

Example 5

8- (benzo [c] thiadiazol-4-yl) -3-methyl-6- (pyridin-4-ylmethyl) quinoline

The title compound is obtained in an analogous manner to that described in Example 4, except that it is used

4-bromo-benzo [c] thiadiazole.

Mass spectrometry (EI): 367 (100, (M-H) < + >), 276

The hydrogen maleate of the product had a melting point of 147-148 ° C.

Example 6

8- (2-Methyl-2H-benzo [d] triazol-5-yl) -6- (pyridin-4-ylmethyl) quinoline

a) 5-Bromo-2-methyl-2H-benzotriazole (Sandmeyer reaction)

To 1.64 g (11 mmol) of 5-amino-2-methyl-2H-benzo [d] triazole (Eur. J. Med. Chem. 1992, 161) is added in 30 ml of concentrated sulfuric acid at 10 ° C. 830 mg (12 mmol) of sodium nitrite. After 30 minutes, this solution is added to 1.66 g (11.6 mmol) of copper (I) bromide in 9 ml of 48% hydrobromic acid and 9 ml of water at 5 ° C, and then the mixture is heated at 90 ° C for 15 minutes. C. After extraction with ethyl acetate, the crude oil is subjected to flash chromatography on silica gel, eluting with hexanes / ethyl acetate (2: 1). 5-Bromo-2-methyl-2H-benzo [d] triazole crystallizes as white-yellow needles, m.p. 51-54 ° C.

^X H-NMR (DMSO): 8.25 (s, 1H), 7.93 (d,

1H), 7.55 (d, 1H), 4.50 (s, 3H)

b) 2-methyl-2H-benzo [d] triazole-5-boronic acid

500 mg (2.4 mmol) of 5-bromo-2-methyl-2H-benzo [d] triazole and 500 mg (2.6 mmol) of triisopropylborate were dissolved in 20 ml of tetrahydrofuran at -78 ° C and 1, 6 ml (2.6 mmol) of n-butyllithium in hexanes. The reaction mixture was stirred for 30 minutes at -78 ° C and then for 3 hours at room temperature. 20 ml of water are added to the reaction mixture, the mixture is acidified with 4N hydrochloric acid and extracted three times with 50 ml of ethyl acetate each time. The organic phase is dried over sodium sulfate, filtered and evaporated to give the title compound as a white solid, m.p. > 260 °.

^X H-NMR (DMSO): 8.39 (s, 1H), 8.24 (s,

2H), 7.88-7.75 (AB system, 2H), 4.51 (s, 3H)

c) 8- (2-Methyl-2H-benzo [d] triazol-5-yl) -6- (pyridin-4-yl-methyl) quinoline

240 mg (1.36 mmol) of 2-methyl-2H-benzo [d] triazole-5-boronic acid and 470 mg (1.56 mmol) of 8-bromo-6- (4-methylpyridyl) quinoline at 90 ° C is maintained for 20 hours in 40 ml of toluene in the presence of 12 mg of palladium diacetate, 17 mg of tri- (o-tolyl) phosphine, 1.8 ml of 2M sodium carbonate solution and 0.5 ml of ethanol. The cold reaction mixture is filtered, diluted with 80 ml of sodium chloride solution and extracted three times with 50 ml of ethyl acetate each, dried over sodium sulfate, filtered and evaporated. The crude product was purified on silica gel using ethyl acetate as eluent to give a yellowish oil. The melting point of the product oxalate is 98-103'C.

^X H-NMR (CDCl₃, free base): 8.91 (dd, 1H), 8.55 (d, 2H), 8.18 (dd, 1H), 8.08 (s, 1H), 7.92 (d, 1H), 7.71 (dd, 1H), 7.62 (s, 2H), 7.42 (dd, 1H), 7.20 (d, 2H), 4.53 (s, 3H) .

4.20 (s, 2H)

Mass Spectrometry (EI): 351 (70, M < + >), 350 (100), 259 (64)

Analysis for CH NO:

H, 4.30; N, 15.86. Found: C, 65.17; H, 4.61; N, 15.84.

8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl 13)

-2H-benzo [d] triazolyl) quinolines, for example of formula I or Ia, and in particular the compounds of the above examples, in free form, in the N-oxide form, pharmaceutically acceptable acid addition salts or ammonium salts, hereinafter referred to as reagents according to the invention, exhibit pharmacological activity and can be used as medicaments, for example for use in the treatment of the diseases and conditions mentioned below.

the agents of the invention are selective inhibitors of the cAMP-phosphodiesterase type IV isoenzyme family, and exhibit a relatively low effect on types I, II, III and V phosphodiesterase isoenzymes. As a result, the agents of the invention can be used in conditions where elevated levels are appropriate cAMP by selective inhibition of type IV phosphodiesterase isoenzymes. Since an increase in cAMP levels in inflammatory cells, such as eosinophils, inhibits their activation, the agents of the invention are suitable for use in inflammatory conditions in which activation of eosinophils plays a role.

