AP823A

AP823A - Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase.

Info

Publication number: AP823A
Application number: APAP/P/1998/001351A
Authority: AP
Inventors: Michael Dennis Dowle; Harry Finch; Lee Andrew Harrison; Graham George Adam Inglis; Martin Redpath Johnson
Original assignee: Glaxo Group Ltd
Priority date: 1996-03-28
Filing date: 1997-03-26
Publication date: 2000-04-25
Also published as: EA199800773A1; JP2000507950A; YU41198A; IS4837A; CZ309798A3; DE69728139T2; HUP9900567A3; NZ331490A; AU726649B2; SK132498A3; US6057457A; US5994344A; IL125859A0; NO984470D0; AP9801351A0; JP4118337B2; PL329153A1; DK0891362T3; CO4790152A1; EP0891362A1

Abstract

There are described according to the invention compounds of formula (I) (relative stereochemistry indicated), wherein RI, R2, R3 and X are as defined in the specification, together with processes for preparing them, compositions containing them and their use as pharmaceuticals. Compounds of formula (I) are indicated inter alia for the treatment of chronic bronchitis.

Description

PYRROLOPYRROLONE DERIVATIVES AS INHIBITORS OF NEUTROPHIL ELASTASE

The present invention relates-to therapeutically active bicyclic compounds, processes for the manufacture of said compounds, pharmaceutical formulations containing said compounds and the use of said compounds in chemotherapy.

In particular, we have found a novel group of bicyclic compounds which are effective in treating inflammatory diseases.

Inflammation is a primary response to tissue injury or microbial invasion and is characterised by circulating leukocytes binding to and extravasation through vascular endothelium. Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes and lymphocytes. Different forms of inflammation involve different types of infiltrating leukocytes.

The inflammatory process can be triggered in a number of ways, including by infection, tissue damage and autoimmune reactions. As part of the inflammatory process, neutrophils move from the bloodstream into the tissue at the site of tissue lesion. The neutrophils contain large numbers of different intracellular granules and when activated at the site of inflammation the contents of these granules are secreted into the tissue. The different granules contain a variety of enzymes and other proteins, many of which have antibacterial properties.

One of the enzymes found in the azurophilic granules is neutrophil elastase. Neutrophil elastase has a wide spectrum of activities in the body. For example, within the lung the enzyme increases mucus production and changes the cellular composition of the epithelium The enzyme also causes vascular permeability changes within the microcirculation of many tissues and it is a potent destructive agent against a number of connective tissue components.

Although there.are within the body endogenous inhibitors of elastase, including the anti-trypsin and the leukocyte protease inhibitor, elastase activity has been implicated in the pathogenesis of a number of disease states including inflammatory diseases of the airways, the joints and the skin. The enzyme is also responsible for some or most of the symptoms of acute respiratory distress syndrome (ARDS) and other acute inflammatory states brought about by trauma and/or sepsis.

We have now found a novel group of compounds which inhibit neutrophil elastase. The compounds are therefore of potential therapeutic benefit in the treatment and amelioration of symptoms of diseases where elastase activity is implicated. _Thus, according to one aspect of this invention, we provide a compound of the general formula (I) wherein: R., represents C^alkyl; C2_g alkenyl; aryl, aryl-CMalkyl, aryl-C^alkenyl, heteroaryl, heteroaryl-C alkyl, or heteroaryl-C^alkenyl, or such a group in which the aryl or heteroaryl moiety is substituted by one or more CMalkyl, halo, tetrazolyl, trifluoromethyl-sulphonamide, NRgCO-C^alkyl, -(CH2)m-NR4R5, -CN, -COOR9, -CONR9R10 -NO2, -SO2-C^alkyl, -CF3 or alkoxy groups; -(CH2)n-NR4R5; C2.8alkenyl-NR4R5; -(CH2)nCONR4R5; -(CH2)nNR9CO-C145alkyl; C2.8alkenyl-COOR9; (CH2)nCOOR9; and C2.8alkenyl CONR4 R5; X represents

