Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-09
2002-09-24
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S642000, C514S826000, C514S394000, C514S230800, C514S383000, C424S043000
Reexamination Certificate
active
06455524
ABSTRACT:
The present invention relates to new medicament compositions based on anticholinergic compounds, which have a long-lasting effect, and &bgr;-mimetics, which have a long-lasting effect, processes for their production and their use in the therapy of respiratory ailments.
BACKGROUND OF THE INVENTION
It is known from the prior art that &bgr;-mimetics and anticholinergics can successfully be used as bronchospasmolytics for the treatment of obstructive respiratory ailments, such as, e.g., asthma, Substances with &bgr;-sympatho-mimetic effectiveness, such as, e.g., the active substance formnoterol, also known from the prior art, can, however, be associated with undesirable side-effects when administered to humans.
Generally, the central effects manifest as unease, excitation, sleeplessness, fear, shaking fingers, outbreaks of sweating and headaches. Here, inhalative application does not exclude these side-effects although they are generally less severe than with peroral or parenteral application.
The side-effects of the &bgr;-sympatho-mimetics used as asthma agents are primarily associated with a more or less pronounced &bgr;1-stimulating effect on the heart. It generates tachycardia, palpitation, angina pectoris-like complaints and arrhythmia [P. T. Ammon (Ed.), Medicament Side-effects and Interactions,
Wissenschaftliche Verlagsgesellschaft
, Stuttgart 1986, S. 584].
DESCRIPTION OF THE INVENTION
Surprisingly, it has now been found that the above-mentioned side-effects can be substantially reduced by a combination of a &bgr;-sympatho-mimetic, which has a long-lasting effect, with an anticholinergic, which has a long-lasting effect.
In addition, it was also very surprisingly discovered that the bronchospasmolytic effects of the anticholinergic, which has a long-lasting effect, and the &bgr;-mimetic, which has a long-lasting effect, increase in a superadditive manner.
Hence with the combination of active ingredients according to the invention, a substantial increase in effectiveness can be expected—in comparison to the individual substances and combinations known from the prior art—in the case of both COPD and asthma.
The following active ingredients can preferably be used as &bgr;-mimetics, which have a long-lasting effect, in the active ingredients combination according to the invention: bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenalin, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulfonterol, terbutalin, tolubuterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}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-1,4-3-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 or 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol, optionally in the form of their racemates, their enantiomers, their diastereomers, and mixtures thereof, and optionally their pharmacologically-compatible acid addition salts.
The following are preferably used as &bgr;-mimetics, which have a long-lasting effect, in the active ingredients combination according to the invention: formoterol, salmeterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}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 or 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 their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally their pharmacologically-compatible acid addition salts.
Especially preferably, the following are used as &bgr;-mimetics in the medicament compositions according to the invention: formoterol or salmeterol, optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally their pharmacologically-compatible acid addition salts.
As stated above, the &bgr;-mimetics which have a long-lasting effect can be converted and used in the form of their physiologically and pharmacologically-compatible salts. The following can be considered, by way of example, to represent the acid addition salts: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanosulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid or maleic acid. Furthermore, mixtures of the aforementioned acids can be used.
From the viewpoint of the superadditive bronchospasmolytic effect, the fumarate of formoterol (abbreviated to formoterol FU) is especially preferred as a &bgr;-mimetic which has a long-lasting effect. Here, the active substance formoterol can be used as an enantiomer or diastereomer mixture or in the form of the individual enantiomers/diastereomers. With the same preferred significance, according to the invention, salmeterol can also be used as a &bgr;-mimetic which has a long-lasting effect, optionally in the form of its racemates, enantiomers, of which the (R) enantiomer is most especially preferred, and optionally its pharmacologically-acceptable addition salts.
As anticholinergics which have a long-lasting effect, basically those which are already known from the prior art, such as glycopyrronium bromide and esters of bi- and tricyclic amino alcohols, are suitable, such as are known from European disclosure document 0 418 716 and International Patent Application WO 92/16528, and to the full contents of which reference is hereby made.
Within the framework of the invention, glycopyrroniumbromide can especially be considered as an anticholinergic which has a long-lasting effect, and compounds of formula (I)
can be considered as esters of bi- and tricyclic amino alcohols wherein
A denotes a group of general formula (II)
in which
Q denotes one of the double-bonded groups —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—,
—CH═CH—, or;
R denotes an optionally halogen- or hydroxy-substituted C
1
-C
4
alkyl group,
R′ denotes a C
1
-C
4
alkyl group and R and R′ can also combine to form a
C
4
-C
6
alkylene group, and
an equivalent of an anion X is counters the positive charge of the N atom,
Z denotes one of the groups
wherein
Y represents a single bond, an O or S atom or one of the groups —CH
2
—, —CH
2
—CH
2
—, —CH═CH—, —OCH
2
— or —SCH
2
—;
R
1
denotes hydrogen, OH, C
1
-C
4
alkoxy or C
1
-C
4
alkyl, which can optionally be substituted by hydroxy;
R
2
denotes a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl group, wherein these groups can also be substituted by methyl, and thienyl and phenyl can also be substituted by fluorine or chlorine,
R
3
denotes hydrogen or a thienyl or pheny
Bozung Karl-Heinz
Pairet Michel
Reichl Richard
Walland Alexander
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen
Nguyen Helen
Raymond Robert P.
Webman Edward J.
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