Due to their phosphodiesterase type IV inhibitory effect in human eosinophils, the agents of the invention are suitable for the treatment of atopic and non-atopic asthma, as evidenced by the PDE (phosphodiesterase) inhibition, eosinophil activation and bronchodilation models described below.

Inhibition of PDE isoenzymes

The ability of the compounds of the invention to selectively inhibit type IV cAMP-phosphodiesterase (PDE) is demonstrated by the following assay:

Human phosphodiesterase inhibition assay

All isoenzyme preparations are obtained from human sources. Type III and IV preparations are obtained using predominant type III isozymes in platelets and type IV isoenzymes in neutrophils using the following procedure:

Human blood is drawn, treated with citrate, and neutrophils are separated by dextran sedimentation, density gradient centrifugation on Histopaque 1077 and 1119, with a final density of 1.089 g / L and hypotonic erythrocyte lysis. Human plates from the same source are washed with PBS (phosphate buffered saline, composed of: 140 mM sodium chloride, 2.7 mM potassium chloride, 1.5 mM potassium dihydrogen phosphate and 8.1 mM sodium hydrogen phosphate, pH 7.4). Neutrophils and plates are suspended in 10 ml of buffer (0.24 M sucrose, 1 mM EDTA (ethylenediaminetetraacetic acid), 1 mM dithiothreitol and 10 mM tris-HCl (tris = tris (hydroxymethyl) aminomethane), pH 7.4), which it contains the following protease inhibitor solutions: a solution of phenylmethylsulphonyl fluoride at a concentration of 5 μΐ / ml (7 mg / ml in 2-propanol), a solution of lepeptin and pepstatin A at a concentration of 1 μΐ / ml (1 mg / ml in ethanol each). After sonication for 15 seconds at 4 ' C using a sonicator for sample sonication, the homogenates are centrifuged at 2200 g. The sediment is resuspended in 10 ml of buffer and the sonication is repeated. The mixed supernatants are stored at -20 ° C.

Other isoenzymes are partially purified using chromatographic procedures described in the art (types I and V from human lung cells, and type II from human platelets). PDE (phosphodiesterase) activity is assayed in the presence or absence of test substance at various concentrations using an ion exchange column method as described by Thompson et al., Nucleotide Res., 10, 69-92 (1979), using 1 µΜ [ ³ H]. ] -cyclic AMP as substrate (types III and IV) or 0.5 μΜ of potassium, 0.125 μΜ calmodulin and 1.0 μΜ [ ³ H] -cyclic AMP (type I) or 100 μΜ [ ³ H] -cyclic AMP (type II) or 1.0 μΜ of [ ³ H] -cyclic GMP (type V).

In this assay, the agents of the invention inhibit predominantly type IV PDE isoenzymes while showing a relatively small effect on types I, II, III and V. Within the PDE IV isotype, the agents of the invention are further characterized by PDE IV D selectivity, e.g. 2 inhibits PDE IV D at lower than nanomolar concentrations.

Anti-inflammatory efficacy

Inhibition of eosinophil activation

50 ml blood samples are taken from non-atopic laboratory staff with eosinophil counts ranging between 0.06 and 0.47 x 10 < ^{-1 >} (Microcellcounter F300, Sysmex). Blood from the vein is collected in centrifuge tubes containing 5 ml of 3.8% trisodium acetate (pH 7.4, Sigma).

Anticoagulant-treated blood is diluted 1: 1 (v / v) with phosphate buffered saline (containing neither calcium nor magnesium, Gibco) and layered onto a 15 ml isotonic Percell (density 1.082 - 1.085) in a 50 ml centrifuge cell (Falcon). g / ml, pH 7.4, Pharmacia). After centrifugation for 30 minutes at 1000 g and 20 ° C, the mononuclear cells at the plasma / Percoll interface are carefully aspirated and discarded.

The neutrophil, eosinophil, and red blood cells with a volume of about 5 ml is gently resuspended in 35 ml of isotonic ammonium chloride solution (155 mM ammonium chloride, 10 mM potassium bicarbonate, 0.1 mM EDTA) at 0-4 ⁰ C. After 15 minutes, cells are washed twice (10 minutes, 400 g, 4 ° C) in PBS (phosphate buffered saline) containing fetal calf serum (2%, FCS, Gibco).

