Title of Invention

A PHARMACEUTICAL COMPOSITION FOR TREATMENT OF INFLAMMATORY AND OBSTRUCTIVE AIRWAYS DISEASES

Abstract A pharmaceutical composition containing a compound of formula in free or pharmaceutically acceptable salt or solvate form and (B) a corticosteroid, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease, the molar ratio of (A) to (B) being from 100:1 to 1:300.
Full Text A PHARMACEUTICAL COMPOSITION FOR TREATMENT OF INFLAMMATORY AND OBSTRUCTIVE AIRWAYS DISEASES
This invention relates to a pharmaceutical composition for treatment of inflammatory and obstructive airways diseases.
In one aspect, the present invention provides a medicament comprising, separately or together, (A) a compound of formula

in free or pharmaceutically acceptable salt or solvate form and (B) a corticosteroid, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease.
In another aspect, the present invention provides a method of treating an inflammatory or obstructive airways disease which comprises administering to a subject in need of such treatment effective amounts of (A) as hereinbefore defined and (B) as hereinbefore defined.
In a further aspect, the present invention provides a pharamceutical composition comprising a mixture of effective amounts of (A) as hereinbefore defined and (B) as hereinbefore defined, optionally together with at least one pharmaceutically acceptable carrier.
The invention further provides the use of (A) as hereinbefore defined and/or (B) as hereinbefore defined in the preparation of a medicament for combination therapy by simultaneous, sequential or separate administration of (A) and (B) in the treatment of an inflammatory or obstructive airways disease.
The compound of formula I may be prepared in free or salt or solvate form by reacting (R)-8-benzyloxy-5-oxiranylcarbostyril with 5,6-diethylindan-2-ylamine to give 8-benzyloxy-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-IH-quinolin-2-one, subjecting the latter to a deprotecting reaction to replace the benzyl group by hydrogen, and recovering the resultant

compound of formula I in free or salt or solvate form. The reactions may be carried out using the procedures hereinafter described in the Examples or analogous procedures. (R)-8-benzyloxy-5-oxiranylcarbostyril may be prepared as described in W095/25104. 5,6-Diethylindan-2-ylamine may be prepared by known methods or analogues thereof, for example as described hereinafter in the Examples.
Pharmaceutically acceptable salts of the compound of formula I may be acid addition salts, including those of inorganic acids, for example hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydriodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, p-chlorobenzoic acid, di phenyl acetic acid, triphenylacetic acid, l-hydroxynaphthalene-2- carboxylic acid, 3-hydroxynaphthalene-2-carboxylic acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as fumaric acid, maleic acid or succinc acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid. These salts may be prepared from compounds of formula I by known salt-forming procedures. Pharmaceutically acceptable solvates are generally hydrates. A particularly preferred form of the compound of Formula I is the maleate salt.

or a 1,2-dihydro derivative thereof, where
Ri is Ci-C4-alkyl optionally substituted by halogen (preferably chlorine or fluorine), hydroxy,
Ci-C4-alkoxy, acyloxy or by acylthio, or Ri is Ci-C4-alkoxy or Ci-C4-alkylthio optionally
substituted by halogen, or Ri is 5-or 6-membered heterocyclylthio,
either R’ is acyloxy and R’ is hydrogen or Ci-C4-alkyl, or R’ and R’ together denote a group of
formula


where R"* is Ci-C4-alkyl or Cs-Ce-cycloalkyI and R’ is hydrogen or Ci-C4-alkyl, and X’ and X2 are each independently hydrogen, chlorine or fluorine.
Ci-C4-alkyl as used herein may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
Ci-C4-alkoxy as used herein may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
Ci-C4-alkylthio as used herein may be methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio.
When R’ is acyloxy-substituted Ci-C4-alkyI, the acyloxy group may be, for example, C1-C20-alkylcarbonyloxy, e.g. acetyloxy, n-propionyloxy, isopropionyloxy or hexadecanoyloxy, or C3-Cg-cycloalkylcarbonyloxy, e.g. cyclohexylcarbonyloxy. When R’ is acylthio-substituted C1-C4-alkyl, the acylthio group may be, for example, Ci-C4-alkylcarbonylthio, e.g. acetylthio or n-propionylthio. When R’ is 5-or-6-membered heterocyclylthio, the heterocyclyl group may be an O-heterocyclyl group, for example a furanonyl group.
When R2 is acyloxy, it may be, for example, Ci-C4-alkylcarbonyloxy, e.g. acetyloxy, n-propionyloxy, or n-butyroyloxy, Cs-Cg-cycloalkylcarbonyloxy e.g. cyclopropylcarbonyloxy, or 5-or 6-membered heterocyclylcarbonyloxy e.g. furoyloxy.
When R’ is Ci-C4-alkyl it may be in the alpha or beta conformation, more usually in the alpha conformation.
When R’ and R’ together denote a group of formula III, R"* as Cs-C’-cycloalkyl may be, for example, cyclohexyl.
Corticosteroids of formula I and their 1,2-dihydro derivatives include beclamethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, ciclesonide, triamcinolone acetonide, flunisolide, rofleponide palmitate, butixocort propionate and

