Patent Application
20090017036
The present invention relates to novel pharmaceutical compositions comprising at least one EGFR kinase inhibitor, and at least one additional active compound, and their use in the treatment of respiratory or gastrointestinal complaints, as well as inflammatory diseases of the joints, the skin or the eyes.
In a first aspect the present invention relates to pharmaceutical compositions comprising at least one EGFR kinase inhibitor 1 selected from the group consisting of
optionally in the form of tautomers, racemates, enantiomers, diastereomers, pharmacologically acceptable acid addition salts, solvates or hydrates thereof,
and further comprising one or more additional active compounds 2 selected from the groups consisting of beta-2 mimetics 2a, steroids 2b, PDE-IV inhibitors 2c, p38 MAP kinase inhibitors 2d, NK1 antagonists 2e and endothelin-antagonists 2f, optionally together with one or more pharmaceutically acceptable excipients or carriers. All active components should be present in effective amounts.
The active compounds 1.1 to 1.105 are disclosed in the prior art, e.g. in WO 96/30347; WO 97/02266; WO 99/35146; WO 00/31048; WO 00/78735; WO 01/34574; WO 01/61816; WO 01/77104; WO02/18351; WO 02/18372; WO 02/18373; WO 02/18376; WO 02/50043; WO 03/082290; Cancer Research 2004, 64:11 (3958-3965); Am J Health-Syst Pharm 2000, 57(15), 2063-2076; Clinical Therapeutics 1999, 21(2), 309-318; WO 98/50433; and WO 95/20045.
In the pharmaceutical compositions according to the present invention the EGFR kinase inhibitors 1 may be contained in a form selected from tautomers, optical isomers, enantiomers, racemates, diastereomers, pharmacologically acceptable acid addition salts, solvates or hydrates, as far as such forms exist, depending on the individual compound. Pharmaceutical compositions comprising one or more, preferably one, compound 1 in form of a substantially pure enantiomer are preferred. Pharmacological acceptable acid addition salts of EGFR kinase inhibitors 1 comprise salts selected from the group consisting of the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrolactate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluolsulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydromaleate, hydrofumarate and hydromethansulphonate. Some of the compounds 1 may add more than one equivalent acid, e.g. two equivalents. The salts of hydrochloric acid, methanesulphonic acid, maleic acid, benzoic acid and acetic acid are especially preferred.
The pharmaceutical compositions according to the invention comprising at least one EGFR kinase inhibitor 1 and at least one additional active compound 2 are not restricted to binary combinations of actives. The combinations disclosed exemplary below comprising an EGFR kinase inhibitor 1 together with an additional active compound 2 may comprise a third or a third and a fourth, preferably a third active compound, also selected from the group consisting of beta-2 mimetics 2a, steroids 2b, PDE-IV inhibitors 2c, p38 MAP kinase inhibitors 2d, NK1 antagonists 2e and endothelin-antagonists 2f. All components 2a to 2f mentioned specifically hereinafter are described in the prior art.
In a first preferred embodiment of the invention the pharmaceutical combination is binary, comprising an EGFR kinase inhibitor 1 and an active compound selected from one of the classes 2a, 2b, 2c, 2d, 2e and 2f.
In a second preferred embodiment of the invention the pharmaceutical combination is ternary, comprising an EGFR kinase inhibitor 1, an active compound selected from the class of beta-2 mimetics 2a and an active drug selected from the class of steroids 2b.
In a third embodiment of the invention the pharmaceutical combination is ternary, comprising two EGFR kinase inhibitors 1 and an active compound selected from one of the classes 2a, 2b, 2c, 2d, 2e and 2f, preferably selected from one of the classes 2b, 2d and 2e.
In a fourth embodiment of the invention the pharmaceutical combination is quanternary, comprising two EGFR kinase inhibitors 1 and two active compounds selected from either one or from two different classes of 2a, 2b, 2c, 2d, 2e and 2f, preferably selected from either one or from two different classes of 2b, 2d and 2e.
Any reference to an EGFR kinase inhibitor 1 within the scope of the present invention should be understood as a reference to any specific EGFR kinase inhibitor selected from compounds 1.1 to 1.105. mentioned hereinbefore. Analogously, any reference to an active compound selected from the classes 2a, 2b, 2c, 2d, 2e and 2f within the scope of the present invention should be understood as a reference to any active compound of these classes mentioned specifically hereinbelow.
In the pharmaceutical combinations according to the invention the active substances may be combined in a single preparation, e.g. as a fixed dose combination comprising the active ingredients in one formulation together, or contained in two or more separate formulations, e.g. as a kit of parts adapted for simultaneous, separate or sequential administration. Pharmaceutical compositions containing the active substances 1 and 2 in a single preparation are preferred according to the invention.
In all embodiments of the invention the EGFR kinase inhibitors 1.1 to 1.101 are preferred, especially the EGFR kinase inhibitors
1.1, 1.4, 1.6, 1.8, 1.9, 1.14, 1.17, 1.19, 1.21, 1.23, 1.24, 1.27, 1.28, 1.30, 1.34, 1.35, 1.37, 1.38, 1.40, 1.42, 1.43, 1.44, 1.48, 1.52, 1.55, 1.57, 1.59, 1.60, 1.63, 1.64, 1.66, 1.67, 1.69, 1.70, 1.71, 1.72, 1.78, 1.82, 1.83, 1.84, 1.88, 1.90, 1.91, 1.94 and 1.95.
All pharmaceutical compositions of the present invention can be advantageously used in the following indications (A):
for the prevention and treatment of diseases of the airways and lungs which are accompanied by increased or altered production of mucus and/or in inflammatory and/or obstructive diseases of the airways such as
Pharmaceutical compositions of the present invention comprising at least one EGFR kinase inhibitor 1 and further comprising one or more additional active compounds 2 selected from the groups consisting of steroids 2b, p38 MAP kinase inhibitors 2d and NK1 antagonists 2e, e.g.
binary compositions comprising an EGFR kinase inhibitor 1 and an active compound selected from one of the classes 2b, 2d and 2e,
ternary compositions comprising two EGFR kinase inhibitors 1 and an active compound selected from one of the classes 2b, 2d and 2e, or
quanternary compositions comprising two EGFR kinase inhibitors 1 and two active compounds selected from either one or from two different classes of 2b, 2d and 2e, can be advantageously used in the following indications (B):
for treatment of inflammatory or hypersecretory diseases of the gastrointestinal tract of various origins or polyps of the gastrointestinal tract of various origins such as
Preferred fields of application are inflammatory and/or obstructive diseases of the respiratory organs or of the intestine, such as chronic (obstructive) bronchitis (COPD), chronic sinusitis, chronic rhinosinusitis, nasal polyposis, asthma, Crohn's disease, ulcerative colitis or polyposis of the intestines.
Particularly preferred fields of application are inflammatory diseases of the airways or lungs such as chronic (obstructive) bronchitis (COPD) or asthma and chronic rhinosinusitis.
Thus a second aspect of the invention is a method of treating any of the indications mentioned hereinbefore comprising administering to a patient in need thereof a pharmaceutical composition according to the invention, comprising at least one of the selected EGFR kinase inhibitors 1 in combination with one or more additional active compounds 2 selected from the groups consisting of beta-2 mimetics 2a, steroids 2b, PDE-IV inhibitors 2c, p38 MAP kinase inhibitors 2d, NK1 antagonists 2e and endothelin-antagonists 2f, optionally together with one or more pharmaceutically acceptable excipients. The expression “patient” is meant to comprise the mammal animal body, preferably the human body. The method of treatment is meant to encompass simultaneous as well as successive administration of the active components.
A third aspect of the invention is the use of any of the selected EGFR kinase inhibitors 1 in combination with one or more additional active compounds 2 selected from the groups consisting of beta-2 mimetics 2a, steroids 2b, PDE-IV inhibitors 2c, p38 MAP kinase inhibitors 2d, NK1 antagonists 2e and endothelin-antagonists 2f, optionally together with one or more pharmaceutically acceptable excipients, for the manufacture of a pharmaceutical composition for treating any of the indications mentioned hereinbefore in a patient in need thereof. This aspect encompasses the preparation of all pharmaceutical compositions according to the invention mentioned hereinbefore or below.
Preferred embodiments of the pharmaceutical compositions of the invention as well as the indications to be treated apply analogously regarding to the second and third aspect of the invention.
Pharmaceutical Compositions Comprising an EGFR Kinase Inhibitor 1 and a Beta-2 Mimetic 2a:
One embodiment of the invention is a pharmaceutical composition comprising an EGFR kinase inhibitor 1 and a beta-2 mimetic 2a. Binary compositions containing only one active 1 and one active 2a, optionally together with one or more pharmaceutically acceptable excipients or carriers, are preferred. In the pharmaceutical combinations according to the invention preferred beta2 agonists 2a are selected from the group consisting of albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmeterol, salmefamol, soterenot, sulphonterol, tiaramide, terbutaline, tolubuterol, CHF-1035, CHF 4226 (TA2005), HOKU-81, KUL-1248, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfonamide, 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butyl-amino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol and 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol, optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts and the hydrates thereof.
According to the instant invention more preferred beta2 agonists 2a are selected from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulphonterol, terbutaline, tolubuterol, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfonamide, 5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]-ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol and 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol, optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts and the hydrates thereof.
More preferably, the betamimetics 2a used as within the compositions according to the invention are selected from among fenoterol, formoterol, salmeterol, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfonamide, 5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts thereof, and the hydrates thereof.
Of the betamimetics mentioned above the compounds formoterol 2a.1, salmeterol 2a.2, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfonamide 2a.3, and 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one 2a.4 are particularly preferred, optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts thereof, and the hydrates thereof.
Of the betamimetics mentioned above the compounds formoterol and salmeterol are particularly preferred, optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts thereof, and the hydrates thereof.
Examples of pharmacologically acceptable acid addition salts of the betamimetics 2a according to the invention are the pharmaceutically acceptable salts which are selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid, 4-phenylcinnamic acid, 5-(2,4-difluorophenyl)salicylic acid or maleic acid. If desired, mixtures of the abovementioned acids may also be used to prepare the salts of 2a.
According to the invention, the salts of the betamimetics 2a selected from among the hydrochloride, hydrobromide, sulphate, phosphate, fumarate, methanesulphonate, 4-phenylcinnamate, 5-(2,4-difluorophenyl)salicylate, maleate and xinofoate are preferred. Particularly preferred are the salts of 2a in the case of salmeterol selected from among the hydrochloride, sulphate, 4-phenylcinnamate, 5-(2,4-difluorophenyl)salicylate and xinofoate, of which the 4-phenylcinnamate, 5-(2,4-difluorophenyl)salicylate and especially xinofoate are particularly important. Particularly preferred are the salts of 2a in the case of formoterol selected from the hydrochloride, sulphate and fumarate, of which the hydrochloride and fumarate are particularly preferred. Of exceptional importance according to the invention is formoterol fumarate.
Salts of salmeterol, formoterol, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfonamide, and 5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, are preferably used as the betamimetics 2a according to the invention. Of particular importance according to the invention are salmeterol and formoterol salts. Any reference to the term betamimetics 2a also includes a reference to the relevant enantiomers or mixtures thereof.
In the pharmaceutical compositions according to the invention, the compounds 2a may be present in the form of their racemates, enantiomers or mixtures thereof. The separation of the enantiomers from the racemates may be carried out using methods known in the art (e.g. by chromatography on chiral phases, etc.). If the compounds 2a are used in the form of their enantiomers, it is particularly preferable to use the enantiomers in the R configuration at the C—OH group.
As an example, any reference to the most preferred compounds 2a according to the invention, the salts of salmeterol and formoterol, also includes the relevant enantiomeric salts of R-salmeterol, S-salmeterol, R,R-formoterol, S,S-formoterol, R,S-formoterol, S,R-formoterol and the mixtures thereof, while the enantiomeric salts of R-salmeterol and R,R-formoterol are of particular importance. The compounds 2a may also be present according to the invention in the form of the hydrates or solvates thereof.
Preferred betamimetics 2a according to the invention which are not in salt form include the free base of formoterol, salmeterol whereas the particularly preferred compounds 2a according to the invention are salmeterol xinofoate or formoterol fumarate.
Within the scope of the present invention the betamimetics 2a may possibly also be referred to as sympathomimetics or beta-2-agonists (β2-agonists). All these terms are to be regarded as interchangeable for the purposes of the present invention.
Besides therapeutically effective quantities of 1 and 2a the pharmaceutical compositions may contain in addition a pharmaceutically acceptable carrier. The present invention encompasses both pharmaceutical compositions with or without pharmaceutically acceptable carriers.
Especially preferred pharmaceutical compositions according to the invention comprise the following specific combinations of EGFR kinase inhibitors 1 and beta-2 mimetics 2a, either as free bases or pharmacologically acceptable acid addition salts:
1.1 and 2a.1, 1.4 and 2a.1, 1.6 and 2a.1, 1.8 and 2a.1, 1.9 and 2a.1, 1.14 and 2a.1, 1.17 and 2a.1, 1.19 and 2a.1, 1.21 and 2a.1, 1.23 and 2a.1, 1.24 and 2a.1, 1.27 and 2a.1, 1.28 and 2a.1, 1.30 and 2a.1, 1.34 and 2a.1, 1.35 and 2a.1, 1.37 and 2a.1, 1.38 and 2a.1, 1.40 and 2a.1, 1.42 and 2a.1, 1.43 and 2a.1, 1.44 and 2a.1, 1.48 and 2a.1, 1.52 and 2a.1, 1.55 and 2a.1, 1.57 and 2a.1, 1.59 and 2a.1, 1.60 and 2a.1, 1.63 and 2a.1, 1.64 and 2a.1, 1.66 and 2a.1, 1.67 and 2a.1, 1.69 and 2a.1, 1.70 and 2a.1, 1.71 and 2a.1, 1.72 and 2a.1, 1.78 and 2a.1, 1.82 and 2a.1, 1.83 and 2a.1, 1.84 and 2a.1, 1.88 and 2a.1, 1.90 and 2a.1, 1.91 and 2a.1, 1.94 and 2a.1, 1.95 and 2a.1;
1.1 and 2a.2, 1.4 and 2a.2, 1.6 and 2a.2, 1.8 and 2a.2, 1.9 and 2a.2, 1.14 and 2a.2, 1.17 and 2a.2, 1.19 and 2a.2, 1.21 and 2a.2, 1.23 and 2a.2, 1.24 and 2a.2, 1.27 and 2a.2, 1.28 and 2a.2, 1.30 and 2a.2, 1.34 and 2a.2, 1.35 and 2a.2, 1.37 and 2a.2, 1.38 and 2a.2, 1.40 and 2a.2, 1.42 and 2a.2, 1.43 and 2a.2, 1.44 and 2a.2, 1.48 and 2a.2, 1.52 and 2a.2, 1.55 and 2a.2, 1.57 and 2a.2, 1.59 and 2a.2, 1.60 and 2a.2, 1.63 and 2a.2, 1.64 and 2a.2, 1.66 and 2a.2, 1.67 and 2a.2, 1.69 and 2a.2, 1.70 and 2a.2, 1.71 and 2a.2, 1.72 and 2a.2, 1.78 and 2a.2, 1.82 and 2a.2, 1.83 and 2a.2, 1.84 and 2a.2, 1.88 and 2a.2, 1.90 and 2a.2, 1.91 and 2a.2, 1.94 and 2a.2, 1.95 and 2a.2;
1.1 and 2a.3, 1.4 and 2a.3, 1.6 and 2a.3, 1.8 and 2a.3, 1.9 and 2a.3, 1.14 and 2a.3, 1.17 and 2a.3, 1.19 and 2a.3, 1.21 and 2a.3, 1.23 and 2a.3, 1.24 and 2a.3, 1.27 and 2a.3, 1.28 and 2a.3, 1.30 and 2a.3, 1.34 and 2a.3, 1.35 and 2a.3, 1.37 and 2a.3, 1.38 and 2a.3, 1.40 and 2a.3, 1.42 and 2a.3, 1.43 and 2a.3, 1.44 and 2a.3, 1.48 and 2a.3, 1.52 and 2a.3, 1.55 and 2a.3, 1.57 and 2a.3, 1.59 and 2a.3, 1.60 and 2a.3, 1.63 and 2a.3, 1.64 and 2a.3, 1.66 and 2a.3, 1.67 and 2a.3, 1.69 and 2a.3, 1.70 and 2a.3, 1.71 and 2a.3, 1.72 and 2a.3, 1.78 and 2a.3, 1.82 and 2a.3, 1.83 and 2a.3, 1.84 and 2a.3, 1.88 and 2a.3, 1.90 and 2a.3, 1.91 and 2a.3, 1.94 and 2a.3, 1.95 and 2a.3;
1.1 and 2a.4, 1.4 and 2a.4, 1.6 and 2a.4, 1.8 and 2a.4, 1.9 and 2a.4, 1.14 and 2a.4, 1.17 and 2a.4, 1.19 and 2a.4, 1.21 and 2a.4, 1.23 and 2a.4, 1.24 and 2a.4, 1.27 and 2a.4, 1.28 and 2a.4, 1.30 and 2a.4, 1.34 and 2a.4, 1.35 and 2a.4, 1.37 and 2a.4, 1.38 and 2a.4, 1.40 and 2a.4, 1.42 and 2a.4, 1.43 and 2a.4, 1.44 and 2a.4, 1.48 and 2a.4, 1.52 and 2a.4, 1.55 and 2a.4, 1.57 and 2a.4, 1.59 and 2a.4, 1.60 and 2a.4, 1.63 and 2a.4, 1.64 and 2a.4, 1.66 and 2a.4, 1.67 and 2a.4, 1.69 and 2a.4, 1.70 and 2a.4, 1.71 and 2a.4, 1.72 and 2a.4, 1.78 and 2a.4, 1.82 and 2a.4, 1.83 and 2a.4, 1.84 and 2a.4, 1.88 and 2a.4, 1.90 and 2a.4, 1.91 and 2a.4, 1.94 and 2a.4, 1.95 and 2a.4.
The proportions in which the active substances 1 and 2a may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2a may possibly be present in the form of salts, solvates or hydrates. Depending on the choice of the compounds 1 and 2a, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various salt forms. The pharmaceutical combinations according to the invention may contain 1 and 2a generally in ratios by weight ranging from 15 000:1 to 1:10, preferably from 6 000:1 to 10:1, e.g. 3 000:1 to 100:1.
The weight ratios specified hereinbefore and below are based on the free bases of the actives.
The pharmaceutical combinations according to the invention may contain 1 and formoterol 2a.1, for example, in ratios by weight ranging from 15 000:1 to 1:1, preferably from 10 000:1 to 100:1, more preferably from 5000:1 to 500:1, e.g. from 5000:1 to 1 000:1.
For example, without restricting the scope of the invention thereto, combinations of 1 and 2 according to the invention may contain the EGFR-inhibitor 1 and formoterol 2a.1 in the following weight ratios: 15000:1, 14500:1, 14000:1, 13500:1, 13000:1, 12500:1, 12000:1, 11500:1, 11000:1, 10500:1, 10000:1, 9500:1, 9000:1, 8500:1, 8000:1, 7500:1, 7000:1, 6500:1, 6000:1, 5500:1, 5000:1, 4500:1, 4000:1, 3500:1, 3000:1, 2500:1, 2000:1, 1500:1, 1000:1, 900:1, 800:1, 700:1, 600:1, 500:1, 400:1, 300:1, 200:1.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2a.1 are normally administered so that 1 and formoterol 2a.1 are present together in doses of 5 to 15000 μg, preferably from 10 to 10000 μg, more preferably from 15 to 5000 μg, better still from 20 to 2000 μg per single dose.
For example, combinations of any of EGFR-inhibitors 1.1 to 1.101, especially those characterized as preferred hereinbefore, and 2a.1 according to the invention contain a quantity of the actives such that the total dosage per single dose is about 100 μg, 105 μg, 110 μg, 115 μg, etc. (add stepwise 5 μg) up to 15000 μg.
It is clear to anyone skilled in the art that the suggested dosages per single dose specified above are not to be regarded as being limited to the numerical values actually stated. Fluctuations of about ±2.5 μg, particularly in the decimal range, are also included, as will be apparent to the skilled man. In these dosage ranges, the active substances 1 and 2a may be present in the weight ratios given above.
