WO2008012290A2 - Quinuclidine derivatives as m3 antagonists - Google Patents

Quinuclidine derivatives as m3 antagonists Download PDF

Info

Publication number
WO2008012290A2
WO2008012290A2 PCT/EP2007/057585 EP2007057585W WO2008012290A2 WO 2008012290 A2 WO2008012290 A2 WO 2008012290A2 EP 2007057585 W EP2007057585 W EP 2007057585W WO 2008012290 A2 WO2008012290 A2 WO 2008012290A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
optionally substituted
fluorophenyl
quinuclidine
Prior art date
Application number
PCT/EP2007/057585
Other languages
French (fr)
Other versions
WO2008012290A3 (en
Inventor
Gabriele Amari
Andrea Rizzi
Riccardo Patacchini
Valentina Cenacchi
Gino Villetti
Juan Lorenzo Catena Ruiz
Isabel Masip Masip
Original Assignee
Chiesi Farmaceutici S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chiesi Farmaceutici S.P.A. filed Critical Chiesi Farmaceutici S.P.A.
Priority to EP07787828A priority Critical patent/EP2049533A2/en
Priority to CA002658649A priority patent/CA2658649A1/en
Priority to JP2009521244A priority patent/JP5331688B2/en
Priority to AU2007278231A priority patent/AU2007278231B2/en
Priority to MX2009000999A priority patent/MX2009000999A/en
Priority to EA200970158A priority patent/EA017698B1/en
Priority to BRPI0713826 priority patent/BRPI0713826A2/en
Publication of WO2008012290A2 publication Critical patent/WO2008012290A2/en
Publication of WO2008012290A3 publication Critical patent/WO2008012290A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to antimuscarinic agents, in particular to quinuclidine derivatives provided with adequate selectivity for the muscarinic M3-receptor and a long duration of action.
  • M3 receptor is responsible of the contractile effect of acetylcholine in the smooth muscle of intestinal tract, urinary bladder and bronchi.
  • M3 antagonist are currently used in therapy to induce bronchodilation and inhibit gastrointestinal motility and urinary bladder contraction.
  • M2 receptors are also present; since M2 receptors are a major population in the smooth cardiac muscle, in order to avoid side-effects on the cardiac muscle the research has focused on the finding of selective M3 antagonists.
  • tiotropium the first drug in a new generation of antimuscarinic drugs, possesses unique properties of "kinetic selectivity" with fast dissociation from M2 receptors and very slow dissociation from Ml and M3 receptors.
  • WO 02/00652 and WO 03/053966 relate to quinuclidyl-carbamate derivatives provided with affinity for the human M3 receptor and selectivity for the M3 receptors over the M2 receptors.
  • WO 02/051841 and WO 2004/000840 disclose antimuscarinic quinuclidine derivatives showing high affinity and selectivity for the muscarinic M3 receptors over the M2 receptors, that, according to the inventors, also show bronchodilator activity in the test on bronchospasm in guinea pig, with high potency and a long duration of action, but no data are reported.
  • the muscarinic antagonists of the prior art are mainly characterised by their selectivity for the M3 receptors over the M2 receptors and even though in
  • the present invention relates to the use of an antimuscarinic agent, in particular to a quinuclidine derivative of the general formula (I) in the form of single enantiomers or mixtures thereof in the manufacture of a medicament for the prevention and therapy of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema
  • respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema
  • R 1 is selected from H, F, Cl, Br, I and (C 1 -C 4 )- alkyl; R 2 is
  • R 3 is (CH 2 ) 1-4 -COR 4 or (CH 2 ) 1-4 -S(O) n R 4 , wherein R 4 is
  • - phenyl optionally substituted with one or more substituents independently selected from OH, NO 2 , CN, F, Cl, Br, I, NH 2 , (C 1 - C 5 )- alkanoylamino, (Q-C ⁇ -alkyl, (Q-C ⁇ -cycloakyl, (C 1 -C 4 )- alkoxyl, (Q-C ⁇ -alkylthio, (Q-C ⁇ -alkoxycarbonyl, optionally substituted phenyl or phenoxy;
  • n is O, 1 or 2;
  • X " is a pharmaceutically acceptable anion.
  • the present invention relates also to particular quinuclidine derivatives in the form of single enantiomers or mixtures thereof belonging to formula (I) which are novel per se and are represented by: the formula (Ic)
  • R 1 in position 2 or 3, is selected from the group consisting of F, Cl, Br and I;
  • R 2 is 3,4,5-trifluorophenyl, 3,4-difluorophenyl, 2-hydroxyphenyl or 4- hydroxyphenyl;
  • X " is a pharmaceutically acceptable anion;
  • R 1 in position 2 or 3, is selected from the group consisting of F, Cl, Br and I;
  • R 2 is 3,4,5-trifluorophenyl or 4-fluorophenyl; m is 1 or 2; n is 0, 1 or 2; R 5 is selected from the group consisting of H, CN, F, Cl, Br, I and (C 1 -
  • X " is a pharmaceutically acceptable anion
  • R 1 in position 2 or 3, is selected from the group consisting of F, Cl, Br, I and (C r C 4 )-alkyl;
  • R 2 is selected from the group consisting of 2-hydroxyphenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3,4,5-trifluorophenyl or 2,4,5- trifluorophenyl;
  • R 5 is selected from the group consisting of H, CN, F, Cl, Br, I and (C 1 - C 4 )-alkoxyl;
  • X " is a pharmaceutically acceptable anion.
  • the present invention relates to the use of a quinuclidine derivative of the general formula (Ia) and/or (Ib) and or (Ic) in the form of single enantiomers or mixtures thereof in the manufacture of a medicament for the prevention and therapy of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema.
  • respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema.
  • the present invention relates to a method for treating respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema by administering a therapeutically effective amount of a compound of formula (I) and/or (Ia) and/or (Ib) and/or (Ic).
  • respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema
  • Said quinuclidine derivatives are quinuclidine carbamate esters characterised by the fact that the nitrogen atom of the carbamate is substituted by an arylalkyl or heteroarylalkyl group selected from optionally substituted phenylmethyl, 2- or 3- thienylmethyl groups and the nitrogen atom of the quinuclidine ring is quaternarized with phenyl-carbonylalkyl, thienyl-carbonylalkyl or phenyl- thioalkyl groups.
  • the present invention relates, in a first embodiment, to the use of quinuclidine derivatives of the general formula (I) in the manufacture of a medicament for the prevention and therapy of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema.
  • respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema.
  • R 1 is selected from H, F, Cl, Br, I and (C 1 -C 4 )- alkyl;
  • R 2 is - 2- or 3-thienyl, optionally substituted with one or more substituents independently selected from F, Cl, Br, I and (Ci-C 4 )-alkyl optionally substituted with one or more F or OH;
  • - phenyl substituted with one or more substituents independently selected from F, Cl, Br, I, OH and (Ci-C 4 )-alkyl optionally substituted with one or more F or OH;
  • R 3 is (CH 2 ) I-4 -COR 4 or (CH 2 ) 1-4 -S(O) n R 4 , wherein R 4 is
  • - phenyl optionally substituted with one or more substituents independently selected from OH, NO 2 , CN, F, Cl, Br, I, NH 2 , (C 1 - C 5 )-alkanoylamino, (Q-C ⁇ -alkyl, (Q-C ⁇ -cycloakyl, (C 1 -C 4 )- alkoxyl, (Q-C ⁇ -alkylthio, (Q-C ⁇ -alkoxycarbonyl, optionally substituted phenyl or phenoxy;
  • n is O, 1 or 2.
  • X " is a pharmaceutically acceptable anion, preferably selected from chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate, and more preferably selected from chloride, bromide, formate, trifluoroacetate or methanesulfonate.
