Pharmaceutical compositions based on anticholinergics and NK1-receptor antagonists

• US 6,696,042 B2
• Filed: 04/21/2003
• Issued: 02/24/2004
• Est. Priority Date: 03/08/2001
• Status: Expired due to Fees

• Current Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Pharmaceuticals Incorporated (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Pairet, Michel, Pieper, Michael P., Meade, Christopher J. M.
• Primary Examiner(s): Reamer, James H
• Application Number:
  US10/419,358
• Publication Number:
  US 20030212075A1
• Time in Patent Office: 309 Days
• Field of Search: 424/45, 514/291
• US Class Current: 424/45
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]

Abstract

The present invention relates to novel pharmaceutical compositions based on anticholinergics and NK₁-receptor antagonists, processes for preparing them and their use in the treatment of respiratory tract diseases.

Claims

1. An inhalation aerosol pharmaceutical formulation which comprises as an active substance a salt of tiotropium combined with a second active substance which is one or more NK₁-receptor antagonists, in a propellant gas 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 or in mixtures thereof, wherein the active substances may be formulated together and combined with the propellant gas or the active substances may be separately formulated and then the separate formulations combined with the propellant gas.

2. The inhalation aerosol formulation as recited in claim 1 wherein the propellant gas is selected from TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof.

3. The inhalation aerosol formulation as recited in claim 1 wherein the salt of tiotropium is the chloride, bromide, iodide, methane sulphonate or paratoluene sulphonate salt.

4. The inhalation aerosol formulation as recited in claim 3 wherein the salt of tiotropium is the bromide salt.

5. The inhalation aerosol formulation as recited in claim 1 wherein the NK₁-receptor antagonist is selected from among 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-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]-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 arylglycinamide derivatives of general formula 3

wherein

R¹ and R² together with the N to which they are bound form a ring of formula

 

wherein r and s are 2 or 3;

R⁶ denotes H, —

C₁-C₅-alkyl, C₃-C₅-alkenyl, propynyl, 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 to perfluoro(C₁-C₂)alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,

R⁷ has one of the meanings (a) to (d),

(a) hydroxy

(b) 4-piperidinopiperidyl,

 

wherein R¹⁶ and R¹⁷ independently of each other denote H, (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₂-C₄)alkyl, dihydroxy(C₂-C₄)alkyl, (C₁-C₃)alkoxy(C₂-C₄)alkyl, phenyl(C₁-C₄)alkyl or di(C₁-C₃)alkylamino(C₂-C₄)alkyl,

R⁸ denotes H,

optionally in the form of the enantiomers and mixtures of enantiomers thereof, optionally in the form of the racemates thereof.

6. The inhalation aerosol formulation as recited in claim 5 wherein the NK₁-receptor antagonist is selected from 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]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-2-phenyl-acetamide and the arylglycinamide derivatives of general formula 3, wherein

R¹ and R² together with the N to which they are bound form a ring of formula

 

wherein s is 2 or 3;

R⁷ denotes a group

 

wherein R¹⁶ and R¹⁷ independently of each other denote H, (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₂-C₄)alkyl, dihydroxy(C₂-C₄)alkyl, (C₁-C₃)alkoxy(C₂-C₄)alkyl, phenyl(C₁-C₄)alkyl or di(C₁-C₃)alkylamino(C₂-C₄)alkyl,

R⁸ denotes H,

optionally in the form of the enantiomers and mixtures of enantiomers thereof and optionally in the form of the racemates thereof.

7. The inhalation aerosol formulation as recited in claim 6 wherein the NK₁-receptor antagonist is selected from (S)-N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide or an acid addition salt thereof.

8. The inhalation aerosol formulation as recited in claim 1 wherein the weight ratio of the tiotropium salt to the NK₁-receptor antagonist is about 1:

300 to about 50;

1.

9. The inhalation aerosol formulation in claim 8 wherein the weight ratio of the tiotropium salt to the NK₁-receptor antagonist is about 1:

250 to about 40;

1.

10. A method for treatment of asthma in a warm-blooded animal which comprises administering a therapeutically effective amount of an inhalation aerosol formulation as recited in claim 1.

11. A method for treatment of chronic obstructive pulmonary disease in a warm-blooded animal which comprises administering a therapeutically effective amount of an inhalation aerosol formulation as recited in claim 1.

12. The method for treatment of chronic obstructive pulmonary disease in a warm-blooded animal as recited in claim 11 wherein the tiotropium salt and the NK₁-receptor antagonist are present in separate formulations.