For example, without restricting the scope of the invention thereto, the combinations in which any of the preferred EGFR inhibitors 1.1, 1.4, 1.6, 1.8, 1.9, 1.14, 1.17, 1.19, 1.21, 1.23, 1.24, 1.27, 1.28, 1.30, 1.34, 1.35, 1.37, 1.38, 1.40, 1.42, 1.43, 1.44, 1.48, 1.52, 1.55, 1.57, 1.59, 1.60, 1.63, 1.64, 1.66, 1.67, 1.69, 1.70, 1.71, 1.72, 1.78, 1.82, 1.83, 1.84, 1.88, 1.90, 1.91, 1.94 and 1.95 is used and in which 2a denotes formoterol fumarate, the pharmaceutical compositions according to the invention may contain for instance the following quantities for each single dose: 10 μg of 1 and 2.9 μg of 2a, 10 μg of 1 and 5.7 μg of 2a, 10 μg of 1 and 11.5 μg of 2a, 10 μg of 1 and 17.2 μg of 2a, 10 μg of 1 and 22.9 μg of 2a, 10 μg of 1 and 28.5 μg of 2a,
100 μg of 1 and 2.9 μg of 2a, 100 μg of 1 and 5.7 μg of 2a, 100 μg of 1 and 11.5 μg of 2a, 100 μg of 1 and 17.2 μg of 2a, 100 μg of 1 and 22.9 μg of 2a, 100 μg of 1 and 28.5 μg of 2a,
500 μg of 1 and 2.9 mg of 2a, 500 μg of 1 and 5.7 μg of 2a, 500 μg of 1 and 11.5 μg of 2a, 500 μg of 1 and 17.2 μg of 2a, 500 μg of 1 and 22.9 μg of 2a, 500 μg of 1 and 28.5 μg of 2a,
1000 μg of 1 and 2.9 μg of 2a, 1000 μg of 1 and 5.7 μg of 2a, 1000 μg of 1 and 11.5 μg of 2a, 1000 μg of 1 and 17.2 μg of 2a, 1000 μg of 1 and 22.9 μg of 2a, 1000 μg of 1 and 28.5 μg of 2a, 1000 μg of 1 and 2.9 μg of 2a,
2000 μg of 1 and 5.7 μg of 2a, 2000 μg of 1 and 11.5 μg of 2a, 200 μg of 1 and 17.2 μg of 2a, 2000 μg of 1 and 22.9 μg of 2a, 200 μg of 1 and 28.5 μg of 2a,
3000 μg of 1 and 5.7 μg of 2a, 3000 μg of 1 and 11.5 μg of 2a, 300 μg of 1 and 17.2 μg of 2a, 3000 μg of 1 and 22.9 μg of 2a, 300 μg of 1 and 28.5 μg of 2a,
4000 μg of 1 and 5.7 μg of 2a, 4000 μg of 1 and 11.5 μg of 2a, 400 μg of 1 and 17.2 μg of 2a, 4000 μg of 1 and 22.9 μg of 2a, 400 μg of 1 and 28.5 μg of 2a,
5000 μg of 1 and 5.7 μg of 2a, 5000 μg of 1 and 11.5 μg of 2a, 5000 μg of 1 and 17.2 μg of 2a, 5000 μg of 1 and 22.9 μg of 2a, 5000 μg of 1 and 28.5 μg of 2a,
6000 μg of 1 and 5.7 μg of 2a, 6000 μg of 1 and 11.5 μg of 2a, 600 μg of 1 and 17.2 μg of 2a, 6000 μg of 1 and 22.9 μg of 2a, 600 μg of 1 and 28.5 μg of 2a,
7000 μg of 1 and 5.7 μg of 2a, 7000 μg of 1 and 11.5 μg of 2a, 700 μg of 1 and 17.2 μg of 2a, 7000 μg of 1 and 22.9 μg of 2a, 700 μg of 1 and 28.5 μg of 2a,
8000 μg of 1 and 5.7 μg of 2a, 8000 μg of 1 and 11.5 μg of 2a, 800 μg of 1 and 17.2 μg of 2a, 8000 μg of 1 and 22.9 μg of 2a, 800 μg of 1 and 28.5 μg of 2a,
9000 μg of 1 and 5.7 μg of 2a, 9000 μg of 1 and 11.5 μg of 2a, 900 μg of 1 and 17.2 μg of 2a, 9000 μg of 1 and 22.9 μg of 2a, 900 μg of 1 and 28.5 μg of 2a,
10000 μg of 1 and 5.7 μg of 2a, 10000 μg of 1 and 11.5 μg of 2a, 10000 μg of 1 and 17.2 μg of 2a, 10000 μg of 1 and 22.9 μg of 2a, 1000 μg of 1 and 28.5 μg of 2a,
12500 μg of 1 and 5.7 μg of 2a, 12500 μg of 1 and 11.5 μg of 2a, 12500 μg of 1 and 17.2 μg of 2a, 12500 μg of 1 and 22.9 μg of 2a, 12500 μg of 1 and 28.5 μg of 2a,
15000 μg of 1 and 5.7 μg of 2a, 15000 μg of 1 and 11.5 μg of 2a, 15000 μg of 1 and 17.2 μg of 2a, 15000 μg of 1 and 22.9 μg of 2a, 15000 μg of 1 and 28.5 μg of 2a.
For example, the active substance combinations according to the invention may contain the component 1 together with salmeterol 2a.2 in ratios by weight in the range from about 5000:1 to 20:1, preferably 2500:1 to 50:1, more preferably 1000:1 to 100:1, most preferred from 500:1 to 150:1.
For example, without restricting the scope of the invention thereto, preferred combinations of 1 and 2a.2 according to the invention may contain any of EGFR-inhibitors 1.1 to 1.101, especially those characterized as preferred hereinbefore, and salmeterol 2a.2 in the following ratios by weight:
5000:1, 4500:1, 4000:1, 3500:1, 3000:1, 2500:1, 2000:1, 1500:1, 1000:1, 900:1, 800:1, 700:1, 600:1, 500:1, 400:1, 300:1, 200:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2a.2 are usually administered so that 1 and salmeterol 2a.2 are present together in dosages of 100 μg to 100000 μg, preferably from 500 μg to 50000 μg, more preferably from 1000 μg to 10000 μg per single dose.
For example, combinations of any of EGFR-inhibitors 1.1 to 1.101, especially those characterized as preferred hereinbefore, and salmeterol 2a.2 according to the invention contain a quantity of the actives such that the total dosage per single dose is about 100 μg, 150 μg, 200 μg, 250 μg, etc. (add stepwise 50 μg) up to 50000 μg.
It is clear to anyone skilled in the art that the suggested dosages per single dose specified above are not to be regarded as being limited to the numerical values actually stated. Fluctuations of about ±2.5 μg, particularly in the decimal range, are also included, as will be apparent to the skilled man. In these dosage ranges, the active substances 1 and 2a.2 may be present in the weight ratios given above.
For example, without restricting the scope of the invention thereto, the combinations in which any of the preferred EGFR inhibitors 1.1, 1.4, 1.6, 1.8, 1.9, 1.14, 1.17, 1.19, 1.21, 1.23, 1.24, 1.27, 1.28, 1.30, 1.34, 1.35, 1.37, 1.38, 1.40, 1.42, 1.43, 1.44, 1.48, 1.52, 1.55, 1.57, 1.59, 1.60, 1.63, 1.64, 1.66, 1.67, 1.69, 1.70, 1.71, 1.72, 1.78, 1.82, 1.83, 1.84, 1.88, 1.90, 1.91, 1.94 and 1.95 is used and in which 2a denotes salmeterol xinofoate, the pharmaceutical compositions according to the invention may contain for instance the following quantities for each single dose: 100 μg of 1 and 18.2 μg of 2a, 100 μg of 1 and 36.3 μg of 2a, 100 μg of 1 and 72.6 μg of 2a, 100 μg of 1 and 108.9 μg of 2a, 100 μg of 1 and 145.2 μg of 2a, 100 μg of 1 and 290.4 μg of 2a, 200 μg of 1 and 18.2 μg of 2a, 200 μg of 1 and 36.3 μg of 2a, 200 μg of 1 and 72.6 μg of 2a, 200 μg of 1 and 108.9 μg of 2a, 200 μg of 1 and 145.2 μg of 2a, 200 μg of 1 and 290.4 μg of 2a, 500 μg of 1 and 18.2 μg of 2a, 500 μg of 1 and 36.3 μg of 2a, 500 μg of 1 and 72.6 μg of 2a, 500 μg of 1 and 108.9 μg of 2a, 500 μg of 1 and 145.2 μg of 2a, 500 μg of 1 and 290.4 μg of 2a, 1000 μg of 1 and 18.2 μg of 2a, 1000 μg of 1 and 36.3 μg of 2a, 1000 μg of 1 and 72.6 μg of 2a, 1000 μg of 1 and 108.9 μg of 2a, 1000 μg of 1 and 145.2 μg of 2a, 1000 μg of 1 and 290.4 μg of 2a, 10000 μg of 1 and 18.2 μg of 2a, 10000 μg of 1 and 36.3 μg of 2a, 10000 μg of 1 and 72.6 μg of 2a, 10000 μg of 1 and 108.9 μg of 2a, 10000 μg of 1 and 145.2 μg of 2a, 10000 μg of 1 and 290.4 μg of 2a, 25000 μg of 1 and 18.2 μg of 2a, 25000 μg of 1 and 36.3 μg of 2a, 25000 μg of 1 and 72.6 μg of 2a, 25000 μg of 1 and 108.9 μg of 2a, 25000 μg of 1 and 145.2 μg of 2a, 25000 μg of 1 and 290.4 μg of 2a, 50000 μg of 1 and 18.2 μg of 2a, 50000 μg of 1 and 36.3 μg of 2a, 50000 μg of 1 and 72.6 μg of 2a, 50000 μg of 1 and 108.9 μg of 2a, 50000 μg of 1 and 145.2 μg of 2a, 50000 μg of 1 and 290.4 μg of 2a.
Pharmaceutical Compositions Comprising an EGFR Kinase Inhibitor 1 and a Steroid 2b:
One embodiment of the invention is a pharmaceutical composition comprising an EGFR kinase inhibitor 1 and a steroid 2b. Binary compositions containing only one active 1 and one active 2b, optionally together with one or more pharmaceutically acceptable excipients or carriers, are preferred. In the pharmaceutical combinations according to the invention preferred steroids 2b, which are optionally also referred to as corticosteroids, are selected from the group consisting of methyl prednisolone, prednisone, butixocort propionate, RPR-106541, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid (S)-fluoromethyl ester, and 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioic acid (S)-(2-oxo-tetrahydro-furan-3S-yl)ester.
Preferably, the compound 2b is selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid (S)-fluoromethyl ester, and 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioic acid (S)-(2-oxo-tetrahydro-furan-3S-yl)ester.
More preferably, the compound 2b is selected from among budesonide 2b.1, fluticasone 2b.2 (in particular fluticasone propionate ester), mometasone 2b.3 (for instance as the furoate ester), ciclesonide 2b.4, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid (S)-fluoromethyl ester 2b.5, and 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioic acid (S)-(2-oxo-tetrahydrofuran-3S-yl)ester 2b.6.
Especially preferred pharmaceutical compositions according to the invention comprise the following specific combinations of EGFR kinase inhibitors 1 and steroids 2b, either as free bases or pharmacologically acceptable acid addition salts, wherein in case of fluticasone 2b.2 the propionate ester and in case of mometasone 2b.3 the furoate ester are particularly preferred:
1.1 and 2b.1, 1.4 and 2b.1, 1.6 and 2b.1, 1.8 and 2b.1, 1.9 and 2b.1, 1.14 and 2b.1, 1.17 and 2b.1, 1.19 and 2b.1, 1.21 and 2b.1, 1.23 and 2b.1, 1.24 and 2b.1, 1.27 and 2b.1, 1.28 and 2b.1, 1.30 and 2b.1, 1.34 and 2b.1, 1.35 and 2b.1, 1.37 and 2b.1, 1.38 and 2b.1, 1.40 and 2b.1, 1.42 and 2b.1, 1.43 and 2b.1, 1.44 and 2b.1, 1.48 and 2b.1, 1.52 and 2b.1, 1.55 and 2b.1, 1.57 and 2b.1, 1.59 and 2b.1, 1.60 and 2b.1, 1.63 and 2b.1, 1.64 and 2b.1, 1.66 and 2b.1, 1.67 and 2b.1, 1.69 and 2b.1, 1.70 and 2b.1, 1.71 and 2b.1, 1.72 and 2b.1, 1.78 and 2b.1, 1.82 and 2b.1, 1.83 and 2b.1, 1.84 and 2b.1, 1.88 and 2b.1, 1.90 and 2b.1, 1.91 and 2b.1, 1.94 and 2b.1, 1.95 and 2b.1;
1.1 and 2b.2, 1.4 and 2b.2, 1.6 and 2b.2, 1.8 and 2b.2, 1.9 and 2b.2, 1.14 and 2b.2, 1.17 and 2b.2, 1.19 and 2b.2, 1.21 and 2b.2, 1.23 and 2b.2, 1.24 and 2b.2, 1.27 and 2b.2, 1.28 and 2b.2, 1.30 and 2b.2, 1.34 and 2b.2, 1.35 and 2b.2, 1.37 and 2b.2, 1.38 and 2b.2, 1.40 and 2b.2, 1.42 and 2b.2, 1.43 and 2b.2, 1.44 and 2b.2, 1.48 and 2b.2, 1.52 and 2b.2, 1.55 and 2b.2, 1.57 and 2b.2, 1.59 and 2b.2, 1.60 and 2b.2, 1.63 and 2b.2, 1.64 and 2b.2, 1.66 and 2b.2, 1.67 and 2b.2, 1.69 and 2b.2, 1.70 and 2b.2, 1.71 and 2b.2, 1.72 and 2b.2, 1.78 and 2b.2, 1.82 and 2b.2, 1.83 and 2b.2, 1.84 and 2b.2, 1.88 and 2b.2, 1.90 and 2b.2, 1.91 and 2b.2, 1.94 and 2b.2, 1.95 and 2b.2;
1.1 and 2b.3, 1.4 and 2b.3, 1.6 and 2b.3, 1.8 and 2b.3, 1.9 and 2b.3, 1.14 and 2b.3, 1.17 and 2b.3, 1.19 and 2b.3, 1.21 and 2b.3, 1.23 and 2b.3, 1.24 and 2b.3, 1.27 and 2b.3, 1.28 and 2b.3, 1.30 and 2b.3, 1.34 and 2b.3, 1.35 and 2b.3, 1.37 and 2b.3, 1.38 and 2b.3, 1.40 and 2b.3, 1.42 and 2b.3, 1.43 and 2b.3, 1.44 and 2b.3, 1.48 and 2b.3, 1.52 and 2b.3, 1.55 and 2b.3, 1.57 and 2b.3, 1.59 and 2b.3, 1.60 and 2b.3, 1.63 and 2b.3, 1.64 and 2b.3, 1.66 and 2b.3, 1.67 and 2b.3, 1.69 and 2b.3, 1.70 and 2b.3, 1.71 and 2b.3, 1.72 and 2b.3, 1.78 and 2b.3, 1.82 and 2b.3, 1.83 and 2b.3, 1.84 and 2b.3, 1.88 and 2b.3, 1.90 and 2b.3, 1.91 and 2b.3, 1.94 and 2b.3, 1.95 and 2b.3;
1.1 and 2b.4, 1.4 and 2b.4, 1.6 and 2b.4, 1.8 and 2b.4, 1.9 and 2b.4, 1.14 and 2b.4, 1.17 and 2b.4, 1.19 and 2b.4, 1.21 and 2b.4, 1.23 and 2b.4, 1.24 and 2b.4, 1.27 and 2b.4, 1.28 and 2b.4, 1.30 and 2b.4, 1.34 and 2b.4, 1.35 and 2b.4, 1.37 and 2b.4, 1.38 and 2b.4, 1.40 and 2b.4, 1.42 and 2b.4, 1.43 and 2b.4, 1.44 and 2b.4, 1.48 and 2b.4, 1.52 and 2b.4, 1.55 and 2b.4, 1.57 and 2b.4, 1.59 and 2b.4, 1.60 and 2b.4, 1.63 and 2b.4, 1.64 and 2b.4, 1.66 and 2b.4, 1.67 and 2b.4, 1.69 and 2b.4, 1.70 and 2b.4, 1.71 and 2b.4, 1.72 and 2b.4, 1.78 and 2b.4, 1.82 and 2b.4, 1.83 and 2b.4, 1.84 and 2b.4, 1.88 and 2b.4, 1.90 and 2b.4, 1.91 and 2b.4, 1.94 and 2b.4, 1.95 and 2b.4;
1.1 and 2b.5, 1.4 and 2b.5, 1.6 and 2b.5, 1.8 and 2b.5, 1.9 and 2b.5, 1.14 and 2b.5, 1.17 and 2b.5, 1.19 and 2b.5, 1.21 and 2b.5, 1.23 and 2b.5, 1.24 and 2b.5, 1.27 and 2b.5, 1.28 and 2b.5, 1.30 and 2b.5, 1.34 and 2b.5, 1.35 and 2b.5, 1.37 and 2b.5, 1.38 and 2b.5, 1.40 and 2b.5, 1.42 and 2b.5, 1.43 and 2b.5, 1.44 and 2b.5, 1.48 and 2b.5, 1.52 and 2b.5, 1.55 and 2b.5, 1.57 and 2b.5, 1.59 and 2b.5, 1.60 and 2b.5, 1.63 and 2b.5, 1.64 and 2b.5, 1.66 and 2b.5, 1.67 and 2b.5, 1.69 and 2b.5, 1.70 and 2b.5, 1.71 and 2b.5, 1.72 and 2b.5, 1.78 and 2b.5, 1.82 and 2b.5, 1.83 and 2b.5, 1.84 and 2b.5, 1.88 and 2b.5, 1.90 and 2b.5, 1.91 and 2b.5, 1.94 and 2b.5, 1.95 and 2b.5;
1.1 and 2b.6, 1.4 and 2b.6, 1.6 and 2b.6, 1.8 and 2b.6, 1.9 and 2b.6, 1.14 and 2b.6, 1.17 and 2b.6, 1.19 and 2b.6, 1.21 and 2b.6, 1.23 and 2b.6, 1.24 and 2b.6, 1.27 and 2b.6, 1.28 and 2b.6, 1.30 and 2b.6, 1.34 and 2b.6, 1.35 and 2b.6, 1.37 and 2b.6, 1.38 and 2b.6, 1.40 and 2b.6, 1.42 and 2b.6, 1.43 and 2b.6, 1.44 and 2b.6, 1.48 and 2b.6, 1.52 and 2b.6, 1.55 and 2b.6, 1.57 and 2b.6, 1.59 and 2b.6, 1.60 and 2b.6, 1.63 and 2b.6, 1.64 and 2b.6, 1.66 and 2b.6, 1.67 and 2b.6, 1.69 and 2b.6, 1.70 and 2b.6, 1.71 and 2b.6, 1.72 and 2b.6, 1.78 and 2b.6, 1.82 and 2b.6, 1.83 and 2b.6, 1.84 and 2b.6, 1.88 and 2b.6, 1.90 and 2b.6, 1.91 and 2b.6, 1.94 and 2b.6, 1.95 and 2b.6;
Any reference to steroids 2b within the scope of the present invention includes a reference to the salts or derivatives which may be formed from the steroids. Examples of possible salts or derivatives include: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. In some cases the compounds of formula 2b may also occur in the form of their hydrates. Any reference to steroids 2b within the scope of the present invention also includes a reference to the compounds 2b in the form of their diastereomers, mixtures of diastereomers or in the form of the racemates.
The proportions in which the active substances 1 and 2b may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2b may possibly be present in the form of their solvates or hydrates. Depending on the choice of the compounds 1 and 2b, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various compounds and their different potencies.
As a rule, the pharmaceutical combinations according to the invention may contain the EGFR-inhibitor 1 and the steroid 2b in ratios by weight ranging from 5000:1 to 1:250, preferably from 2500:1 to 1:150, more preferably 1000:1 to 1:100, most preferred from 250:1 to 1:25.
In the particularly preferred pharmaceutical combinations which contain in addition to 1a compound selected for instance from among the group consisting of budesonide 2b.1, fluticasone 2b.2, mometasone 2b.3, and ciclesonide 2b.4 as the steroid 2b, the weight ratios of 1 to 2b are preferably in a range from about 750:1 to 1:50, more preferably from 500:1 to 1:50.
For example, without restricting the scope of the invention thereto, preferred combinations according to the invention may contain an EGF kinase inhibitor 1 and one of the most preferred steroids selected from 2b.1, 2b.2, 2b.3 and 2b.4, for example in the following ratios by weight (all based on free base): 500:1, 450:1, 400:1, 350:1, 300:1, 250:1, 200:1, 150:1, 100:1, 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20: 1:25, 1:30, 1:35, 1:40, 1:45, 1:50.
The pharmaceutical compositions according to the invention containing the combinations of 1 together with one of the most preferred steroids selected from 2b.1, 2b.2, 2b.3 and 2b.4 preferably are administered so that 1 and the steroid 2b (values based on free base) are present together in dosages of 100 μg to 50000 μg, preferably from 500 μg to 25000 μg, more preferably from 200 μg to 12000 μg per single dose.
For example, combinations of 1 and 2b according to the invention contain an amount of 1 and 2b (values based on free base) such that the total dosage per single dose is about 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 150 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1000 μg, 1100 μg, 1200 μg, etc. (add stepwise 1000 μg) up to 50000 μg, or similar. It is clear to anyone skilled in the art that the suggested dosages per single dose specified above are not to be regarded as being limited to the numerical values actually stated. Fluctuations of about ±2.5 μg, particularly in the decimal range, are also included, as will be apparent to the skilled man. In these dosage ranges, the active substances 1 and 2b may be present in the weight ratios given above.