icometasone enbutate. In particularly preferred emodiments of the invention, the corticosteroid (B) is budesonide, fluticasone propionate or mometasone furoate.
Administration of the medicament or pharmaceutical composition as hereinbefore described, i.e. with (A) and (B) in admixture or separate, is preferably by inhalation, i.e. (A) and (B) or the mixture thereof are in inhalable form. The inhalable form of the medicament i.e. of (A) and/or (B) may be, for example, an atomizable composition such as an aerosol comprising the active ingredient, i.e. (A) and (B) separately or in admixture, in solution or dispersion in a propellant, or a nebulizable composition comprising a solution or dispersion of the active ingredient in an aqueous, organic or aqueous/organic medium. For example, the inhalable form of the medicament may be an aerosol comprising a mixture of (A) and (B) in solution or dispersion in a propellant, or a combination of an aerosol containing (A) in solution or dispersion in a propellant with an aerosol containing (B) in solution or dispersion in a propellant. In another example, the inhalable form is a nebulizable composition comprising a dispersion of (A) and (B) in an aqueous, organic or aqueous/organic medium, or a combination of a dispersion of (A) in such a medium with a dispersion of (B) in such a medium.
An aerosol composition suitable for use as the inhalable form of the medicament may comprise the active ingredient in solution or dispersion in a propellant, which may be chosen from any of the propellants known in the art. Suitable such propellants include hydrocarbons such as n-propane, n-butane or isobutane or mixtures of two or more such hydrocarbons, and halogen-substituted hydrocarbons, for example chlorine and/or fluorine-substituted methanes, ethanes, propanes, butanes, cyclopropanes or cyclobutanes, such as dichlorodifluoromethane (CFC 12), trichlorofluoromethane (CFCll), l,2-dichloro-l,l,2,2-tetrafluoroethane (CFC114) or, particularly, 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA227), or mixtures of two or more such halogen-substituted hydrocarbons. Where the active ingredient is present in suspension in the propellant, i.e. where it is present in particulate form dispersed in the propellant, the aerosol composition may also contain a lubricant and a surfactant, which may be chosen from those lubricants and surfactants known in the art. Other suitable aerosol compositions include surfactant-free or substantially surfactant-free aerosol compositions. The aerosol composition may contain up to about 5% by weight, for example 0.0001 to 5%, 0.001 to 5%, 0.001 to 3%, 0.001 to 2%, 0.001 to 1%, 0.001 to 0.1%, or 0.001 to 0.01% by weight of the active ingredient, based on the weight of the propellant. Where present, the lubricant and surfactant may be in an amount up to 5% and 0.5% respectively by weight of the aerosol composition. The aerosol composition may also contain a co-solvent such as ethanol in an amount up to 30% by weight of the composition.

particularly for administration from a pressurised metered dose inhalation device. The aerosol composition may further contain a bulking agent, for example a sugar such as lactose, sucrose, dextrose, mannitol or sorbitol, in an amount, for example, of up to 20%, usually 0.001 to 1%, by weight of the composition.
In another embodiment of the invention, the inhalable form is a dry powder, i.e. (A) and/or (B) are present in a dry powder comprising finely divided (A) and/or (B) optionally together with at least one particulate pharmaceutically acceptable carrier, which may be one or more materials known as pharmaceutically acceptable carriers, preferably chosen from materials known as carriers in dry powder inhalation compositions, for example saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran, mannitol or sorbitol. An especially preferred carrier is lactose. The dry powder may be contained as unit doses in capsules of, for example, gelatin or plastic, or in blisters (e.g. of aluminium or plastic), for use in a dry powder inhalation device, which may be a single dose or multiple dose device, preferably in dosage units of (A) and/or (B) together with the carrier in amounts to bring the total weight of powder per capsule to from 5 mg to 50 mg. Alternatively, the dry powder may be contained in a reservoir in a multi-dose dry powder inhalation device adapted to deliver, for example, 3-25mg of dry powder per actuation.
In the finely divided particulate form of the medicament, and in the aerosol composition where the active ingredient is present in particulate form, the active ingredient may have an average particle diameter of up to about 10 |a.m, for example 0.1 to 5 \xm, preferably 1 to 5 jim. The particulate carrier, where present, generally has a maximum particle diameter up to 300 )im, preferably up to 212 j’m, and conveniently has a mean particle diameter of 40 to 100 \im, e.g. 50 to 75 fim. The particle size of the active ingredient, and that of a particulate carrier where present in dry powder compositions, can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, sieving, microprecipitation, spray-drying, lyophilisation or controlled crystallisation from conventional solvents or from supercritical media.
The inhalable medicament may be administered using an inhalation device suitable for the inhalable form, such devices being well known in the art. Accordingly, the invention also provides a pharmaceutical product comprising a medicament or pharmaceutical composition as hereinbefore described in inhalable form as hereinbefore described in association with one or more inhalation devices. In a further aspect, the invention provides an inhalation device, or