A magnetic cell separation system (Miltenyi Biotec) is used to separate eosinophils and neutrophils. This system is designed to separate cells in suspension according to surface markers, and includes a permanent magnet in which a column containing a magnetizable steel matrix is placed. Prior to use, the column was equilibrated for 1 hour with PBS / FCS and then back-flushed with ice-cold PBS / FCS using a 20 ml syringe. A hypodermic needle (21G) is attached to the base of the column and 1-2 ml of ice-cold buffer is drained through the needle.

After centrifugation of the granulocytes, the supernatant is aspirated and the cells are carefully resuspended with 100 μΐ of magnetic particles (anti-CD16 monoclonal antibody conjugated to superparamagnetic particles from Miltenyi Biotec, Germany). The mixture of eosinophils, neutrophils and magnetic particles of anti-CD16 is incubated on ice for 40 minutes and then diluted to a volume of 5 ml with ice-cold PBS / FCS. The cell suspension is slowly applied to the top of the column and the valve is opened, allowing the cells to move slowly into the steel matrix. The column is then washed with 35 ml PBS / FCS, the solution being carefully added to the top of the column so as not to swirl magnetically labeled neutrophils already trapped in the steel matrix. Unlabeled eosinophils are isolated in a 50 ml centrifuge tube and washed (10 minutes, 400 g, temperature 4 ° C). The resulting sediment is resuspended in 5 ml of Hank's Balanced Salt Solution (HBSS) so that cell number and purity can be determined before use. The separation column is removed from the magnet and the non-trophile fraction is eluted. The column is then washed with 50 ml PBS and absolute ethanol, and stored at 4 ° C.

The total cell count is determined by a microcellcounter (Sysmex). One drop of lysis solution (Sysmex) is added to the sample, and after 30 seconds the number of cells is counted again to determine erythrocyte contamination. Centrifuge on a Shandon Cytospin 2 cytospinner (100 μΐ samples, 3 minutes at 500 rpm). These preparations are stained (Diff, Quick, Baxter) and differential cell counts are determined by light microscopy, at least 500 cells being examined. Cell viability is determined by trypan blue exclusion.

Eosinophils are diluted in HBSS and pipetted into 96-well microtiter plates at 1-10x10 ³ cells per well. Each well contains 200 μΐ samples containing:

100 μΐ suspension of eosinophils, μΐ HBSS, μΐ lucigenin, μΐ activator stimulator, and μΐ test compound.

The samples are incubated with the test compound or vehicle for 10 minutes before adding the fMLP activator stimulator (10 μ 10) dissolved in dimethylsulfoxide and then with diluted buffer so that the highest solvent concentration used is 1% (at 100 μΜ of test compound). The microtiter plates are shaken on a Titertek MTP (Flow) mixer to facilitate mixing of cells and media, and the microtiter plates are placed in a Hamamatsu luminometer. The total chemiluminescence and time profile of each well are simultaneously measured over 20 minutes, and the results are expressed in relative units or as a percentage of fMLP-induced chemiluminescence in the absence of test compound. Results are fitted to the Hill equation and values are calculated automatically _with IC.

In the above test, the agents of the invention are effective at concentrations of the order of from 0.0001 to 0.5 μΜ, in the case of the compounds of the examples generally of the order of about 1 nM. For example, the compound of Example 2 exhibits an IC _{50 of} 1.9 nM in this assay, while the compound of Example 4 exhibits an IC of 0.71 nM.

'50'

Bronchodilator efficacy

Relaxation of human bronchi

Samples of human lungs selected during cancer surgery are obtained within 3 days of collection. Small bronchi of about 2-5 mm in diameter are cut, sectioned and placed in 2 ml liquid nitrogen vials filled with fetal calf serum (FCS) containing 1.8 M dimethylsulfoxide (DMSO). and 0.1 M sucrose as cryoprotective agents. The vials are placed in a 11 x 11 x 22 cm polystyrene box and slowly frozen at an average cooling rate of about 0.6 C / min in a -70 C. C freezer. After 3-15 hours, the vials are transferred to liquid nitrogen (-196 ° C) for storage until use. Tissues are exposed to -70 ° C for 30-60 minutes before use, and then fused over time

2.5 minutes by placing the ampoules in a 37 ° C water bath. The bronchial portions are then washed by placing in a dish containing a Krebs-Henseleite solution (composition: 118 mM sodium chloride, 4.7 mM potassium chloride, 1.2 mM magnesium sulfate, 1.2 mM calcium chloride, 1.2 mM potassium dihydrogen phosphate, 25 mM sodium bicarbonate, 11 mM glucose and 0.03 mM EDTA) at 37 ° C, cut into rings and suspended in a 10 ml isometric pressure organ preservation solution, biased at about 1 g. By cumulative addition, concentration response curves are generated, with the concentration increasing each time the maximum effect of the previous concentration is achieved. At the end of the concentration response curve, 300 µM papaverine is added to induce complete relaxation of the bronchial rings. This effect is considered 100% relaxation.

