USRE46417E1 - Quinuclidine derivatives and their use as muscarinic M3 receptor ligands - Google Patents
Quinuclidine derivatives and their use as muscarinic M3 receptor ligands Download PDFInfo
- Publication number
- USRE46417E1 USRE46417E1 US15/019,009 US201615019009A USRE46417E US RE46417 E1 USRE46417 E1 US RE46417E1 US 201615019009 A US201615019009 A US 201615019009A US RE46417 E USRE46417 E US RE46417E
- Authority
- US
- United States
- Prior art keywords
- octane
- hydroxy
- azoniabicyclo
- bromide
- ylacetoxy
- Prior art date
- Legal status (The legal status 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 status listed.)
- Active, expires
Links
- 0 BC(=O)OC.C.CC*C[N+]1(C)CCC(C)CC1.[1*]C.[2*]C.[3*]C.[CH3-] Chemical compound BC(=O)OC.C.CC*C[N+]1(C)CCC(C)CC1.[1*]C.[2*]C.[3*]C.[CH3-] 0.000 description 16
- BOMNTZSYEZFQFE-UHFFFAOYSA-M BC(=O)Cl.BC(=O)N1C=CN=C1.BC(=O)OC.BC(=O)OC.C1CN2CCC1C2.C1CN2CCC1C2.C1CN2CCC1C2.C1CN2CCC1C2.CO.CO.CO.I[IH]I.[H]OC(B)=O.[V].[V].[V].[V]I Chemical compound BC(=O)Cl.BC(=O)N1C=CN=C1.BC(=O)OC.BC(=O)OC.C1CN2CCC1C2.C1CN2CCC1C2.C1CN2CCC1C2.C1CN2CCC1C2.CO.CO.CO.I[IH]I.[H]OC(B)=O.[V].[V].[V].[V]I BOMNTZSYEZFQFE-UHFFFAOYSA-M 0.000 description 1
- WXQAJKHRTKDHBF-UHFFFAOYSA-N BC(=O)OC.C1CN2CCC1C2 Chemical compound BC(=O)OC.C1CN2CCC1C2 WXQAJKHRTKDHBF-UHFFFAOYSA-N 0.000 description 1
- GHBWLSJFYHJGLS-UHFFFAOYSA-N C.CC1CC(C)CC(C)C1 Chemical compound C.CC1CC(C)CC(C)C1 GHBWLSJFYHJGLS-UHFFFAOYSA-N 0.000 description 1
- PQXKWPLDPFFDJP-UHFFFAOYSA-N CC1OC1C Chemical compound CC1OC1C PQXKWPLDPFFDJP-UHFFFAOYSA-N 0.000 description 1
- WWYPDEQRBDJXFE-UHFFFAOYSA-N [H]C1(C)C2=C(C=CC=C2)CC2=C1C=CC=C2 Chemical compound [H]C1(C)C2=C(C=CC=C2)CC2=C1C=CC=C2 WWYPDEQRBDJXFE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- 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
- A61P11/02—Nasal agents, e.g. decongestants
-
- 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
- A61P11/08—Bronchodilators
-
- 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
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/06—Anti-spasmodics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- Y10S514/826—
Definitions
- This invention relates to new therapeutically useful quinuclidine derivatives, to some processes for their preparation and to pharmaceutical compositions containing them.
- novel structures according to the invention are antimuscarinic agents with a potent and long lasting effect.
- these compounds show high affinity for muscarinic M 3 receptors(Hm3).
- the new compounds are suitable for treating the following diseases: respiratory disorders such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, bronchial hyperreactivity, asthma and rhinitis; urological disorders such as urinary incontinence, pollakinuria in neuripenia pollakinuria, neurogenic or unstable bladder, cystospasm and chronic cystitis; and gastrointestinal disorders such as irritable bowel syndrome, spastic colitis, diverticulitis and peptic ulceration.