a pack of two or more inhalation devices, containing a medicament or pharmaceutical composition as hereinbefore described in inhalable form as hereinbefore described.
Where the inhalable form of the active ingredient is an aerosol composition, the inhalation device may be an aerosol vial provided with a valve adapted to deliver a metered dose, such as 10 to 100 1’1, e.g. 25 to 50 |4.1, of the composition, i.e. a device known as a metered dose inhaler. Suitable such aerosol vials and procedures for containing within them aerosol compositions under pressure are well known to those skilled in the art of inhalation therapy. For example, an aerosol composition may be administered from a coated can, for example as described in EP-A-0642992. Where the inhalable form of the active ingredient is a nebulizable aqueous, organic or aqueous/organic dispersion, the inhalation device may be a known nebulizer, for example a conventional pneumatic nebulizer such as an airjet nebulizer, or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 ml, commonly 1 to 10 ml, of the dispersion; or a hand-held nebulizer, sometimes referred to as a soft mist or soft spray inhaler, for example an electronically controlled device such as an AERx (Aradigm, US) or Aerodose (Aerogen), or a mechanical device such as a RESPIMAT (Boehringer Ingelheim) nebulizer which allows much smaller nebulized volumes, e.g. 10 to 100 |j.l, than conventional nebulizers. Where the inhalable form of the active ingredient is the finely divided particulate form, the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing a dry powder comprising a dosage unit of (A) and/or (B) or a multidose dry powder inhalation (MDPI) device adapted to deliver, for example, 3-25 mg of dry powder comprising a dosage unit of (A) and/or (B) per actuation. Suitable such dry powder inhalation devices are well known. For example, a suitable device for delivery of dry powder in encapsulated form is that described in US3 991761, while a suitable MDPI device is that described in WO97/20589.
The medicament of the invention is preferably a pharmaceutical composition comprising a mixture of (A) as hereinbefore defined and (B) as hereinbefore defined, preferably together with at least one pharmaceutically acceptable carrier as hereinbefore described.
The molar ratio of the compound (A) to the steroid (B) may be, in general, from 100:1 to 1:300, for example from 50:1 to 1:100 or from 20:1 to 1:50, preferably from 10:1 to 1:20, more preferably from 5:1 to 1:10, from 3:1 to 1:7 or from 2:1 to 1:2. The compound (A) and the steroid (B) may be administered separately in the same ratio.