In the above assay, the agents of the invention induce relaxation of the human bronchial rings, which is concentration-dependent at concentrations ranging from 0.001 to 1.0 µM.

Suppression of bombesin-induced bronchoconstriction

Male Dunkin-Hartley guinea pigs weighing 400-800 g, who had free access to food and water prior to the experiment, are anesthetized by intraperitoneal administration of 100 mg / kg sodium phenobarbital and also 30 mg / kg sodium pentabarbital intraperitoneally, and then paralyzed by intramuscular administration of galamine at 10 mg / kg. Animals whose temperature is maintained at 37 ° C by means of a heated blanket, controlled by a rectal thermometer, are vented through a tracheal cannula (about 8 mL / kg, 1 Hz) with a 45: 55 (v / v) air / oxygen mixture. Ventilation is monitored in the trachea by a pneumotachograph (Fleisch, type 0000) connected to a differential pressure transducer (MP 4514871, Va lidyne, USA) coupled to a respiratory pump. Chest pressure changes are directly monitored by the intratoracal cannula, using a differential pressure transducer (MP 4524, Validyne, USA) so that the pressure differences between the trachea and thorax can be measured and displayed. From these airflow and transpulmonary pressure measurements, respiratory (PMS 300, Mumetd Ltd., UK) respiratory resistance (R ₁ , cmH ₂ 0 / l / s) and compliance (C) are calculated for each respiratory cycle using a digital electronic analyzer. ^). Blood pressure and heart rate are measured on the carotid artery using a pressure transducer (P23Dd, Gould, USA).

Once the basal resistance and compliance values are stable, continuous bronchoconstriction is induced by continuous intravenous infusion of bombesin at 100 ng / kg / min. Bombesin is taken dissolved in 100% ethanol and diluted with phosphate buffered saline.

Test compounds are administered when the response to bombesin is maximal and stable (about 2 minutes after the start of bombesin infusion). The anti-bronchoconstriction action is determined within 1 hour after intratracheal or intraduodenal • intravenous bolus injection. Bronchospasmolytic efficacy is expressed as% inhibition of initial peak resistance (R) after bombesin infusion. Calculate the value _of ED, which represent the dose causing 50% reduction of the increase in resistance induced by bombesin. Duration of action is defined as the time in minutes during which bronchoconstriction is reduced by 50% or more. The effects on blood pressure and heart rate are characterized by ED values, i

0 doses that lower blood pressure or heart rate by 20% (5 minutes after administration).

The test compounds are administered either as solutions or in the case of intratracheal or intraduodenal instillation, also in the form of aqueous suspensions containing, in the case of insoluble compounds, 0.5% tragacanth. The suspensions are sonicated for 5 minutes before application to achieve a small particle size.

Each drug is tested in 2 to 4 different doses (with the number of repetitions (n) = 3-4 for each dose). An adequate number of controls (5-6) shall be used.

In the above test, the agents of the invention exhibit marked bronchodilator efficacy at doses of the order of from 0.001 to 0.1 mg / kg (for intravenous administration) or 0.1 to 5.0 mg / kg (for intraduodenal administration).

Accordingly, the agents of the invention are useful for the treatment of inflammatory or obstructive airways diseases or other conditions that include airway obstruction. They are particularly suitable for the treatment of bronchial asthma.

In view of their anti-inflammatory activity, their effect on airway hyperreactivity and their profile with respect to inhibition of PDE isoenzymes, in particular their action as selective type IV inhibitors, the agents of the invention are suitable for the treatment, in particular prophylactic treatment, obstructive and inflammatory airway diseases . Thus, with continuous and regular administration over a prolonged period of time, the agents of the invention are suitable for providing pre-acting protection against the return of bronchoconstriction or other symptomatic attack due to obstructive or inflammatory airway disease or to control, alleviate or counteract the basal condition of such disease.

Because of their bronchodilation activity, the agents of the invention are useful as bronchodilators, for example for the treatment of chronic or acute bronchoconstriction, for example for the symptomatic treatment of obstructive or inflammatory airways disease.

It is understood that the word treatment ¹ 'as used in the specification and claims in relation to obstructive or inflammatory airway diseases includes both prophylactic and symptomatic therapies.