  • the compounds of the invention have an asymmetric carbon on the quinuclidine carbon bound to the carbamic oxygen, they may be in the form of single enatiomers or mixtures thereof.
  • the preferred compounds of the invention are optically active and are in the (R) configuration.
  • a first preferred embodiment of the invention comprises compounds of formula (Ia)
  • R 1 in position 2, 3 or 4, is selected from the group consisting of F, Cl, Br, I and (C r C 4 )-alkyl;
  • R 2 is:
  • R 5 is selected from the group consisting of H, OH, NO 2 , CN, F, Cl, Br, I, (C 1 -C 4 )- alkyl and (C 1 -C 4 )-alkoxyl.
  • Preferred compounds of formula (Ia) are those wherein:
  • R 1 in position 2 or 3, is selected from the group consisting of F, Cl, Br, I and (C 1 -C 4 HIkVl;
  • R 2 is phenyl, substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I and OH;
  • R 5 is selected from the group consisting of H, OH, NO 2 , CN, F, Cl, Br, I,
  • R 1 in position 2 or 3, is selected from the group consisting of F, Cl, Br, I and (C r C 4 )-alkyl;
  • R 2 is selected from the group consisting of 2-hydroxyphenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3,4,5-trifluorophenyl or 2,4,5- trifluorophenyl;
  • R 5 is selected from the group consisting of H, CN, F, Cl, Br, I and (C 1 -
  • a second preferred embodiment of the invention comprises compounds of formula (Ib)
  • R 1 in position 2 or 3, is selected from the group consisting of F, Cl, Br, I and (d-C 4 )-alkyl;
  • R 2 is phenyl substituted with one or more substituents independently selected from the group consisting of F, Cl, Br and I; m is 1 or 2; n is 0, 1 or 2;
  • R 5 is selected from the group consisting of H, OH, NO 2 , CN, F, Cl, Br, I,
  • Preferred compounds of formula (Ib) are those wherein
  • R 1 in position 2 or 3, is selected from the group consisting of F, Cl, Br and I;
  • R 2 is 3,4,5-trifluorophenyl or 4-fluorophenyl; m is 1 or 2; n is 0, 1 or 2
  • R 5 is selected from the group consisting of H, CN, F, Cl, Br, I and (C 1 -
  • a third preferred embodiment of the invention comprises compounds of formula (Ic)
  • R 1 in position 2, 3 or 4, is selected from the group consisting of F, Cl, Br, I and (C r C 4 )-alkyl;
  • R 2 is phenyl substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I and OH;
  • Preferred compounds of formula (Ic) are those wherein
  • R 1 in position 2 or 3, is selected from the group consisting of F, Cl, Br and I;
  • R 2 is 3,4,5-trifluorophenyl, 3,4-difluorophenyl, 2-hydroxyphenyl or 4- hydroxyphenyl.
  • Representative compounds of the third preferred embodiment of the invention are: (3R)-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl) carbamoyloxy]- 1 -(2-oxo-2-thiophen-2-ylethyl)- 1 -azoniabicyclo [2.2.2] octane bromide [Compound 6] and (3R)-3-[(3-fluorophenyl)-(3,4,5- trifluorobenzyl) carbamoyloxy]- 1 -(2-oxo-2-thiophen-2-ylethyl)- 1 - azoniabicyclo [2.2.2] octane chloride [Compound 7].
  • the compounds of the invention can be prepared according to the methods disclosed, for instance, in WO 03/053966.
  • the compounds of the invention can be used for the preparation of inhalation compositions for the prevention and therapy of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema.
  • respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema.
  • COPD chronic obstructive pulmonary disease
  • chronic bronchitis chronic bronchitis
  • cough emphysema
  • the present invention further relates to the use of the compounds of formula (I) for the preparation of pharmaceutical compositions for pulmonary administration comprising one or more pharmaceutically acceptable excipient or carrier.
  • the compounds of the invention may be used for the preparation of inhalation compositions in the form of aqueous solutions or suspensions, pressurised hydrofluoroalkane solutions or suspensions, or of dry powder formulations.
  • the compounds are characterised by an adequate selectivity for the muscarinic M3 receptor and a long duration of action.
  • compounds with adequate selectivity for the muscarinic M3 receptor are those showing, in a binding test to human M2 and M3 muscarinic receptors, a M2/M3 receptor inhibition constants (Ki) ratio greater than 1.
  • Compounds endowed with a suitable duration of action are those for which, in the in vitro model of isolated guinea pig trachea, at a concentration of 10 nM, a percentage of the recovery of the contracting response to carbachol lower than 50%, four hours after the washout, has been detected, and whose bronchodilator activity in a guinea pig model of bronchospasm persisted unchanged up to 24 hours after the administration with percentages of inhibition higher than 50%.
  • other important parameters were the lung retention, measuring the MRT L (Mean Residence Time in the Lung), i.e.
  • the compounds of the invention showed very slow lung elimination with MRT L higher than 10 hours and QgL/Co . sL higher than 6
  • M3 muscarinic receptors The interaction with M3 muscarinic receptors can be estimated by the results of in vitro studies which evaluated the potency of the test compounds and the offset of the inhibitory activity produced after washout of the antagonists in isolated guinea pig trachea and by the in vivo duration of action against acetylcholine - induced bronchospasm in the guinea pig. In vitro interaction with the M3 receptors
  • the potency of the antagonist activity in isolated guinea pig trachea was investigated following a method previously described by Haddad EB et al. in Br J Pharmacol 127, 413-420, 1999, with few modifications.
  • a cumulative concentration-response curve to test antagonists was constructed on preparations precontracted by carbachol, until a complete inhibition of smooth muscle tone was achieved.
  • the concentration of antagonist producing a 50% reversal of carbachol-induced tonic contraction (IC50) was taken as a measure of its potency in this bioassay.
  • the inhibitory effects of the compounds of the invention was expressed as percentage of the recovery of the contracting response to carbachol.
  • the percentage of recovery four hours after the washout was lower than 50%.
  • test compounds were instilled intratracheally in anaesthetised mechanically ventilated guinea pigs. Bronchial response to intravenous acetylcholine challenge was determined before and after drug administration and changes in pulmonary resistance at several time-points were expressed as percent of inhibition of bronchospasm.
  • Lung retention was measured by means of two parameters: the MRT L (Mean Residence Time in the Lung), i.e. the residence of the compound in the lung, which is the time of the last measurable concentration of the compound in the guinea pig lung after intratracheal administration of 10 nmol/kg, determined after lung homogenization, and the C 48 L/Co .5 L (%), i.e. the percentage of the amount of the compound in the lung 48 hours after intratracheal administration vs the amount the same compound in the lung 0.5 hours after administration.
  • MRT L Mean Residence Time in the Lung
  • the residence of the compound in the lung which is the time of the last measurable concentration of the compound in the guinea pig lung after intratracheal administration of 10 nmol/kg, determined after lung homogenization
  • C 48 L/Co .5 L (%) i.e. the percentage of the amount of the compound in the lung 48 hours after intratracheal administration vs the amount the same compound in the lung 0.5 hours
  • MRT L and C 48 L/Co .5 L (%) are two meaningful and predictive parameters of the duration of a drug's effect after single dose pulmonary administration.
  • the compounds of the invention showed very slow lung elimination with MRT L higher than 10 hours and C 48 LZCa 5 L higher than 6%.