A suitable daily dose of the compound (A), particularly as the maleate salt, for inhalation may be from 20’g to 2000M.g, for example from 20 to 1500’g, from 20 to lOOOjig, preferably from 50 to SOOjig, e.g. from 100 to 600’g or from 100 to 500/ig. A suitable daily dose of steriod (B) for inhalation may be from 20)ig to 5000’g, for example from 20 to 4000’g, from 50 to 3000’g, from 50 to 2000’g, from 50 to lOOO’g, from 50 to 500’g, from 50 to 400ng, from 50 to 300|Ag, from 50 to 200|ag or from 50 to lOO’ig. Where (B) is budesonide, a suitable daily dose may be from 25 to 4800jig, for example from 25 to 4000fig, from 25 to 3200’g, from 25 to 2400ng, from 25 to 1600|ig, from 50 to 4800’g, from 50 to 4000)ag, from 50 to 3200’g, from 50 to 2400’g, from 50 to 1600’g, from 100 to 4000’g, from 100 to 3200’g, from 100 to 2400’g, from 100 to 1600|ig, from 100 to SOO’ig, from 100 to 400ng, from 200 to 4000’g, from 200 to 1600ng, from 200 to 800|ng or from 200 to 400ng, 100 to 1600ng being preferred. Where (B) is mometasone furoate, a suitable daily dose may be from 50)xg to 2000)ag, for example from 100 to 200ng, from 100 to 1600|ig, from 100 to lOOO’ig or from 100 to SOOfig, preferably from 200 to 500)j.g, for instance from 200 to 400|xg. Where (B) is fluticasone propionate, a suitable daily dose may be for inhalation may be from 25 to 2000|ig, for example from 25 to 1500|ig, from 25 to 1000|ig, from 25 to 500’g, from 25 to 250jig, from 50 to 1500ng, from 50 to lOOO’g, from 50 to 500}ig, from 50 to 250|ig, from 100 to 1500|ag, from 100 to lOOO’g, from 100 to SOOyig, from 100 to 250ng, from 200 to 1500’g, from 200 to lOOOfxg or from 200 to 500\ig, 100 to lOOO’g being preferred.
A suitable unit dose of compound (A), particularly as the maleate salt, may be from 20 to 2000)xg, for example from 20 to 1500|J.g, from 20 to 1000|ag, preferably from 50 to 800)j.g, from 50 to 600)ig or from 50 to 500’g. A suitable unit dose of budesonide may be from 25 to 2400(a,g, for example from 50 to 2400|xg, from 50 to 2000(xg, from 50 to 1600’g, from 50 to SOO’g, from 50 to 400|ag, from 50 to 200’g, from 100 to 1600’g, from 100 to SOO’g, from 100 to 400’g, from 100 to 200’g, from 200 to 1600|ig, from 200 to SOO’g or from 200 to 400’g, 100 to 400’g being preferred. A suitable unit dose of mometasone furoate for inhalation may be from 25 to 2000jj,g, for example from 50’g to 1500[ig, from 50 to 1000|ig, from 50 to SOOjig, from 50 to 400’g, from 50 to 200ng, from 50 to lOO’g, from 100 to SOO’g, from 100 to 400jig or from 100 to 200ng, 100 to 400’g being preferred. A suitable unit dose of fluticasone propionate for inhalation may be from 25 to 1000|j.g, for example from 25 to 500/ig, from 25 to 250’g, from 25 to 200|xg, from 50 to lOOOng, from 50 to 500|ag, from 50 to 250’g, from 50 to 200ng, from 100 to lOOO’ig, from 100 to 500jig, from 100 to 250\ig, from 100 to 200’g, from 150 to 500ng or from 150 to 250’g, 100 to 500|ag being preferred. These unit doses may be administered once or twice daily in accordance with

the daily doses mentioned hereinbefore. The precise unit and daily dose used will of course depend on the condition to be treated, the patient and the efficiency of the inhalation device.
In one preferred embodiment of the invention, the medicament of the invention is a pharmaceutical composition which is a dry powder in a capsule containing a unit dose of (A) and (B), for example for inhalation from a single capsule inhaler, the capsule suitably containing a unit dose of (A) e.g. as hereinbefore described, and a unit dose of (B), e.g. as hereinbefore described, together with a pharmaceutically acceptable carrier as hereinbefore described in an amount to bring the total weight of dry powder per capsule to between 5 mg and 50mg, for example 5mg, lOmg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg or 50mg.
In another preferred embodiment of the invention, the medicament of the invention is a pharmaceutical composition which is a dry powder for administration from a reservoir of a multi-dose dry powder inhaler adapted to deliver, for example, 3mg to 25mg of powder containing a unit dose of (A) and (B) per actuation, for example, where (A) is in the form of the maleate salt, a powder comprising, by weight, 20 to 2000 parts, for example 60 to 1000 parts, 100 to 500 parts, or 100 to 300 parts of (A); 25 to 800 parts, e.g. 25 to 500 parts, 50 to 400 parts, or 100 to 400 parts of (B); and 2000 to 25000 parts, e.g. 4000 to 15000 parts or 4000 to 10000 parts of a pharmaceutically acceptable carrier as hereinbefore described.
In a further preferred embodiment of the invention, the medicament of the invention is a pharmaceutical composition which is an aerosol comprising (A) and (B), e.g. in a ratio as hereinbefore described, in a propellant as hereinbefore described, optionally together with a surfactant and/or a bulking agent and/or a co-solvent such as ethanol as hereinbefore described, for administration from a metered dose inhaler adapted to deliver an amount of aerosol containing a unit dose of (A) and a unit dose of (B), or a known fraction of a unit dose of (A) and a known fraction of a unit dose of (B), per actuation. Thus if, for example, the inhaler delivers half of the unit doses of (A) and (B) per actuation, the unit doses can be administered by two actuations of the inhaler.
In accordance with the above, the invention also provides a pharmaceutical kit comprising (A) and (B) as hereinbefore defined in separate unit dosage forms, said forms being suitable for administration of (A) and (B) in effective amounts. Such a kit suitably further comprises one or more inhalation devices for administration of (A) and (B). For example, the kit may comprise one or more dry powder inhalation devices adapted to deliver dry powder from a capsule, together with capsules containing a dry powder comprising a dosage unit of (A) and