Accordingly, the invention further describes:

A. Method

a) treatment of airway hyperreactivity,

(b) inducing bronchodilation, or in particular

c) treating an obstructive or inflammatory airways disease, particularly asthma, in a patient in need thereof, the method comprising administering to said patient an effective amount of an agent of the invention.

Obstructive or inflammatory airway diseases to which the invention relates include asthma, pneumoconiosis, chronic obstructive airway disease or chronic obstructive pulmonary disease (COAD or COPD) and adult distress syndrome (ARDS) as well as exacerbation airway hyperreactivity due to treatment with other drugs, such as aspirin or a β-agonist.

The invention can be used to treat asthma of any type or origin, including intrinsic and especially extrinsic asthma. It can be used to treat allergic (atopic / IgE-mediated) asthma. It can also be used to treat non-atopic asthma, including, for example, bronchitis asthma, exercise-induced or occupational asthma, asthma due to bacterial infection, or non-allergic types of asthma. It can be further used to treat wheezy infant syndrome, childhood, initial asthma.

The invention can be used to treat pneumoconiosis of any type or origin, including, for example, aluminosis, anthracnose, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tobacosis, and byssinosis.

The invention can be used to treat chronic obstructive airway diseases or chronic obstructive pulmonary diseases, including chronic bronchitis, pulmonary emphysema, or dyspnoea associated therewith.

The invention may also be used to treat bronchitis of any type or origin, including, for example, acute, arachidic, catarrhal, chronic, croupous or phthinoid bronchitis, etc.

Because of their efficacy as selective inhibitors of TNF-α release, the agents of the invention are also suitable for decreasing or inhibiting TNF-α release, for example for the treatment of diseases or conditions in which TNF-α release is involved or in which TNF-α release is involved a mediating role, for example, diseases or conditions whose etiology includes pathological, for example undesirable, excessive or unregulated TNF-α release, particularly for the treatment of cachexia or endotoxic shock and the treatment of AIDS.

The method of the invention can be used to treat cachexia associated with diseased TNF-α release or serum TNF-α levels of any origin, including cachexia due to, for example, bacterial, viral or parasitic infection, or failure or aggravation of humoral or other organic, e.g. renal function. The invention can be used, for example, for the treatment of cancerous, malarial and vermal cachexia, cachexia due to pituitary, thyroid or thymus dysfunction, as well as uremic cachexia. In particular, the invention can be used for the treatment of AIDS-related cachexia, for example cachexia due to or associated with HIV infection.

The method of the invention can also be used to treat septic shock, for example shock conditions due to bacterial infection. In this regard, the invention relates to a method of treating septic shock as well as conditions resulting from septic shock or that are symptoms of septic shock, for example ARDS (adult respiratory distress syndrome).

The method of the invention can further be used to treat a disease resulting from an HIV infection, for example AIDS, for example to ameliorate or control the development of the disease.

In view of their profile of inhibiting PDE isoenzymes and / or inhibiting TNF-α release and their immunosuppressive activity, the agents of the invention are also useful as immunosuppressive agents, for example for the treatment of autoimmune diseases, in particular for the treatment of autoimmune diseases, which are involved in inflammatory processes or which exhibit an inflammatory component or aetiology, or as anti-inflammatory agents for the treatment of inflammatory diseases, in particular for the treatment of inflammatory diseases in which autoimmune reactions are involved, or which exhibit an autoimmune component or aetiology.

Examples of diseases for which the invention can be treated include autoimmune hematological disorders (e.g., haemolytic anemia, aplastic anemia, red blood cell only anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, chronosomatic dysfatitis, Wegenerit granatomatosis, Wegenerit granatomatosis , myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, alveolitis, chronic hypersensitivity diabetes, cirrhosis, cirrhosis, cirrhosis, diarrhea mellitus type I), uveitis (anterior and posterior), dry keratoconjunctivitis and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome, including, for example, 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 such as allergic contact dermatitis.

The agents of the invention are particularly suitable for the treatment of arthritis and other rheumatic or inflammatory diseases, in particular for the treatment of rheumatoid arthritis.

As immunosuppressants, the agents of the invention are further indicated for use in preventing graft rejection, for example, to maintain an allogeneic organ transplant or the like, for example, for a kidney, liver, lung, heart and lung transplant, intestine, bone marrow, skin or cornea.

Because of their anti-inflammatory activity, particularly with respect to inhibiting eosinophil activation, the agents of the invention are also suitable for the treatment of eosinophil-related disorders, for example eosinophilia, particularly eosinophil-related respiratory disorders (e.g. involving disease eosinophil infiltration of pulmonary tissues) respiratory tract and / or lung, as well as, for example, airway disorders associated with eosinophils resulting from or associated with Loffler's syndrome, eosinophilia pneumonia, parasitic (especially metazoic) attack (including tropical eosinophilia), bronchopulmonary aspergillosis, nodular adipose (node) Strauss syndrome), eosinophil granuloma, and eosinophils-related airway disorders caused by drug responses.