Abstract

Quinuclidine derivative of the general formula (I) in the form of single enantiomers or mixtures thereof are useful in the manufacture of a medicament for the prevention and therapy of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema wherein: R1 is selected from H, F, C1, Br, I and (C1-C4)- alkyl; R2 is optionally substituted 2- or 3-thienyl, or substituted phenyl; R3 is (CH2)1-4-COR4 or (CH2)1-4-S(O)nR4, wherein R4 is optionally substituted phenyl or optionally substituted 2- or 3-thienyl; n is 0, 1 or 2; X- is a pharmaceutically acceptable anion.

Description

QUINUCLIDINE DERIVATIVES AS M3 ANTAGONISTS
Field of the invention
The present invention relates to antimuscarinic agents, in particular to quinuclidine derivatives provided with adequate selectivity for the muscarinic M3-receptor and a long duration of action. Background of the invention
Acetylcholine muscarinic receptors have been thoroughly studied for some time and it is now commonly acknowledged that the M3 receptor is responsible of the contractile effect of acetylcholine in the smooth muscle of intestinal tract, urinary bladder and bronchi. M3 antagonist are currently used in therapy to induce bronchodilation and inhibit gastrointestinal motility and urinary bladder contraction. However, in the above-mentioned tissues, M2 receptors are also present; since M2 receptors are a major population in the smooth cardiac muscle, in order to avoid side-effects on the cardiac muscle the research has focused on the finding of selective M3 antagonists.
Recently it has been reported that tiotropium, the first drug in a new generation of antimuscarinic drugs, possesses unique properties of "kinetic selectivity" with fast dissociation from M2 receptors and very slow dissociation from Ml and M3 receptors.
Therefore both good selectivity for, and slow dissociation from the M3 receptors are deemed important for new antimuscarinic drugs efficacious by inhalation in a once a day administration for the treatment of respiratory diseases and in particular inflammatory or obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Selective M3 antagonists containing the quinuclidine nucleus are, for instance, disclosed in WO 02/00652, WO 02/051841, WO 03/053966 and WO
2004/000840.
In particular, WO 02/00652 and WO 03/053966 relate to quinuclidyl-carbamate derivatives provided with affinity for the human M3 receptor and selectivity for the M3 receptors over the M2 receptors.
WO 02/051841 and WO 2004/000840 disclose antimuscarinic quinuclidine derivatives showing high affinity and selectivity for the muscarinic M3 receptors over the M2 receptors, that, according to the inventors, also show bronchodilator activity in the test on bronchospasm in guinea pig, with high potency and a long duration of action, but no data are reported.
Therefore, the muscarinic antagonists of the prior art are mainly characterised by their selectivity for the M3 receptors over the M2 receptors and even though in
WO 02/051841 and WO 2004/000840 it is also said in generic terms that the compounds are provided with a bronchodilator activity and a long duration of action, no demonstration is given.
Summary of the invention
The present invention relates to the use of an antimuscarinic agent, in particular to a quinuclidine derivative of the general formula (I) in the form of single enantiomers or mixtures thereof in the manufacture of a medicament for the prevention and therapy of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema
Figure imgf000004_0001
(I) wherein:
R1 is selected from H, F, Cl, Br, I and (C1-C4)- alkyl; R2 is
- 2- or 3-thienyl, optionally substituted with one or more substituents independently selected from F, Cl, Br, I and (Q-C^-alkyl optionally substituted with one or more F or OH;
- phenyl substituted with one or more substituents independently selected from F, Cl, Br, I, OH and (Q-C^-alkyl optionally substituted with one or more F or OH;
R3 is (CH2)1-4-COR4 or (CH2)1-4-S(O)nR4, wherein R4 is
- phenyl optionally substituted with one or more substituents independently selected from OH, NO2, CN, F, Cl, Br, I, NH2, (C1- C5)- alkanoylamino, (Q-C^-alkyl, (Q-C^-cycloakyl, (C1-C4)- alkoxyl, (Q-C^-alkylthio, (Q-C^-alkoxycarbonyl, optionally substituted phenyl or phenoxy;
- 2- or 3-thienyl, optionally substituted with one or more substituents independently selected from OH, NO2, CN, F, Cl, Br, I, NH2, (C1- C5)-alkanoylamino, (Q-C^-alkyl, (Q-C^-cycloakyl, (C1-C4)- alkoxyl, (Q-C^-alkylthio, (Q-C^-alkoxycarbonyl, optionally substituted phenyl or phenoxy; n is O, 1 or 2;
X" is a pharmaceutically acceptable anion. The present invention relates also to particular quinuclidine derivatives in the form of single enantiomers or mixtures thereof belonging to formula (I) which are novel per se and are represented by: the formula (Ic)
Figure imgf000005_0001
(Ic) wherein
R1, in position 2 or 3, is selected from the group consisting of F, Cl, Br and I;
R2 is 3,4,5-trifluorophenyl, 3,4-difluorophenyl, 2-hydroxyphenyl or 4- hydroxyphenyl; X" is a pharmaceutically acceptable anion;
the formula (Ib)
Figure imgf000005_0002
(Ib) wherein
R1, in position 2 or 3, is selected from the group consisting of F, Cl, Br and I;
R2 is 3,4,5-trifluorophenyl or 4-fluorophenyl; m is 1 or 2; n is 0, 1 or 2; R5 is selected from the group consisting of H, CN, F, Cl, Br, I and (C1-
C4)-alkoxyl;
X" is a pharmaceutically acceptable anion; and
formula (Ia)
Figure imgf000006_0001
(Ia) wherein
R1, in position 2 or 3, is selected from the group consisting of F, Cl, Br, I and (CrC4)-alkyl;
R2 is selected from the group consisting of 2-hydroxyphenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3,4,5-trifluorophenyl or 2,4,5- trifluorophenyl;
R5 is selected from the group consisting of H, CN, F, Cl, Br, I and (C1- C4)-alkoxyl; X" is a pharmaceutically acceptable anion.
Moreover the present invention relates to the use of a quinuclidine derivative of the general formula (Ia) and/or (Ib) and or (Ic) in the form of single enantiomers or mixtures thereof in the manufacture of a medicament for the prevention and therapy of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema. In addition the present invention relates to a method for treating respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema by administering a therapeutically effective amount of a compound of formula (I) and/or (Ia) and/or (Ib) and/or (Ic).
Description of the invention
It has now been found that some particular quinuclidine derivatives, besides the affinity for the M3 muscarinic receptors, possess a long lasting bronchodilating activity due to their potent and prolonged interaction with the M3 muscarinic receptor and high lung retention.
Said quinuclidine derivatives are quinuclidine carbamate esters characterised by the fact that the nitrogen atom of the carbamate is substituted by an arylalkyl or heteroarylalkyl group selected from optionally substituted phenylmethyl, 2- or 3- thienylmethyl groups and the nitrogen atom of the quinuclidine ring is quaternarized with phenyl-carbonylalkyl, thienyl-carbonylalkyl or phenyl- thioalkyl groups.