(where carbonyl is bound to the ring nitrogen) : R2 represents C^alkyl, C2J,alkenyl, C1.3alkoxy or C^alkylthio; R3 represents C^alkyl; -CH2(CF2)MCF3; aryl or heteroaryl, which aryl or heteroaryl are mono-ring, or have two fused rings one of which may be saturated, and which aryl and heteroaryl groups may be substituted by one or more C^alkyl, halo, -NR7R8,-SO2NR7R8, -CONR7R8, -C^alkyl ester, -CN,

-CH2OH, -O-C^alkyl, -CF3, or nitro groups; aryl-Cwalkyl, aryl-C^alkyl-NH- or aryl-C2^ alkenyl, or such groups wherein aryl is substituted by one or more C^alkyl or halo groups; R4 and R5 independently represent hydrogen, C1J} alkyl, C^alkoxy, -(CH^^CONR^R^, -CO-C^alkyl or phenyl optionally substituted by one or more C^alkyl or halogen groups or R4 and R5 may be joined such that NR4R5 represents a mono, bi- ortri-cyclic ring system containing 4-15 ring carbon atoms, wherein one or more rings may be optionally interrupted by one or more heteroatoms selected from Ο, N and S and wherein one or more ring carbon atoms may have carbonyl functionality; or -(CH2)n -NR4R5 may represent a group of formula 1a:

wherein R6 is hydrogen or a carboxy alkyl ester, n1 is 0-6 and a and b independently represent an integer 0-3 provided a+b is in the range 3-5; R7, R8, R9i R10, Rti, Ri2 independently represent hydrogen or alkyl; m represents an integer 0 to 8; n represents an integer 1 to 9; and salts and solvates thereof.

Formula (I) shows the relative stereochemistry of the chiral centres.

The invention embaces compounds of formula (I) in racemic form as well as in a form in which one enantiomer predominates or is present exclusively.

Generally, we prefer to provide a compound of formula (l) in enantiomerically pure form.

When used herein "alkyl" includes branched as well as straight chain alkyl and may also include cycloalkyl when 3 or more carbon atoms are present.

When R4 and R5 are joined such that -NR4R5 represents a mono- bi- or tri-cyclic ring system, one or more rings may be unsaturated or aromatic. Examples of ringsystems which -NR4R5 may represent include unsaturated monocycles such as azetidine, pyrrolidine, piperidine, azepine, piperazine, morpholine; bicycles such as dihydrosoquinoiine, tetrahydrosoquinoline, octahydroisoquinoline, desmethyl tropane; and tricycles such as hexahydrobenzoisoindole. Carbonyl containing ring systems include pyrrolone (e.g. pyrrol-2-one) and oxopyridine (e.g. 2-oxo-2H-pyridine and 4-oxo-4H-pyridine). Ring carbon atoms may be substituted by alkyl, CONR'R", COOR' (R', R" independently represent hydrogen or alkyl) or halogen groups and ring nitrogen atoms may be substituted by C^ alkyl or -CO-C^alkyl groups. Particularly suitable carbon substituents include methyl (for example as in 2,5-dimethy! pyrrolidine and 2,6-dimethyi piperidine), -CONH2 (for example as in 4-(H2NCO)-piperidine) and -COOMe (for example as in 2-(MeOCO)-pyrrolidine). Suitable nitrogen substituents include methyl (for example as in 4-methyl-piperazine), and -COMe (for example as in 4-(MeCO)-piperazine).

Suitable R4, R5 alkyl groups include methyl, ethyl, n-propyl, isopropyl and cyclopropyl.

Suitable R4,R5 alkoxy groups include methoxy.

Suitable R4,R5 -(CH^^CONR^R^ groups include -CH2CONH2.

Suitable R4,R5 -CO-CMalkyl groups include -COMe.

Suitable R1 alkyl groups include methyl, ethyl and propyl.

Suitable R-, C2_6 alkenyl groups include CH=CH-CH3.

Suitable R-, aryl groups have up to two rings. They suitably include phenyl and naphthyl, most suitably phenyl.

Suitable R., arylalkyl groups include phenylmethyl and phenylethyl.