Because of their ability to synergistically interact with immunosuppressants and / or anti-inflammatory drug substances, the agents of the invention are also useful as co-therapeutic agents for use in combination with these drugs, for example, as potentiators of therapeutic efficacy of these drugs or as dose reducing or potential side effects of these drugs. drugs. Medicaments with which the agents of the invention may be suitably co-administered include, for example, cyclopeptide, cyclopeptolide or macrolide immunosuppressants or anti-inflammatory agents, for example, drugs belonging to the cyclosporin family, e.g. 506), ascomycin and rapamycin, and their various known forms and derivatives, as well as glucocorticosteroid drugs. Diseases in which such combination therapy (co-therapy) may be used include, for example, any diseases or conditions in which treatment with immunosuppressive or anti-inflammatory drugs is desirable, such as those listed above. The agents of the invention are particularly suitable for use in combination therapy as described above, for example for the purpose of immunosuppressive, anti-inflammatory or antiasthmatic treatment, for example to achieve savings of cyclosporin, for example cyclosporin A, macrolide or steroid.

In view of their profile of inhibiting PDE isoenzymes, in particular their profile as selective type IV inhibitors, the agents of the invention are further useful as inhibitors of type IV PDE, for example for the treatment of diseases involving tissue calcium loss, particularly bone and joint degenerative diseases including loss calcium, especially osteoporosis. In this regard, they are further suitable for the treatment of allergic inflammatory diseases such as rhinitis, conjunctivitis, atopic dermatitis, urticaria and gastrointestinal allergy; as vasodilators, for example, for the treatment of angina, hypertension, multiple heart failure and dementia due to multiple heart attacks, and for the treatment of other conditions and diseases for which PDE IV inhibition, for example depression, and conditions and diseases characterized by impaired cognitive function are indicated, including Alzheimer's disease, Parkinson's disease and stroke.

Efficiency on the central nervous system

Parkinson's neuropathology is characterized by degeneration of dopaminergic neurons in black matter. Increasing 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 present invention reduce MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced dopamine loss in the in vivo corpus striatum of C57BL / 6 mice. Furthermore, these inhibitors partially prevent the toxin-induced reduction in the number of tyrosine hydroxylase-positive neurons.

Cell culture, dopamine uptake or MPP * (1-methyl-4-phenylpyridinium ion) and survival of dopaminergic neurons

Primary cultures containing dopaminergic neurons are prepared from ventral mesencephalon of rat fetal E14 and dopamine uptake or MPP * is measured as described by Hartikka et al., J. Neurosci. Res., 32, 190-201, 1992. culture wells with a diameter of 15 mm usually contains 6xlO ^with neurons. Dopamine or MPP * uptake is measured using tritiated dopamine and MPP *, respectively, at concentrations of 50 nM (specific activity 45 Ci / mmol, New England Nuclear). The survival of dopaminergic neurons in culture is determined by counting the tyrosine hydroxylase (TH *) positive neurons pre-stained with mouse anti-tyrosine hydroxylase antibody (Boehringer Mannheim).

Mice injected with MPTP

C57BL / 6 mice are injected subcutaneously with MPTP or saline. The second, and in some experiments the third, MPTP injection follows two and four hours later. At 0, 2 and 4 hours, mice are orally administered test compound in saline or an equal volume of saline alone. Seven days later, animals are sacrificed by decapitation and monoamines are determined by HPLC (Schneider et al., Science 256, 843-846 (1992)) or brains are immunocytochemically examined for tyrosine hydroxylase (TH). For this purpose, mice are perfused intracardially with 4% paraformaldehyde and whole brains are further fixed overnight in cold 4% paraformaldehyde. Cryosections (40 μπι) are excised from the midbrain, blocked for 15 minutes with 0.3% peroxide in methanol for endogenous peroxidases, and digested with 0.1% trypsin in PBS (phosphate buffered saline) for 10 minutes.

Incubation is then performed for 48 hours at 4 ° C with a polyclonal rabbit anti-tyrosine hydroxylase antiserum (Eugene Tech. International Inc., New Jersey) diluted 1:50 in PBS with 2% goat serum and 0.2% Triton. -X. Cryosections are further developed using the Vectastain Elite ABC Kit (Vector Laboratories, CA, USA) and amplified with nickel diaminobenzidine (DAB). Before reaction with DAB, sections are incubated for 10 minutes in 2% nickel sulfate in 0.1 M Tris-HCl, pH 7.4. This solution was removed and replaced with 0.05% DAB, 0.2% nickel sulfate and 0.3% hydrogen peroxide in 0.1 M Tris.