capsules containing a dry powder comprising a dosage unit of (B). In another example, the kit may comprise a multidose dry powder inhalation device containing in the reservoir thereof a dry powder comprising (A) and a muhidose dry powder inhalaiton device containing in the reservoir thereof a dry powder comprising (B). In a further example, the kit may comprise a metered dose inhaler containing an aerosol comprising comprising (A) in a propellant and a metered dose inhaler containing an aerosol comprising (B) in a propellant.
The medicaments of the invention are advantageous in the treatment of inflammatory or
obstructive airways disease, exhibiting highly effective bronchodilatory and anti-inflammatory
properties. For instance, it is possible using the combination therapy of the invention to reduce
the dosages of corticosteroid required for a given therapeutic effect compared with those
Required using treatment with a corticosteroid alone, thereby minimising possibly undesirable
side effects. In particular, these combinations, particularly where (A) and (B) are in the same
/composition, facilitate achievement of a high anti-inflammatory effect, such that the amount of
I corticosteroid needed for a given anti-inflammatory effect may be reduced when used in
admixture with a compound of formula I, thereby reducing the risk of undesirable side effects
from the repeated exposure to the steroid involved in the treatment of inflammatory or
obstructive airways diseases. Furthermore, using the combinations of the invention,
particularly using compositions containing (A) and (B), medicaments which have a rapid onset
of action and a long duration of action may be prepared. Moreover, using such combination
jtherapy, medicaments which result in a significant improvement in lung function may be
I prepared. In another aspect, using the combination therapy of the invention, medicaments
! which provide effective control of obstructive or inflammatory airways diseases, or a reduction
in exacerbations of such diseases, may be prepared. In a further aspect, using compositions of
the invention containing (A) and (B), medicaments which reduce or eliminate the need for
treatment with short-acting rescue medicaments such as salbutamol or terbutaline, may be
prepared; thus compositions of the invention containing (A) and (B) facilitate the treatment of
an obstructive or inflammatory airways disease with a single medicament.
Treatment of inflammatory or obstructive airways diseases in accordance with the invention may be symptomatic or prophylactic treatment. Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (dlergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood as embracing treatment of sub>flcts, e.g. of less than 4 or 5 years of age, exhibiting

wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "wheezy-infant syndrome".)
Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
Other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis and emphysema, bronchiectasis and exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. Further inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tobacosis and byssinosis.
The invention is illustrated by the following Examples, in which parts are by weight unless stated otherwise. In the Examples, Compound A is the compound of formula I in the form of the maleate salt, Bud denotes budesonide, FP denotes fluticasone propionate, MF denotes mometasone furoate and OA denotes oleic acid (surfactant).
Preparation Examples
Preparation 1 - 3-chloro-l-(3.4-diethylphenyl)- 1-propanone

1,2-Diethylbenzene (10.9 g, 74.6 mmol) and propionyl chloride (9.7 g, 74.6 mmol) are added dropwise to AICI3 (22.3 g, 167.8 mmol) in nitromethane (75 mL) over 30 min. The reaction mixture is stirred at room temperature for 2 hours, after which 70 g of ice and 14 mL concentrated sulphuric acid are added. The aqueous phase is extracted with ether, and the combined organic phases extracted with 2N HCl and saturated aqueous NaCl. The organic phase is further treated with activated charcoal, magnesium sulphate, and filtered, and the solvent removed in vacuo.
IH-NMR (CDCI3) ppm: 7.8 (IH, s, Ar); 7.7 (IH, d, Ar); 7.2 (IH, d, Ar); 3.9 (2H, t, CH2); 3.4 (2H, t, CH2); 2.8 (4H, q, CH2CH3); 1.2 (6H, m, CH3).
Preparation 2 - 5.6-diethyl-indan-l-one
3-chloro-l-(3,4-diethylphenyl)- 1-propanone (15.5 g) is dissolved in 66 mL concentrated
sulphuric acid and heated to 90 °C for 4 hours. The reaction mixture is cooled, ice (70 g) is
added, and the aqueous solution extracted twice with toluene. The organic layer is washed
with sodium bicarbonate, saturated aqueous NaCl, and treated with activated charcoal and
magnesium suphate. After filtration, the solvent is removed in vacuo. The product is purified
by flash column chromatography (silica, hexane / ethylacetate 10:1), and further crystallised in
hexane.
IH-NMR (CDC13) ppm: 7.6 (IH, s, Ar); 7.3 (IH, d, Ar); 3.1 (2H, m, CH2); 2.7 (6H, m,
CH2+CH2CH3); 1.2 (6H, m, CH3).
Preparation 3 - 5.6-Diethyl- indan-1, 2-dione 2-oxime
5,6-diethyl-indan-l-one (5 g, 26 mmol) in methanol (75 mL) is brought to 40 °C, n-butyl
nitrite (3,0 g, 28.6 mmol) is added dropwise, followed by the addition of concentrated HCl
(1,25 mL). After 1 hour, the reaction is brought to room temperature and the precipitated
product filtered off, washed with ice-cold methanol and dried.
IH-NMR (d6-DMSO) ppm: 12.6 (IH, s, OH); 7.4 (IH, s, Ar); 7.3 (IH, d, Ar); 3.6 (2H, s,
CH2); 2.6 (4H, m, CH2CH3); 1.1 (6H, m, CH3).
Preparation 4 - 5.6-Diethyl-indan-2-ylamine hydrochloride
5,6-Diethyl-indan-l, 2-dione 2-oxime (4.5 g) is added to a mixture of acetic acid (150 mL), and concentrated sulphuric acid (4.5 mL). Pd/C 5% (1.5 g) is added, the reaction mixture degassed with nitrogen, and hydrogenated for 5 hours. The catalyst is then removed by filtration, the pH brought to pH 10 with 4M NaOH, and the solution extracted with chloroform. The organic phase is dried with magnesium sulphate, and the solvent removed in vacuo. The residue is redisolved in a minimum amount of ether, and HCl saturated ether