Suitable R, arylalkenyl groups include styryl.

Especially suitable R-, aryl substituents include C1u} alkyl, such as methyl or ethyl; alkoxy, such as methoxy, ethoxy and n-butyloxy; halo such as chloro, bromo or iodo; -SO2C·,^ alkyl, such as -SO2Me; tetrazolyl bonded through carbon; -CF3; -NO2; -CN; -(CH2)m-NR4R5 such as -NH2, -CH2NH2, -CH2NH(cyclopropyl), -CH2N(Me)(nPr), -CH2(4-Me-piperazin-1-yl) and 2-oxopyrrolidin-1-yl; and -NR9COCV8 alkyl such as -NHCOMe. Often there will be 1, 2 or 3 such substituents.

Suitable R-, heteroaryl groups include those containing sulphur, nitrogen or oxygen heteroatoms. Suitable R-, heteroaryl groups will have up to two rings. Examples include imidazolyl, optionally N-substituted by C^alkyl; pyridyl; furanyl; pyrrolyl and thienyl.

Suitable Rt heteroaryl alkyl and alkenyl groups include pyridylmethyl, pyridylethyl and pyridylethenyl. .Suitable R·, heteroaryl substituents include those as described above in regard to aryl substituents.

Suitable -(CH2)n-NR4R5 groups for R., also include those of the above formula (la) in which n1 is 0, a is 2 and b is 2 or n1 is 0, a is 0 and b is 3. Re carboxy alkyl ester groups include t-butyl.

Suitable R-, C2.8 alkenyl NR4R5 groups especially include -CH=CH-CH2-NR4R5 groups. Suitable such NR4R5 groups include morpholine, azepine; pyrrolidine (optionally substituted by COOMe or methyl); piperidine (optionally substituted by -CONH2 or methyl); piperazine (optionally 4-substituted by methyl or -MeCO); -NHCi_4 alkyl, such as -NH(cyclopropyl) and -NH(iPr); -N(C^alkyl)2, such as -NMe(nPr), -N(iPr)2, -N(Et)2 -N(Me)2; and -NiC^alkylX C^alkoxy) such as -NMe(OMe).

Suitable R·, -(CH2)n CONR4R5 groups include -(CH2)2 CONH2.

Suitable R1 -(CH2)nNR9COC1_6 alkyl groups include - (CH2)2 NHCOMe and -CH2 NHCOMe.

Suitable -(CH2)n-COOR9 groups include -CH2COOH, -CH2COOMe, -(CH2)2COOH and -(CH2)2COOMe.

Suitable Ri -C2_8alkenyI-COOR9 groups include -CH=CH-COOEt and -CH=CH-COOH.

Suitable R-, -C2.8alkenylCONR4R5 groups include CH=CH-CO-(4-methyl-1-piperazine).

Preferred R, groups include C2.8 alkenyl-NR4R5; phenyl, furanyl, thiophenyl or pyrrolyl substituted by the group (CH2)n-NR4R5 (wherein n’ represents an integer 1 to 5) and phenyl substituted by -NHCO-Cvealkyl. Particularly preferred Ri groups include those just defined in which NR4R5 together represents morpholine, pyrrolidine, piperidine, azepine, piperazine or 4-methyl-piperazine or one or both of R4 and R5 represent alkyl (for example, methyl, n-propyl or cyclopropyl) and the other (if it is does not represent CM alkyl) represents hydrogen. It is also preferred that n’ represents an integer· 1 to 3, particularly 1. When R1 represents phenyl substituted by -NHCO-C1.8alkyl, the preferred C^galkylgroup is methyl.

When R-ι represents C2.8 alkenyl-NR4R5 the preferred group is Cs^alkenyl-NR4R5, particularly CH=CH-CH2-NR4R5.

Preferred X groups include -CO- and -SO2-. It is particularly preferred that X represents -CO-.

Suitable R2 alkyl groups include ethyl, n-propyl and isopropyl.

Suitable R2 alkenyl groups include -CH2-CH=CH2.