Accordingly, the present invention relates, in a first embodiment, to the use of quinuclidine derivatives of the general formula (I) in the manufacture of a medicament for the prevention and therapy of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema.
Figure imgf000007_0001
(I) wherein:
R1 is selected from H, F, Cl, Br, I and (C1-C4)- alkyl; R2 is - 2- or 3-thienyl, optionally substituted with one or more substituents independently selected from F, Cl, Br, I and (Ci-C4)-alkyl optionally substituted with one or more F or OH;
- phenyl substituted with one or more substituents independently selected from F, Cl, Br, I, OH and (Ci-C4)-alkyl optionally substituted with one or more F or OH;
R3 is (CH2)I-4-COR4 or (CH2)1-4-S(O)nR4, wherein R4 is
- phenyl optionally substituted with one or more substituents independently selected from OH, NO2, CN, F, Cl, Br, I, NH2, (C1- C5)-alkanoylamino, (Q-C^-alkyl, (Q-C^-cycloakyl, (C1-C4)- alkoxyl, (Q-C^-alkylthio, (Q-C^-alkoxycarbonyl, optionally substituted phenyl or phenoxy;
- 2- or 3-thienyl, optionally substituted with one or more substituents independently selected from OH, NO2, CN, F, Cl, Br, I, NH2, (C1- C5)-alkanoylamino, (Q-C^-alkyl, (Q-C^-cycloakyl, (C1-C4)- alkoxyl, (Q-C^-alkylthio, (Q-C^-alkoxycarbonyl, optionally substituted phenyl or phenoxy; n is O, 1 or 2.
X" is a pharmaceutically acceptable anion, preferably selected from chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate, and more preferably selected from chloride, bromide, formate, trifluoroacetate or methanesulfonate. As the compounds of the invention have an asymmetric carbon on the quinuclidine carbon bound to the carbamic oxygen, they may be in the form of single enatiomers or mixtures thereof. The preferred compounds of the invention are optically active and are in the (R) configuration. A first preferred embodiment of the invention comprises compounds of formula (Ia)
Figure imgf000009_0001
(Ia) wherein
R1, in position 2, 3 or 4, is selected from the group consisting of F, Cl, Br, I and (CrC4)-alkyl; R2 is:
- 2-thienyl, optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, (C1- C4)-alkyl;
- phenyl, substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I and OH;
R5 is selected from the group consisting of H, OH, NO2, CN, F, Cl, Br, I, (C1-C4)- alkyl and (C1-C4)-alkoxyl.
Preferred compounds of formula (Ia) are those wherein:
R1, in position 2 or 3, is selected from the group consisting of F, Cl, Br, I and (C1-C4HIkVl;
R2 is phenyl, substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I and OH;
R5 is selected from the group consisting of H, OH, NO2, CN, F, Cl, Br, I,
(C1-C4)- alkyl and (C1-C4)-alkoxyl. More preferred compounds of formula (Ia) are those wherein:
R1, in position 2 or 3, is selected from the group consisting of F, Cl, Br, I and (CrC4)-alkyl;
R2 is selected from the group consisting of 2-hydroxyphenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3,4,5-trifluorophenyl or 2,4,5- trifluorophenyl;
R5 is selected from the group consisting of H, CN, F, Cl, Br, I and (C1-
C4)-alkoxyl.
These compounds are also novel per se.
Representative compounds of the first preferred embodiment of the invention are:
(3R)-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl)-carbamoyloxy]-l-(2- oxo-2-phenylethyl)-l-azoniabicyclo [2.2.2] octane, bromide [Compound
1] (3R)-3-[2-fluorophenyl)-(3,4,5-trifluorobenzyl)-carbamoyloxy]-l-(2-oxo-
2-phenylethyl)- 1 -azoniabicyclo [2.2.2] octane, bromide [Compound 2] (3R)-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl)-carbamoyloxy]-l-(2- oxo-2-(4-fluorophenyl)ethyl)- 1 -azoniabicyclo [2.2.2] octane, bromide [Compound 3].
A second preferred embodiment of the invention comprises compounds of formula (Ib)
Figure imgf000010_0001
(Ib) wherein
R1, in position 2 or 3, is selected from the group consisting of F, Cl, Br, I and (d-C4)-alkyl;
R2 is phenyl substituted with one or more substituents independently selected from the group consisting of F, Cl, Br and I; m is 1 or 2; n is 0, 1 or 2;
R5 is selected from the group consisting of H, OH, NO2, CN, F, Cl, Br, I,
(C1-C4)- alkyl and (C1-C4)-alkoxyl.
Preferred compounds of formula (Ib) are those wherein
R1, in position 2 or 3, is selected from the group consisting of F, Cl, Br and I;
R2 is 3,4,5-trifluorophenyl or 4-fluorophenyl; m is 1 or 2; n is 0, 1 or 2
R5 is selected from the group consisting of H, CN, F, Cl, Br, I and (C1-
C4)-alkoxyl.
These compounds are also novel per se.
Representative compounds of the second preferred embodiment of the invention are:
(3R)-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl)-carbamoyloxy]-l-(2-
(phenylsulfanyl)ethyl)-l-azonia- bicyclo [2.2.2] octane, bromide
[Compound 4] (3R)-3-[(2-fluorophenyl)-(4-fluorobenzyl)-carbamoyloxy]- 1 - (phenylsulfanyl-methyl)-l-azonia- bicyclo [2.2.2] octane, bromide [Compound 5]
A third preferred embodiment of the invention comprises compounds of formula (Ic)
Figure imgf000012_0001
(Ic) wherein
R1, in position 2, 3 or 4, is selected from the group consisting of F, Cl, Br, I and (CrC4)-alkyl;
R2 is phenyl substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I and OH;
Preferred compounds of formula (Ic) are those wherein
R1, in position 2 or 3, is selected from the group consisting of F, Cl, Br and I;
R2 is 3,4,5-trifluorophenyl, 3,4-difluorophenyl, 2-hydroxyphenyl or 4- hydroxyphenyl.
These compounds are also novel per se.
Representative compounds of the third preferred embodiment of the invention are: (3R)-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl) carbamoyloxy]- 1 -(2-oxo-2-thiophen-2-ylethyl)- 1 -azoniabicyclo [2.2.2] octane bromide [Compound 6] and (3R)-3-[(3-fluorophenyl)-(3,4,5- trifluorobenzyl) carbamoyloxy]- 1 -(2-oxo-2-thiophen-2-ylethyl)- 1 - azoniabicyclo [2.2.2] octane chloride [Compound 7].
The compounds of the invention can be prepared according to the methods disclosed, for instance, in WO 03/053966.
In view of their potent and prolonged interaction with the M3 muscarinic receptor and of their long retention time in the lungs, the compounds of the invention can be used for the preparation of inhalation compositions for the prevention and therapy of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema.
Therefore, the present invention further relates to the use of the compounds of formula (I) for the preparation of pharmaceutical compositions for pulmonary administration comprising one or more pharmaceutically acceptable excipient or carrier.
Preferably the compounds of the invention, optionally in combination with one or more suitable carrier, vehicle or excipient, may be used for the preparation of inhalation compositions in the form of aqueous solutions or suspensions, pressurised hydrofluoroalkane solutions or suspensions, or of dry powder formulations.