39 200
40 220
41 240
42 300
43 500
44 1000
45 2000
46 20
47 40
48 80
49 100
50 120
51 140
52 160
53 180
54 200
55 220
56 240
57 300
58 500
59 1000
60 2000
Examples 61-90

200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200

14600
14580
14560
14500
14300
13800
12800
24780
24760
24720
24700
24680
24660
24640
24620
24600
24580
24560
24500
24300
23800
22800

Examples 1-60 are repeated, but replacing the budesonide by mometasone furoate, and using amounts as shown in the following table:

Example Compound A MF Lactose
(Parts) (Parts) (Parts)
61 20 100 24880
62 40 100 24860
63 80 100 24820
64 100 100 24800
65 120 100 24780
66 140 100 24760


67 160
68 180
69 200
70 220
71 240
72 300
73 500
74 1000
75 2000
76 20
77 40
78 80
79 100
80 120
81 140
82 160
83 180
84 200
85 220
86 240
87 300
88 500
89 1000
‘Q 2000
Examples 91-135

100 24740
100 24720
100 24700
100 24680
100 24660
100 24600
100 24400
100 23900
100 22900
200 14780
200 14760
200 14720
200 14700
200 14680
200 14660
200 14640
200 14620
200 14600
200 14580
200 14560
200 14500
200 14300
200 13800
200 12800

A dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in W097/20589 is prepared by mixing Compound A and fluticasone propionate which have been ground to a mean particle diameter of \-S\’vs\ and lactose monohydrate having a particle diameter below 212’m, the amounts being as shown in the table below

Example Compound A FP Lactose
(Parts) (Parts) (Parts)
91 20 100 4880
92 40 100 4860




129 200
130 220
131 240
132 300
133 500
134 1000
135 2000
Examples 136-163

250 250 250 250 250 250 250

14550 14530 14510 14450 14250 13750 12750

Aerosol formulations are prepared by dispensing micronised active ingredients and, if required, lactose as bulking agent into a vial, sealing the vial w’ith a metering valve, injecting the premixed ethanol/propellant and optional surfactant into the vial through the valve and subjecting the vial to ultrasonic energy to disperse the solid particles. The components and amounts used are shown in the following tables:

Ex, Cpd.A MF HFA134a HFA227 Ethanol OA Lactose
(Parts) (Parts) (Parts) (Parts) (Parts) (Parts) (Parts)
136 2 10 36500 60750 2500 - 70
137 4 10 3410 6340 230 0.3 -
138 8 10 97000 - 2500 - 90
139 10 10 30500 67000 2500 0.5 100
140 12 10 3150 6550 250 1 -
141 14 10 3700 6050 250 0.8 -
142 16 10 3800 5900 230 0.4 -
143 18 10 4700 5050 250 1 -
144 20 20 3600 6150 225 1 -
145 22 20 3500 6200 230 1 -
146 24 20 98000 - 2500 1 -
147 30 20 3900 5900 250 1 -
148 2 20 30000 67000 2250 0.2 90
149 10 20 3500 6200 250 0.5 -
150 14 20 3200 6500 230 1 -
151 18 20 3100 6200 225 0.8 -
152 20 20 3150 6100 225 1 -
153 24 20 30000 60000 2000 0.8 -

E2L Cpd.A FP HFA134a HFA227 Ethanol OA Lactose
(Parts) (Parts) (Parts) (Parts) (Parts) (Parts) (Parts)
154 4 10 34000 63000 2250 0.3 50
155 8 10 92000 - 2500 0.5 70
156 12 10 3000 5500 200 - -
157 16 10 2500 5000 200 0.3 -
158 20 10 2000 3000 150 0.2 -
159 30 10 2000 2000 150 0.2 -
160 8 20 20000 25000 1500 0.2 -
161 12 20 2500 2500 200 0.2 -
162 20 20 2000 2000 150 0.2 -
163 30 20 20000 20000 1500 0.2 -
Examples 164-199
The procedure of Examples 91-135 is repeated, but replacing fluticasone propionate by mometasone furoate, and using amounts as shown in the following table.