- COPD chronic obstructive pulmonary disease
- COPD chronic obstructive pulmonary disease
- chronic bronchitis chronic bronchitis
- bronchial hyperreactivity asthma and rhinitis
- urological disorders such as urinary incontinence, pollakinuria in neuripenia pollakinuria, neurogenic or unstable bladder, cystospasm and chronic cystitis
- gastrointestinal disorders such as irritable bowel syndrome, spastic colitis, diverticulitis and
- the compounds claimed are also useful for the treatment of the respiratory diseases detailed above in association with ⁇ 2 agonists, steroids, antiallergic drugs or phosphodiesterase IV inhibitors.
- Compounds of the present invention may also be expected to have anti-tussive properties.
- the new compounds may be suitable for treating vagally induced sinus bradycardia.
- R is H, OH or an alkyl group having 1 to 4 carbon atoms
- R 1 is a phenyl or thienyl group
- R 2 is a cyclohexyl, cyclopentyl or thienyl group, or, when R is H, R 1 and R 2 together with the carbon atom to which they are attached, form a tricyclic group of the formula:
- X is —O—, —S— or —CH 2 —, or an acid addition or quaternary ammonium salt thereof.
- EP-418716 describes thienyl carboxylate esters of formula
- R is an optionally halo- or hydroxy-substituted C 1-4 alkyl group; R is a C 1-4 alkyl group; or R and R ⁇ together form a C 4-6 alkylene group;
- X ⁇ is an anion; and
- R 1 is H, OH, —CH 2 OH, C 1-4 alkyl or C 1-4 alkoxy.
- the present invention provides new quinuclidine derivatives with potent antagonist activity at muscarinic M 3 receptors which have the chemical structure described in formula (I):
- an equivalent of an anion (X ⁇ ) is associated with the positive charge of the N atom.
- X ⁇ may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate, and organic acids such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
- X ⁇ is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate or succinate. More preferably X ⁇ is chloride, bromide or trifluoroacetate.
- the compounds of the present invention represented by the formula (I) described above, which may have one or more assymetric carbons, include all the possible stereoisomers.
- the single isomers and mixtures of the isomers fall within the scope of the present invention.
- R 1 to R 7 or R 11 represents an alkyl group
- said alkyl group contains 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms.
- any alkyl group is represented by a methyl, ethyl, propyl, including i-propyl, butyl including a n-butyl, sec-butyl and tert-butyl.
- the alicyclic and heterocyclic rings mentioned in relation to formula (I) preferably comprise from 3 to 10, preferably from 5 to 7 members.
- the aromatic rings mentioned in relation to formula (I) above preferably contain from 6 to 14, preferably 6 or 10 members.
- Preferred compounds of formula (I) are those wherein ⁇ represents a phenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl or benzothiazolyl group, in particular a phenyl, pyrrolyl, or thienyl group;
- R 1 , R 2 and R 3 each independently represent a hydrogen or halogen atom, or a hydroxyl, methyl, tert-butyl, —CH 2 OH, 3-hydroxypropyl, —OMe, —NMe 2 , —NHCOMe, —CONH 2 , —CN, —NO 2 , —COOMe or —CF 3 group, in particular a hydrogen atom, a hydroxy group or a halogen atom, wherein the halogen atom is preferably flu
- B is a group of formula i) or ii) as defined above wherein, if B is a group of formula (i), R 8 and R 9 each independently represent a phenyl, 2-thienyl, 3-thienyl, 2-furyl or 3-furyl group, wherein R 11 is hydrogen atom; and, if B is a group of formula (Ii), Q represents a single bond, —CH 2 —, —CH 2 —CH 2 —, —O— or —S— group, in particular a single bond, —CH 2 —, —CH 2 —CH 2 — or —O— group, most preferably a single bond or —O— group; and in any case R 10 is a hydrogen atom or a hydroxy or methyl group; and when i) or ii) contain a chiral centre they may represent either the (R) or the (S) configuration.