As said before, the compounds are characterised by an adequate selectivity for the muscarinic M3 receptor and a long duration of action. For the purposes of the invention compounds with adequate selectivity for the muscarinic M3 receptor are those showing, in a binding test to human M2 and M3 muscarinic receptors, a M2/M3 receptor inhibition constants (Ki) ratio greater than 1.
Compounds endowed with a suitable duration of action are those for which, in the in vitro model of isolated guinea pig trachea, at a concentration of 10 nM, a percentage of the recovery of the contracting response to carbachol lower than 50%, four hours after the washout, has been detected, and whose bronchodilator activity in a guinea pig model of bronchospasm persisted unchanged up to 24 hours after the administration with percentages of inhibition higher than 50%. Moreover, as far as the evaluation of the duration of action is concerned, other important parameters were the lung retention, measuring the MRTL (Mean Residence Time in the Lung), i.e. the residence of the compound in the guinea pig lung after intratracheal administration of 10 nmol/kg, and the QgL/Co.sL (%), i.e. the percentage of the amount of the compound in the lung 48 hours after intratracheal administration vs the amount the same compound in the lung 0.5 hours after administration. The compounds of the invention showed very slow lung elimination with MRTL higher than 10 hours and QgL/Co.sL higher than 6
/O.
The invention will be illustrated in greater detail in the following experimental section.
EXPERIMENTAL SECTION Preparation example
(3R)-3-r(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxyl-l-(2-oxo-2- thiophen-2-yl-ethviy 1 -azoniabicvclor2.2.2~|octane bromide [Compound 6]. A solution of (3R)-(3-fluorophenyl)-(3,4,5-trifluorobenzyl)carbamic acid 1-aza- bicyclo[2.2.2]oct-3-yl ester hydrochloride (prepared as described in WO03/053966 as Intermediate 15) (1 g, 2.248 mmol) in water (5 ml) was added with an excess of sodium carbonate (1 g) in water (4 ml) and extracted with ethyl acetate (2x10 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated under vacuum.
The resulting free base (750 mg, 1.836 mmol) was dissolved in acetonitrile (4 ml) and added dropwise with a solution of 2-bromo-l-thiophen-2-yl-ethanone (750 mg, 3.657 mmol) in chloroform (6 ml). The resulting solution was refluxed for 12 hours. The solvent was evaporated and the residue dissolved in acetonitrile (7.5 ml). Crystallisation occurred after some minutes of stirring. The solid was filtered, washed with acetonitrile (1 ml) and dried under vacuum at 45°
C. 760 mg of the title compound was obtained as white solid.
Mother liquors were evaporated to dryness and purified by column chromatography (SiO2, eluent: dichloromethane/methanol =95/5 to 80/20) to give further 120 mg of the title compound.
Analogously (3R)-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]- 1 -
(2-oxo-2-thiophen-2-yl-ethyl)- 1 -azoniabicyclo[2.2.2]octane chloride [Compound
7] was prepared starting from the free base of (3R)-(3-fluorophenyl)-(3,4,5- trifluorobenzyl)carbamic acid l-aza-bicyclo[2.2.2]oct-3-yl ester by reaction with
2-chloro- 1 -thiophen-2-yl-ethanone.
Other compounds of the invention can be prepared with analogous procedures as in the preparation example.
Biological characterisation
The interaction with M3 muscarinic receptors can be estimated by the results of in vitro studies which evaluated the potency of the test compounds and the offset of the inhibitory activity produced after washout of the antagonists in isolated guinea pig trachea and by the in vivo duration of action against acetylcholine - induced bronchospasm in the guinea pig. In vitro interaction with the M3 receptors
The potency of the antagonist activity in isolated guinea pig trachea was investigated following a method previously described by Haddad EB et al. in Br J Pharmacol 127, 413-420, 1999, with few modifications. A cumulative concentration-response curve to test antagonists was constructed on preparations precontracted by carbachol, until a complete inhibition of smooth muscle tone was achieved. The concentration of antagonist producing a 50% reversal of carbachol-induced tonic contraction (IC50) was taken as a measure of its potency in this bioassay.
In the experiments aiming at assessing the offset of the inhibitory effects produced by test compounds, the minimal concentration of the test compounds known to produce a maximal inhibitory effect was administered to carbachol- precontracted preparations. As soon as the tonic contraction was completely reversed, the organ bath solution was renewed and preparations were thoroughly washed with fresh Krebs solution. Carbachol (0.3 μM) was administered again (at 30 min interval between washout and next administration) during the next 4 hours.
After the administration of carbachol, the inhibitory effects of the compounds of the invention, administered at a concentration of 10 nM, was expressed as percentage of the recovery of the contracting response to carbachol. The percentage of recovery four hours after the washout was lower than 50%.
In vivo studies
The in vivo tests on acetylcholine-induced bronchospasm in guinea pig were performed according to H. Konzett H and Rδssler F Arch Exp Path Pharmacol
195, 71-74, 1940. Aqueous solutions of the test compounds were instilled intratracheally in anaesthetised mechanically ventilated guinea pigs. Bronchial response to intravenous acetylcholine challenge was determined before and after drug administration and changes in pulmonary resistance at several time-points were expressed as percent of inhibition of bronchospasm.
The bronchodilator activity of the tested compounds persisted unchanged up to
24 hours after the administration.
Kinetic characterisation: Lung retention
Lung retention was measured by means of two parameters: the MRTL (Mean Residence Time in the Lung), i.e. the residence of the compound in the lung, which is the time of the last measurable concentration of the compound in the guinea pig lung after intratracheal administration of 10 nmol/kg, determined after lung homogenization, and the C48L/Co.5L (%), i.e. the percentage of the amount of the compound in the lung 48 hours after intratracheal administration vs the amount the same compound in the lung 0.5 hours after administration.
MRTL and C48L/Co.5L (%) are two meaningful and predictive parameters of the duration of a drug's effect after single dose pulmonary administration.
The compounds of the invention showed very slow lung elimination with MRTL higher than 10 hours and C48LZCa5L higher than 6%.
In the same tests tiotropium bromide, utilized as reference compound, showed a
MRTL of 7.1 hours and a C48L/C0.5L of 2.3%, whereas another known antimuscarinic, ipratropium bromide, showed a MRTL of 3.9 hours and a
C48L/C0.5L of 0.3%. In addition to having high lung retention no plasma levels of the present compounds were detected. These results would suggest that the compounds of the invention are retained in the lung and do not reach the systemic circulation. Therefore, potential undesirable secondary effects in other tissues could be avoided.