The agents of the invention are effective in this assay. For example, MPTP-injected mice that were orally administered the compound of Example 2 at 4 mg / kg at 0, 2, and 4 hours showed dopamine levels 25% greater than those found in untreated controls. Thus, the agents of the invention may be used to inhibit dopamine loss and increase dopamine levels and are thus useful, for example, in the treatment of Parkinson's disease.

The agents of the invention further promote the survival of both noradrenergic as well as serotoninergic neurons in culture. Thus, the agents of the invention are useful in the treatment of neurodegenerative diseases.

Such neurodegenerative diseases include primary degenerative dementia, such as senile dementia, especially senile dementia of the Alzheimer type, as well as senile mental decline, such as senile cognitive decline, and confusion states in the elderly.

The agents of the invention further improve the survival of motor neurons and sensory neurons in culture and suppress the expression of tumor necrosis factors.

The agents of the invention are therefore suitable for the treatment of multiple sclerosis, amyotrophic lateral sclerosis and other motor neuron diseases or autoimmune diseases.

Moreover, following injection of the agents of the invention into mice, the ratios of DOPAC / dopamine as well as 5-HIAA / serotonin in the annealed body (corpus striatum) are increased with a factor of 2 and 1.5, respectively. Thus, the agents of the invention are useful in the treatment of depression.

Accordingly, the invention further describes:

B. Method

(a) reducing or inhibiting TNF-α release;

b) inhibition of PDE IV isoenzyme activity,

c) performing immunosuppression,

d) treatment of inflammatory or autoimmune diseases or conditions,

(e) the treatment of depression or conditions or diseases characterized by impaired cognitive function, including Alzheimer's disease, Parkinson's disease and stroke; or

f) treating any particular condition or disease as described above in a patient in need of such treatment, the method comprising administering to said patient an effective amount of an agent of the invention.

The invention also describes:

C. according to the invention for use as a medicament, for example for use in any method or for the treatment of any disease or condition as described above, for example as de29 fined above under A or B, and

D. A pharmaceutical composition comprising an agent of the invention, optionally in combination or in conjunction with a pharmaceutically acceptable diluent or carrier therefor, for example, using any of the methods described above, e.g. as defined above under A or B, e.g. in inhalable form or in an oral dosage form.

The dosages employed in practicing the invention will, of course, vary depending upon, for example, the particular disease or condition being treated, the particular agent of the invention being used, the mode of administration and the effect desired. However, it is generally indicated that satisfactory results, for example in the treatment of obstructive or inflammatory disease, for example in the treatment of asthma, will be achieved at doses of the order of about 0.01 to 2.0 mg / kg when administered orally. In larger mammals, such as humans, a daily dose for oral administration, in the treatment of airway hyperreactivity or in the treatment of inflammatory conditions of obstructive or inflammatory airway disease will be indicated, ranging from about 0.75 to 150 mg, conveniently administered once. daily or in divided doses two to four times daily or in sustained release form. Thus, unit dosage forms for oral administration suitably contain from about 0.2 to 75 or 150 mg, for example from about 0.2 or 2.0 to 50, 75 or 100 mg of agents of the invention, together with a pharmaceutically acceptable diluent or carrier.

For use in the treatment of chronic or obstructive airway disease, for example asthma, the agents of the invention may also be administered by inhalation. The dosages employed will also vary, for example, depending upon the particular disease or condition, the particular agent of the invention being used, the particular mode of administration (for example, whether the administration is by dry powder inhalation or otherwise) and the desired effect. Generally, however, the inhaled daily dose will be from about 2.5 to about 130.0 µg / kg / day, for example from about 13.0 to about 60.0 Mg / kg / day. In the case of larger mammals, for example humans, a daily dose for inhalation, for example for the treatment of asthma, will be indicated in the range of about 0.2 to about 10.0 mg, for example about 1 to about 5 mg, conveniently administered once. daily or two or three separate administrations during the day. Thus, the corresponding dose for each administration will be of the order of from about 200 pg to about 3.3 mg, administered up to three times a day, suitably by a dry powder inhaler in a series of two to eight applications per administration.