- the —OC(O)B group in formula (I) is diphenylacetoxy, 2-hydroxy-2,2-diphenyl-acetoxy, 2,2-diphenylpropionyloxy, -hydroxy-2-phenyl-2-thien-2-yl-acetoxy, 2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2,2-dithien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-3-ylacetoxy, 9-hydroxy-9[H]-fluorene-9-carbonyloxy, 9-methyl-9[H]-fluorene-9-carbonyloxy, 9[H]-xanthene-9-carbonyloxy, 9-hydroxy-9[H]-xanthene-9-carbonyloxy, 9-methyl-9[H]-xanthene-9-carbonyloxy, 2,2-bis(4-fluorophenyl)-2-hydroxyacetoxy, 2-hydroxy-2,2-d
- —OC(O)B group in formula (I) is diphenylacetoxy, 2-hydroxy-2,2-diphenyl-acetoxy, 2,2-diphenylpropionyloxy, 2-hydroxy-2-phenyl-2-thien-2-yl-acetoxy, 2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2,2-dithien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-3-ylacetoxy, 9-hydroxy-9[H]-fluorene-9-carbonyloxy, 9-methyl-9[H]-fluorene-9-carbonyloxy, 9[H]-xanthene-9-carbonyloxy, 9-hydroxy-9[H]-xanthene-9-carbonyloxy or 9-methyl-9[H]-xanthene-9-carbonyloxy.
- the most preferred compounds of formula (I) are those wherein the azoniabicyclo group is substituted on the nitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 4-phenylbutyl, 3-phenylpropyl, 3-[2-hydroxyphenoxy]propyl, 3-[4-fluorophenoxy]propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl, 3-thien-2-ylpropyl, 3-phenylaminopropyl, 3(methylphenylamino)propyl, 3-phenylsulfanylpropyl, 3-o-tolyloxypropyl, 3-(2,4,6-trimethylphenoxy)propyl, 3-(2-tert-butyl-6-methylphenoxy)propyl, 3-(biphenyl-4-yloxy)propyl, 3-(5,6,7,8-te
- Especially preferred compounds are those wherein the azoniabicyclo group is substituted on the nitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 4-phenylbutyl, 3-phenylpropyl, 3-[2-hydroxyphenoxy]propyl, 3-[4-fluorophenoxy]propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl or 3-thien-2-ylpropyl group.
- the present invention also provides processes for preparing compounds of formula (I).
- the quaternary ammonium derivatives of general Formula I may be prepared by reaction of an alkylating agent of general Formula II with compounds of general Formula III.
- R 1 , R 2 , R 3 , ⁇ , A, X, B, n, m and p are as defined above.
- This alkylation reaction may be carried out by two different experimental procedures, a) and b) which are described below.
- method b) provides a new experimental process, using solid phase extraction methodologies, that allows the parallel preparation of several compounds. Methods a) and b) are described in the experimental section.
- Compounds of general Formula II which are not commercially available have been prepared by synthesis according to standard methods.
- R 8 and R 9 are as described above and R 10 is a hydroxy group, may also be prepared from the glyoxalate esters of general formula VII by reaction with the corresponding organometallic derivative.
- Methyl ester derivatives of general Formula VI were prepared by standard methods of esterification from the corresponding carboxylic acid or following the procedures described in examples I-1e, I-1f and I-1g or according to procedures described in literature: FR 2012964; Larsson. L et al. Acta Pharm. Suec. (1974), 11(3), 304-308; Nyberg, K. et. al. Acta Chem. Scand. (1970), 24, 1590-1596; and Cohen, V. I. et. al. J. Pharm. Sciences (1992), 81, 326-329.
- Diastereomer 1 2(*)—(Furan-2-yl)hydroxyphenylacetic Acid 1-azabicyclo[2.2.2]oct-3(R)-yl Ester.
