NOVEL QUINUCLIDINE DERIVATIVES AND MEDICINAL COMPOSITIONS CONTAINING THE SAME

• US 20150246026A1
• Filed: 05/14/2015
• Published: 09/03/2015
• Est. Priority Date: 07/14/1999
• Status: Active Grant

• Current Assignee: Almirall, S.A. (Grupo Corporativo Landon SL)
• Original Assignee: Almirall, S.A. (Grupo Corporativo Landon SL)
• Inventors: FERNANDEZ FORNER, Maria Dolors, PRAT QUINONES, Maria, BUIL ALBERO, Maria Antonia
• Granted Patent: US 9,333,195 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• 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 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• 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: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/06 Anti-spasmodics
• CPC Class Codes: A61P 13/10 : of the bladder
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 453/02 : containing not further condensed quinuclidine ring systems

Abstract

A compound according to formula (I) wherein z© is a phenyl ring, a C₄ to C₉ heteroaromatic compound containing one or more heteroatoms, or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R¹, R² and R³ each independently represent a hydrogen or halogen atom, or a hydroxy group, or a phenyl, —OR⁴, —SR⁴, —NR⁴R⁵, —NHCOR⁴, —CONR⁴R⁵, —CN, —NO₂, —COOR⁴ or —CF₃ group, or a straight or branched lower alkyl group which may optionally be substituted, for example, with a hydroxy or alcoxy group, wherein R⁴ and R⁵ each independently represent a hydrogen atom, straight or branched lower alkyl group, or together form an alicyclic ring; or R¹ and R² together form an aromatic, alicyclic or heterocyclic ring; n is an integer from 0 to 4; A represents a —CH₂—, —CH═CR⁶, —CR⁶═CH—, —CR⁶12²—, —CO—, —O—, —S—, —S(O)—, SO₂ or NR⁶— group, wherein R⁶ and R² each independently represent a hydrogen atom, straight or branched lower alkyl group, or R⁶ and 12² together form an alicyclic ring; m is an integer from 0 to 8; provided that when m=0, A is not —CH₂—; p is an integer from 1 to 2 and the substitution in the azoniabicyclic ring may be in the 2,3 or 4 position including all possible configurations of the asymmetric carbons; B represents a group of formula (i) or (ii), wherein R¹⁰ represents a hydrogen atom, a hydroxy or methyl group; and R⁸ and R⁹ each independently represents formulae (a), (b), (c), (d) and wherein R¹¹ represents a hydrogen or halogen atom, or a straight or branched lower alkyl group and Q represents a single bond, —CH₂—, —CH₂—CH₂, —O—, —O—CH₂—, —S—, —S—CH₂— or —CH═CH—, and when (i) or (ii) contain a chiral centre they may represent either configuration; X represents a pharmaceutically acceptable anion of a mono or polyvalent acid, which shows high affinity for muscarinic M₃ receptors (Hm3).

Claims

1-35. -35. (canceled)

36. A powder inhalant comprising 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane wherein an anion X⁻

is associated with the positive charge of the nitrogen atom and wherein X⁻

is a pharmaceutically acceptable anion of a mono- or polyvalent acid.

37. The powder inhalant of claim 36 further comprising a pharmaceutically acceptable carrier or diluent.

38. The powder inhalant of claim 37 wherein the pharmaceutically acceptable carrier or diluent is lactose.

39. The powder inhalant of claim 36 further comprising a P2 agonist.

40. The powder inhalant of claim 39 further comprising a steroid or a phosphodiesterase IV inhibitor.

41. The powder inhalant of claim 36 further comprising a steroid.

42. The powder inhalant of claim 41 further comprising a phosphodiesterase IV inhibitor.

43. The powder inhalant of claim 36 further comprising a phosphodiesterase IV inhibitor.

44. A method for treating chronic obstructive pulmonary disease, chronic bronchitis, bronchial hyperreactivity, asthma, or rhinitis which method comprises administering to a human or animal patient in need of such treatment an effective amount of the powder inhalant of claim 36.

45. The method of claim 44 further comprising administering an effective amount of a P₂ agonist.

46. The method of claim 45 further comprising administering an effective amount of a steroid or a phosphodiesterase IV inhibitor.

47. The method of claim 44 further comprising administering an effective amount of a steroid.

48. The method of claim 47 further comprising administering an effective amount of a phosphodiesterase IV inhibitor.

49. The method of claim 44 further comprising administering an effective amount of a phosphodiesterase IV inhibitor.