Example Compound A MF Lactose
(Parts) (Parts) (Parts)
164 100 100 4800
165 200 100 4700
166 300 100 4600
167 400 100 4500
168 500 100 4400
169 600 100 4300
170 700 100 4200
171 800 100 4100
172 2000 100 2900
173 100 200 4700
174 200 200 4600
175 300 200 4500
176 400 200 4400
177 500 200 4300
178 600 200 4200
179 700 200 4100


180 800
181 1200
182 100
183 200
184 300
185 400
186 500
187 600
188 700
189 800
190 100
191 200
192 300
193 400
194 500
195 100
196 200
197 300
198 400
199 500
Examples 200-236

200
200
400
400
400
400
400
400
400
400
100
100
100
100
100
200
200
200
200
200

4000
3600
4500
4400
4300
4200
4100
4000
3900
3800
9800
9700
9600
9500
9400
9700
9600
9500
9400
9300

The procedures of Examples 136-163 is repeated, but using the amounts shown in the following table, the ethanol being omitted in some of the Examples:

Ex. Cpd.A MF HFA134a HFA227 Ethanol OA Lactose
(Parts) (Parts) (Parts) (Parts) (Parts) (Parts) (Parts)
200 20 20 5000 - 200 0.5 -
201 40 2 2500 2500 - - -
202 75 25 1500 3500 500 - 1
203 20 20 3600 6150 225 - 0.5
204 2 20 30000 67000 - - -
205 14 20 3200 6500 1500 - 4
206 20 20 3150 6100 1500 4 -
207 10 20 4700 5050 500 . 0.2

208 60 20 10000 10000 - - -
209 60 20 10000 10000 200 - -
210 60 20 10000 10000 - 0.5 -
211 30 20 8000 12000 - 1 1
212 40 20 5000 15000 500 0.5 0.5
213 50 20 9000 11000 400 0.8 0.2
214 20 20 4600 5000 400 0.4 0.2
215 30 10 20000 25000 - - -
216 40 10 20000 30000 - - -
217 60 10 35000 65000 - - -
EJL Cpd.A FP HFA134a HFA227 Ethanol OA Lactose
(Parts) (Parts) (Parts) (Parts) (Parts) (Parts) (Parts)
218 20 10 5000 5000 - - 1
219 10 10 3650 6350 - - 1
220 30 10 3200 6800 100 0.5 0.5
221 30 20 7400 7600 100 - -
222 40 20 8300 6700 200 0.5 -
223 60 20 3100 6900 300 1 -
224 10 10 8000 12000 - - -
225 50 20 1600 3400 500 2 0.5
E2L Cpd.A Bud HFA134a HFA227 Ethanol OA Lactose
(Parts) (Parts) (Parts) (Parts) (Parts) (Parts) (Parts)
226 10 20 5500 4500 - - -
227 2 20 3500 6500 - - 1
228 1 20 2500 7500 - - 1
229 20 20 3800 6100 100 0.5 -
230 15 20 3300 6600 100 0.5 0.5
231 30 20 3600 5900 500 4 -
232 40 20 4600 4900 500 3 -
233 30 10 3100 6800 100 0.2 0.5
234 40 10 1400 3100 500 0.2 -
235 60 10 8000 12000 - - 1
236 80 10 30000 70000 . - -

Example 237 - 245
The procedure of Examples 136-163 is repeated, but using sorbitan trioleate (ST) as surfactant in place of oleic acid, the amounts of the ingredients being as shown in the following table:

EJL Cpd.A MP HFA134a HFA227 Ethanol ST Lactose
(Parts) (Parts) (Parts) (Parts) (Parts) (Parts) (Parts)
237 60 40 10000 10000 300 4 -
238 60 20 8000 12000 200 8 -
239 50 20 12000 8000 400 10 -
240 40 20 5000 5000 600 2.5 1
241 30 20 3500 6500 - 4 2
242 20 20 6000 4000 - 3 3
243 10 20 4500 5500 100 2 1
244 20 10 4100 5900 50 1 2
245 15 5 1550 3450 200 0.5 1