For example, without restricting the scope of the invention thereto, the combinations of 1 and one of the most preferred steroids 2b selected from 2b.1, 2b.2, 2b.3 and 2b.4 may in particular contain a quantity of 1 and steroid 2b (values based on free base) such that, for each single dose,
100 μg of 1 and 25 μg of 2b, 100 μg of 1 and 50 μg of 2b, 100 μg of 1 and 75 μg of 2b, 100 μg of 1 and 100 μg of 2b, 100 μg of 1 and 125 μg of 2b, 100 μg of 1 and 150 μg of 2b, 100 μg of 1 and 200 μg of 2b, 100 μg of 1 and 250 μg of 2b,
200 μg of 1 and 25 μg of 2b, 200 μg of 1 and 50 μg of 2b, 200 μg of 1 and 75 μg of 2b, 200 μg of 1 and 100 μg of 2b, 200 μg of 1 and 125 μg of 2b, 200 μg of 1 and 150 μg of 2b, 200 μg of 1 and 200 μg of 2b, 200 μg of 1 and 250 μg of 2b,
500 μg of 1 and 25 μg of 2b, 500 μg of 1 and 50 μg of 2b, 500 μg of 1 and 75 μg of 2b, 500 μg of 1 and 100 μg of 2b, 500 μg of 1 and 125 μg of 2b, 500 μg of 1 and 150 μg of 2b, 500 μg of 1 and 200 μg of 2b, 500 μg of 1 and 250 μg of 2b,
1000 μg of 1 and 25 μg of 2b, 1000 μg of 1 and 50 μg of 2b, 1000 μg of 1 and 75 μg of 2b, 1000 μg of 1 and 100 μg of 2b, 1000 μg of 1 and 125 μg of 2b, 1000 μg of 1 and 150 μg of 2b, 1000 μg of 1 and 200 μg of 2b, 1000 μg of 1 and 250 μg of 2b,
5000 μg of 1 and 25 μg of 2b, 5000 μg of 1 and 50 μg of 2b, 5000 μg of 1 and 75 μg of 2b, 5000 μg of 1 and 100 μg of 2b, 5000 μg of 1 and 125 μg of 2b, 5000 μg of 1 and 150 μg of 2b, 5000 μg of 1 and 200 μg of 2b, 5000 μg of 1 and 250 μg of 2b,
10000 μg of 1 and 25 μg of 2b, 10000 μg of 1 and 50 μg of 2b, 10000 μg of 1 and 75 μg of 2b, 10000 μg of 1 and 10000 μg of 2b, 10000 μg of 1 and 125 μg of 2b, 1000 μg of 1 and 150 μg of 2b, 10000 μg of 1 and 200 μg of 2b, 10000 μg of 1 and 250 μg of 2b,
25000 μg of 1 and 25 μg of 2b, 25000 μg of 1 and 50 μg of 2b, 25000 μg of 1 and 75 μg of 2b, 25000 μg of 1 and 100 μg of 2b, 25000 μg of 1 and 125 μg of 2b, 25000 μg of 1 and 150 μg of 2b, 25000 μg of 1 and 200 μg of 2b, 25000 μg of 1 and 250 μg of 2b,
50000 μg of 1 and 25 μg of 2b, 50000 μg of 1 and 50 μg of 2b, 50000 μg of 1 and 75 μg of 2b, 50000 μg of 1 and 100 μg of 2b, 50000 μg of 1 and 125 μg of 2b, 50000 μg of 1 and 150 μg of 2b, 50000 μg of 1 and 200 μg of 2b, 50000 μg of 1 and 250 μg of 2b.
From the aforementioned examples for suitable doses of the 1 and 2b containing combinations according to the invention, the corresponding amounts of the preferably used acid addition salts of 1 and 2b are readily calculable.
Pharmaceutical Compositions Comprising an EGFR Kinase Inhibitor 1, a beta-2 Mimetic 2a and a Steroid 2b:
One embodiment of the invention is a pharmaceutical composition comprising an EGFR kinase inhibitor 1, a beta-2 mimetic 2a and a steroid 2b. Ternary compositions containing one active 1, one active 2a and one active 2b, optionally together with one or more pharmaceutically acceptable excipients or carriers, are preferred. Furthermore, specific components 1, 2a and 2b are the same as mentioned hereinbefore with regard to pharmaceutical compositions comprising only two of these classes of actives. Analogously, derivatives or racemates, enantiomers, diastereomers, pharmacologically acceptable acid addition salts and hydrates as well as preferred specific components 1, 2a and 2b are the same as mentioned herein before.
Especially preferred ternary pharmaceutical compositions according to the invention comprise the following specific combinations of EGFR kinase inhibitors 1, beta-2 mimetics 2a and steroids 2b, either as free bases or pharmacologically acceptable acid addition salts, wherein in case of formoterol 2a.1 the fumarate, in case of salmeterol 2a.2 the xinofoate, in case of fluticasone 2b.2 the propionate ester and in case of mometasone 2b.3 the furoate ester are particularly preferred:
Further specific ternary combinations are those wherein the combinations listed under [Ter-1] to [Ter-4] the component 2b.1 is replaced by any of 2b.2, 2b.3, 2b.4, 2b.5 and 2b.6.
The proportions in which the active substances 1, 2a and 2b may be used in the active substance combinations according to the invention are variable. Active substances 1, 2a and 2b may possibly be present in the form of their solvates or hydrates. Depending on the choice of the compounds 1, 2a and 2b, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various compounds and their different potencies. As a rule, the pharmaceutical combinations according to the invention may contain compounds 1 and 2a in ratios by weight ranging from 15000:1 to 1:1, preferably from 6000:1 to 200:1, more preferably from 3000:1 to 500:1. At the same time the ratio of 1 to 2b may be 250:1 to 1:250, preferably from 150:1 to 1:150, more preferably from 30:1 to 1:70, most preferably from 15:1 to 1:35.
The weight ratios specified hereinbefore and below are based on the free bases of the actives.
The ternary pharmaceutical combinations according to the invention may contain 1 and formoterol 2a.1 for example, in ratios by weight ranging from 15 000:1 to 200:1, preferably from 10 000:1 to 500:1, more preferably 5000:1 to 1 000:1.
For example, without restricting the scope of the invention thereto, preferred ternary combinations according to the invention may contain an EGF kinase inhibitor 1, together with formoterol 2a.1 or salmeterol 2a.2 as component 2a and budesonide or fluticasone as component 2b in the following proportions 1:2a:2b by weight:
15000:1:60, 14500:1:60, 14000:1:60, 13500:1:60, 13000:1:60, 12500:1:60, 12000:1:60, 11500:1:60, 11000:1:60, 10500:1:60, 10000:1:60, 9500:1:60, 9000:1:60, 8500:1:60, 8000:1:60, 7500:1:60, 7000:1:60, 6500:1:60, 6000:1:60, 5500:1:60, 5000:1:60, 4500:1:60, 4000:1:60, 3500:1:60, 3000:1:60, 2500:1:60, 2000:1:60, 1500:1:60, 1000:1:60, 900:1:60, 800:1:60, 700:1:60, 600:1:60, 500:1:60, 400:1:60, 300:1:60, 200:1:60,
15000:1:100, 14500:1:200, 14000:1:500, 13500:1:1000, 13000:1:2000, 12500:1:3000, 12000:1:4000, 11500:1:5000, 11000:1:6000, 10500:1:7000, 10000:1:8000, 9500:1:9000, 9000:1:10000, 9000:1:11000, 9000:1:12000, 9000:1:13000, 9000:1:14000, 9000:1:15000, 8500:1:15000, 8000:1:16000, 7500:1:17000, 7000:1:18000, 6500:1:19000, 6000:1:20000, 5500:1:21000, 5000:1:22000, 4500:1:23000, 4000:1:24000, 3500:1:25000, 3000:1:26000, 2500:1:27000, 2000:1:28000, 1500:1:29000, 1000:1:30000, 900:1:31000, 800:1:32000, 700:1:33000, 600:1:34000, 500:1:35000, 400:1:40500, 300:1:45000, 200:1:50000,
200:1:100, 200:1:200, 200:1:500, 200:1:750, 200:1:1000, 200:1:1500, 200:1:2000, 200:1:3000, 200:1:4000, 200:1:5000, 200:1:6000, 200:1:7000, 200:1:8000, 200:1:9000, 200:1:10000, 200:1:12500, 200:1:15000, 200:1:17500, 200:1:20000, 200:1:22500, 200:1:25000, 200:1:30000, 200:1:35000, 200:1:40000, 200:1:45000, 200:1:50000.
The pharmaceutical compositions according to the invention containing the combinations of 1, 2a and 2b are normally administered so that 1, 2a and 2b are present together in doses of 10 to 50000 μg, preferably from 50 to 40000 μg, more preferably from 60 to 10000 μg, even more preferably from 70 to 5000 μg, preferably according to the invention from 100 to 1000 μg, preferably from 150 to 750 μg per single dose. For example, combinations of 1, 2a and 2b according to the invention contain a quantity of one EGFR kinase inhibitor selected from compounds of 1.1 to 1.105, formoterol 2a.1 or salmeterol 2a.2, and budesonide 2b.1 or fluticasone 2b.2, such that the total dosage per single dose is about 50 μg, 60 μg, 70 μg, 80 μg, etc. (add stepwise 10 μg) up to 50000 μg. The amounts specified hereinbefore and below are based on the free bases of the actives.
It is clear to anyone skilled in the art that the suggested dosages per single dose specified above are not to be regarded as being limited to the numerical values actually stated. Fluctuations of about ±2.5 μg, particularly in the decimal range, are also included, as will be apparent to the skilled man. In these dosage ranges, the active substances 1 and 2a and 2b may be present in the weight ratios given above.
For example and without restricting the scope of the invention thereto, the combinations of 1, 2a and 2b according to the invention may contain an amount of an EGFR kinase inhibitor 1 selected from compounds of 1.1 to 1.101, a steroid 2b selected from budesonide 2b.1 and fluticasone 2b.2, and a beta2 agonist 2a selected from formoterol 2a.1 and salmeterol 2a.2, such that in each single dose 100 μg of 1 and 25 μg of 2b and 25 μg of 2a, 100 μg of 1 and 50 μg of 2b and 25 μg of 2a, 100 μg of 1 and 100 μg of 2b and 25 μg of 2a, 100 μg of 1 and 125 μg of 2b and 25 μg of 2a, 100 μg of 1 and 200 μg of 2b and 25 μg of 2a, 100 μg of 1 and 250 μg of 2b and 25 μg of 2a, 1000 μg of 1 and 25 μg of 2b and 25 μg of 2a, 1000 μg of 1 and 50 μg of 2b and 25 μg of 2a, 1000 μg of 1 and 100 μg of 2b and 25 μg of 2a, 1000 μg of 1 and 125 μg of 2b and 25 μg of 2a, 1000 μg of 1 and 200 μg of 2b and 25 μg of 2a, 1000 μg of 1 and 250 μg of 2b and 25 μg of 2a, 10000 μg of 1 and 25 μg of 2b and 25 μg of 2a, 10000 μg of 1 and 50 μg of 2b and 25 μg of 2a, 10000 μg of 1 and 100 μg of 2b and 25 μg of 2a, 10000 μg of 1 and 125 μg of 2b and 25 μg of 2a, 10000 μg of 1 and 200 μg of 2b and 25 μg of 2a, 10000 μg of 1 and 250 μg of 2b and 25 μg of 2a, 25000 μg of 1 and 25 μg of 2b and 25 μg of 2a, 25000 μg of 1 and 50 μg of 2b and 25 μg of 2a, 25000 μg of 1 and 100 μg of 2b and 25 μg of 2a, 25000 μg of 1 and 125 μg of 2b and 25 μg of 2a, 25000 μg of 1 and 200 μg of 2b and 25 μg of 2a, 25000 μg of 1 and 250 μg of 2b and 25 μg of 2a, 50000 μg of 1 and 25 μg of 2b and 25 μg of 2a, 50000 μg of 1 and 50 μg of 2b and 25 μg of 2a, 50000 μg of 1 and 100 μg of 2b and 25 μg of 2a, 50000 μg of 1 and 125 μg of 2b and 25 μg of 2a, 50000 μg of 1 and 200 μg of 2b and 25 μg of 2a, 50000 μg of 1 and 250 μg of 2b and 25 μg of 2a, 75000 μg of 1 and 25 μg of 2b and 25 μg of 2a, 75000 μg of 1 and 50 μg of 2b and 25 μg of 2a, 75000 μg of 1 and 100 μg of 2b and 25 μg of 2a, 75000 μg of 1 and 125 μg of 2b and 25 μg of 2a, 75000 μg of 1 and 200 μg of 2b and 25 μg of 2a, 100 μg of 1 and 25 μg of 2b and 50 μg of 2a, 100 μg of 1 and 50 μg of 2b and 50 μg of 2a, 100 μg of 1 and 100 μg of 2b and 50 μg of 2a, 100 μg of 1 and 125 μg of 2b and 50 μg of 2a, 100 μg of 1 and 200 μg of 2b and 50 μg of 2a, 100 μg of 1 and 250 μg of 2b and 50 μg of 2a,1000 μg of 1 and 25 μg of 2b and 50 μg of 2a,1000 μg of 1 and 50 μg of 2b and 50 μg of 2a, 1000 μg of 1 and 100 μg of 2b and 50 μg of 2a, 1000 μg of 1 and 125 μg of 2b and 50 μg of 2a, 1000 μg of 1 and 200 μg of 2b and 50 μg of 2a, 1000 μg of 1′ and 250 μg of 2b and 50 μg of 2a, 10000 μg of 1 and 25 μg of 2b and 50 μg of 2a, 10000 μg of 1 and 50 μg of 2b and 50 μg of 2a, 10000 μg of 1 and 100 μg of 2b and 50 μg of 2a, 10000 μg of 1 and 125 μg of 2b and 50 μg of 2a, 10000 μg of 1 and 200 μg of 2b and 50 μg of 2a, 10000 μg of 1 and 250 μg of 2b and 50 μg of 2a, 25000 μg of 1 and 25 μg of 2b and 50 μg of 2a, 25000 μg of 1 and 50 μg of 2b and 50 μg of 2a, 25000 μg of 1 and 100 μg of 2b and 50 μg of 2a, 25000 μg of 1 and 125 μg of 2b and 50 μg of 2a, 25000 μg of 1 and 200 μg of 2b and 50 μg of 2a, 25000 μg of 1 and 250 μg of 2b and 50 μg of 2a, 50000 μg of 1 and 25 μg of 2b and 50 μg of 2a, 75000 μg of 1 and 50 μg of 2b and 50 μg of 2a, 50000 μg of 1 and 100 μg of 2b and 50 μg of 2a, 50000 μg of 1 and 125 μg of 2b and 50 μg of 2a, 50000 μg of 1 and 200 μg of 2b and 50 μg of 2a, 50000 μg of 1 and 250 μg of 2b and 50 μg of 2a, 75000 μg of 1 and 25 μg of 2b and 50 μg of 2a, 75000 μg of 1 and 50 μg of 2b and 50 μg of 2a, 75000 μg of 1 and 100 μg of 2b and 50 μg of 2a, 75000 μg of 1 and 125 μg of 2b and 50 μg of 2a, 75000 μg of 1 and 200 μg of 2b and 50 μg of 2a, 75000 μg of 1 and 250 μg of 2b and 50 μg of 2a, 10000 μg of 1 and 25 μg of 2b and 50 μg of 2a, 10000 μg of 1 and 50 μg of 2b and 50 μg of 2a, 10000 μg of 1 and 100 μg of 2b and 50 μg of 2a, 10000 μg of 1 and 125 μg of 2b and 50 μg of 2a, 100000 μg of 1 and 200 μg of 2b and 50 μg of 2a, 100000 μg of 1 and 250 μg of 2b and 50 μg of 2a,100 μg of 1 and 25 μg of 2b and 50 μg of 2a, 100 μg of 1 and 50 μg of 2b and 50 μg of 2a, 100 μg of 1 and 100 μg of 2b and 50 μg of 2a, 100 μg of 1 and 125 μg of 2b and 50 μg of 2a, 100 μg of 1 and 200 μg of 2b and 50 μg of 2a, 100 μg of 1 and 250 μg of 2b and 50 μg of 2a, 100 μg of 1 and 25 μg of 2b and 100 μg of 2a, 100 μg of 1 and 50 μg of 2b and 100 μg of 2a, 100 μg of 1 and 100 μg of 2b and 100 μg of 2a, 100 μg of 1 and 125 μg of 2b and 100 μg of 2a,100 μg of 1 and 200 μg of 2b and 100 μg of 2a, 100 μg of 1 and 250 μg of 2b and 100 μg of 2a, 1000 μg of 1 and 25 μg of 2b and 100 μg of 2a, 1000 μg of 1 and 50 μg of 2b and 100 μg of 2a, 1000 μg of 1 and 100 μg of 2b and 100 μg of 2a, 1000 μg of 1 and 125 μg of 2b and 100 μg of 2a, 1000 μg of 1 of 1′ and 200 μg of 2b and 100 μg of 2a, 1000 μg of 1 and 250 μg of 2b and 100 μg of 2a, 10000 μg of 1 and 25 μg of 2b and 100 μg of 2a, 10000 μg of 1 and 50 μg of 2b and 100 μg of 2a, 10000 μg of 1 and 100 μg of 2b and 100 μg of 2a, 10000 μg of 1 and 125 μg of 2b and 100 μg of 2a, 10000 μg of 1 and 200 μg of 2b and 100 μg of 2a, 10000 μg of 1 and 250 μg of 2b and 100 μg of 2a, 25000 μg of 1 and 25 μg of 2b and 100 μg of 2a, 25000 μg of 1 and 50 μg of 2b and 100 μg of 2a, 25000 μg of 1 and 100 μg of 2b and 100 μg of 2a, 25000 μg of 1 and 125 μg of 2b and 100 μg of 2a, 25000 μg of 1 and 200 μg of 2b and 100 μg of 2a, 25000 μg of 1 and 250 μg of 2b and 100 μg of 2a, are administered.
Particularly preferred pharmaceutical combinations according to the invention contain 100-5000 μg of one EGFR kinase inhibitor selected from compounds of 1.1 to 1.101, 125-250 μg of budesonide 2b.1 or fluticasone 2b.2 and 10 to 40 μg of formoterol 2a.1 or salmeterol 2a.2.
The active substance combinations of 1, 2a and 2b according to the invention are preferably administered by inhalation.
Pharmaceutical Compositions Comprising an EGFR Kinase Inhibitor 1 and a PDE-IV Inhibitor 2c:
One embodiment of the invention is a pharmaceutical composition comprising an EGFR kinase inhibitor 1 and a PDE IV inhibitor 2c. Binary compositions containing only one active 1 and one active 2c, optionally together with one or more pharmaceutically acceptable excipients or carriers, are preferred. In the pharmaceutical combinations according to the invention preferred PDE IV inhibitors 2c are selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropyl methoxybenzamide, NCS-613, pumafentine, (−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide, (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone, 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone, cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid], 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate, (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)-pyrrolidine-2-ylidene]acetate, CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, arofylline, atizoram, V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts thereof, and the hydrates thereof.
In a preferred embodiment according to the invention the PDE IV inhibitors 2c are selected from the group consisting of enprofylline, roflumilast, ariflo (cilomilast), AWD-12-281 (GW-842470), N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide, T-440, T-2585, arofylline, cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid], 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], PD-168787, atizoram, V-11294A, CI-1018, CDC-801, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts thereof, and the hydrates thereof.
In another preferred embodiment according to the invention the PDE IV inhibitors 2c are selected from the group consisting of ariflo (cilomilast) 2c.1, roflumilast 2c.2, AWD-12-281 (GW-842470) 2c.3, arofylline, Z-15370, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], atizoram, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, while roflumilast, Z-15370, and AWD-12-281 are particularly preferred as compound 2c according to the invention.
In a yet another preferred embodiment according to the invention the PDE IV inhibitors 2c are selected from the group consisting of 2-(4-fluoro-phenoxy)-N-{4-[(6-fluoro-2-hydroxy-benzoylamino)-methyl]-benzyl}nicotinamide, 2-(4-fluoro-phenoxy)-N-{4-[(5-fluoro-2-hydroxy-benzoylamino)-methyl]-benzyl}nicotinamide, 2-(4-fluoro-phenoxy)-N-{4-[(3-hydroxy-4-methyl-benzoylamino)methyl]benzyl}nicotinamide, 2-(4-fluoro-phenoxy)-N-{4-[(3hydroxy-benzoylamino)-methyl]-benzyl}nicotinamide, 2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-benzoylamino)methyl]-benzyl}nicotinamide, 2-(4-fluoro-phenoxy)-N-{4-[(4-hydroxy-benzoylamino)methyl]-benzyl}nicotinamide, 2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-4-methyl-benzoylamino)methyl]-benzyl}nicotinamide, 2-(4-fluoro-phenoxy)-N-{4-[(3-hydroxy-2-methyl-benzoylamino)methyl]-benzyl}nicotinamide, 2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-5-methyl-benzoylamino)methyl]-benzyl}nicotinamide, 5-fluoro-2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-benzoylamino)-methyl]-benzyl}nicotinamide, 5-fluoro-2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-acetylamino)methyl]-benzyl}nicotinamide, 5-fluoro-2-(4-fluoro-phenoxy)-N-{4-[(4-hydroxy-benzoylamino)methyl]-benzyl}nicotinamide, 3-(3-{4-[(3-hydroxy-benzoylamino)methyl]-benzylcarbamoyl}-pyridin-2-yloxy)benzoic acid ethylester, 3-(3-{4-[(2-hydroxy-phenacetylamino)methyl]-benzylcarbamoyl}-pyridin-2-yloxy)benzoic acid ethylester, 3-(3-{4-[(3-hydroxy-phenacetylamino)methyl]-benzylcarbamoyl}-pyridin-2-yloxy)benzoic acid ethylester, 3-(3-{4-[(4-hydroxy-phenacetylamino)methyl]-benzylcarbamoyl}-pyridin-2-yloxy)benzoic acid ethylester, compound 2c.4
and compound 2c.5
optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts thereof, and the hydrates thereof.
Pharmaceutically acceptable salt forms of the active compounds within the pharmaceutical composition of the present invention are prepared for the most part by conventional means. Where the component compound contains a carboxylic acid group, a suitable salt thereof may be formed by reacting the compound with an appropriate base to provide the corresponding base addition salt. Examples of such bases are alkali metal hydroxides including potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, e.g., potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine, and N-methylglutamine. Also included are the aluminum salts of the component compounds of the present invention.
For certain component compounds acid addition salts may be formed by treating said compounds with pharmaceutically acceptable organic and inorganic acids, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.; and alkyl- and mono-arylsulfonates such as ethanesulfonate, toluenesulfonate, and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, etc.
Accordingly, the pharmaceutically acceptable acid addition salts of the component compounds of the present invention include, but are not limited to: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate.
Particularly preferred examples of pharmacologically acceptable acid addition salts of the compounds 2c according to the invention are the pharmaceutically acceptable salts which are selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid or maleic acid. If desired, mixtures of the abovementioned acids may also be used to prepare the salts 2c.
In the pharmaceutical compositions according to the invention, the compounds 2c may be present in the form of their racemates, enantiomers or mixtures thereof. The separation of the enantiomers from the racemates may be carried out using methods known in the art (e.g. by chromatography on chiral phases, etc.).