Suitable R2 alkoxy and alkylthio groups include methoxy and methylthio.

We prefer R2 to represent C^afkyl, especially n-propyl or isopropyl, most especially isopropyl.

Suitable R3 alkyl groups include methyl, ethyl and propyl, especially methyl. 5 ·

Suitable R3 -CH2(CF2)cm CF3 groups include CH2 CF3.

Suitable R3 aryl groups include phenyl, naphthyl, and tetrahydronaphthalene.

Suitable substituents of such R3 aryl groups include NH2, N(CH3)2, SO2N(CH3)2, NO2, and alkyl, alkoxy and halo groups stated to be suitable above regarding R-! aryl substituents. Suitable other substituents also include CONH2, methyl ester (-COOMe) and methoxy.

Suitable R3 heteroaryl groups include those containing sulphur, nitrogen or oxygen, such as benzothiophenyl, benzothiadiazolyl, thiophenyl, isoxazolyl, pyridinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, and tetrahydro-isoquinolinyl. Suitable substituents for such groups include those R3 aryl substituents mentioned above.

Suitable R3 arylalkyl and arylalkyl amino groups include phenylmethyl, phenylethyl, phenylpropyl, phenylmethylamino and phenylethylamino. Suitable R3 aralkenyl groups include styryl. Suitable substituents for such R3 groups include alkyl (especially methyl) or halo,

We prefer R3 to represent C^ alkyl, especially methyl or ethyl, most especially methyl. R7, R8, R9, R10, R11, and R12 preferably represent hydrogen or methyl. n preferably represents an integer 1 to 5, more preferably an integer 1 to 3, particularly 1. m preferably represents an integer 0 to 3, especially 1 or 2.

Where compounds of formula (I) are able to form salts the present invention covers the physiologically acceptable salts of the compounds of formula (I). Suitable physiologically acceptable salts of the compounds of formula (I) include inorganic base salts such as alkali metal salts (for example sodium and potassium salts) and ammonium salts and organic base salts. Suitable organic base salts include amine salts such as trialkylamine (e.g. triethylamine), dialkylamine (e.g. dicyclohexylamine), optionally substituted benzylamine (e.g. phenylbenzylamine or p-bromobenzylamine), procaine, ethanolamine, diethanolamine, N-methylglucosamine and tri(hydroxymethyl)methylamine salts and amino acid salts (e.g. lysine and arginine salts). Suitable inorganic and organic acid salts include the hydrochloride, trifluoroacetate and tartrate.

The most preferred compounds of the invention have structure as follows:

(relative stereochemistry indicated) wherein R100 represents a moiety of formula -CH=CH-CH2-piperidin-1-yl (E-isomer), CH=CH-CH2-NH(cyclopropyl) (E-isomer), -phenyl-4-[CH2-(4-methyl-piperazin-1-yl)], phenyl-4-[CH2-NH(cyclopropyl)] or phenyl-4-[CH2-N(Me)(n-propyl)]. The (3S, 3aS, 6aR) enantiomer is particularly preferred.

The potential for compounds of formula (I) to inhibit neutrophil elastase activity may be demonstrated, for example, using the following in vitro and in vivo assays:

In vitro assays of human neutrophil elastase

Assay contents: 50mM Tris/HCI (pH 8.6)

150mM NaCI 11.8nM purified human neutrophil elastase

Suitable concentrations of compound under test diluted with water from a 10mM stock solution in dimethylsulphoxide. Values above are final concentrations after the addition of substrate solution (see below).

The mixture above is incubated for fifteen minutes at 30°C at which time the remaining elastase activity is measured for 10 minutes in a BioTek 340i plate-reader, after the addition of 0.6mM MeO-succinyl-alanyl-alanyl-prolyl-valyl-p-

nitroanilide. The rate of increase in absorbance at 405nm is proportional to elastase activity. Enzyme activity is plotted against concentration of inhibitor and an IC50 determined using curve fitting software.