Claims

1. A quinuclidine derivative of formula (Ic) in the form of single enatiomers or mixtures thereof
Figure imgf000019_0001
(Ic) wherein
R1, in position 2 or 3, is selected from the group consisting of F, Cl, Br and I;
R2 is 3,4,5-trifluorophenyl, 3,4-difluorophenyl, 2-hydroxyphenyl or 4- hydroxyphenyl; X" is a pharmaceutically acceptable anion.
2. A quinuclidine derivative of formula (Ib) in the form of single enatiomers or mixtures thereof
Figure imgf000019_0002
(Ib) wherein
R1, in position 2 or 3, is selected from the group consisting of F, Cl, Br and I;
R2 is 3,4,5-trifluorophenyl or 4-fluorophenyl; m is 1 or 2; n is 0, 1 or 2; R5 is selected from the group consisting of H, CN, F, Cl, Br, I and (C1-
C4)-alkoxyl;
X" is a pharmaceutically acceptable anion.
3. A quinuclidine derivative of formula (Ia) in the form of single enatiomers or mixtures thereof
Figure imgf000020_0001
(Ia) wherein
R1, in position 2 or 3, is selected from the group consisting of F, Cl, Br, I and (CrC4)-alkyl;
R2 is selected from the group consisting of 2-hydroxyphenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3,4,5-trifluorophenyl or 2,4,5- trifluorophenyl;
R5 is selected from the group consisting of H, CN, F, Cl, Br, I and (C1-
C4)-alkoxyl;
X" is a pharmaceutically acceptable anion.
4. Quinuclidine derivatives according to any one of claims 1 to 3 wherein the quinuclidine carbon bound to the carbamic oxygen is optically active and is in the (R) configuration.
5. Quinuclidine derivatives according to any one of claims 1 to 3 wherein X" is an anion selected from chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methane sulfonate and p-toluenesulfonate.
6. (3R)-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl)-carbamoyloxy]-l-(2-oxo-
2-phenylethyl)- 1 -azoniabicyclo [2.2.2] octane, bromide; (3R)-3-[2-fluorophenyl)-(3 ,4, 5-trifluorobenzyl)-carbamoyloxy]-l -(2-0X0-2- phenylethyl)- 1 -azoniabicyclo [2.2.2] octane, bromide; (3R)-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl)-carbamoyloxy]-l-(2-oxo-
2-(4-fluorophenyl)ethyl)- 1 -azoniabicyclo [2.2.2] octane, bromide; (3R)-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl)-carbamoyloxy]-l-(2-
(phenylsulfanyl)ethyl)-l-azonia- bicyclo [2.2.2] octane, bromide; (3R)-3-[(2-fluorophenyl)-(4-fluorobenzyl)-carbamoyloxy]-l-(phenyl- sulfanyl-methyl)-l-azonia- bicyclo [2.2.2] octane, bromide; (3R)-3-[(3-fluorophenyl)-(3 ,4,5-trifluorobenzyl)carbamoyloxy]-l -(2-0X0-2- thiophen-2-ylethyl)- 1 -azoniabicyclo [2.2.2] octane bromide. (3R)-3-[(3-fluorophenyl)-(3 ,4, 5-trifluorobenzyl)carbamoyloxy]-l -(2-0X0-2- thiophen-2-yl-ethyl)- 1 -azoniabicyclo[2.2.2]octane chloride.
7. Pharmaceutical compositions for pulmonary administration comprising a quinuclidine derivative according to any one of claims 1 to 6 and one or more pharmaceutically acceptable excipient or carrier.
8. Use of a quinuclidine derivative of the general formula (I) in the form of single enantiomers or mixtures thereof in the manufacture of a medicament for the prevention and therapy of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough and emphysema
Figure imgf000022_0001
(I) wherein:
R1 is selected from H, F, Cl, Br, I and (C1-C4)- alkyl; R2 is
- 2- or 3-thienyl, optionally substituted with one or more substituents independently selected from F, Cl, Br, I and (Q-C^-alkyl optionally substituted with one or more F or OH;
- phenyl substituted with one or more substituents independently selected from F, Cl, Br, I, OH and (Q-C^-alkyl optionally substituted with one or more F or OH;
R3 is (CH2)1-4-COR4 or (CH2)1-4-S(O)nR4, wherein R4 is
- phenyl optionally substituted with one or more substituents independently selected from OH, NO2, CN, F, Cl, Br, I, NH2, (C1- C5)- alkanoylamino, (Q-C^-alkyl, (Q-C^-cycloakyl, (C1-C4)- alkoxyl, (Q-C^-alkylthio, (Q-C^-alkoxycarbonyl, optionally substituted phenyl or phenoxy;
- 2- or 3-thienyl, optionally substituted with one or more substituents independently selected from OH, NO2, CN, F, Cl, Br, I, NH2, (C1- C5)-alkanoylamino, (Q-C^-alkyl, (Q-C^-cycloakyl, (C1-C4)- alkoxyl, (Q-C^-alkylthio, (Q-C^-alkoxycarbonyl, optionally substituted phenyl or phenoxy; n is O, 1 or 2;
X" is a pharmaceutically acceptable anion.
9. Use of a quinuclidine derivative according to claim 8 wherein X" is an anion selected from chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methane sulfonate and p-toluenesulfonate.
10. Use of a quinuclidine derivative according to claims 8 or 9 belonging to the formula (Ia)
Figure imgf000023_0001
(Ia) wherein
R1, in position 2, 3 or 4, is selected from the group consisting of F, Cl, Br, I and (CrC4)-alkyl; R2 is:
- 2-thienyl, optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, (C1- C4)-alkyl;
- phenyl, substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I and OH;
R5 is selected from the group consisting of H, OH, NO2, CN, F, Cl, Br, I, (C1-C4)- alkyl and (C1-C4)-alkoxyl.
11. Use of a quinuclidine derivative according to claims 8 or 9 belonging to the formula (Ib)
Figure imgf000024_0001
(Ib) wherein
R1, in position 2 or 3, is selected from the group consisting of F, Cl, Br, I and (CrC4)-alkyl;
R2 is phenyl substituted with one or more substituents independently selected from the group consisting of F, Cl, Br and I; m is 1 or 2; n is 0, 1 or 2;
R5 selected from the group consisting of H, OH, NO2, CN, F, Cl, Br, I,
(C1-C4)- alkyl and (C1-C4)-alkoxyl.
12. Use of a quinuclidine derivative according to claims 8 or 9 belonging to the formula (Ic)
Figure imgf000024_0002
(Ic) wherein
R1, in position 2, 3 or 4, is selected from the group consisting of F, Cl, Br, I and (CrC4)-alkyl; R2 is phenyl substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I and OH.
13. Use of a quinuclidine derivative according to any one of claims 8 to 12 wherein the quinuclidine carbon bound to the carbamic oxygen is optically active and is in the (R) configuration.
PCT/EP2007/057585 2006-07-26 2007-07-23 Quinuclidine derivatives as m3 antagonists WO2008012290A2 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP07787828A EP2049533A2 (en) 2006-07-26 2007-07-23 Quinuclidine derivatives as m3 antagonists
CA002658649A CA2658649A1 (en) 2006-07-26 2007-07-23 Quinuclidine derivatives as m3 antagonists
JP2009521244A JP5331688B2 (en) 2006-07-26 2007-07-23 Quinuclidine derivatives as M3 antagonists
AU2007278231A AU2007278231B2 (en) 2006-07-26 2007-07-23 Quinuclidine derivatives as M3 antagonists
MX2009000999A MX2009000999A (en) 2006-07-26 2007-07-23 Quinuclidine derivatives as m3 antagonists.
EA200970158A EA017698B1 (en) 2006-07-26 2007-07-23 Quinuclidine derivatives as m3 antagonists
BRPI0713826 BRPI0713826A2 (en) 2006-07-26 2007-07-23 Quinuclidine derivatives as m3 muscarinic receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP06117883.6 2006-07-26
EP06117883A EP1882691A1 (en) 2006-07-26 2006-07-26 Quinuclidine derivatives as M3 antagonists