Especially preferred pharmaceutical compositions according to the invention comprise the following specific combinations of EGFR kinase inhibitors 1 and PDE IV inhibitors 2c, either as free bases or pharmacologically acceptable acid addition salts:
1.1 and 2c.1, 1.4 and 2c.1, 1.6 and 2c.1, 1.8 and 2c.1, 1.9 and 2c.1, 1.14 and 2c.1, 1.17 and 2c.1, 1.19 and 2c.1, 1.21 and 2c.1, 1.23 and 2c.1, 1.24 and 2c.1, 1.27 and 2c.1, 1.28 and 2c.1, 1.30 and 2c.1, 1.34 and 2c.1, 1.35 and 2c.1, 1.37 and 2c.1, 1.38 and 2c.1, 1.40 and 2c.1, 1.42 and 2c.1, 1.43 and 2c.1, 1.44 and 2c.1, 1.48 and 2c.1, 1.52 and 2c.1, 1.55 and 2c.1, 1.57 and 2c.1, 1.59 and 2c.1, 1.60 and 2c.1, 1.63 and 2c.1, 1.64 and 2c.1, 1.66 and 2c.1, 1.67 and 2c.1, 1.69 and 2c.1, 1.70 and 2c.1, 1.71 and 2c.1, 1.72 and 2c.1, 1.78 and 2c.1, 1.82 and 2c.1, 1.83 and 2c.1, 1.84 and 2c.1, 1.88 and 2c.1, 1.90 and 2c.1, 1.91 and 2c.1, 1.94 and 2c.1, 1.95 and 2c.1;
1.1 and 2c.2, 1.4 and 2c.2, 1.6 and 2c.2, 1.8 and 2c.2, 1.9 and 2c.2, 1.14 and 2c.2, 1.17 and 2c.2, 1.19 and 2c.2, 1.21 and 2c.2, 1.23 and 2c.2, 1.24 and 2c.2, 1.27 and 2c.2, 1.28 and 2c.2, 1.30 and 2c.2, 1.34 and 2c.2, 1.35 and 2c.2, 1.37 and 2c.2, 1.38 and 2c.2, 1.40 and 2c.2, 1.42 and 2c.2, 1.43 and 2c.2, 1.44 and 2c.2, 1.48 and 2c.2, 1.52 and 2c.2, 1.55 and 2c.2, 1.57 and 2c.2, 1.59 and 2c.2, 1.60 and 2c.2, 1.63 and 2c.2, 1.64 and 2c.2, 1.66 and 2c.2, 1.67 and 2c.2, 1.69 and 2c.2, 1.70 and 2c.2, 1.71 and 2c.2, 1.72 and 2c.2, 1.78 and 2c.2, 1.82 and 2c.2, 1.83 and 2c.2, 1.84 and 2c.2, 1.88 and 2c.2, 1.90 and 2c.2, 1.91 and 2c.2, 1.94 and 2c.2, 1.95 and 2c.2;
1.1 and 2c.3, 1.4 and 2c.3, 1.6 and 2c.3, 1.8 and 2c.3, 1.9 and 2c.3, 1.14 and 2c.3, 1.17 and 2c.3, 1.19 and 2c.3, 1.21 and 2c.3, 1.23 and 2c.3, 1.24 and 2c.3, 1.27 and 2c.3, 1.28 and 2c.3, 1.30 and 2c.3, 1.34 and 2c.3, 1.35 and 2c.3, 1.37 and 2c.3, 1.38 and 2c.3, 1.40 and 2c.3, 1.42 and 2c.3, 1.43 and 2c.3, 1.44 and 2c.3, 1.48 and 2c.3, 1.52 and 2c.3, 1.55 and 2c.3, 1.57 and 2c.3, 1.59 and 2c.3, 1.60 and 2c.3, 1.63 and 2c.3, 1.64 and 2c.3, 1.66 and 2c.3, 1.67 and 2c.3, 1.69 and 2c.3, 1.70 and 2c.3, 1.71 and 2c.3, 1.72 and 2c.3, 1.78 and 2c.3, 1.82 and 2c.3, 1.83 and 2c.3, 1.84 and 2c.3, 1.88 and 2c.3, 1.90 and 2c.3, 1.91 and 2c.3, 1.94 and 2c.3, 1.95 and 2c.3;
1.1 and 2c.4, 1.4 and 2c.4, 1.6 and 2c.4, 1.8 and 2c.4, 1.9 and 2c.4, 1.14 and 2c.4, 1.17 and 2c.4, 1.19 and 2c.4, 1.21 and 2c.4, 1.23 and 2c.4, 1.24 and 2c.4, 1.27 and 2c.4, 1.28 and 2c.4, 1.30 and 2c.4, 1.34 and 2c.4, 1.35 and 2c.4, 1.37 and 2c.4, 1.38 and 2c.4, 1.40 and 2c.4, 1.42 and 2c.4, 1.43 and 2c.4, 1.44 and 2c.4, 1.48 and 2c.4, 1.52 and 2c.4, 1.55 and 2c.4, 1.57 and 2c.4, 1.59 and 2c.4, 1.60 and 2c.4, 1.63 and 2c.4, 1.64 and 2c.4, 1.66 and 2c.4, 1.67 and 2c.4, 1.69 and 2c.4, 1.70 and 2c.4, 1.71 and 2c.4, 1.72 and 2c.4, 1.78 and 2c.4, 1.82 and 2c.4, 1.83 and 2c.4, 1.84 and 2c.4, 1.88 and 2c.4, 1.90 and 2c.4, 1.91 and 2c.4, 1.94 and 2c.4, 1.95 and 2c.4;
1.1 and 2c.5, 1.4 and 2c.5, 1.6 and 2c.5, 1.8 and 2c.5, 1.9 and 2c.5, 1.14 and 2c.5, 1.17 and 2c.5, 1.19 and 2c.5, 1.21 and 2c.5, 1.23 and 2c.5, 1.24 and 2c.5, 1.27 and 2c.5, 1.28 and 2c.5, 1.30 and 2c.5, 1.34 and 2c.5, 1.35 and 2c.5, 1.37 and 2c.5, 1.38 and 2c.5, 1.40 and 2c.5, 1.42 and 2c.5, 1.43 and 2c.5, 1.44 and 2c.5, 1.48 and 2c.5, 1.52 and 2c.5, 1.55 and 2c.5, 1.57 and 2c.5, 1.59 and 2c.5, 1.60 and 2c.5, 1.63 and 2c.5, 1.64 and 2c.5, 1.66 and 2c.5, 1.67 and 2c.5, 1.69 and 2c.5, 1.70 and 2c.5, 1.71 and 2c.5, 1.72 and 2c.5, 1.78 and 2c.5, 1.82 and 2c.5, 1.83 and 2c.5, 1.84 and 2c.5, 1.88 and 2c.5, 1.90 and 2c.5, 1.91 and 2c.5, 1.94 and 2c.5, 1.95 and 2c.5;
1.1 and 2c.6, 1.4 and 2c.6, 1.6 and 2c.6, 1.8 and 2c.6, 1.9 and 2c.6, 1.14 and 2c.6, 1.17 and 2c.6, 1.19 and 2c.6, 1.21 and 2c.6, 1.23 and 2c.6, 1.24 and 2c.6, 1.27 and 2c.6, 1.28 and 2c.6, 1.30 and 2c.6, 1.34 and 2c.6, 1.35 and 2c.6, 1.37 and 2c.6, 1.38 and 2c.6, 1.40 and 2c.6, 1.42 and 2c.6, 1.43 and 2c.6, 1.44 and 2c.6, 1.48 and 2c.6, 1.52 and 2c.6, 1.55 and 2c.6, 1.57 and 2c.6, 1.59 and 2c.6, 1.60 and 2c.6, 1.63 and 2c.6, 1.64 and 2c.6, 1.66 and 2c.6, 1.67 and 2c.6, 1.69 and 2c.6, 1.70 and 2c.6, 1.71 and 2c.6, 1.72 and 2c.6, 1.78 and 2c.6, 1.82 and 2c.6, 1.83 and 2c.6, 1.84 and 2c.6, 1.88 and 2c.6, 1.90 and 2c.6, 1.91 and 2c.6, 1.94 and 2c.6, 1.95 and 2c.6.
The proportions in which the active substances 1 and 2c may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2c may possibly be present in the form of their solvates or hydrates. Depending on the choice of the compounds 1 and 2c, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various salt forms.
As a rule, the pharmaceutical combinations according to the invention may contain compounds 1 and 2c in ratios by weight ranging from 10000:1 to 1:500, preferably from 4000:1 to 1:100, more preferred from 2000:1 to 1:50, most preferred 1000:1 to 1:20. In particularly preferred pharmaceutical combinations that contain as component 2 one of the most preferred compounds ariflo 2c.1, roflumilast 2c.2, or AWD-12-281 2c.3, the weight ratios of 1 to 2c are most preferably in a range in which 1 and 2c are present in proportions of 4000:1 to 20:1, more preferably from 2000:1 to 100:1.
For example, without restricting the scope of the invention thereto, preferred combinations may contain 1 and PDE-IV inhibitor 2c (as for instance ariflo, roflumilast or AWD-12-281) in the following weight ratios:
4000:1, 3900:1, 3800:1, 3700:1, 3600:1, 3500:1, 3400:1, 3300:1, 3200:1, 3100:1, 3000:1, 2900:1, 2800:1 2700:1, 2600:1, 2500:1, 2400:1, 2300:1, 2200:1 2100:1, 2000:1, 1900:1, 1800:1, 1700:1, 1600:1, 1500:1, 1400:1, 1300:1, 1200:1, 1100:1, 1000:1, 900:1, 800:1, 700:1, 600:1, 500:1, 400:1, 300:1, 200:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 35:1, 30:1, 25:1, 20:1.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2c are normally administered so that 1 and 2c are present together in doses of 1 to 100000 μg, preferably from 10 to 50000 μg, more preferably from 100 to 25000 μg, better still from 500 to 10000 μg per single dose. For example, combinations of 1 and 2c according to the invention contain a quantity of 1 and PDE-IV inhibitor 2c (as for instance 2c.1, 2c.2 or 2c.3) such that the total dosage per single dose is about 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, etc. (add stepwise 100 μg) up to 50000 μg, or similar.
The suggested dosages per single dose specified above are not to be regarded as being limited to the numerical values actually stated, but are intended as dosages which are disclosed by way of example. Of course, dosages which may fluctuate about the abovementioned numerical values within a range of about +/−2.5 μg are also included in the values given above by way of example. In these dosage ranges, the active substances 1 and 2c may be present in the weight ratios given above.
For example, without restricting the scope of the invention thereto, the combinations of 1 and 2c according to the invention may contain a quantity of 1 and PDE-IV inhibitor 2 (as for instance 2c.1, 2c.2 or 2c.3) in such an amount that the following quantities of the active substances are administered per single dose:
100 μg of 1 and 25 μg of 2c, 100 μg of 1 and 50 μg of 2c, 100 μg of 1 and 100 μg of 2c, 100 μg of 1 and 200 μg of 2c, 100 μg of 1 and 300 μg of 2c, 100 μg of 1 and 400 μg of 2c, 100 μg of 1 and 500 μg of 2c, 100 μg of 1 and 600 μg of 2c, 100 μg of 1 and 700 μg of 2c, 100 μg of 1 and 800 μg of 2c, 100 μg of 1 and 900 μg of 2c, 100 μg of 1 and 1000 μg of 2c, 100 μg of 1 and 1250 μg of 2c, 100 μg of 1 and 1500 μg of 2c, 100 μg of 1 and 1750 μg of 2c, 100 μg of 1 and 2000 μg of 2c,
200 μg of 1 and 25 μg of 2c, 200 μg of 1 and 50 μg of 2c, 200 μg of 1 and 100 μg of 2c, 200 μg of 1 and 200 μg of 2c, 200 μg of 1 and 300 μg of 2c, 200 μg of 1 and 400 μg of 2c, 200 μg of 1 and 500 μg of 2c, 200 μg of 1 and 600 μg of 2c, 200 μg of 1 and 700 μg of 2c, 200 μg of 1 and 800 μg of 2c, 200 μg of 1 and 900 μg of 2c, 200 μg of 1 and 1000 μg of 2c, 200 μg of 1 and 1250 μg of 2c, 200 μg of 1 and 1500 μg of 2c, 200 μg of 1 and 1750 μg of 2c, 200 μg of 1 and 2000 μg of 2c,
500 μg of 1 and 25 μg of 2c, 500 μg of 1 and 50 μg of 2c, 500 μg of 1 and 100 μg of 2c, 500 μg of 1 and 200 μg of 2c, 500 μg of 1 and 300 μg of 2c, 500 μg of 1 and 400 μg of 2c, 500 μg of 1 and 500 μg of 2c, 500 μg of 1 and 600 μg of 2c, 500 μg of 1 and 700 μg of 2c, 500 μg of 1 and 800 μg of 2c, 500 μg of 1 and 900 μg of 2c, 500 μg of 1 and 1000 μg of 2c, 500 μg of 1 and 1250 μg of 2c, 500 μg of 1 and 1500 μg of 2c, 500 μg of 1 and 1750 μg of 2c, 500 μg of 1 and 2000 μg of 2c,
1000 μg of 1 and 25 μg of 2c, 1000 μg of 1 and 50 μg of 2c, 1000 μg of 1 and 100 μg of 2c, 1000 μg of 1 and 200 μg of 2c, 1000 μg of 1 and 300 μg of 2c, 1000 μg of 1 and 400 μg of 2c, 1000 μg of 1 and 500 μg of 2c, 1000 μg of 1 and 600 μg of 2c, 1000 μg of 1 and 700 μg of 2c, 1000 μg of 1 and 800 μg of 2c, 1000 μg of 1 and 900 μg of 2c, 1000 μg of 1 and 1000 μg of 2c, 1000 μg of 1 and 1250 μg of 2c, 1000 μg of 1 and 1500 μg of 2c, 1000 μg of 1 and 1750 μg of 2c, 1000 μg of 1 and 2000 μg of 2c,
5000 μg of 1 and 25 μg of 2c, 5000 μg of 1 and 50 μg of 2c, 5000 μg of 1 and 100 μg of 2c, 5000 μg of 1 and 200 μg of 2c, 5000 μg of 1 and 300 μg of 2c, 5000 μg of 1 and 400 μg of 2c, 5000 μg of 1 and 500 μg of 2c, 5000 μg of 1 and 600 μg of 2c, 5000 μg of 1 and 700 μg of 2c, 5000 μg of 1 and 800 μg of 2c, 5000 μg of 1 and 900 μg of 2c, 5000 μg of 1 and 1000 μg of 2c, 5000 μg of 1 and 1250 μg of 2c, 5000 μg of 1 and 1500 μg of 2c, 5000 μg of 1 and 1750 μg of 2c, 5000 μg of 1 and 200 μg of 2c,
10000 μg of 1 and 25 μg of 2c, 10000 μg of 1 and 50 μg of 2c, 10000 μg of 1 and 100 μg of 2c, 1000 μg of 1 and 200 μg of 2c, 1000 μg of 1 and 300 μg of 2c, 1000 μg of 1 and 400 μg of 2c, 1000 μg of 1 and 500 μg of 2c, 1000 μg of 1 and 600 μg of 2c, 10000 μg of 1 and 700 μg of 2c, 10000 μg of 1 and 800 μg of 2c, 10000 μg of 1 and 900 μg of 2c, 10000 μg of 1 and 1000 μg of 2c, 10000 μg of 1 and 1250 μg of 2c, 10000 μg of 1 and 1500 μg of 2c, 10000 μg of 1 and 1750 μg of 2c, 10000 μg of 1 and 2000 μg of 2c,
25000 μg of 1 and 25 μg of 2c, 25000 μg of 1 and 50 μg of 2c, 25000 μg of 1 and 100 μg of 2c, 25000 μg of 1 and 200 μg of 2c, 25000 μg of 1 and 300 μg of 2c, 25000 μg of 1 and 400 μg of 2c, 25000 μg of 1 and 500 μg of 2c, 25000 μg of 1 and 600 μg of 2c, 25000 μg of 1 and 700 μg of 2c, 25000 μg of 1 and 800 μg of 2c, 25000 μg of 1 and 900 μg of 2c, 25000 μg of 1 and 1000 μg of 2c, 25000 μg of 1 and 1250 μg of 2c, 25000 μg of 1 and 1500 μg of 2c, 25000 μg of 1 and 1750 μg of 2c, 25000 μg of 1 and 2000 μg of 2c,
50000 μg of 1 and 25 μg of 2c, 50000 μg of 1 and 50 μg of 2c, 50000 μg of 1 and 100 μg of 2c, 50000 μg of 1 and 200 μg of 2c, 50000 μg of 1 and 300 μg of 2c, 50000 μg of 1 and 400 μg of 2c, 50000 μg of 1 and 500 μg of 2c, 50000 μg of 1 and 600 μg of 2c, 50000 μg of 1 and 700 μg of 2c, 50000 μg of 1 and 800 μg of 2c, 50000 μg of 1 and 900 μg of 2c, 50000 μg of 1 and 1000 μg of 2c, 50000 μg of 1 and 1250 μg of 2c, 50000 μg of 1 and 1500 μg of 2c, 50000 μg of 1 and 1750 μg of 2c, 50000 μg of 1 and 2000 μg of 2c.
Pharmaceutical Compositions Comprising an EGFR Kinase Inhibitor 1 and a p38 MAP Kinase Inhibitor 2d:
One embodiment of the invention is a pharmaceutical composition comprising an EGFR kinase inhibitor 1 and a p38 MAP kinase inhibitor 2d. Binary compositions containing only one active 1 and one active 2d, optionally together with one or more pharmaceutically acceptable excipients or carriers, are preferred.
p38 Kinase inhibitors applicable within the scope of the invention are known in the art. Within the scope of the present invention the term p38 kinase inhibitors 2d denotes compounds selected from the compounds that are disclosed for instance in U.S. Pat. No. 5,716,972, U.S. Pat. No. 5,686,455, U.S. Pat. No. 5,656,644, U.S. Pat. No. 5,593,992, U.S. Pat. No. 5,593,991, U.S. Pat. No. 5,663,334, U.S. Pat. No. 5,670,527, U.S. Pat. Nos. 5,559,137, 5,658,903, U.S. Pat. No. 5,739,143, U.S. Pat. No. 5,756,499, U.S. Pat. No. 6,277,989, U.S. Pat. No. 6,340,685, and U.S. Pat. No. 5,716,955 and PCT applications WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851, WO 95/09847, WO 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO 97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO 97/16441, WO 97/12876, WO 98/25619, WO 98/06715, WO 98/07425, WO 98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO 98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO 98/52941, WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO 98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99/58523, WO 99/01452, WO 99/01131, WO 99/01130, WO 99/01136, WO 99/17776, WO 99/32121, WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426, WO 99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441, WO 99/01449, WO 99/03484, WO 99/15164, WO 99/32110, WO 99/32111, WO 99/32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO 99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO 00/17175, WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991, WO 00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO 00/23072, WO 00/31065, WO 00/35911, WO 00/39116, WO 00/43384, WO 00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO 00/59904, WO 00/71535, WO 00/10563, WO 00/25791, WO 00/55152, WO 00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO 00/56738, WO 01/21591, WO 01/29041, WO 01/29042, WO 01/62731, WO 01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751, WO 01/27315, WO 01/42189, WO 01/00208, WO 01/42241, WO 01/34605, WO 01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/36403, WO 01/38314, WO 01/47921, WO 01/27089, DE 19842833, and JP 2000 86657 whose disclosures are all incorporated herein by reference in their entirety.
Of particular interest for the pharmaceutical compositions according to the invention are those p38 inhibitors 2d disclosed in U.S. Pat. No. 6,277,989, U.S. Pat. No. 6,340,685, WO 00/12074, WO 00/12497, WO 00/59904, WO 00/71535, WO 01/64676, WO 99/61426, WO 00/10563, WO 00/25791, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/38314, WO 01/47921, WO 99/61437, WO 99/61440, WO 00/17175, WO 00/17204, WO 00/36096, WO 98/27098, WO 99/00357, WO 99/58502, WO 99/64400, WO 99/01131, WO 00/43384, WO 00/55152, WO 00/55139, and WO 01/36403.
In a preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (I) as disclosed in WO 99/01131
wherein
In the aforementioned compounds of formula (I) R2 is a substituted alkyl derivative. It is recognised that the first methylene carbon in this chain is a tertiary carbon, and it will contain one hydrogen moiety. This ethylene group has two additional substituents, an R22 moiety and an A moiety, —C(H)(A)(R22). Both A and R22 may not be unsubstituted C1-10 alkyl moiety.
In a preferred embodiment, R2 is a —C(AA1)(A) moiety, wherein AA1 is the R22 moiety, but is specifically the side chain residue (R) of an amino acid, as is further described herein.
Suitably, A is an optionally substituted C13-7 cycloalkyl, aryl, heteroaryl, or heterocyclic ring, or A is a substituted C1-10 alkyl moiety.
When A is an aryl, heteroaryl and heterocyclic ring, the ring may be substituted independently one or more times, preferably, 1 to 3 times by C1-10 alkyl; halogen; halo substituted C1-10 alkyl such as CF3; (CR10R20)tOR11; (CR10R20)tNR12R14, especially amino or mono- or di-C1-4 alkylamino; (CR10R20)tS(O)m R18, wherein m is 0, 1 or 2; SH; NR10C(Z)R3 (such NHCO(C1-10 alkyl)); or NR10S(O)m R8 (such as NHSO2(C1-10 alkyl)).
Suitably, t is 0, or an integer of 1 to 4.
When A is an optionally substituted cycloalkyl it is as defined below with the R22 substitution.
When A is an optionally substituted heterocyclyl ring, the ring is preferably a morpholino, pyrrolidinyl, piperazinyl or a piperidinyl ring.
When A is an optionally substituted aryl moiety, it is preferably a phenyl ring.
When A is an optionally substituted heteroaryl ring, it is as defined below in the definition section.