In vivo activity of inhibitors of human neutrophil elastase

Female hamsters (100-150g) are anaesthetised and 0.1ml of vehicle (7% dimethylsulphoxide) or inhibitor solution is instilled (via a small incision) into the trachea. At a specified time after application of inhibitor human neutrophil elastase (75 international units in 0.1 ml) is instilled by the same route. 45 minutes after instillation of elastase animals are sacrificed. Sterile saline is delivered to the lungs via a 23 gauge cannula attached to a hypodermic syringe. After flushing five times with 2.5ml aliquots, bronchoalveolar lavage fluid (approximately 1.5-2.0ml) is collected. Lavage fluids are diluted with an equal volume of 2% sodium carbonate solution. Sonication is used to ensure cellular disruption prior to spectrophotometric determination of haemoglobin concentration. The level of haemorrhage is expressed as concentration of haemoglobin and the effects of an elastase inhibitor expressed as % inhibition of haemorrhage in comparison to a vehicle control.

Accordingly, compounds of formula (I) are of potential therapeutic benefit in the treatment and amelioration of symptoms of diseases where elastase activity is implicated. Such diseases particularly include bronchitis, including chronic bronchitis. Also any chronic obstructive pulmonary disease (COPD).

Examples of disease states in which the compounds of the invention have potentially beneficial effects include inflammatory diseases of the respiratory tract such as bronchitis (including chronic bronchitis), bronchiectasis, asthma and hyper-reactivity states of the lung, acute respiratory distress syndrome and septic shock, inflammatory or destructive conditions of the lung such as . emphysema and cystic fibrosis and inflammatory or destructive conditions of external tissue such as skin diseases (e.g. lupus and psoriasis) and periodontal disease including gingivitis.

Further examples of disease states and conditions in which compounds of the invention have potentially beneficial effects include wound healing and treatment of burns, cardiovascular diseases such as myocardial infarction and stroke, peripheral vascular disease including intermittent claudication, atherosclerosis, reperfusion injury, cardiovascular changes occurring during cardiopulmonary bypass surgery and septicemia.

Compounds of the invention may also be useful in the treatment of connective tissue disorders such as rheumatoid arthritis, osteoarthritis and spondylitis and inflammatory conditions of the kidney such as glomerulonephritis.

They may also be useful in the treatment of certain leukemias including acute myelogenous leukemia, acute myelomonocytic leukemia and the chronic monocytic leukemias and in prevention or inhibition of metastasis of solid tumours e.g. lung, breast, prostate and stomach cancers and melanomas. A particular aspect of the present invention is the use of compounds of formula (I) in the treatment of chronic bronchitis. Chronic bronchitis is a condition which results from the exposure of the airway surface to noxious chemicals or agents or is secondary to another disease. The symptoms of the condition are caused by the excessive secretion of mucus onto the surface of the airways. This excess mucus cannot be cleared effectively and the result is reduced gas exchange within the lungs resulting in laboured breathing and hypoxemia, recurrent microbial infections and persistent cough associated with the expectoration of mucoid material. The proposed mechanism for the excessive secretion of mucus involves the recruitment of neutrophils into the airways following the exposure of the epithelium to irritant materials; the neutrophils secrete elastase onto the surface of the airways and the enzyme brings about both an increase in the amount of mucus secreted onto the airway surfaces and a dramatic change in the cellular composition of the airway epithelium. Inhibition of elastase activity by the administration of compounds of this invention is therefore an approach to the treatment of chronic bronchitis. Reduced lung function in COPD (eg in chronic bronchitics with airflow obstruction) is also due to elastase mediated lung damage leading to airway narrowing and inflammation. Thus an elastase inhibitor will improve lung function.

As indicated above, compounds of formula (I) are useful in human or veterinary medicine, in particular as inhibitors of the enzyme neutrophil elastase.

Thus, there is provided as a further aspect of the present invention a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in human or veterinary medicine, particularly in the treatment of conditions where elastase activity is implicated such as chronic bronchitis.

It will be appreciated that references herein to treatment extend to prophylaxis as well as the treatment of established conditions. -According to another aspect of the invention, there is provided the use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of conditions where elastase activity is implicated, particularly in chronic bronchitis.

