JP2004519484A5

JP2004519484A5 -

Info

Publication number: JP2004519484A5
Application number: JP2002569121A
Authority: JP
Filing date: 2002-02-26
Publication date: 2005-12-22

Claims

One or more anticholinergics (1) in combination with one or more NK ₁ -receptor antagonists (2), optionally as enantiomers, enantiomeric mixtures, or as racemates, and optionally as solvates or hydrates. And optionally with a pharmaceutically acceptable excipient.

The pharmaceutical composition according to claim 1, wherein the active substances 1 and 2 are present together in a single formulation or in two different formulations.

The pharmaceutical composition according to claim 1 or 2, wherein the active substance 1 is selected from the group consisting of tiotropium salt, oxitropium salt or ipratropium salt, preferably tiotropium salt.

4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the active substance 1 is present as chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate or methyl sulfate, preferably bromide.

The active substance 2 is 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, MK-869, L-754030, CJ-11974, L-758298, DNK-33A 6b-I, CJ-11974, TAK-637, GR 205171, N- [2- (3,5-bis-trifluoromethyl-phenyl) -ethyl] -2- {4-[(3-hydroxypropyl) -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-phen Ruacetamide, BIIM1310, 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 arylglycinamide derivatives of general formula 3 below:

(Where R ¹ and R ² together with the atom N to which they are attached form a ring represented by the following formula:

(Where r and s are 2 or 3,
R ⁶ is 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₎ alkyl amino, mono-fluoro or perfluoro (C ₁ -C ₂₎ alkyl, Represents an N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl group;
R ⁷ means any of the following (a) to (d):
(a) hydroxyl, (b) 4-piperidinopiperidyl, (c) a group represented by the following formula:

(Where R ¹⁶ and R ¹⁷ are each independently 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 Represents
R ⁸ represents H,)))
The pharmaceutical composition according to any one of claims 1 to 4, which is selected from the group consisting of optionally present as its enantiomer and enantiomeric mixture or as its racemate.

The active substance 2 is BIIF 1149, CP-122721, 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, BIIM1310, 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] -piperidine-1 -Yl} -N-methyl-2-phenyl-acetamide, N- [2- (3,5-bis-trifluoromethyl-phenyl) -eth Ru] -2- {4- [cyclopropylmethyl- (3-hydroxy-propyl) -amino] -piperidin-1-yl} -N-methyl-2-phenyl-acetamide and arylglycinamide derivatives of general formula 3 above (Where R ¹ and R ² together with the atom N to which they are bonded form a ring represented by the following formula:

(Where s is 2 or 3,
R ⁷ is a group represented by the following formula:

(Where R ¹⁶ and R ¹⁷ are each independently 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 And R ⁸ represents H))), and is selected from the group consisting of:
6. The pharmaceutical composition according to any one of claims 1 to 5, optionally present as its enantiomer and mixture of enantiomers and as its racemate.

The pharmaceutical composition according to any one of claims 1 to 6 , which is in a formulation suitable for inhalation.

8. A pharmaceutical composition according to claim 7 , wherein the composition is a formulation selected from the group consisting of inhalable powders, propellant-containing metered aerosols and propellant-free inhalable solutions or suspensions. object.

The pharmaceutical composition is an inhalable powder, wherein the powder is selected from the group consisting of monosaccharides, disaccharides, oligo- and polysaccharides, polyhydric alcohols, salts, or mixtures thereof 9. The pharmaceutical composition according to claim 8 , comprising the active substances 1 and 2 as a mixture with other physiologically acceptable excipients.

9. A pharmaceutical composition according to claim 8 , which is a propellant-containing inhalable aerosol comprising said active substances 1 and 2 in dissolved or dispersed state.

The propellant gas includes hydrocarbons such as n-propane, n-butane or isobutane or halohydrocarbons such as chlorinated and / or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. Item 10. A pharmaceutical composition according to Item 10 .

The pharmaceutical composition according to claim 8 , which is a propellant-free inhalable solution or suspension containing water, ethanol or a mixture of water and ethanol as a solvent.

Use of a composition according to any one of claims 1 to 12 for the manufacture of a medicament for the treatment of inflammatory or obstructive diseases of the respiratory tract.