When A is a substituted C1-10alkyl moiety, the alkyl chain may be straight or branched. The chain is substituted independently 1 or more times, preferably 1 to 3 times by halogen, such as fluorine, chlorine, bromine or iodine; halosubstituted C1-10 alkyl, such as CF3; C3-7 cycloalkyl, C1-10 alkyloxy, such as methoxy or ethoxy; hydroxy substituted C1-10 alkoxy; halosubstituted C1-10 alkoxy, such as OCF2CF2H; OR11; S(O)mR18 (wherein m is 0, 1 or 2); NR13R14; C(Z)NR13R14; S(O)m,NR13R14; NR23C(Z)R11; NHS(O)2R18; C(Z)R11; OC(Z)R11; C(Z)OR11; C(Z)NR11OR9; N(OR6)C(Z)NR13R14; N(OR6)C(Z)R11; C(═NOR6)R11; NR23C(═NR19)NR13R14; OC(Z)NR13R14; NR23C(Z)NR13R14; or NR23C(Z)OR10.
Preferably A is a C3-7 cycloalkyl, or a C1-6 alkyl, more preferably a C1-2 alkyl, i.e. a methylene or ethylene moiety, more preferably a methylene moiety which is substituted by one of the above noted groups.
Preferably, when A is a C1-10 alkyl, it is substituted by OR11 where R11 is preferably hydrogen, aryl or arylalkyl; NR13R14; OC(Z)R11; C(Z)OR11.
More preferably, A is substituted by OR11 where R11 is hydrogen.
Suitably, R22 is a C1-10 alkyl chain, which chain may be straight or branched and which may be optionally substituted independently, one or more times, preferably 1 to 3 times, by halogen, such as fluorine, chlorine or iodine; halo substituted C1-10alkyl; C1-10alkoxy, such as methoxy or ethoxy; hydroxy substituted C1-10alkoxy; halosubstituted C1-10alkoxy, such as OCF2CF2H; OR11; S(O)mR18; NR13R14; C(Z)NR13R14; S(O)m,NR13R14; NR23C(Z)R11; NHS(O)2R18; C(Z)R11; OC(Z)OR11; C(Z)OR11; C(Z)NR11OR9; N(OR6)C(Z)NR13R14; N(OR6)C(Z)R11; C(═NOR6)R11; NR23C(═NR19)NR13R14; OC(Z)NR13R14; NR23C(Z)NR13R14; NR23C(Z)OR10; optionally substituted C3-7cycloalkyl; optionally substituted aryl, such as phenyl; optionally substituted heteroaryl; or an optionally substituted heterocyclic. The optional substituents on these cycloalkyl, aryl, heteroaryl, and heterocyclic moieties are as defined herein below.
It is noted that those R22 substituent groups which contain carbon as the first connecting group, i.e. C(Z)OR11; C(Z)NR11OR9, C(Z)R11, C(Z)NR13R14, and C(═NOR6)R11, may be the sole carbon in alkyl chain. Therefore, the R22 group may, for instance, be a carboxy, an aldehyde, or an amide, as well as being a substituent of a methylene unit, such as carbamoylmethyl, or acetamidomethyl.
Preferably R22 is a C1-6 unsubstituted or substituted alkyl group, such as a C1-3 alkylene such as methyl, ethyl or isopropyl, or a methylene or ethylene moiety substituted by one of the above noted moieties, or as noted above those substituent groups which contain a carbon may substituent for the first methylene unit of the alkyl chain, such as carboxy, C(O)OR11; C(O)NR13R14 or R22 is an optionally substituted aryl group, such as a benzyl or phenethyl. In other words, R22 can be an optionally substituted alkyl group, or R22 can be C(Z)OR11; C(Z)NR11OR9, C(Z)R11, C(Z)NR13R14, or C(═NOR6)R11.
Preferably R22 is C1-6 unsubstituted or substituted alkyl group, more preferably a C1-2 alkylene chain, such as a methylene or ethylene moiety, more preferably methylene.
Preferably the alkyl chain is substituted by OR11, where R11 is preferably hydrogen, aryl or arylalkyl; S(O)mR18, where m is 0 and R18 is a C1-6 alkyl; or an optionally substituted aryl, i.e. a benzyl or phenethyl moiety.
More preferably, R22 is phenyl, benzyl, CH2OH, or CH2—O-aryl.
Preferably, one or both of A and R22 contain hydroxy moieties, such as in C1-6 alkyl OR11, wherein R11 is hydrogen, i.e. CH2CH2OH.
Suitably, when AA1 is the (R) side chain residue of an amino acid, it is a C1-6 alkyl group, which may be straight or branched. This means the R group of the core amino acid of the structure R—C(H)(COOH)(NH2). The R residue term is for example, CH3 for alanine, (CH3)2CH— for valine, (CH3)2CH—CH2-f or leucine, phenyl-CH2— for phenylalanine, CH3—S—CH2—CH2— for methionine, etc. All generally recognised primary amino acids are included in this groups, such as but not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, hydroxylysine, methylhistidine, and other naturally occurring amino acids not found in proteins, such as β-alanine, γ-aminobutyric acid, homocysteine, homoserine, citrulline, ornithine, canavanine, djenkolic acid, and β-cyanoalanine, or other naturally occurring non-mammalian amino acids.
Preferably AA1 is the residue of phenylalanine, or alanine.
Preferably A is a hydroxy substituted C1-10 alkyl and R22 is a C1-10 alkyl or a hydroxy substituted C1-10 alkyl.
In a further preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds disclosed in WO 99/01131:
In yet another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (II) as disclosed in U.S. Pat. No. 6,277,989
and the pharmaceutically acceptable salts thereof,
wherein
Preferably the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (II) as disclosed in U.S. Pat. No. 6,277,989, wherein
R1 is H;
R2 is halo, m is 0, 1, or 2, and I is 1 or 2;
Ar is 4-pyridyl.
In a particularly preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds disclosed U.S. Pat. No. 6,277,989:
In yet another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (IIIa), (IIIb), (IIIc), or (IIId) as disclosed in U.S. Pat. No. 6,340,685
and the pharmaceutically acceptable salts thereof,
wherein each of Z1 and Z2 is independently CR4 or N;
where each R4 is independently selected from H and alkyl(1-6C);
wherein said alkyl optionally includes one or more heteroatoms selected from O, S and N, and wherein said alkyl is optionally substituted by one or more substituents selected from halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, ═O, a 5 or 6 membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a 6-membered aromatic ring optionally containing 1-2 N heteroatoms, wherein R in the foregoing optional substituents is H or alkyl (1-6C);
R1 is
wherein
In a particularly preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds disclosed U.S. Pat. No. 6,340,685:
In another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (IV) as disclosed in WO 00/43384
wherein
In a preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (IV) as disclosed in WO 00/43384 wherein Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl.
A more preferred subgeneric aspect of the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is a compound of the formula (IV) wherein Ar2 is naphthyl.
A yet more preferred subgeneric aspect of the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from compounds of the formula (IV), as described in the immediate previous paragraph, wherein:
A yet further preferred subgeneric aspect of the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from compounds of the formula (IV), as described in the immediate previous paragraph, wherein Ar1 is pyrazole.
A still yet further preferred subgeneric aspect of previous the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from compounds of the formula (IV), as described in the immediate paragraph, wherein L is C1-5 saturated carbon chain wherein one or more methylene groups are optionally independently replaced by O, N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C1-4 branched or unbranched alkyl which may be substituted by one or more halogen atoms;
Particularly preferred embodiments of L are propoxy, ethoxy, methoxy, methyl, propyl, C3-5 acetylene or methylamino each being optionally substituted are described herein.
A more particularly preferred embodiment of L is ethoxy optionally substituted.
The following compounds are representative of the compounds of formula (IV) and are of particular interest as component 2d in the compositions according to the invention:
In a particularly preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (IV) as disclosed in WO 00/43384:
Particularly preferred p38 kinase inhibitors 2d within the scope of the present invention are the following compounds of the formula (IV):
In another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (V) as disclosed in WO 00/55139
wherein:
Ar1 is selected from the group consisting of:
Ar2 is:
X is:
Y is:
Z is:
R1 is:
R2 is:
R3 is:
In another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (V) as disclosed in WO 00/55139
wherein:
Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and
In another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (V) as disclosed in WO 00/55139
wherein:
In yet another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (V) as disclosed in WO 00/55139
wherein:
In yet still another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (V) as disclosed in WO 00/55139
wherein:
In a further embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (V) as disclosed in WO 00/55139 wherein:
In another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (V) as disclosed in WO 00/55139
wherein X is pyridinyl.
In another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (V) as disclosed in WO 00/55139
wherein the pyridinyl is attached to Ar1 via the 3-pyridinyl position.
In another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (V) as disclosed in WO 00/55139 that are mentioned below:
Preferably the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (V):
In another embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (Va) as disclosed in WO 00/55139
wherein:
Ar1 is:
Ar2 is:
X is:
Y is:
Z is:
R1 is:
R2 is:
R3 is:
hydrogen and C1-4 branched or unbranched alkyl optionally partially or fully halogenated;
each R4, R5, R6, R7, R9, R10, R11 and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
m is 0, 1 or 2;
W is O or S;
wherein X is directly attached to one or two —Y-Z, and
pharmaceutically acceptable derivatives thereof.
In another embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (Va) wherein:
Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and
W is O.
In another embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (Va) wherein:
hydrogen and C1-4 branched or unbranched alkyl optionally partially or fully halogenated;
and
each R4, R5, R6, R7, R9, R10, R11 and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
wherein X is directly attached to one —Y-Z.
In another embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (Va) wherein:
Ar1 is pyrazole;
X is:
Z is:
R1 is:
R2 is:
R3 is:
In another embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (Va) wherein:
R1 is:
R2 is:
R3 is:
In a further embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (Va) wherein:
R3 is:
In a still further embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (Va) wherein X is pyridinyl.
In a yet still further embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (Va) wherein the pyridinyl is attached to Ar1 via the 3-pyridinyl position.
Preferably the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (Va):
In another embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (Va):
In another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (VI) as disclosed in WO 00/55139
wherein:
G is:
Ar is:
X is:
Y is:
Z is:
each R1 is independently:
each R2, R4, and R5 is
each R3 is independently:
R6 is a:
each R11 and R16 is independently:
R18 is independently:
R20 is independently:
R21 is independently:
each R22, R23 and R24 is independently:
or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
m=0, 1 or 2;
W is O or S and
pharmaceutically acceptable derivatives thereof.
In another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (VI) wherein
G is:
In a further preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (VI) wherein
R23 and R24 taken together optionally form imidazolyl, piperidinyl, morpholinyl, piperazinyl or a pyridinyl ring.
In yet another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (VI) wherein:
In yet another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (VI) wherein
In a further preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (VI) wherein
G is
X is:
Y is:
Z is morpholino;
each R1 is independently:
R2 is chloro;
R3 is independently:
In yet a further preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (VI) wherein X is pyridinyl.
In yet a still further preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the compounds of formula (VI) wherein the pyridinyl is attached to Ar via the 3-pyridinyl position.
Preferably the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (VI):
More preferably the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (VI):
In another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (VII) as disclosed in WO 00/55139
wherein:
E is carbon or a heteroatom group chosen from —O—, —NH— and —S—;
G is:
Ar is:
X is:
Y is:
Z is:
each R1 is independently:
or R1 is
each R2, R4, and R5 is
each R3 is independently:
R6 is a:
each R7, R8, R9, R10, R12, R13, R14, R15, R17, R19, R25 and R26 is independently:
each R11 and R16 is independently:
R18 is independently:
R20 is independently:
R21 is independently:
each R22, R23 and R24 is independently:
or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
m=0, 1 or 2;
W is O or S and
pharmaceutically acceptable derivatives thereof.
In a preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (VII) wherein:
E is —CH2—, —NH— or —O—;
W is O;
G is:
In yet another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (VII) wherein:
each R1 is independently:
R2 is independently:
R3 is independently:
R23 and R24 taken together optionally form imidazolyl, piperidinyl, morpholino, piperazinyl or a pyridinyl ring.
In yet another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (VII) wherein:
each R1 is independently:
each R2 is independently:
each R3 is independently:
R23 and R24 taken together optionally form morpholino.
In another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (VII) wherein:
each R3 is independently:
R23 and R24 are H or R23 and R24 taken together optionally form morpholino; and
R26 is morpholino.
In another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (VII) wherein:
In yet another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (VII) wherein X is pyridinyl.
In still another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (VII) wherein the pyridinyl is attached to Ar via the 3-pyridinyl position.
Preferably the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (VII):
In another preferred embodiment the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds of formula (VII):
Particularly preferred the invention relates to pharmaceutical compositions comprising 1 and 2d, characterized in that the p38 kinase inhibitor 2d is selected from the following compounds:
and the pharmaceutically acceptable derivatives thereof.
Any reference to the abovementioned p38 kinase inhibitors 2d within the scope of the present invention includes a reference to any pharmaceutically acceptable acid addition salts thereof which may exist. By the physiologically or pharmaceutically acceptable acid addition salts which may be formed from 2d are meant, according to the invention, pharmaceutically acceptable salts selected from among the salts of hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids.
Any reference to the abovementioned p38 kinase inhibitors 2d within the scope of the present invention includes a reference to any alkali metal and alkaline earth metal salts thereof which may exist. If the compounds 2d are present in the form of their basic salts, the sodium or potassium salts are particularly preferred.
The pharmaceutical combinations of 1 and 2d according to the invention are preferably administered by parenteral or oral route or by inhalation, the latter being particularly preferred. For oral or parenteral administration the pharmaceutical compositions according to the invention may be administered e.g. in the form of solutions and tablets. For inhalation, as preferred according to the invention, suitable inhalable powders may be used which are packed into suitable capsules (inhalettes) and administered using suitable powder inhalers. Alternatively, the drug may be inhaled by the application of suitable inhalation aerosols. These include inhalation aerosols which contain HFA134a, HFA227 or a mixture thereof as propellant gas. The drug may also be inhaled using suitable solutions of the pharmaceutical combination consisting of 1 and 2d.
Especially preferred pharmaceutical compositions according to the invention comprise one EGFR kinase inhibitors 1 selected from the group consisting of
1.1, 1.4, 1.6, 1.8, 1.9, 1.14, 1.17, 1.19, 1.21, 1.23, 1.24, 1.27, 1.28, 1.30, 1.34, 1.35, 1.37, 1.38, 1.40, 1.42, 1.43, 1.44, 1.48, 1.52, 1.55, 1.57, 1.59, 1.60, 1.63, 1.64, 1.66, 1.67, 1.69, 1.70, 1.71, 1.72, 1.78, 1.82, 1.83, 1.84, 1.88, 1.90, 1.91, 1.94 and 1.95
and one p38 kinase inhibitors selected from the group consisting of
2d.1, 2d.2, 2d.3, 2d.4, 2d.5, 2d.6, 2d.7, 2d.8, 2d.9, 2d.10, 2d.11, 2d.12, 2d.13, 2d.14, 2d.15, 2d.16, 2d.17, 2d.18, and 2d.19,
either as free bases or pharmacologically acceptable acid addition salts, e.g.
1.1 and 2d.1, 1.4 and 2d.1, 1.6 and 2d.1, 1.8 and 2d.1, 1.9 and 2d.1, 1.14 and 2d.1, 1.17 and 2d.1, 1.19 and 2d.1, 1.21 and 2d.1, 1.23 and 2d.1, 1.24 and 2d.1, 1.27 and 2d.1, 1.28 and 2d.1, 1.30 and 2d.1, 1.34 and 2d.1, 1.35 and 2d.1, 1.37 and 2d.1, 1.38 and 2d.1, 1.40 and 2d.1, 1.42 and 2d.1, 1.43 and 2d.1, 1.44 and 2d.1, 1.48 and 2d.1, 1.52 and 2d.1, 1.55 and 2d.1, 1.57 and 2d.1, 1.59 and 2d.1, 1.60 and 2d.1, 1.63 and 2d.1, 1.64 and 2d.1, 1.66 and 2d.1, 1.67 and 2d.1, 1.69 and 2d.1, 1.70 and 2d.1, 1.71 and 2d.1, 1.72 and 2d.1, 1.78 and 2d.1, 1.82 and 2d.1, 1.83 and 2d.1, 1.84 and 2d.1, 1.88 and 2d.1, 1.90 and 2d.1, 1.91 and 2d.1, 1.94 and 2d.1, 1.95 and 2d.1;
1.1 and 2d.2, 1.4 and 2d.2, 1.6 and 2d.2, 1.8 and 2d.2, 1.9 and 2d.2, 1.14 and 2d.2, 1.17 and 2d.2, 1.19 and 2d.2, 1.21 and 2d.2, 1.23 and 2d.2, 1.24 and 2d.2, 1.27 and 2d.2, 1.28 and 2d.2, 1.30 and 2d.2, 1.34 and 2d.2, 1.35 and 2d.2, 1.37 and 2d.2, 1.38 and 2d.2, 1.40 and 2d.2, 1.42 and 2d.2, 1.43 and 2d.2, 1.44 and 2d.2, 1.48 and 2d.2, 1.52 and 2d.2, 1.55 and 2d.2, 1.57 and 2d.2, 1.59 and 2d.2, 1.60 and 2d.2, 1.63 and 2d.2, 1.64 and 2d.2, 1.66 and 2d.2, 1.67 and 2d.2, 1.69 and 2d.2, 1.70 and 2d.2, 1.71 and 2d.2, 1.72 and 2d.2, 1.78 and 2d.2, 1.82 and 2d.2, 1.83 and 2d.2, 1.84 and 2d.2, 1.88 and 2d.2, 1.90 and 2d.2, 1.91 and 2d.2, 1.94 and 2d.2, 1.95 and 2d.2;
etc.
1.1 and 2d.19, 1.4 and 2d.19, 1.6 and 2d.19, 1.8 and 2d.19, 1.9 and 2d.19, 1.14 and 2d.19, 1.17 and 2d.19, 1.19 and 2d.19, 1.21 and 2d.19, 1.23 and 2d.19, 1.24 and 2d.19, 1.27 and 2d.19, 1.28 and 2d.19, 1.30 and 2d.19, 1.34 and 2d.19, 1.35 and 2d.19, 1.37 and 2d.19, 1.38 and 2d.19, 1.40 and 2d.19, 1.42 and 2d.19, 1.43 and 2d.19, 1.44 and 2d.19, 1.48 and 2d.19, 1.52 and 2d.19, 1.55 and 2d.19, 1.57 and 2d.19, 1.59 and 2d.19, 1.60 and 2d.19, 1.63 and 2d.19, 1.64 and 2d.19, 1.66 and 2d.19, 1.67 and 2d.19, 1.69 and 2d.19, 1.70 and 2d.19, 1.71 and 2d.19, 1.72 and 2d.19, 1.78 and 2d.19, 1.82 and 2d.19, 1.83 and 2d.19, 1.84 and 2d.19, 1.88 and 2d.19, 1.90 and 2d.19, 1.91 and 2d.19, 1.94 and 2d.19, 1.95 and 2d.19.
The proportions in which the active substances 1 and 2d may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2d may possibly be present in the form of their solvates or hydrates. Depending on the choice of the compounds 1 and 2d, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various compounds and their different potencies.
As a rule, the pharmaceutical combinations according to the invention may contain compounds 1 and 2d in ratios by weight ranging from 100:1 to 1:100, preferably from 50:1 to 1:50, more preferred from 25:1 to 1:25, most preferred 20:1 to 1:20.
For example, without restricting the scope of the invention thereto, preferred combinations may contain 1 and 2d in the following weight ratios:
100:1, 95:1, 90:1, 85:1, 80:1, 75:1, 70:1, 65:1, 60:1, 55:1, 50:1, 45:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, 1:95, 1:100.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2d are normally administered so that 1 and 2d are present together in doses of about 100 to 50000 μg, preferably 1000 to 25000 μg, more preferably 1500 to 10000 μg, better still from about 2000 to about 7000 μg, more preferably 2500 to 600 μg per single dose. For example about 3000 to about 5500 μg of the combination of 1 and 2d according to the invention may be administered once or twice daily to the patient in need thereof. For example, combinations of 1 and 2d according to the invention contain a quantity of 1 and 2d such that the total dosage per single dose is about 100 μg, 150 μg, 200 μg, 250 μg, 300 μg etc. (add stepwise 50 μg) up to 50000 μg, or similar.
The suggested dosages per single dose specified above are not to be regarded as being limited to the numerical values actually stated, but are intended as dosages which are disclosed by way of example. Of course, dosages which may fluctuate about the abovementioned numerical values within a range of about +/−2.5 μg are also included in the values given above by way of example. In these dosage ranges, the active substances 1 and 2d may be present in the weight ratios given above.