Similarly, satisfactory results in the treatment of Parkinson's disease and other neurodegenerative diseases, motor neuron diseases or autoimmune diseases such as those listed above, and depression are indicated to be achieved at doses of the order of about 0.5 to 5.0 mg / kg. orally. In larger mammals, such as humans, a daily dose for oral administration will be indicated for the treatment of said neurodegenerative diseases and depression in the range of about 40 to 400 mg, suitably administered once daily or in divided doses two to four times daily or in divided doses. sustained release form. Thus, unit dosage forms for oral administration suitably contain from about 10 to 200 or 400 mg of the agents of the invention, together with a pharmaceutically acceptable diluent or carrier.

The agents of the invention are possible in some other suitable manner, for example, for the treatment of septic shock, nasal, rhinitis, ocular, for example, in eye diseases, dermal, i. also topically administered by any infusion, for example in the treatment of skin autoimmune treatments, for example in the treatment of dermatosis or psoriasis, or rectally, for example, using enemas or suppositories, for example in the treatment of inflammatory bowel disease. Suitable dosages for administration by these methods will generally be lower, for example of the order of 10 to 100 times lower than those required for oral administration.

Pharmaceutical compositions containing the agents of the invention may be prepared using conventional diluents or carrier and auxiliary agents, as known in the art, and by any of the methods known in the art of making pharmaceutical compositions.

Oral dosage forms may include tablets, capsules and the like. Compositions for inhalation may contain aerosol or other atomizable formulations, as well as inhalable dry powders, with or without the presence of a diluent, for administration by any suitable dry powder inhalation system as known in the art. Formulations for dermal administration may be in the form of creams, ointments, gels, or transdermal delivery systems, for example patches, and may conveniently contain, in addition to inert diluents or carriers, skin penetration enhancers as also known in the art.

7 \ /

Claims (8)

8- (Benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) quinoline in free form, in the form of an N-oxide or a pharmaceutically acceptable acid addition salt or ammonium salt. 8- (Benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) quinoline according to claim 1, wherein I is O, S or -N ( CH ₃ ) -, R ¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ² represents an alkyl group or a pyridyl group, s 1 to 4 atoms carbon within in free form or in form N-oxide or in a a pharmaceutically acceptable acid addition salt or ammonium salt. 3. 8- (Benzo [c] thiadiazolyl, Benzo [c] furazanyl or 2-Methyl-2H-benzo [d] triazolyl) quinoline according to claim 1 or 2 selected from the group consisting of: (i) 8- (benzo [c] furazan-4-yl) -6- (pyridin-4-yl) quinoline; ii) 8- (benzo [c] furazan-4-yl) -3-methyl-6- ( iii) 8- (benzo [c] furazan-3-yl) -6- (pyridin-4-ylmethyl) quinoline; iv) 8- (benzo [c] thiadiazol-4-yl); ) -6- (pyridin-4-yl) quinoline, v) 8- (benzo [c] thiadiazol-4-yl) -3-methyl-6- (pyridin-4-yl) quinoline; and vi) 8- (2-methyl-2H-benzo [d] triazole- 5-yl) -6- (pyridin-4-ylmethyl) quinoline, in free form or in the form of a pharmaceutically acceptable ammonium addition salt. Of an N-oxide or in a salt with an acid form or 8- (Benzo [c] thiadiazolyl, Benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) quinoline according to claim 1, 2 or 3 for use as a medicament. A pharmaceutical composition comprising 8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) quinoline according to claim 1, 2 or 3, optionally in combination with a pharmaceutical an acceptable carrier or diluent. Use of 8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl] quinoline according to claim 1, 2 or 3 for the preparation of a medicament for the treatment of (a) obstructive or inflammatory airways disease; (b) inflammatory or autoimmune diseases or conditions; or c) depression, Alzheimer's disease, Parkinson's disease or stroke. 7. Method of treatment (a) obstructive or inflammatory airways disease; (b) inflammatory or autoimmune diseases or conditions; or c) depression, Alzheimer's disease, Parkinson's disease or stroke, characterized in that an effective amount of 8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo) is administered to a patient in need thereof. [d] triazolyl) quinoline according to claim 1, 2 or 3. A process for the preparation of 8- (benzo [c] thiadiazolyl, benzofurfurazanyl or 2-methyl-2H-benzo [d] triazolyl] quinoline according to claim 1, 2 or 3, characterized in that (i) 3-Q- or 4- Q-benzo [c] thiadiazole, -benzo [c] furazan or -2-methyl-2H-benzo [d] triazole is reacted with 8-Q'-quinoline, wherein Q and Q 'represent leaving groups capable of participating (ii) the product is optionally N-alkylated or N-oxidized and the 8- (benzo [c] thiadiazolyl, benzo [c] furazanyl or 2-methyl-2H-benzo [d] triazolyl) quinoline thus obtained isolated in the free form, in the form of the N-oxide or in the form of a pharmaceutically acceptable acid addition salt or ammonium salt.