Publications (2)

Publication Number Publication Date
WO2008012290A2 true WO2008012290A2 (en) 2008-01-31
WO2008012290A3 WO2008012290A3 (en) 2008-03-13

Family

ID=37890216

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/057585 WO2008012290A2 (en) 2006-07-26 2007-07-23 Quinuclidine derivatives as m3 antagonists

Country Status (16)

Country Link
US (1) US7838534B2 (en)
EP (2) EP1882691A1 (en)
JP (1) JP5331688B2 (en)
KR (1) KR20090033443A (en)
CN (1) CN101490049A (en)
AR (1) AR062104A1 (en)
AU (1) AU2007278231B2 (en)
BR (1) BRPI0713826A2 (en)
CA (1) CA2658649A1 (en)
CL (1) CL2007002159A1 (en)
EA (1) EA017698B1 (en)
MX (1) MX2009000999A (en)
PE (1) PE20080407A1 (en)
TW (1) TW200817398A (en)
WO (1) WO2008012290A2 (en)
ZA (1) ZA200901124B (en)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2080507A1 (en) 2008-01-15 2009-07-22 CHIESI FARMACEUTICI S.p.A. Pharmaceutical formulations comprising an anticholinergic drug
EP2080523A1 (en) 2008-01-15 2009-07-22 CHIESI FARMACEUTICI S.p.A. Compositions comprising an antimuscarinic and a long-acting beta-agonist
EP2080508A1 (en) 2008-01-15 2009-07-22 CHIESI FARMACEUTICI S.p.A. Dry powder formulation comprising an anticholinergic drug
EP2154136A1 (en) 2008-08-08 2010-02-17 CHIESI FARMACEUTICI S.p.A. Quinuclidine carbonate derivatives and medicinal compositions thereof
WO2010072338A1 (en) 2008-12-23 2010-07-01 Chiesi Farmaceutici S.P.A. Alkaloid aminoester derivatives and medicinal composition thereof
US7776879B2 (en) 2000-12-22 2010-08-17 Almirall, S.A. Quinuclidine carbamate derivatives and their use as M3 antagonists
WO2011160920A1 (en) 2010-06-22 2011-12-29 Chiesi Farmaceutici S.P.A. Dry powder formulation comprising an antimuscarinic drug
WO2011160919A1 (en) 2010-06-22 2011-12-29 Chiesi Farmaceutici S.P.A. Alkaloid aminoester derivatives and medicinal composition thereof
WO2011160918A1 (en) 2010-06-22 2011-12-29 Chiesi Farmaceutici S.P.A. Alkaloid aminoester derivatives and medicinal composition thereof
WO2011161018A1 (en) 2010-06-22 2011-12-29 Chiesi Farmaceutici S.P.A. Alkaloid aminoester derivatives and medicinal compositions thereof
WO2012069275A1 (en) 2010-11-26 2012-05-31 Chiesi Farmaceutici S.P.A. Glycine derivatives and their use as muscarinic receptor antagonists
WO2012110462A1 (en) 2011-02-17 2012-08-23 Chiesi Farmaceutici S.P.A. Liquid propellant-free formulation comprising an antimuscarinic drug
WO2012146515A1 (en) 2011-04-29 2012-11-01 Chiesi Farmaceutici S.P.A. Alkaloid ester and carbamate derivatives and medicinal compositions thereof
WO2013098145A1 (en) 2011-12-30 2013-07-04 Chiesi Farmaceutici S.P.A. Quinuclidine esters of 1-azaheterocyclylacetic acid as antimuscarinic agents, process for their preparation and medicinal compositions thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2246170B1 (en) * 2004-07-29 2007-04-01 Almirall Prodesfarma, S.A. NEW PROCEDURE TO PREPARE DERIVATIVES OF QUINUCLIDIN CARBAMATE.