For example, without restricting the scope of the invention thereto, the combinations of 1 and 2d according to the invention may contain a quantity of 1 and p38 kinase inhibitor 2d such that, in each individual dose,
100 μg of 1 and 1000 μg of 2d, 100 μg of 1 and 1500 μg of 2d, 100 μg of 1 and 2000 μg of 2d, 100 μg of 1 and 2500 μg of 2d, 100 μg of 1 and 300 μg of 2d, 100 μg of 1 and 3500 μg of 2d, 100 μg of 1 and 4000 μg of 2d, 100 μg of 1 and 4500 μg of 2d, 100 μg of 1 and 5000 μg of 2d, 100 μg of 1 and 6000 μg of 2d, 100 μg of 1 and 700 μg of 2d, 100 μg of 1 and 8000 μg of 2d, 100 μg of 1 and 9000 μg of 2d, 100 μg of 1 and 10000 μg of 2d,
200 μg of 1 and 1000 μg of 2d, 200 μg of 1 and 1500 μg of 2d, 200 μg of 1 and 2000 μg of 2d, 200 μg of 1 and 2500 μg of 2d, 200 μg of 1 and 300 μg of 2d, 200 μg of 1 and 3500 μg of 2d, 200 μg of 1 and 4000 μg of 2d, 200 μg of 1 and 4500 μg of 2d, 200 μg of 1 and 5000 μg of 2d, 200 μg of 1 and 6000 μg of 2d, 200 μg of 1 and 700 μg of 2d, 200 μg of 1 and 8000 μg of 2d, 200 μg of 1 and 900 μg of 2d, 200 μg of 1 and 10000 μg of 2d,
500 μg of 1 and 1000 μg of 2d, 500 μg of 1 and 1500 μg of 2d, 500 μg of 1 and 2000 μg of 2d, 500 μg of 1 and 2500 μg of 2d, 500 μg of 1 and 300 μg of 2d, 500 μg of 1 and 3500 μg of 2d, 500 μg of 1 and 4000 μg of 2d, 500 μg of 1 and 4500 μg of 2d, 500 μg of 1 and 5000 μg of 2d, 500 μg of 1 and 600 μg of 2d, 500 μg of 1 and 700 μg of 2d, 500 μg of 1 and 8000 μg of 2d, 500 μg of 1 and 900 μg of 2d, 500 μg of 1 and 10000 μg of 2d,
1000 μg of 1 and 1000 μg of 2d, 1000 μg of 1 and 1500 μg of 2d, 1000 μg of 1 and 2000 μg of 2d, 1000 μg of 1 and 2500 μg of 2d, 1000 μg of 1 and 300 μg of 2d, 1000 μg of 1 and 3500 μg of 2d, 1000 μg of 1 and 400 μg of 2d, 1000 μg of 1 and 4500 μg of 2d, 1000 μg of 1 and 5000 μg of 2d, 1000 μg of 1 and 600 μg of 2d, 1000 μg of 1 and 7000 μg of 2d, 1000 μg of 1 and 8000 μg of 2d, 1000 μg of 1 and 9000 μg of 2d, 1000 μg of 1 and 10000 μg of 2d,
5000 μg of 1 and 1000 μg of 2d, 5000 μg of 1 and 1500 μg of 2d, 5000 μg of 1 and 2000 μg of 2d, 5000 μg of 1 and 2500 μg of 2d, 5000 μg of 1 and 3000 μg of 2d, 5000 μg of 1 and 3500 μg of 2d, 5000 μg of 1 and 4000 μg of 2d, 5000 μg of 1 and 4500 μg of 2d, 5000 μg of 1 and 5000 μg of 2d, 5000 μg of 1 and 6000 μg of 2d, 5000 μg of 1 and 7000 μg of 2d, 5000 μg of 1 and 8000 μg of 2d, 5000 μg of 1 and 9000 μg of 2d, 5000 μg of 1 and 1000 μg of 2d,
10000 μg of 1 and 1000 μg of 2d, 10000 μg of 1 and 1500 μg of 2d, 10000 μg of 1 and 2000 μg of 2d, 10000 μg of 1 and 2500 μg of 2d, 10000 μg of 1 and 300 μg of 2d, 10000 μg of 1 and 3500 μg of 2d, 10000 μg of 1 and 400 μg of 2d, 10000 μg of 1 and 4500 μg of 2d, 10000 μg of 1 and 5000 μg of 2d, 10000 μg of 1 and 6000 μg of 2d, 10000 μg of 1 and 7000 μg of 2d, 10000 μg of 1 and 8000 μg of 2d, 10000 μg of 1 and 9000 μg of 2d, 10000 μg of 1 and 10000 μg of 2d,
25000 μg of 1 and 1000 μg of 2d, 25000 μg of 1 and 1500 μg of 2d, 25000 μg of 1 and 2000 μg of 2d, 25000 μg of 1 and 2500 μg of 2d, 25000 μg of 1 and 3000 μg of 2d, 25000 μg of 1 and 3500 μg of 2d, 25000 μg of 1 and 4000 μg of 2d, 25000 μg of 1 and 4500 μg of 2d, 25000 μg of 1 and 5000 μg of 2d, 25000 μg of 1 and 6000 μg of 2d, 25000 μg of 1 and 7000 μg of 2d, 25000 μg of 1 and 8000 μg of 2d, 25000 μg of 1 and 9000 μg of 2d, 25000 μg of 1 and 10000 μg of 2d,
50000 μg of 1 and 1000 μg of 2d, 50000 μg of 1 and 1500 μg of 2d, 50000 μg of 1 and 2000 μg of 2d, 50000 μg of 1 and 2500 μg of 2d, 50000 μg of 1 and 3000 μg of 2d, 50000 μg of 1 and 3500 μg of 2d, 50000 μg of 1 and 4000 μg of 2d, 50000 μg of 1 and 4500 μg of 2d, 50000 μg of 1 and 5000 μg of 2d, 50000 μg of 1 and 6000 μg of 2d, 50000 μg of 1 and 7000 μg of 2d, 50000 μg of 1 and 8000 μg of 2d, 50000 μg of 1 and 9000 μg of 2d, 50000 μg of 1 and 10000 μg of 2d, are administered.
Pharmaceutical Compositions Comprising an EGFR Kinase Inhibitor 1 and an NK1 Antagonist 2e:
One embodiment of the invention is a pharmaceutical composition comprising an EGFR kinase inhibitor 1 and an NK1 antagonist 2e. Binary compositions containing only one active 1 and one active 2e, optionally together with one or more pharmaceutically acceptable excipients or carriers, are preferred. In the pharmaceutical combinations according to the invention preferred NK1 antagonists 2e are selected from the group consisting of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-cyclopropylmethyl-piperazin-1-yl}-N-methyl-2-phenyl-acetamide (BIIF 1149), CP-122721, FK-888, NKP 608C, NKP 608A, CGP 60829, SR 48968(Saredutant), SR 140333 (Nolpitantium besilate/chloride), LY 303 870 (Lanepitant), MEN-11420 (Nepadutant), SB 223412, MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, SR-144190, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, Aprepitant (MK-869), L-754030, CJ-11974, L-758298, DNK-33A, 6b-I, CJ-11974, TAK-637, GR 205171 and the arylglycine amide derivates of general formula (VIII)
wherein
R1 and R2 together with the N-atom they are bound to form a ring of formula
wherein r and s independently denote the number 2 or 3;
R6 denotes H, —C1-C5-alkyl, C3-C5-alkenyl, propinyl, hydroxy(C2-C4)alkyl, methoxy(C2-C4)alkyl, di(C1-C3)alkylamino(C2-C4)alkyl, amino(C2-C4)alkyl, amino, di(C1-C3)alkylamino, monofluoro- up to perfluoro(C1-C2)alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,
R7 denotes any of the groups defined under (a) to (d):
(a) hydroxy
(b) 4-piperidinopiperidyl,
(c)
R8 denotes H,
optionally in the form of enantiomers, mixtures of enantiomers or the racemates.
The compounds of formula (VIII) mentioned hereinbefore are described in WO 96/32386, WO 97/32865 and WO 02/32865. The disclosure of these international patent applications is incorporated herein by reference in its entirety.
According to the instant invention preferred NK1 antagonists 2e are selected from the group consisting of BIIF 1149, CP-122721, CGP 60829, MK-869, CJ-11974, GR 205171 and the
arylglycine amide derivates of general formula (VIII), wherein
R1 and R2 together with the N-atom they are bound to form a ring of formula
wherein r and s independently denote the number 2 or 3;
R6 denotes H, —C1-C5-alkyl, C3-C5-alkenyl, propinyl, hydroxy(C2-C4)alkyl, methoxy-(C2-C4)alkyl, di(C1-C3)alkylamino(C2-C4)alkyl, amino(C2-C4)alkyl, amino, di-(C1-C3)alkylamino, monofluoro- up to perfluoro(C1-C2)alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,
R7 denotes the group
R8 denotes H,
optionally in the form of enantiomers, mixtures of enantiomers or the racemates.
More preferred NK1 antagonists 2e according to the instant invention are selected from the group consisting of BIIF 1149 and the arylglycine amide derivates of general formula (VIII), wherein
R1 and R2 together with the N-atom they are bound to form a ring of formula
wherein s denotes the number 2;
R7 denotes the group
R8 denotes H,
optionally in the form of enantiomers, mixtures of enantiomers or the racemates.
Even more preferred representatives of component 2e are selected from the group consisting of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(3-hydroxy-propyl)-methyl-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide 2e.1, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide 2e.2, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(cyclopropylmethyl-methyl-amino)-piperidin-1-yl]-N-methyl-2-phenyl-acetamide 2e.3, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(2-hydroxy-ethyl)-(3-hydroxypropyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide 2e.4 and N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide 2e.5, optionally in the form of enantiomers, mixtures of enantiomers or the racemates.
Of exceptional importance according to the invention is N-[2-(3,5-bis-trifluoromethylphenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide as component 2e, optionally in the form of its enantiomers, preferably in form of the (S)-enantiomer, and optionally in the form of mixtures of enantiomers or the racemates.
As far as not defined specifically, in the definitions used hereinbefore an alkyl group (also as part of other groups) is meant to include branched as well as unbranched alkyl groups having one to five carbon atoms, e.g. methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl(tert.butyl), etc. The groups defined as propyl, butyl and pentyl encompass the respective isomers thereof. Hydroxy- or dihydroxyalkyl groups are meant to be alkyl groups substituted by one or two hydroxy groups.
Alkenyl groups (also as part of other groups) are meant to include branched as well as unbranched alkenyl groups having one to five carbon atoms possessing at least one double bond, e.g., propenyl, iso-propenyl, butenyl etc.
Cycloalkyl is meant to comprise a saturated cyclic hydrocarbon moiety having three to six carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl etc.
Alkyloxy is synonymous for alkoxy and means a branched or unbranched alkyl group bound via an oxygen atom. The methoxy group is preferred.
Any reference to NK1 receptor antagonists 2e within the scope of the present invention includes a reference to the salts, preferably pharmacologically acceptable acid addition salts, or derivatives which may be formed from the NK1 antagonists. Examples of pharmacologically acceptable acid addition salts of the NK1 antagonists 2e according to the invention are the pharmaceutically acceptable salts which are selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid. Preferred salts are selected from the group consisting of acetate, hydrochloride, hydrobromide, sulphate, phosphate, maleate and methanesulphonate.
The pharmaceutical combinations of 1 and 2e according to the invention are preferably administered by inhalation. For inhalation suitable inhalable powders may be used which are packed into suitable capsules (inhalettes) and administered using suitable powder inhalers. Alternatively, the drug may be inhaled by the application of suitable inhalation aerosols. These include inhalation aerosols which contain HFA134a, HFA227 or a mixture thereof as propellant gas. The drug may also be inhaled using suitable solutions of the pharmaceutical combination consisting of 1 and 2e.
Especially preferred pharmaceutical compositions according to the invention comprise the following specific combinations of EGFR kinase inhibitors 1 and NK1 antagonist 2e, either as free bases or pharmacologically acceptable acid addition salts:
1.1 and 2e.1, 1.4 and 2e.1, 1.6 and 2e.1, 1.8 and 2e.1, 1.9 and 2e.1, 1.14 and 2e.1, 1.17 and 2e.1, 1.19 and 2e.1, 1.21 and 2e.1, 1.23 and 2e.1, 1.24 and 2e.1, 1.27 and 2e.1, 1.28 and 2e.1, 1.30 and 2e.1, 1.34 and 2e.1, 1.35 and 2e.1, 1.37 and 2e.1, 1.38 and 2e.1, 1.40 and 2e.1, 1.42 and 2e.1, 1.43 and 2e.1, 1.44 and 2e.1, 1.48 and 2e.1, 1.52 and 2e.1, 1.55 and 2e.1, 1.57 and 2e.1, 1.59 and 2e.1, 1.60 and 2e.1, 1.63 and 2e.1, 1.64 and 2e.1, 1.66 and 2e.1, 1.67 and 2e.1, 1.69 and 2e.1, 1.70 and 2e.1, 1.71 and 2e.1, 1.72 and 2e.1, 1.78 and 2e.1, 1.82 and 2e.1, 1.83 and 2e.1, 1.84 and 2e.1, 1.88 and 2e.1, 1.90 and 2e.1, 1.91 and 2e.1, 1.94 and 2e.1, 1.95 and 2e.1;
1.1 and 2e.2, 1.4 and 2e.2, 1.6 and 2e.2, 1.8 and 2e.2, 1.9 and 2e.2, 1.14 and 2e.2, 1.17 and 2e.2, 1.19 and 2e.2, 1.21 and 2e.2, 1.23 and 2e.2, 1.24 and 2e.2, 1.27 and 2e.2, 1.28 and 2e.2, 1.30 and 2e.2, 1.34 and 2e.2, 1.35 and 2e.2, 1.37 and 2e.2, 1.38 and 2e.2, 1.40 and 2e.2, 1.42 and 2e.2, 1.43 and 2e.2, 1.44 and 2e.2, 1.48 and 2e.2, 1.52 and 2e.2, 1.55 and 2e.2, 1.57 and 2e.2, 1.59 and 2e.2, 1.60 and 2e.2, 1.63 and 2e.2, 1.64 and 2e.2, 1.66 and 2e.2, 1.67 and 2e.2, 1.69 and 2e.2, 1.70 and 2e.2, 1.71 and 2e.2, 1.72 and 2e.2, 1.78 and 2e.2, 1.82 and 2e.2, 1.83 and 2e.2, 1.84 and 2e.2, 1.88 and 2e.2, 1.90 and 2e.2, 1.91 and 2e.2, 1.94 and 2e.2, 1.95 and 2e.2;
1.1 and 2e.3, 1.4 and 2e.3, 1.6 and 2e.3, 1.8 and 2e.3, 1.9 and 2e.3, 1.14 and 2e.3, 1.17 and 2e.3, 1.19 and 2e.3, 1.21 and 2e.3, 1.23 and 2e.3, 1.24 and 2e.3, 1.27 and 2e.3, 1.28 and 2e.3, 1.30 and 2e.3, 1.34 and 2e.3, 1.35 and 2e.3, 1.37 and 2e.3, 1.38 and 2e.3, 1.40 and 2e.3, 1.42 and 2e.3, 1.43 and 2e.3, 1.44 and 2e.3, 1.48 and 2e.3, 1.52 and 2e.3, 1.55 and 2e.3, 1.57 and 2e.3, 1.59 and 2e.3, 1.60 and 2e.3, 1.63 and 2e.3, 1.64 and 2e.3, 1.66 and 2e.3, 1.67 and 2e.3, 1.69 and 2e.3, 1.70 and 2e.3, 1.71 and 2e.3, 1.72 and 2e.3, 1.78 and 2e.3, 1.82 and 2e.3, 1.83 and 2e.3, 1.84 and 2e.3, 1.88 and 2e.3, 1.90 and 2e.3, 1.91 and 2e.3, 1.94 and 2e.3, 1.95 and 2e.3;
1.1 and 2e.4, 1.4 and 2e.4, 1.6 and 2e.4, 1.8 and 2e.4, 1.9 and 2e.4, 1.14 and 2e.4, 1.17 and 2e.4, 1.19 and 2e.4, 1.21 and 2e.4, 1.23 and 2e.4, 1.24 and 2e.4, 1.27 and 2e.4, 1.28 and 2e.4, 1.30 and 2e.4, 1.34 and 2e.4, 1.35 and 2e.4, 1.37 and 2e.4, 1.38 and 2e.4, 1.40 and 2e.4, 1.42 and 2e.4, 1.43 and 2e.4, 1.44 and 2e.4, 1.48 and 2e.4, 1.52 and 2e.4, 1.55 and 2e.4, 1.57 and 2e.4, 1.59 and 2e.4, 1.60 and 2e.4, 1.63 and 2e.4, 1.64 and 2e.4, 1.66 and 2e.4, 1.67 and 2e.4, 1.69 and 2e.4, 1.70 and 2e.4, 1.71 and 2e.4, 1.72 and 2e.4, 1.78 and 2e.4, 1.82 and 2e.4, 1.83 and 2e.4, 1.84 and 2e.4, 1.88 and 2e.4, 1.90 and 2e.4, 1.91 and 2e.4, 1.94 and 2e.4, 1.95 and 2e.4;
1.1 and 2e.5, 1.4 and 2e.5, 1.6 and 2e.5, 1.8 and 2e.5, 1.9 and 2e.5, 1.14 and 2e.5, 1.17 and 2e.5, 1.19 and 2e.5, 1.21 and 2e.5, 1.23 and 2e.5, 1.24 and 2e.5, 1.27 and 2e.5, 1.28 and 2e.5, 1.30 and 2e.5, 1.34 and 2e.5, 1.35 and 2e.5, 1.37 and 2e.5, 1.38 and 2e.5, 1.40 and 2e.5, 1.42 and 2e.5, 1.43 and 2e.5, 1.44 and 2e.5, 1.48 and 2e.5, 1.52 and 2e.5, 1.55 and 2e.5, 1.57 and 2e.5, 1.59 and 2e.5, 1.60 and 2e.5, 1.63 and 2e.5, 1.64 and 2e.5, 1.66 and 2e.5, 1.67 and 2e.5, 1.69 and 2e.5, 1.70 and 2e.5, 1.71 and 2e.5, 1.72 and 2e.5, 1.78 and 2e.5, 1.82 and 2e.5, 1.83 and 2e.5, 1.84 and 2e.5, 1.88 and 2e.5, 1.90 and 2e.5, 1.91 and 2e.5, 1.94 and 2e.5, 1.95 and 2e.5.
The proportions in which the active substances 1 and 2e may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2e may possibly be present in the form of their solvates or hydrates. Depending on the choice of the compounds 1 and 2e, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various compounds and their different potencies.
As a rule, the pharmaceutical combinations according to the invention may contain compounds 1 and 2e in ratios by weight ranging from 100:1 to 1:100, preferably from 50:1 to 1:50, more preferred from 25:1 to 1:25, most preferred 20:1 to 1:20.
With respect to the preferred subgroup of pharmaceutical combinations comprising an EGFR kinase inhibitor 1 and an NK1 antagonist 2e selected from the group consisting of BIIF 1149, CGP 60829, MK-869, CJ-11974, GR 205171, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(3-hydroxy-propyl)-methyl-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(cyclopropylmethyl-methyl-amino)-piperidin-1-yl]-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide and the arylglycine amide derivates of formula (VIII) the weight ratios of 1:2e especially preferred are in the range of 50:1 to 4:1.
For example, without restricting the scope of the invention thereto, preferred combinations may contain 1 and 2e in the following weight ratios:
100:1, 95:1, 90:1, 85:1, 80:1, 75:1, 70:1, 65:1, 60:1, 55:1, 50:1, 45:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, 1:95, 1:100.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2e are normally administered so that 1 and 2e are present together in doses of about 100 to 50000 μg, preferably 1000 to 25000 μg, more preferably 1500 to 10000 μg, better still from about 2000 to about 7000 μg, more preferably 2500 to 6000 μg per single dose. For example about 3000 to about 5500 μg of the combination of 1 and 2e according to the invention may be administered once or twice daily to the patient in need thereof. For example, combinations of 1 and 2e according to the invention contain a quantity of 1 and 2e such that the total dosage per single dose is about 100 μg, 150 μg, 200 μg, 250 μg, 300 μg etc. (add stepwise 50 μg) up to 50000 μg, or similar.
The suggested dosages per single dose specified above are not to be regarded as being limited to the numerical values actually stated, but are intended as dosages which are disclosed by way of example. Of course, dosages which may fluctuate about the abovementioned numerical values within a range of about +/−2.5 μg are also included in the values given above by way of example. In these dosage ranges, the active substances 1 and 2e may be present in the weight ratios given above.
