Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2003-04-21
2004-02-24
Reamer, James H (Department: 3761)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C514S291000
Reexamination Certificate
active
06696042
ABSTRACT:
The present invention relates to novel pharmaceutical compositions based on anticholinergics and NK
1
-receptor antagonists, processes for preparing them and their use in the treatment of respiratory diseases.
DESCRIPTION OF THE INVENTION
The present invention relates to novel pharmaceutical compositions based on anticholinergics and NK
1
-receptor antagonists, processes for preparing them and their use in the treatment of respiratory diseases.
Surprisingly, an unexpectedly beneficial therapeutic effect, particularly a synergistic effect can be observed in the treatment of inflammatory and/or obstructive diseases of the respiratory tract if one or more, preferably one, anticholinergic is used with one or more, preferably one, NK
1
-receptor antagonist. In view of this synergistic effect the pharmaceutical combinations according to the invention can be used in smaller doses than would be the case with the individual compounds used in monotherapy in the usual way.
The combinations of active substances according to the invention are surprisingly also characterised by a rapid onset of activity and also by a long-lasting effect. This is of great importance to the wellbeing of the patient as on the one hand he experiences a rapid improvement in his condition after the combination has been administered and also thanks to the long-lasting effect it is sufficient to take the drug once a day. The effects mentioned above may be observed both when the two active substances are administered simultaneously in a single active substance formulation and when they are administered successively in separate formulations. According to the invention, it is preferable to administer the two active substance ingredients simultaneously in a single formulation.
Within the scope of the present invention the term anticholinergics
1
denotes salts which are preferably selected from among tiotropium salts, oxitropium salts and ipratropium salts, most preferably ipratropium salts and tiotropium salts. In the above-mentioned salts the cations tiotropium, oxitropium and ipratropium are the pharmacologically active ingredients. Within the scope of the present patent application, any reference to the above cations is indicated by the use of the number
1′
. Any reference to compounds
1
naturally also includes a reference to the ingredients
1′
(tiotropium, oxitropium or ipratropium).
By the salts
1
which may be used within the scope of the present invention are meant the compounds which contain, in addition to tiotropium, oxitropium or ipratropium as counter-ion (anion), chloride, bromide, iodide, methanesulphonate or para-toluenesulphonate. Within the scope of the present invention, the methanesulphonate, chloride, bromide and iodide are preferred of all the salts
1
, the methanesulphonate and bromide being of particular importance. Of outstanding importance according to the invention are salts
1
selected from among tiotropium bromide, oxitropium bromide and ipratropium bromide. Tiotropium bromide is particularly preferred.
Within the scope of the present invention, the word NK
1
-receptor antagonists (hereinafter
2
) denotes compounds selected from among 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 arylglycinamide derivatives of general formula
3
wherein
R
1
and R
2
together with the N to which they are bound form a ring of formula
wherein r and s are 2 or 3;
R
6
denotes H, —C
1
-C
5
-alkyl, C
3
-C
5
-alkenyl, propynyl, hydroxy(C
2
-C
4
)alkyl, methoxy(C
2
-C
4
)alkyl, di(C
1
-C
3
)alkylamino(C
2
-C
4
)alkyl, amino(C
2
-C
4
)alkyl, amino, di(C
1
-C
3
)alkylamino, monofluoro to perfluoro(C
1
-C
2
)alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,
R
7
has one of the meanings (a) to (d),
(a) hydroxy
(b) 4-piperidinopiperidyl,
wherein R
16
and R
17
independently of each other denote H, (C
1
-C
4
)alkyl, (C
3
-C
6
)cycloalkyl, hydroxy(C
2
-C
4
)alkyl, dihydroxy(C
2
-C
4
)alkyl, (C
1
-C
3
)alkoxy(C
2
-C
4
)alkyl, phenyl(C
1
-C
4
)alkyl or di(C
1
-C
3
)alkylamino(C
2
-C
4
)alkyl,
R
8
denotes H,
optionally in the form of the enantiomers and mixtures of enantiomers thereof, optionally in the form of the racemates thereof.
The abovementioned compounds of formula
3
are known for example from International Patent Applications WO 96/32386 and WO 97/32865, to which reference is hereby made in their entirety.
Preferably, the compound
2
is selected from among BIIF 1149, CP-122721, CGP 60829, MK-869, CJ-11974, GR 205171 and the arylglycinamide derivatives of general formula
3
, wherein
R
1
and R
2
together with the N to which they are bound form a ring of formula
wherein s is 2 or 3;
R
7
denotes a group
wherein R
16
and R
17
independently of each other denote H, (C
1
-C
4
)alkyl, (C
3
-C
6
)cycloalkyl, hydroxy(C
2
-C
4
)alkyl, dihydroxy(C
2
-C
4
)alkyl, (C
1
-C
3
)alkoxy(C
2
-C
4
)alkyl, phenyl(C
1
-C
4
)alkyl or di(C
1
-C
3
)alkylamino(C
2
-C
4
)alkyl,
R
8
denotes H,
optionally in the form of the enantiomers and mixtures of enantiomers thereof and optionally in the form of the racemates thereof.
Particularly preferably, the compound
2
is selected from among BIIF1149 and the arylglycinamide derivatives of general formula
3
, wherein
R
1
and R
2
together with the N to which they are bound form a ring of formula
wherein s is 2 and
R
7
denotes a group
wherein R
16
and R
17
independently of each other denote H, (C
1
-C
4
)alkyl, (C
3
-C
6
)cycloalkyl, hydroxy(C
2
-C
4
)alkyl or dihydroxy(C
2
-C
4
)alkyl,
R
8
denotes H, optionally in the form of the enantiomers and mixtures of enantiomers thereof and optionally in the form of the racemates thereof.
Most particularly preferred as compounds of formula
2
are 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 and N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide, optionally in the form of the enantiomers and mixtures of enantiomers thereof and optionally in the form of the racemates thereof.
Of particular importance is N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide, optionally in the form of its enantiomers, preferably in the form of its (S)-enantiomer, optionally in the form of the mixtures of enantiomers thereof, and optionally in the form of the racemates thereof.
Examples of alkyl groups (including those which are part of other groups), unless otherwise defined, are branched and unbranched alkyl groups with 1 to 5 carbon atoms, such as, for example: methyl, ethyl, propyl, 1-methylethyl(isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl(tert.butyl), etc. The definitions propyl, butyl and pentyl always include the associated isomeric groups. Hydroxy or dihydroxyalkyl groups are alkyl groups substituted by one or two hydroxy groups.
Examples
Meade Christopher J. M.
Pairet Michel
Pieper Michael P.
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
Raymond Robert P.
Reamer James H
Stempel Alan R.
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