Pharmaceutical compositions based on anticholinergics and NK1-receptor antagonists

• US 6,620,438 B2
• Filed: 03/06/2002
• Issued: 09/16/2003
• 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:
  US10/092,116
• Publication Number:
  US 20020169181A1
• Time in Patent Office: 559 Days
• Field of Search: 514/229.5, 424/46, 424/493, 424/489, 424/499
• US Class Current: 424/489
• 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 inhalable powder comprising a tiotropium salt, one or more NK₁-receptor antagonists and a pharmaceutically acceptable excipient selected from glucose, arabinose, lactose, saccharose and maltose.

2. The inhalable powder as recited in claim 1 wherein the tiotropium salt is present in the form of the chloride, bromide, iodide, methanesulphonate or paratoluene sulphonate.

3. The inhalable powder as recited in claim 2 wherein the tiotropium salt is present in the form of a bromide.

4. The inhalable powder as recited in claim 1 wherein the one or more NK₁-receptor antagonist is selected from among 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, 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,

(c)

 

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,

the enantiomer, or a mixture of enantiomers or the racemate thereof.

5. The inhalable powder as recited in claim 1 wherein one or more NK₁-receptor antagonists is selected from among 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, 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 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,

the enantiomer or a mixture of enantiomers, or the racemate thereof.

6. The inhalable powder as recited in claim 1 wherein one or more NK₁-receptor antagonists is (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.

7. The inhalable powder as recited in claim 1 wherein the weight ratio of the anticholineigic to the NK₁-receptor antagonist is in the range from about 1:

300 to about 50;

1.

8. The inhalable powder as recited in claim 7 wherein the weight ratio of the anticholinergic to the NK₁-resceptor antagonist is about 1:

250 to about 40;

1.