For example, without restricting the scope of the invention thereto, the combinations of 1 and 2e according to the invention may contain a quantity of 1 and NK1 antagonist 2e such that, in each individual dose,
100 μg of 1 and 1000 μg of 2e, 100 μg of 1 and 1500 μg of 2e, 100 μg of 1 and 2000 μg of 2e, 100 μg of 1 and 2500 μg of 2e, 100 μg of 1 and 3000 μg of 2e, 100 μg of 1 and 3500 μg of 2e, 100 μg of 1 and 4000 μg of 2e, 100 μg of 1 and 4500 μg of 2e, 100 μg of 1 and 5000 μg of 2e, 100 μg of 1 and 6000 μg of 2e, 100 μg of 1 and 7000 μg of 2e, 100 μg of 1 and 8000 μg of 2e, 100 μg of 1 and 9000 μg of 2e, 100 μg of 1 and 10000 μg of 2e,
200 μg of 1 and 1000 μg of 2e, 200 μg of 1 and 1500 μg of 2e, 200 μg of 1 and 2000 μg of 2e, 200 μg of 1 and 2500 μg of 2e, 200 μg of 1 and 3000 μg of 2e, 200 μg of 1 and 3500 μg of 2e, 200 μg of 1 and 4000 μg of 2e, 200 μg of 1 and 4500 μg of 2e, 200 μg of 1 and 5000 μg of 2e, 200 μg of 1 and 6000 μg of 2e, 200 μg of 1 and 7000 μg of 2e, 200 μg of 1 and 8000 μg of 2e, 200 μg of 1 and 9000 μg of 2e, 200 μg of 1 and 10000 μg of 2e,
500 μg of 1 and 1000 μg of 2e, 500 μg of 1 and 1500 μg of 2e, 500 μg of 1 and 2000 μg of 2e, 500 μg of 1 and 2500 μg of 2e, 500 μg of 1 and 3000 μg of 2e, 500 μg of 1 and 3500 μg of 2e, 500 μg of 1 and 4000 μg of 2e, 500 μg of 1 and 4500 μg of 2e, 500 μg of 1 and 5000 μg of 2e, 500 μg of 1 and 6000 μg of 2e, 500 μg of 1 and 7000 μg of 2e, 500 μg of 1 and 8000 μg of 2e, 500 μg of 1 and 9000 μg of 2e, 500 μg of 1 and 10000 μg of 2e,
1000 μg of 1 and 1000 μg of 2e, 1000 μg of 1 and 1500 μg of 2e, 1000 μg of 1 and 2000 μg of 2e, 1000 μg of 1 and 2500 μg of 2e, 1000 μg of 1 and 3000 μg of 2e, 1000 μg of 1 and 3500 μg of 2e, 1000 μg of 1 and 4000 μg of 2e, 1000 μg of 1 and 4500 μg of 2e, 1000 μg of 1 and 5000 μg of 2e, 1000 μg of 1 and 6000 μg of 2e, 1000 μg of 1 and 7000 μg of 2e, 1000 μg of 1 and 8000 μg of 2e, 1000 μg of 1 and 9000 μg of 2e, 1000 μg of 1 and 10000 μg of 2e,
5000 μg of 1 and 1000 μg of 2e, 5000 μg of 1 and 1500 μg of 2e, 5000 μg of 1 and 2000 μg of 2e, 5000 μg of 1 and 2500 μg of 2e, 5000 μg of 1 and 3000 μg of 2e, 5000 μg of 1 and 3500 μg of 2e, 5000 μg of 1 and 4000 μg of 2e, 5000 μg of 1 and 4500 μg of 2e, 5000 μg of 1 and 5000 μg of 2e, 5000 μg of 1 and 6000 μg of 2e, 5000 μg of 1 and 7000 μg of 2e, 5000 μg of 1 and 8000 μg of 2e, 5000 μg of 1 and 9000 μg of 2e, 5000 μg of 1 and 10000 μg of 2e,
10000 μg of 1 and 1000 μg of 2e, 10000 μg of 1 and 1500 μg of 2e, 10000 μg of 1 and 2000 μg of 2e, 10000 μg of 1 and 2500 μg of 2e, 10000 μg of 1 and 3000 μg of 2e, 10000 μg of 1 and 3500 μg of 2e, 10000 μg of 1 and 4000 μg of 2e, 10000 μg of 1 and 4500 μg of 2e, 10000 μg of 1 and 5000 μg of 2e, 10000 μg of 1 and 6000 μg of 2e, 10000 μg of 1 and 7000 μg of 2e, 10000 μg of 1 and 8000 μg of 2e, 10000 μg of 1 and 9000 μg of 2e, 10000 μg of 1 and 10000 μg of 2e,
25000 μg of 1 and 1000 μg of 2e, 25000 μg of 1 and 1500 μg of 2e, 25000 μg of 1 and 2000 μg of 2e, 25000 μg of 1 and 2500 μg of 2e, 25000 μg of 1 and 3000 μg of 2e, 25000 μg of 1 and 3500 μg of 2e, 25000 μg of 1 and 4000 μg of 2e, 25000 μg of 1 and 4500 μg of 2e, 25000 μg of 1 and 5000 μg of 2e, 25000 μg of 1 and 6000 μg of 2e, 25000 μg of 1 and 7000 μg of 2e, 25000 μg of 1 and 8000 μg of 2e, 25000 μg of 1 and 9000 μg of 2e, 25000 μg of 1 and 10000 μg of 2e,
50000 μg of 1 and 1000 μg of 2e, 50000 μg of 1 and 1500 μg of 2e, 50000 μg of 1 and 2000 μg of 2e, 50000 μg of 1 and 2500 μg of 2e, 50000 μg of 1 and 3000 μg of 2e, 50000 μg of 1 and 3500 μg of 2e, 50000 μg of 1 and 4000 μg of 2e, 50000 μg of 1 and 4500 μg of 2e, 50000 μg of 1 and 5000 μg of 2e, 50000 μg of 1 and 6000 μg of 2e, 50000 μg of 1 and 7000 μg of 2e, 50000 μg of 1 and 8000 μg of 2e, 50000 μg of 1 and 9000 μg of 2e, 50000 μg of 1 and 10000 μg of 2e, are administered.
Pharmaceutical Compositions Comprising an EGFR Kinase Inhibitor 1 and an Endothelin-Antagonist 2f:
One embodiment of the invention is a pharmaceutical composition comprising an EGFR kinase inhibitor 1 and an endothelin-antagonist 2f. Binary compositions containing only one active 1 and one active 2f, optionally together with one or more pharmaceutically acceptable excipients or carriers, are preferred. In the pharmaceutical combinations according to the invention preferred endothelin-antagonists 2f are selected from the group consisting of Tezosentan 2f.1, Bosentan 2f.2, Enrasentan 2f.3, Sixtasentan 2f.4, T-0201 2f.5, BMS-193884 2f.6, K-8794 2f.7, PD-156123 2f.8, PD-156707 2f.9, PD-160874 2f.10, PD-180988 2f.11, S-0139 2f.12 and ZD-1611 2f.13. According to the instant invention preferred endothelin-antagonists 2f are selected from the group consisting 2f.1, 2f.2, 2f.3, 2f.4, 2f.5 and 2f.6, the endothelin-antagonists 2f.1 and 2f.2 being particularly preferred.
Any reference to endothelin-antagonists 2f within the scope of the present invention includes a reference to the salts, preferably pharmacologically acceptable acid addition salts, or derivatives which may be formed from the endothelin-antagonists. Examples of pharmacologically acceptable acid addition salts of the endothelin-antagonists 2f according to the invention are the pharmaceutically acceptable salts which are selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid. Preferred salts are selected from the group consisting of acetate, hydrochloride, hydrobromide, sulphate, phosphate, maleate and methanesulphonate.
Any reference to the abovementioned endothelin-antagonists 2f within the scope of the present invention includes a reference to any alkali metal and alkaline earth metal salts thereof which may exist. If the compounds 2f are present in the form of their basic salts, the sodium or potassium salts are particularly preferred.
The pharmaceutical combinations of 1 and 2f according to the invention are preferably administered by parenteral or oral route or by inhalation, the latter being particularly preferred. For oral or parenteral administration the pharmaceutical compositions according to the invention may be administered e.g. in the form of solutions and tablets. For inhalation, as preferred according to the invention, suitable inhalable powders may be used which are packed into suitable capsules (inhalettes) and administered using suitable powder inhalers. Alternatively, the drug may be inhaled by the application of suitable inhalation aerosols. These include inhalation aerosols which contain HFA134a, HFA227 or a mixture thereof as propellant gas. The drug may also be inhaled using suitable solutions of the pharmaceutical combination consisting of 1 and 2f.
Especially preferred pharmaceutical compositions according to the invention comprise the following specific combinations of EGFR kinase inhibitors 1 and endothelin-antagonists 2f, either as free bases or pharmacologically acceptable acid addition salts:
1.1 and 2f.1, 1.4 and 2f.1, 1.6 and 2f.1, 1.8 and 2f.1, 1.9 and 2f.1, 1.14 and 2f.1, 1.17 and 2f.1, 1.19 and 2f.1, 1.21 and 2f.1, 1.23 and 2f.1, 1.24 and 2f.1, 1.27 and 2f.1, 1.28 and 2f.1, 1.30 and 2f.1, 1.34 and 2f.1, 1.35 and 2f.1, 1.37 and 2f.1, 1.38 and 2f.1, 1.40 and 2f.1, 1.42 and 2f.1, 1.43 and 2f.1, 1.44 and 2f.1, 1.48 and 2f.1, 1.52 and 2f.1, 1.55 and 2f.1, 1.57 and 2f.1, 1.59 and 2f.1, 1.60 and 2f.1, 1.63 and 2f.1, 1.64 and 2f.1, 1.66 and 2f.1, 1.67 and 2f.1, 1.69 and 2f.1, 1.70 and 2f.1, 1.71 and 2f.1, 1.72 and 2f.1, 1.78 and 2f.1, 1.82 and 2f.1, 1.83 and 2f.1, 1.84 and 2f.1, 1.88 and 2f.1, 1.90 and 2f.1, 1.91 and 2f.1, 1.94 and 2f.1, 1.95 and 2f.1;
1.1 and 2f.2, 1.4 and 2f.2, 1.6 and 2f.2, 1.8 and 2f.2, 1.9 and 2f.2, 1.14 and 2f.2, 1.17 and 2f.2, 1.19 and 2f.2, 1.21 and 2f.2, 1.23 and 2f.2, 1.24 and 2f.2, 1.27 and 2f.2, 1.28 and 2f.2, 1.30 and 2f.2, 1.34 and 2f.2, 1.35 and 2f.2, 1.37 and 2f.2, 1.38 and 2f.2, 1.40 and 2f.2, 1.42 and 2f.2, 1.43 and 2f.2, 1.44 and 2f.2, 1.48 and 2f.2, 1.52 and 2f.2, 1.55 and 2f.2, 1.57 and 2f.2, 1.59 and 2f.2, 1.60 and 2f.2, 1.63 and 2f.2, 1.64 and 2f.2, 1.66 and 2f.2, 1.67 and 2f.2, 1.69 and 2f.2, 1.70 and 2f.2, 1.71 and 2f.2, 1.72 and 2f.2, 1.78 and 2f.2, 1.82 and 2f.2, 1.83 and 2f.2, 1.84 and 2f.2, 1.88 and 2f.2, 1.90 and 2f.2, 1.91 and 2f.2, 1.94 and 2f.2, 1.95 and 2f.2;
1.1 and 2f.3, 1.4 and 2f.3, 1.6 and 2f.3, 1.8 and 2f.3, 1.9 and 2f.3, 1.14 and 2f.3, 1.17 and 2f.3, 1.19 and 2f.3, 1.21 and 2f.3, 1.23 and 2f.3, 1.24 and 2f.3, 1.27 and 2f.3, 1.28 and 2f.3, 1.30 and 2f.3, 1.34 and 2f.3, 1.35 and 2f.3, 1.37 and 2f.3, 1.38 and 2f.3, 1.40 and 2f.3, 1.42 and 2f.3, 1.43 and 2f.3, 1.44 and 2f.3, 1.48 and 2f.3, 1.52 and 2f.3, 1.55 and 2f.3, 1.57 and 2f.3, 1.59 and 2f.3, 1.60 and 2f.3, 1.63 and 2f.3, 1.64 and 2f.3, 1.66 and 2f.3, 1.67 and 2f.3, 1.69 and 2f.3, 1.70 and 2f.3, 1.71 and 2f.3, 1.72 and 2f.3, 1.78 and 2f.3, 1.82 and 2f.3, 1.83 and 2f.3, 1.84 and 2f.3, 1.88 and 2f.3, 1.90 and 2f.3, 1.91 and 2f.3, 1.94 and 2f.3, 1.95 and 2f.3;
1.1 and 2f.4, 1.4 and 2f.4, 1.6 and 2f.4, 1.8 and 2f.4, 1.9 and 2f.4, 1.14 and 2f.4, 1.17 and 2f.4, 1.19 and 2f.4, 1.21 and 2f.4, 1.23 and 2f.4, 1.24 and 2f.4, 1.27 and 2f.4, 1.28 and 2f.4, 1.30 and 2f.4, 1.34 and 2f.4, 1.35 and 2f.4, 1.37 and 2f.4, 1.38 and 2f.4, 1.40 and 2f.4, 1.42 and 2f.4, 1.43 and 2f.4, 1.44 and 2f.4, 1.48 and 2f.4, 1.52 and 2f.4, 1.55 and 2f.4, 1.57 and 2f.4, 1.59 and 2f.4, 1.60 and 2f.4, 1.63 and 2f.4, 1.64 and 2f.4, 1.66 and 2f.4, 1.67 and 2f.4, 1.69 and 2f.4, 1.70 and 2f.4, 1.71 and 2f.4, 1.72 and 2f.4, 1.78 and 2f.4, 1.82 and 2f.4, 1.83 and 2f.4, 1.84 and 2f.4, 1.88 and 2f.4, 1.90 and 2f.4, 1.91 and 2f.4, 1.94 and 2f.4, 1.95 and 2f.4;
1.1 and 2f.5, 1.4 and 2f.5, 1.6 and 2f.5, 1.8 and 2f.5, 1.9 and 2f.5, 1.14 and 2f.5, 1.17 and 2f.5, 1.19 and 2f.5, 1.21 and 2f.5, 1.23 and 2f.5, 1.24 and 2f.5, 1.27 and 2f.5, 1.28 and 2f.5, 1.30 and 2f.5, 1.34 and 2f.5, 1.35 and 2f.5, 1.37 and 2f.5, 1.38 and 2f.5, 1.40 and 2f.5, 1.42 and 2f.5, 1.43 and 2f.5, 1.44 and 2f.5, 1.48 and 2f.5, 1.52 and 2f.5, 1.55 and 2f.5, 1.57 and 2f.5, 1.59 and 2f.5, 1.60 and 2f.5, 1.63 and 2f.5, 1.64 and 2f.5, 1.66 and 2f.5, 1.67 and 2f.5, 1.69 and 2f.5, 1.70 and 2f.5, 1.71 and 2f.5, 1.72 and 2f.5, 1.78 and 2f.5, 1.82 and 2f.5, 1.83 and 2f.5, 1.84 and 2f.5, 1.88 and 2f.5, 1.90 and 2f.5, 1.91 and 2f.5, 1.94 and 2f.5, 1.95 and 2f.5;
1.1 and 2f.6, 1.4 and 2f.6, 1.6 and 2f.6, 1.8 and 2f.6, 1.9 and 2f.6, 1.14 and 2f.6, 1.17 and 2f.6, 1.19 and 2f.6, 1.21 and 2f.6, 1.23 and 2f.6, 1.24 and 2f.6, 1.27 and 2f.6, 1.28 and 2f.6, 1.30 and 2f.6, 1.34 and 2f.6, 1.35 and 2f.6, 1.37 and 2f.6, 1.38 and 2f.6, 1.40 and 2f.6, 1.42 and 2f.6, 1.43 and 2f.6, 1.44 and 2f.6, 1.48 and 2f.6, 1.52 and 2f.6, 1.55 and 2f.6, 1.57 and 2f.6, 1.59 and 2f.6, 1.60 and 2f.6, 1.63 and 2f.6, 1.64 and 2f.6, 1.66 and 2f.6, 1.67 and 2f.6, 1.69 and 2f.6, 1.70 and 2f.6, 1.71 and 2f.6, 1.72 and 2f.6, 1.78 and 2f.6, 1.82 and 2f.6, 1.83 and 2f.6, 1.84 and 2f.6, 1.88 and 2f.6, 1.90 and 2f.6, 1.91 and 2f.6, 1.94 and 2f.6, 1.95 and 2f.6.
The proportions in which the active substances 1 and 2f may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2f may possibly be present in the form of their solvates or hydrates. Depending on the choice of the compounds 1 and 2f, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various salt forms.
As a rule, the pharmaceutical combinations according to the invention may contain compounds 1 and 2f in ratios by weight ranging from 100:1 to 1:100, preferably from 50:1 to 1:50, more preferred from 25:1 to 1:25, most preferred 20:1 to 1:20.
For example, without restricting the scope of the invention thereto, preferred combinations may contain 1 and an endothelin-antagonists 2f in the following weight ratios:
100:1, 95:1, 90:1, 85:1, 80:1, 75:1, 70:1, 65:1, 60:1, 55:1, 50:1, 45:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, 1:95, 1:100.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2f are normally administered so that 1 and 2f are present together in doses of about 100 to 50000 μg, preferably 1000 to 25000 μg, more preferably 1500 to 10000 μg, better still from about 2000 to about 7000 μg, more preferably 2500 to 600 μg per single dose. For example about 3000 to about 5500 μg of the combination of 1 and 2f according to the invention may be administered once or twice daily to the patient in need thereof. For example, combinations of 1 and 2f according to the invention contain a quantity of 1 and an endothelin-antagonist 2f (as for instance 2f.1, 2f.2, 2f.3, 2f.4 or 2f.5) such that the total dosage per single dose is about 100 μg, 150 μg, 200 μg, 250 μg, 300 μg etc. (add stepwise 50 μg) up to 50000 μg, or similar.
For example, without restricting the scope of the invention thereto, the combinations of 1 and 2f according to the invention may contain a quantity of 1 and an endothelin-antagonist 2f (as for instance 2f.1, 2f.2, 2f.3, 2f.4 or 2f.5) in such an amount that the following quantities of the active substances are administered per single dose:
100 μg of 1 and 1000 μg of 2f, 100 μg of 1 and 1500 μg of 2f, 100 μg of 1 and 2000 μg of 2f, 100 μg of 1 and 2500 μg of 2f, 100 μg of 1 and 3000 μg of 2f, 100 μg of 1 and 3500 μg of 2f, 100 μg of 1 and 4000 μg of 2f, 100 μg of 1 and 4500 μg of 2f, 100 μg of 1 and 5000 μg of 2f, 100 μg of 1 and 6000 μg of 2f, 100 μg of 1 and 7000 μg of 2f, 100 μg of 1 and 8000 μg of 2f, 100 μg of 1 and 9000 μg of 2f, 100 μg of 1 and 10000 μg of 2f, 200 μg of 1 and 1000 μg of 2f, 200 μg of 1 and 1500 μg of 2f, 200 μg of 1 and 2000 μg of 2f, 200 μg of 1 and 2500 μg of 2f, 200 μg of 1 and 3000 μg of 2f, 200 μg of 1 and 3500 μg of 2f, 200 μg of 1 and 4000 μg of 2f, 200 μg of 1 and 4500 μg of 2f, 200 μg of 1 and 5000 μg of 2f, 200 μg of 1 and 6000 μg of 2f, 200 μg of 1 and 7000 μg of 2f, 200 μg of 1 and 8000 μg of 2f, 200 μg of 1 and 9000 μg of 2f, 200 μg of 1 and 10000 μg of 2f, 500 μg of 1 and 1000 μg of 2f, 500 μg of 1 and 1500 μg of 2f, 500 μg of 1 and 2000 μg of 2f, 500 μg of 1 and 2500 μg of 2f, 500 μg of 1 and 3000 μg of 2f, 500 μg of 1 and 3500 μg of 2f, 500 μg of 1 and 4000 μg of 2f, 500 μg of 1 and 4500 μg of 2f, 500 μg of 1 and 5000 μg of 2f, 500 μg of 1 and 6000 μg of 2f, 500 μg of 1 and 7000 μg of 2f, 500 μg of 1 and 8000 μg of 2f, 500 μg of 1 and 9000 μg of 2f, 500 μg of 1 and 10000 μg of 2f, 1000 μg of 1 and 1000 μg of 2f, 1000 μg of 1 and 1500 μg of 2f, 1000 μg of 1 and 2000 μg of 2f, 1000 μg of 1 and 2500 μg of 2f, 1000 μg of 1 and 3000 μg of 2f, 1000 μg of 1 and 3500 μg of 2f, 1000 μg of 1 and 4000 μg of 2f, 1000 μg of 1 and 4500 μg of 2f, 1000 μg of 1 and 5000 μg of 2f, 1000 μg of 1 and 6000 μg of 2f, 1000 μg of 1 and 7000 μg of 2f, 1000 μg of 1 and 8000 μg of 2f, 1000 μg of 1 and 9000 μg of 2f, 1000 μg of 1 and 10000 μg of 2f,
5000 μg of 1 and 1000 μg of 2f, 5000 μg of 1 and 1500 μg of 2f, 5000 μg of 1 and 2000 μg of 2f, 5000 μg of 1 and 2500 μg of 2f, 5000 μg of 1 and 3000 μg of 2f, 5000 μg of 1 and 3500 μg of 2f, 5000 μg of 1 and 4000 μg of 2f, 5000 μg of 1 and 4500 μg of 2f, 5000 μg of 1 and 5000 μg of 2f, 5000 μg of 1 and 6000 μg of 2f, 5000 μg of 1 and 7000 μg of 2f, 5000 μg of 1 and 8000 μg of 2f, 5000 μg of 1 and 9000 μg of 2f, 5000 μg of 1 and 10000 μg of 2f,
10000 μg of 1 and 1000 μg of 2f, 10000 μg of 1 and 1500 μg of 2f, 10000 μg of 1 and 2000 μg of 2f, 10000 μg of 1 and 2500 μg of 2f, 10000 μg of 1 and 3000 μg of 2f, 10000 μg of 1 and 3500 μg of 2f, 10000 μg of 1 and 4000 μg of 2f, 10000 μg of 1 and 4500 μg of 2f, 10000 μg of 1 and 5000 μg of 2f, 10000 μg of 1 and 6000 μg of 2f, 10000 μg of 1 and 7000 μg of 2f, 10000 μg of 1 and 8000 μg of 2f, 10000 μg of 1 and 9000 μg of 2f, 10000 μg of 1 and 10000 μg of 2f,
25000 μg of 1 and 1000 μg of 2f, 25000 μg of 1 and 1500 μg of 2f, 25000 μg of 1 and 2000 μg of 2f, 25000 μg of 1 and 2500 μg of 2f, 25000 μg of 1 and 3000 μg of 2f, 25000 μg of 1 and 3500 μg of 2f, 25000 μg of 1 and 4000 μg of 2f, 25000 μg of 1 and 4500 μg of 2f, 25000 μg of 1 and 5000 μg of 2f, 25000 μg of 1 and 6000 μg of 2f, 25000 μg of 1 and 7000 μg of 2f, 25000 μg of 1 and 8000 μg of 2f, 25000 μg of 1 and 9000 μg of 2f, 25000 μg of 1 and 1000 μg of 2f,
50000 μg of 1 and 1000 μg of 2f, 50000 μg of 1 and 1500 μg of 2f, 50000 μg of 1 and 2000 μg of 2f, 50000 μg of 1 and 2500 μg of 2f, 50000 μg of 1 and 3000 μg of 2f, 50000 μg of 1 and 3500 μg of 2f, 50000 μg of 1 and 4000 μg of 2f, 50000 μg of 1 and 4500 μg of 2f, 50000 μg of 1 and 5000 μg of 2f, 50000 μg of 1 and 6000 μg of 2f, 50000 μg of 1 and 7000 μg of 2f, 50000 μg of 1 and 8000 μg of 2f, 50000 μg of 1 and 9000 μg of 2f, 50000 μg of 1 and 10000 μg of 2f, are administered.
The suggested dosages per single dose specified above are not to be regarded as being limited to the numerical values actually stated, but are intended as dosages which are disclosed by way of example. Of course, dosages which may fluctuate about the abovementioned numerical values within a range of about +/−2.5 μg are also included in the values given above by way of example. In these dosage ranges, the active substances 1 and 2f may be present in the weight ratios given above.