In a further or alternative aspect there is provided a method for the treatment of a human or animal subject with a condition caused or mediated by elastase activity which method comprises administering to said human or animal subject an effective amount of a compound of formula (1) or a physiologically acceptable salt or solvate thereof.

The compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions for use in therapy, comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof in admixture with one or more physiologically acceptable diluents or carriers.

There is also provided according to the invention a process for preparation of such a pharmaceutical composition which comprises mixing the ingredients.

The compounds according to the invention may, for example, be formulated for ' oral, buccal, parenteral, topical or rectal administration.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinyl pyrrolidone; fillers, for example, lactose, * microcrystaliine cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p- hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents (e.g. mannitol) as appropriate.

For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compound may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

The compound according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or prefilled syringes, or in multi-dose containers with an added preservative. The compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or toxicity adjusting agents. 1 Alternatively, the active ingredient may be in powder form for constitution with a . suitable vehicle, e.g. sterile, pyrogen-free water, before use. The dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.

I

By topical administration as used herein, we include administration by insufflation and inhalation. Examples of various types of preparation for topical administration include ointments, creams, lotions, powders, pessaries, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e.g. eye or nose drops).

Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents. Such bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil or a solvent such -as a polyethylene glycol. Thickening agents which may be used include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.

Powders for external appiicatiqn may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents or suspending agents.

Spray compositions may be formulated, for example, as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichiorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,2-tetrafluorethane, carbon dioxide or other suitable gas.

Capsules and cartridges for use in an inhaler or insufflator, of for example gelatin, may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch..

The pharmaceutical compositions according to the invention may also be used in combination with other therapeutic agents, for example anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), anti-oxidants (eg N-acetylcysteine), lung surfactants and/or antimicrobial and anti-viral agents. The compositions according to the invention may also be used in combination with gene replacement therapy.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent.

The combination referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof represent a further aspect of the invention.

The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

Compounds of the invention may conveniently be administered in amounts of, for example, 0.01 to 50mg/kg body weight, suitably 0.05 to 25mg/kg body weight orally, one or more times a day. The precise dose will of course depend on the age and condition of the patient, the particular route of administration chosen, and the disease being treated. The compounds specifically named earlier are preferably administered orally for the treatment of bronchitis. Other routes of administration may be needed for other indications, for instance i.v, for ARDS.

The compounds of the formula (I) have useful duration of action.

The compounds of formula (I) and salts and solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention. A process according to the invention for preparing a compound of formula (I) comprises: (i) condensation of a compound of formula (II):

with a compound F^COOH, RCOY, R.,OCO.Y or R1SO2Y, where Y is a reactive group such as halogen; or (ii) sulphonylation of a compound of formula (III):

with a compound YO2SR3, wherein Y is a reactive group such as halogen, e.g. chlorine; or (iii) preparation of a compound of formula (I) wherein X is by reacting a compound of formula (IV)

with a compound R1 OH, wherein Y is a reactive group such as those noted above; or (iv) - preparation of a compound of formula (I) in which R2 represents C2_4 alkyl or C^alkenyl by reacting a compound of formula (V)

sequentially with a base and then with a compound R2Y, wherein Y is a reactive group such as those noted above and R2· represents C2.4alkyI or C^alkenyl; or (v) cyclising a compound of formula (VI):

or a carboxylic acid ester thereof; or (vi) preparation of a compound of formula (I) wherein X represents o o ° by oxidising a compound of formula (VII)

wherein Xa is sulphur or SO; or (vii) ' preparation of a compound of formula (I) by oxidising a corresponding compound of formula (VIII)

wherein Xa is sulphur or SO; or (viii) preparation of a compound of formula I in which R·, represents aryl substituted by -(CH2)m'NR4R5 wherein m’ represents an integer 1 to 8 by reductive amination of a corresponding compound of formula (IX)

with a compound of formula HNR4R5; or (ix) preparation of a compound of formula I in which R-, represents -(CH2)nNR4R5 by reductive amination of a corresponding compound of formula (X)

Claims

Original document published without claims.