We claim
1. A pharmaceutical composition for treatment of inflammatory or obstructive
airways diseases comprising 5-[(R)-2-(5,6-diethyl-indan-2ylmino)-l-hydroxy-
ethyl]-8-hydroxy-lH-quinolin-2-one represented by formula I

and at least one corticosteroid in a molar ratio of 100:1 to 1:300".
2. The composition as claimed in claim 1 which is a pharmaceutical composition comprising a mixture of effective amounts of (A) and (B) optionally together with at least one pharmaceutically acceptable carrier.
3. The composition as claimed in claim 1 or 2, in which (A) is the maleate salt of the compound of formula 1.
4. The composition as claimed in claim 1, 2 or 3 in which the corticosteroid (B) is of formula


or a 1,2-dihydro derivative thereof, where
R" is Ci-C4-alkyl optionally substituted by halogen, hydroxy, Ci-C4-alkoxy, acyloxy or by acylthio, or R" is Ci-C4-alkoxy or Ci-C4-alkylthio optionally substituted by halogen, or R" is 5- or 6-membered heterocyclylthio, either R’ is acyloxy and R’ is hydrogen or Ci-C4-alkyl, or R’ and R’ together denote a group of formula

5. The composition as claimed in any one of claims 1 to 4, in which the corticosteroid (B) is beclamethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, ciclesonide, triamcinolone acetonide, flunisolide, rofleponide palmitate, butixocort propionate or icometasone enbutate.
6. The composition as claimed in claim 5, in which the corticosteroid (B) is budesonide, fluticasone propionate or mometasone furoate.
7. The composition as claimed in any one of claims 1 to 6 in inhalable form as
an aerosol in solution or dispersion in a propellant.
8. The composition as claimed in any one of claims 1 to 6 in the inhalable
form as a nebulizable composition comprising a dispersion of (A) and (B) in an
aqueous, organic or aqueous /organic medium.
9. The composition as claimed in any one of claims 1 to 6, in which (A)
and/or (B) are present in inhalable form as a dry powder comprising finely divided
(A) and/or (B) optionally together with at least one particulate pharmaceutically
acceptable carrier.

10. The composition medicament as claimed in claim 7 or 9, in which (A)
and/or (B) has an average particle diameter up to 10 |Jm.
11. The composition medicament as claimed in any one of the preceding
claims, in which the molar ratio of (A) to (B) is from 5:1 to 1:10.
12. The composition as claimed in claim 2, which is a dry powder in a capsule, the capsule containing a unit dose of (A), a unit dose of (B) and a pharmaceutically acceptable carrier in an amount to bring the total weight of dry powder per capsule to between 5 mg and 50 mg.
13. The composition as claimed in claim 2, which is a dry powder comprising, by weight, from 20 to 2000 parts of (A) in the form of the maleate salt, from 25 to 800 parts of (B) and 2000 to 25000 parts of a pharmaceutically acceptable carrier.
14. The composition as claimed in claim 2, which is an aerosol comprising (A)
and (B) in a ratio as hereinbefore specified in claim 1 or 11, in a propellant,
optionally together with a surfactant and/or a bulking agent and/or a co-solvent
suitable for administration from a metered dose inhaler adapted to deliver an
amount of aerosol containing a unit dose (A) and a unit dose of (B), or a known
fraction of a unit dose of (A) and a known fraction of a unit dose of (B), per
actuation.

Documents:

0856-chenp-2003 abstract-duplicate.pdf

0856-chenp-2003 abstract.pdf

0856-chenp-2003 claims-duplicate.pdf

0856-chenp-2003 claims.pdf

0856-chenp-2003 correspondence-others.pdf

0856-chenp-2003 correspondence-po.pdf

0856-chenp-2003 description (complete)-duplicate.pdf

0856-chenp-2003 description (complete).pdf

0856-chenp-2003 form-1.pdf

0856-chenp-2003 form-19.pdf

0856-chenp-2003 form-26.pdf

0856-chenp-2003 form-3.pdf

0856-chenp-2003 form-5.pdf

0856-chenp-2003 others document.pdf

0856-chenp-2003 others.pdf

0856-chenp-2003 pct.pdf

856-chenp-2003.jpg


Patent Number 214320
Indian Patent Application Number 856/CHENP/2003
PG Journal Number 13/2008
Publication Date 31-Mar-2008
Grant Date 11-Feb-2008
Date of Filing 02-Jun-2003
Name of Patentee NOVARTIS AG
Applicant Address Lichtstrasse 35, CH-4056 Basel,
Inventors:
# Inventor's Name Inventor's Address
1 CUENOUD, Bernard Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH 12 5AB,
2 FAIRHURST, Robin, Alec Novartis Horsham Research Centre, Winblehurst Road, Horsham, West Sussex RH12 5AB,
3 LOWTHER, Nicholas Novartis Horsham Research Centre, Winblehurst Road, Horsham, West Sussex RH12 5AB,
PCT International Classification Number A61K 31/00
PCT International Application Number PCT/EP2001/014122
PCT International Filing date 2001-12-03
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0029562.6 2000-12-04 U.K.