The actives of the combinations according to the invention may be administered simultaneously, separately or sequentially. The preferred route of administration depends on the indication to be treated. In case of gastrointestinal indications, inflammatory joint, skin and eyes disorders both components 1 and 2 may be administered orally, intravenously or rectally, using suitable formulations known in the art, such as tablets, coated tablets, pills, granules or granular powder, syrups, emulsions, suspensions, solutions or suppositories, optionally together with inert and non-toxic pharmaceutically acceptable excipients or solvents. In case of inflammatory joint or skin disorders both components 1 and 2 also may be may be administered topically, using suitable formulations known in the art, such as ointments or transdermal patches. Furthermore, in case of inflammatory disorders of the eye both components 1 and 2 preferably are administered topically using suitable formulations such as ophthalmic solutions, eye drops or viscoelastic gels.
In case of respiratory indications and if administered separately or sequentially preferably at least one of components 1 and 2 is given by inhalative route. If component 1 is administered by inhalation component 2, administered separately, may be given for instance orally, intravenously, subcutaneously, by intramuscular injection, intraperitoneally, intranasally or transdermally, using suitable formulations known in the art, such as tablets, coated tablets, pills, granules or granular powder, aerosols, syrups, emulsions, suspensions, powders, solutions or transdermal patches, optionally together with inert and non-toxic pharmaceutically acceptable excipients or solvents. The same applies with respect to component 1, vice versa, if component 2 is administered by inhalation.
In case of respiratory indications both components 1 and 2 of the pharmaceutical combinations according to the invention preferably are administered by inhalation. Inhalable preparations according to the invention include inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable solutions. Inhalable powders according to the invention containing the combination of active substances 1 and 2 may consist of the active substances on their own or of a mixture of the active substances with physiologically acceptable excipients. Within the scope of the present invention, the term carrier may optionally be used instead of the term excipient. Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile inhalable solutions ready for use. The preparations according to the invention may contain the combination of active substances 1 and 2 either together in one formulation or in two separate formulations. These formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification.
Any aforementioned possible doses applicable for the combinations according to the invention are to be understood as referring to doses per single application. However, these examples are not be understood as excluding the possibility of administering the combinations according to the invention multiple times. Depending on the medical need patients may receive also multiple inhalative applications. As an example patients may receive the combinations according to the invention for instance two or three times (e.g. two or three puffs with a powder inhaler, an MDI etc.) in the morning of each treatment day. As the aforementioned dose examples are only to be understood as dose examples per single application (i.e. per puff) multiple application of the combinations according to the invention leads to multiple doses of the aforementioned examples. The application of the compositions according to the invention can be for instance once a day, or depending on the duration of action of the agents twice a day, or once every 2 or 3 days. Moreover it is emphasized that the aforementioned dosages are to be understood as examples of metered doses only. In other terms, the aforementioned doses are not to be understood as the effective doses of the combinations according to the invention that do in fact reach the lung. It is clear for the person of ordinary skill in the art that the delivered dose to the lung is generally lower than the metered dose of the administered active ingredients.
A) Inhalable Powder Containing the Combinations of Active Substances 1 and 2 According to the Invention:
The inhalable powders according to the invention may contain 1 and 2 either on their own or in admixture with suitable physiologically acceptable excipients.
If the active substances 1 and 2 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose, trehalose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), cyclodextrines (e.g. α-cyclodextrine, β-cyclodextrine, χ-cyclodextrine, methyl-β-cyclodextrine, hydroxypropyl-β-cyclodextrine), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose, trehalose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates.
Within the scope of the inhalable powders according to the invention the excipients have a maximum average particle size of up to 250 μm, preferably between 10 and 150 μm, most preferably between 15 and 80 μm. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9 μm to the excipient mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, micronised active substance 1 and 2, preferably with an average particle size of 0.5 to 10 μm, more preferably from 1 to 6 μm, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and by finally mixing the ingredients together are known from the prior art. The inhalable powders according to the invention may be prepared and administered either in the form of a single powder mixture which contains both 1 and 2 or in the form of separate inhalable powders which contain only 1 or 2.
The inhalable powders according to the invention may be administered using inhalers known from the prior art. Inhalable powders according to the invention which contain one or more physiologically acceptable excipients in addition to 1 and 2 may be administered, for example, by means of inhalers which deliver a single dose from a supply using a measuring chamber as described in U.S. Pat. No. 4,570,630A, or by other means as described in DE 36 25 685 A. The inhalable powders according to the invention which contain 1 and 2 optionally in conjunction with a physiologically acceptable excipient may be administered, for example, using the inhaler known by the name Turbuhaler® or using inhalers as disclosed for example in EP 237507A. Preferably, the inhalable powders according to the invention which contain physiologically acceptable excipient in addition to 1 and 2 are packed into capsules (to produce so-called inhalettes) which are used in inhalers as described, for example, in WO 94/28958.
A particularly preferred inhaler for using the pharmaceutical combination according to the invention in inhalettes is shown in FIG. 1.
This inhaler (Handyhaler) for inhaling powdered pharmaceutical compositions from capsules is characterised by a housing 1 containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen 5 secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 8, and a mouthpiece 12 which is connected to the housing 1, the deck 3 and a cover 11 via a spindle 10 to enable it to be flipped open or shut, as well as airholes 13 for adjusting the flow resistance.
If the inhalable powders according to the invention are packed into capsules (inhalers) for the preferred use described above, the quantities packed into each capsule should be 1 to 30 mg per capsule. These capsules contain, according to the invention, either together or separately, the doses of 1 and 2 or 2′ mentioned hereinbefore for each single dose.
B) Propellant Gas-Driven Inhalation Aerosols Containing the Combinations of Active Substances 1 and 2:
Inhalation aerosols containing propellant gas according to the invention may contain substances 1 and 2 dissolved in the propellant gas or in dispersed form. 1 and 2 may be present in separate formulations or in a single preparation, in which 1 and 2 are either both dissolved, both dispersed or only one component is dissolved and the other is dispersed. The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are halogenated alkane derivatives selected from TG11, TG12, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof, of which the propellant gases TG134a, TG227 and mixtures thereof are preferred.
The propellant-driven inhalation aerosols according to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.
The inhalation aerosols containing propellant gas according to the invention may contain up to 5 wt.-% of active substance 1 and/or 2. Aerosols according to the invention contain, for example, 0.002 to 5 wt.-%, 0.01 to 3 wt.-%, 0.015 to 2 wt.-%, 0.1 to 2 wt.-%, 0.5 to 2 wt.-% or 0.5 to 1 wt.-% of active substance 1 and/or 2.
If the active substances 1 and/or 2 are present in dispersed form, the particles of active substance preferably have an average particle size of up to 10 μm, preferably from 0.1 to 6 μm, more preferably from 1 to 5 μm.
The propellant-driven inhalation aerosols according to the invention mentioned above may be administered using inhalers known in the art (MDIs=metered dose inhalers). Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellant-driven aerosols as hereinbefore described combined with one or more inhalers suitable for administering these aerosols. In addition, the present invention relates to inhalers which are characterised in that they contain the propellant gas-containing aerosols described above according to the invention. The present invention also relates to cartridges fitted with a suitable valve which can be used in a suitable inhaler and which contain one of the above-mentioned propellant gas-containing inhalation aerosols according to the invention. Suitable cartridges and methods of filling these cartridges with the inhalable aerosols containing propellant gas according to the invention are known from the prior art.
C) Propellant-Free Inhalable Solutions or Suspensions Containing the Combinations of Active Substances 1 and 2 According to the Invention:
Propellant-free inhalable solutions and suspensions according to the invention contain, for example, aqueous or alcoholic, preferably ethanolic solvents, optionally ethanolic solvents mixed with aqueous solvents. If aqueous/ethanolic solvent mixtures are used the relative proportion of ethanol compared with water is not limited but preferably the maximum is up to 70 percent by volume, more particularly up to 60 percent by volume of ethanol. The remainder of the volume is made up of water. The solutions or suspensions containing 1 and 2, separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.
According to the invention, the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as stabiliser or complexing agent is unnecessary in the present formulation. Other embodiments may contain this compound or these compounds. In a preferred embodiment the content based on sodium edetate is less than 100 mg/100 ml, preferably less than 50 mg/100 ml, more preferably less than 20 mg/100 ml. Generally, inhalable solutions in which the content of sodium edetate is from 0 to 10 mg/100 ml are preferred.
Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions according to the invention. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols—particularly isopropyl alcohol, glycols—particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
The preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins occurring in the human body.
Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. The preservatives mentioned above are preferably present in concentrations of up to 50 mg/100 ml, more preferably between 5 and 20 mg/100 ml.
Preferred formulations contain, in addition to the solvent water and the combination of active substances 1 and 2, only benzalkonium chloride and sodium edetate. In another preferred embodiment, no sodium edetate is present.
The propellant-free inhalable solutions according to the invention are administered in particular using inhalers of the kind which are capable of nebulising a small amount of a liquid formulation in the therapeutic dose within a few seconds to produce an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, preferred inhalers are those in which a quantity of less than 100 μL, preferably less than 50 μL, more preferably between 20 and 30 μL of active substance solution can be nebulised in preferably one spray action to form an aerosol with an average particle size of less than 20 μm, preferably less than 10 μm, in such a way that the inhalable part of the aerosol corresponds to the therapeutically effective quantity.
An apparatus of this kind for propellant-free delivery of a metered quantity of a liquid pharmaceutical composition for inhalation is described for example in International Patent Application WO 91/14468 and also in WO 97/12687 (cf. in particular FIGS. 6a and 6b). The nebulisers (devices) described therein are known by the name Respimat®.
This nebuliser (Respimat®) can advantageously be used to produce the inhalable aerosols according to the invention containing the combination of active substances 1 and 2. Because of its cylindrical shape and handy size of less than 9 to 15 cm long and 2 to 4 cm wide, this device can be carried at all times by the patient. The nebuliser sprays a defined volume of pharmaceutical formulation using high pressures through small nozzles so as to produce inhalable aerosols.
The preferred atomiser essentially consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a storage container, characterised by
The hollow plunger with valve body corresponds to a device disclosed in WO 97/12687. It projects partially into the cylinder of the pump housing and is axially movable within the cylinder. Reference is made in particular to FIGS. 1 to 4, especially FIG. 3, and the relevant parts of the description. The hollow plunger with valve body exerts a pressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured amount of active substance solution, at its high pressure end at the moment when the spring is actuated. Volumes of 10 to 50 microlitres are preferred, while volumes of 10 to 20 microlitres are particularly preferred and a volume of 15 microlitres per spray is most particularly preferred.
The valve body is preferably mounted at the end of the hollow plunger facing the valve body.
The nozzle in the nozzle body is preferably microstructured, i.e. produced by microtechnology. Microstructured nozzle bodies are disclosed for example in WO 94/07607; reference is hereby made to the contents of this specification, particularly FIG. 1 therein and the associated description.
The nozzle body consists for example of two sheets of glass and/or silicon firmly joined together, at least one of which has one or more microstructured channels which connect the nozzle inlet end to the nozzle outlet end. At the nozzle outlet end there is at least one round or non-round opening 2 to 10 microns deep and 5 to 15 microns wide, the depth preferably being 4.5 to 6.5 microns while the length is preferably 7 to 9 microns.
In the case of a plurality of nozzle openings, preferably two, the directions of spraying of the nozzles in the nozzle body may extend parallel to one another or may be inclined relative to one another in the direction of the nozzle opening. In a nozzle body with at least two nozzle openings at the outlet end the directions of spraying may be at an angle of 20 to 1600 to one another, preferably 60 to 1500, most preferably 80 to 1000. The nozzle openings are preferably arranged at a spacing of 10 to 200 microns, more preferably at a spacing of 10 to 100 microns, most preferably 30 to 70 microns. Spacings of 50 microns are most preferred. The directions of spraying will therefore meet in the vicinity of the nozzle openings.
The liquid pharmaceutical preparation strikes the nozzle body with an entry pressure of up to 600 bar, preferably 200 to 300 bar, and is atomised into an inhalable aerosol through the nozzle openings. The preferred particle or droplet sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
The locking mechanism contains a spring, preferably a cylindrical helical compression spring, as a store for the mechanical energy. The spring acts on the power takeoff flange as an actuating member the movement of which is determined by the position of a locking member. The travel of the power takeoff flange is precisely limited by an upper and lower stop. The spring is preferably biased, via a power step-up gear, e.g. a helical thrust gear, by an external torque which is produced when the upper housing part is rotated counter to the spring housing in the lower housing part. In this case, the upper housing part and the power takeoff flange have a single or multiple V-shaped gear.
The locking member with engaging locking surfaces is arranged in a ring around the power takeoff flange. It consists, for example, of a ring of plastic or metal which is inherently radially elastically deformable. The ring is arranged in a plane at right angles to the atomiser axis. After the biasing of the spring, the locking surfaces of the locking member move into the path of the power takeoff flange and prevent the spring from relaxing. The locking member is actuated by means of a button. The actuating button is connected or coupled to the locking member. In order to actuate the locking mechanism, the actuating button is moved parallel to the annular plane, preferably into the atomiser; this causes the deformable ring to deform in the annular plane. Details of the construction of the locking mechanism are given in WO 97/20590.
The lower housing part is pushed axially over the spring housing and covers the mounting, the drive of the spindle and the storage container for the fluid.
When the atomiser is actuated the upper housing part is rotated relative to the lower housing part, the lower housing part taking the spring housing with it. The spring is thereby compressed and biased by means of the helical thrust gear and the locking mechanism engages automatically. The angle of rotation is preferably a whole-number fraction of 360 degrees, e.g. 180 degrees. At the same time as the spring is biased, the power takeoff part in the upper housing part is moved along by a given distance, the hollow plunger is withdrawn inside the cylinder in the pump housing, as a result of which some of the fluid is sucked out of the storage container and into the high pressure chamber in front of the nozzle.
If desired, a number of exchangeable storage containers which contain the fluid to be atomised may be pushed into the atomiser one after another and used in succession. The storage container contains the aqueous aerosol preparation according to the invention.
The atomising process is initiated by pressing gently on the actuating button. As a result, the locking mechanism opens up the path for the power takeoff member. The biased spring pushes the plunger into the cylinder of the pump housing. The fluid leaves the nozzle of the atomiser in atomised form.
Further details of construction are disclosed in PCT Applications WO 97/12683 and WO 97/20590, to which reference is hereby made.
The components of the atomiser (nebuliser) are made of a material which is suitable for its purpose. The housing of the atomiser and, if its operation permits, other parts as well, are preferably made of plastics, e.g. by injection moulding. For medicinal purposes, physiologically safe materials are used.
FIGS. 6a/b of WO 97/12687, show the nebuliser (Respimat®) which can advantageously be used for inhaling the aqueous aerosol preparations according to the invention.
FIG. 6a of WO 97/12687 shows a longitudinal section through the atomiser with the spring biased while FIG. 6b of WO 97/12687 shows a longitudinal section through the atomiser with the spring relaxed.
The upper housing part (51) contains the pump housing (52) on the end of which is mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle body (54) and a filter (55). The hollow plunger (57) fixed in the power takeoff flange (56) of the locking mechanism projects partially into the cylinder of the pump housing. At its end the hollow plunger carries the valve body (58). The hollow plunger is sealed off by means of the seal (59). Inside the upper housing part is the stop (60) on which the power takeoff flange abuts when the spring is relaxed. On the power takeoff flange is the stop (61) on which the power takeoff flange abuts when the spring is biased. After the biasing of the spring the locking member (62) moves between the stop (61) and a support (63) in the upper housing part. The actuating button (64) is connected to the locking member. The upper housing part ends in the mouthpiece (65) and is sealed off by means of the protective cover (66) which can be placed thereon.
The spring housing (67) with compression spring (68) is rotatably mounted on the upper housing part by means of the snap-in lugs (69) and rotary bearing. The lower housing part (70) is pushed over the spring housing. Inside the spring housing is the exchangeable storage container (71) for the fluid (72) which is to be atomised. The storage container is sealed off by the stopper (73) through which the hollow plunger projects into the storage container and is immersed at its end in the fluid (supply of active substance solution).
The spindle (74) for the mechanical counter is mounted in the covering of the spring housing. At the end of the spindle facing the upper housing part is the drive pinion (75). The slider (76) sits on the spindle.
The nebuliser described above is suitable for nebulising the aerosol preparations according to the invention to produce an aerosol suitable for inhalation.
If the formulation according to the invention is nebulised using the method described above (Respimat®) the quantity delivered should correspond to a defined quantity with a tolerance of not more than 25%, preferably 20% of this amount in at least 97%, preferably at least 98% of all operations of the inhaler (spray actuations). Preferably, between 5 and 30 mg of formulation, most preferably between 5 and 20 mg of formulation are delivered as a defined mass on each actuation.
However, the formulation according to the invention may also be nebulised by means of inhalers other than those described above, e.g. jet stream inhalers or other stationary nebulisers.
Accordingly, in a further aspect, the invention relates to pharmaceutical formulations in the form of propellant-free inhalable solutions or suspensions as described above combined with a device suitable for administering these formulations, preferably in conjunction with the Respimat®. Preferably, the invention relates to propellant-free inhalable solutions or suspensions characterised by the combination of active substances 1 and 2 according to the invention in conjunction with the device known by the name Respimat®. In addition, the present invention relates to the above-mentioned devices for inhalation, preferably the Respimat®, characterised in that they contain the propellant-free inhalable solutions or suspensions according to the invention as described hereinbefore.
According to the invention, inhalable solutions which contain the active substances 1 and 2 in a single preparation are preferred. The term “single preparation” also includes preparations which contain the two ingredients 1 and 2 in two-chamber cartridges, as disclosed for example in WO 00/23037. Reference is hereby made to this publication in its entirety.
The propellant-free inhalable solutions or suspensions according to the invention may take the form of concentrates or sterile inhalable solutions or suspensions ready for use, as well as the above-mentioned solutions and suspensions designed for use in a Respimat®. Formulations ready for use may be produced from the concentrates, for example, by the addition of isotonic saline solutions. Sterile formulations ready for use may be administered using energy-operated free-standing or portable nebulisers which produce inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other principles.
Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellant-free inhalable solutions or suspensions as described hereinbefore which take the form of concentrates or sterile formulations ready for use, combined with a device suitable for administering these solutions, characterised in that the device is an energy-operated free-standing or portable nebuliser which produces inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other methods.
The Examples which follow serve to illustrate the present invention in more detail without restricting the scope of the invention to the following embodiments by way of example.
The following examples of formulations, which may be obtained analogously to methods known in the art, serve to illustrate the present invention more fully without restricting it to the contents of these examples. Examples of formulations comprising an EGFR kinase inhibitor 1 selected from compounds 1.1 to 1.105 as the only active ingredient are disclosed in the prior art, e.g in WO 96/30347; WO 97/02266; WO 99/35146; WO 00/31048; WO 00/78735; WO 01/34574; WO 01/61816; WO 01/77104; WO02/18351; WO 02/18372; WO 02/18373; WO 02/18376; WO 02/50043; WO 03/082290; Cancer Research 2004, 64:11 (3958-3965); Am J Health-Syst Pharm 2000, 57(15), 2063-2076; Clinical Therapeutics 1999, 21(2), 309-318; WO 98/50433; and WO 95/20045.
Formulations Comprising an EGFR Kinase Inhibitor 1 and a beta-2 Mimetic 2a
Inhalable Formulations:
Examples of binary formulations comprising an EGFR kinase inhibitor 1 selected from compounds 1.1 to 1.105 and a beta-2 mimetic 2a as the active ingredients:
Ternary or quartenary formulations containing three or four actives may be prepared in analogy to the binary formulations described in examples 1 to 7, e.g. by incorporating two components 1 and/or two components 2a instead of only one of these components. The amounts given in the tables should in this case be understood as the sum of amounts for the corresponding actives.
Formulations Comprising an EGFR Kinase Inhibitor 1 and a Steroid 2b
Inhalable Formulations:
Examples of binary formulations comprising an EGFR kinase inhibitor 1 selected from compounds 1.1 to 1.105 and a steroid 2b as the active ingredients:
Ternary or quartenary formulations containing three or four actives may be prepared in analogy to the binary formulations described in examples 30 to 33, e.g. by incorporating two components 1 and/or two components 2b instead of only one of these components. The amounts given in the tables should in this case be understood as the sum of amounts for the corresponding actives.
Formulations Comprising an EGFR Kinase Inhibitor 1 and a PDE-IV Inhibitor 2c
Inhalable Formulations:
Examples of binary formulations comprising an EGFR kinase inhibitor 1 selected from compounds 1.1 to 1.101 and a PDE-IV inhibitor 2c as the active ingredients:
*)2c′ = each of the following compounds:
Formulations Comprising an EGFR Kinase Inhibitor 1 and a p38 MAP Kinase Inhibitor 2d
Inhalable Formulations:
Examples of binary formulations comprising an EGFR kinase inhibitor 1 selected from compounds 1.1 to 1.101 and a p38 MAP kinase inhibitor 2d as the active ingredients:
Formulations Comprising an EGFR Kinase Inhibitor 1 and a NK1 Antagonist 2e
Inhalable Formulations:
Examples of binary formulations comprising an EGFR kinase inhibitor 1 selected from compounds 1.1 to 1.101 and a NK1 antagonist 2e as the active ingredients:
Formulations Comprising an EGFR Kinase Inhibitor 1 and an Endothelin-Antagonist 2f
Inhalable Formulations:
Examples of binary formulations comprising an EGFR kinase inhibitor 1 selected from compounds 1.1 to 1.101 and an endothelin-antagonist selected from 2f.1 to 2f.13 as the active ingredients:
| Number | Date | Country | Kind |
|---|---|---|---|
| 04018808 | Aug 2004 | EP | regional |
This is a continuation application of U.S. patent application Ser. No. 11/189,643, filed Jul. 26, 2005, the entirety of which application is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11189643 | Jul 2005 | US |
| Child | 12202784 | US |
