Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-06-04
2004-10-05
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S157000
Reexamination Certificate
active
06800643
ABSTRACT:
This invention relates to organic compounds and their use as pharmaceuticals, in particular for the treatment of inflammatory or 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)-1-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 W095125104. 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, diphenylacetic acid, triphenylacetic acid, 1-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.
The corticosteroid (B) may be, for example, of formula
or a 1,2-dihydro derivative thereof, where
R
1
is C
1
-C
4
-alkyl optionally substituted by halogen (preferably chlorine or fluorine), hydroxy, C
1
-C
4
-alkoxy, acyloxy or by acylthio, or R
1
is C
1
-C
4
-alkoxy or C
1
-C
4
-alkylthio optionally substituted by halogen, or R
1
is 5-or 6-membered heterocyclylthio,
either R
2
is acyloxy and R
3
is hydrogen or C
1
-C
4
-alkyl, or R
2
and R
3
together denote a group of formula
where R
4
is C
1
-C
4
-alkyl or C
3
-C
6
-cycloalkyl and R
5
is hydrogen or C
1
-C
4
-alkyl, and
X
1
and X
2
are each independently hydrogen, chlorine or fluorine.
C
1
-C
4
-alkyl as used herein may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
C
1
-C
4
-alkoxy as used herein may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
C
1
-C
4
-alkylthio as used herein may be methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio.
When R
1
is acyloxy-substituted C
1
-C
4
-alkyl, the acyloxy group may be, for example, C
1
-C
20
-alkylcarbonyloxy, e.g. acetyloxy, n-propionyloxy, isopropionyloxy or hexadecanoyloxy, or C
3
-C
6
-cycloalkylcarbonyloxy, e.g. cyclohexylcarbonyloxy. When R
1
is acylthio-substituted C
1
-C
4
-alkyl, the acylthio group may be, for example, C
1
-C
4
-alkylcarbonylthio, e.g. acetylthio or n-propionylthio.
When R
1
is 5- or 6-membered heterocyclylthio, the heterocyclyl group may be an O-heterocyclyl group, for example a furanonyl group.
When R
2
is acyloxy, it may be, for example, C
1
-C
4
-alkylcarbonyloxy, e.g. acetyloxy, n-propionyloxy, or n-butyroyloxy, C
3
-C
6
-cycloalkylcarbonyloxy e.g. cyclopropylcarbonyloxy, or 5- or 6-membered heterocyclylcarbonyloxy e.g. furoyloxy.
When R
3
is C
1
-C
4
-alkyl it may be in the alpha or beta conformation, more usually in the alpha conformation.
When R
2
and R
3
together denote a group of formula III, R
4
as C
3
-C
6
-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 (CFC11), 1,2-dichloro-1,1,2,2-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
Cuenoud Bernard
Fairhurst Robin Alec
Lowther Nicholas
Houghton Gregory C.
Novartis AG
Seaman D. Margaret
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