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003053966A2 (en) * 2001-12-20 2003-07-03 Laboratorios S.A.L.V.A.T., S.A. 1-alkyl-1-azoniabicyclo [2.2.2] octane carbamate derivatives and their use as muscarinic receptor antagonists

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA72632C2 (en) 2000-06-27 2005-03-15 Лабораторіос С.А.Л.В.А.Т., С.А. Carbamates, derivaties of arylalkylamines
DE10064816A1 (en) * 2000-12-22 2002-06-27 Boehringer Ingelheim Pharma Production of tiotropium bromide useful as an anticholinergic comprises oxidation of di-(2-thienyl)-glycolic acid tropenol ester and subsequent quaternisation
MXPA03005583A (en) * 2000-12-22 2004-05-05 Almirall Prodesfarma Ag Quinuclidine carbamate derivatives and their use as m3 antagonists.
ES2203327B1 (en) * 2002-06-21 2005-06-16 Almirall Prodesfarma, S.A. NEW QUINUCLIDINE CARBAMATES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003053966A2 (en) * 2001-12-20 2003-07-03 Laboratorios S.A.L.V.A.T., S.A. 1-alkyl-1-azoniabicyclo [2.2.2] octane carbamate derivatives and their use as muscarinic receptor antagonists

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7776879B2 (en) 2000-12-22 2010-08-17 Almirall, S.A. Quinuclidine carbamate derivatives and their use as M3 antagonists
EP2080523A1 (en) 2008-01-15 2009-07-22 CHIESI FARMACEUTICI S.p.A. Compositions comprising an antimuscarinic and a long-acting beta-agonist
EP2080508A1 (en) 2008-01-15 2009-07-22 CHIESI FARMACEUTICI S.p.A. Dry powder formulation comprising an anticholinergic drug
EP2080507A1 (en) 2008-01-15 2009-07-22 CHIESI FARMACEUTICI S.p.A. Pharmaceutical formulations comprising an anticholinergic drug
EP2154136A1 (en) 2008-08-08 2010-02-17 CHIESI FARMACEUTICI S.p.A. Quinuclidine carbonate derivatives and medicinal compositions thereof
US8455646B2 (en) 2008-12-23 2013-06-04 Chiesi Farmaceutici S.P.A. Alkaloid aminoester derivatives and medicinal composition thereof
WO2010072338A1 (en) 2008-12-23 2010-07-01 Chiesi Farmaceutici S.P.A. Alkaloid aminoester derivatives and medicinal composition thereof
CN102264734B (en) * 2008-12-23 2015-06-17 奇斯药制品公司 Alkaloid aminoester derivatives and medicinal composition thereof
EA020974B1 (en) * 2008-12-23 2015-03-31 КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. Alkaloid aminoester derivatives and medicinal compositions thereof
US8835682B2 (en) 2008-12-23 2014-09-16 Chiesi Farmaceutici S.P.A. Alkaloid aminoester derivatives and medicinal composition thereof
EP2206712A1 (en) 2008-12-23 2010-07-14 CHIESI FARMACEUTICI S.p.A. "Alkaloid aminoester derivatives and medicinal composition thereof"
JP2012513420A (en) * 2008-12-23 2012-06-14 シエシー ファルマセウティチィ ソシエタ ペル アチオニ Alkaloid amino ester derivatives and pharmaceutical compositions thereof
WO2011161018A1 (en) 2010-06-22 2011-12-29 Chiesi Farmaceutici S.P.A. Alkaloid aminoester derivatives and medicinal compositions thereof
WO2011160918A1 (en) 2010-06-22 2011-12-29 Chiesi Farmaceutici S.P.A. Alkaloid aminoester derivatives and medicinal composition thereof
WO2011160919A1 (en) 2010-06-22 2011-12-29 Chiesi Farmaceutici S.P.A. Alkaloid aminoester derivatives and medicinal composition thereof
WO2011160920A1 (en) 2010-06-22 2011-12-29 Chiesi Farmaceutici S.P.A. Dry powder formulation comprising an antimuscarinic drug
WO2012069275A1 (en) 2010-11-26 2012-05-31 Chiesi Farmaceutici S.P.A. Glycine derivatives and their use as muscarinic receptor antagonists
WO2012110462A1 (en) 2011-02-17 2012-08-23 Chiesi Farmaceutici S.P.A. Liquid propellant-free formulation comprising an antimuscarinic drug
WO2012146515A1 (en) 2011-04-29 2012-11-01 Chiesi Farmaceutici S.P.A. Alkaloid ester and carbamate derivatives and medicinal compositions thereof
WO2013098145A1 (en) 2011-12-30 2013-07-04 Chiesi Farmaceutici S.P.A. Quinuclidine esters of 1-azaheterocyclylacetic acid as antimuscarinic agents, process for their preparation and medicinal compositions thereof

Also Published As

Publication number Publication date
JP2009544659A (en) 2009-12-17
EP2049533A2 (en) 2009-04-22
EA200970158A1 (en) 2009-06-30
EP1882691A1 (en) 2008-01-30
US20080039493A1 (en) 2008-02-14
MX2009000999A (en) 2009-04-15
CA2658649A1 (en) 2008-01-31
AR062104A1 (en) 2008-10-15
KR20090033443A (en) 2009-04-03
AU2007278231B2 (en) 2012-08-16
TW200817398A (en) 2008-04-16
WO2008012290A3 (en) 2008-03-13
AU2007278231A1 (en) 2008-01-31
US7838534B2 (en) 2010-11-23
ZA200901124B (en) 2010-05-26
EA017698B1 (en) 2013-02-28
CL2007002159A1 (en) 2008-01-04
CN101490049A (en) 2009-07-22
JP5331688B2 (en) 2013-10-30
BRPI0713826A2 (en) 2015-05-12
PE20080407A1 (en) 2008-06-17

Similar Documents

Publication Publication Date Title
US7838534B2 (en) Quinuclidine derivatives as M3 antagonists
EP1519933B1 (en) Quinuclidine amide derivatives
EP1725552B1 (en) New quaternized quinuclidine esters
US9433614B2 (en) Amides of acetic and propionic acids
EP2313404B1 (en) Quinuclidine carbonate derivatives and medicinal composition thereof
US20100234332A1 (en) Novel quinuclidine derivatives and medicinal compositions containing the same
HU228594B1 (en) Novel quinuclidine derivatives, process for their preparation and medicinal compositions containing the same
IL94763A (en) R(-)3 quinuclidinol esters of substituted 1-azacycloalkanoic acids, their preparation and pharmaceutical compositions containing them
MXPA06009832A (en) New quaternized quinuclidine esters

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200780027597.7

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07787828

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 1020097000875

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2658649

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2009521244

Country of ref document: JP

Ref document number: MX/A/2009/000999

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2007787828

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2007278231

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 1056/CHENP/2009

Country of ref document: IN

Ref document number: 200970158

Country of ref document: EA

NENP Non-entry into the national phase

Ref country code: RU

ENP Entry into the national phase

Ref document number: PI0713826

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20090123