- Diastereomer 2 2(*)—(Furan-2-yl)hydroxyphenylacetic Acid 1-azabicyclo[2.2.2]oct-3(R)-yl Ester.
- Lithium diisopropylamide (26.7 ml of a 2M solution in heptane/tetrahydrofurane/ethylbenzene, 0.053 mol) was added to a stirred solution of 9[H]-fluorene-9-carboxylic acid (5 g, 0.0237 mol) in THF (70 ml) at between 0 and 51C in N 2 atmosphere. The mixture was warmed to room temperature and refluxed 1.5 hours. The reaction mixture was cooled to room temperature and a solution of CH3I (1.85 ml, 0.03 mol) in THF (1.85 ml) was added. The mixture was stirred overnight at room temperature and evaporated.
- Lithium diisopropylamide (20.3 ml of a 2M solution in heptane/tetrahydrofurane/ethylbenzene, 0.041 mol) was added to a stirred solution of 7 g (0.029 mol) of 9[H]-xantene-9-carboxylic acid methyl ester (prepared by a standard method) in THF (70 ml) at between 0 and 51C in N 2 atmosphere.
- the mixture was stirred 1 h at this temperature and then was added by N2 pressure to a dry solution of oxygen in ether at 01C. After 30 min, an equal volum of NaHSO3, 40% aqueous solution, was added, and the reaction mixture was warmed to room temperature and stirred for 30 min.
- 9,10-Dihydro-anthracene-9-carboxylic acid was prepared as described in E. L. May and E. Mossettig; J. Am. Chem. Soc., (1948), Vol 70, 1077-9.
- a solution of 2-thienylmagnesium bromide was prepared from 220 mg (9 mmols)of Magnesium and 0.86 ml (9 mmols) of 2-bromothiophene in 15 ml of THF. This solution was added to 1.95 g (7 mmols) of oxothien-2-yl -acetic acid 1-azabicyclo[2.2.2]oct-4-yl ester (intermediate I-4b) dissolved in 20 ml of THF. The mixture was stirred at room temperature for 1 hour, refluxed for 1 hour, cooled, treated with a saturated solution of ammonium chloride and extracted with ether.
- Oxalyl chloride (1.5 ml, 0.017 mol) was added to a solution of oxothien-2-yl-acetic acid (2.24 g, 0,014 mol) and dimethylformamide (one drop) in 30 ml of chloroform (etanol free) at 01C. The mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times.
- the product obtained was disolved in CHCl3 (30 ml) and added to a suspension of 1.1 g (0.009 mols) of 4-hydroxy-1-azabicyclo[2.2.2]octane, 1.8 ml of triethylamine (0,013 mols), 0.6 g (0.9 mmols) of N-(methylpolystyrene)-4-(methylamino) pyridine at 70° C.
- the mixture was refluxed for 1 hour, cooled, filtered and washed with water.
- the title product was extracted with a solution of diluted HCl, washed with CHCl3, basified with K2CO3 and extracted again with CHCl3.
- Phenylmagnesium bromide 0.0057 mol (5.7 ml of a solution 1M in THF), was added to a solution of 1.3 g (0.0052 mol) of oxofuran-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4e-) dissolved in 15 ml of THF, at ⁇ 701C in N2 atmosphere. The mixture was stirred at this temperature for 10 minuts, and then warmed to room temperature. After 1 hour, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted three times with ethyl acetate The organic phases were combined, washed with water and dried over Na2SO4.
- Oxalyl chloride (9.75 ml, 0.112 mol) was added to a solution of oxofuran-2-ylacetic acid (10 g, 0.071 mol) and dimethylformamide (one drop) in 150 ml of chloroform (etanol free) at 01C. The mixture was stirred and allowed to warm at room temperature. After five hours the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHCl3 (150 ml) and a solution of 3(R)-quinuclidinol (10.90 g, 0.086 mol) in CHCl3 (150 ml) was added to this at 01C.
- Diastereomer 1 2(R)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic Acid 1-azabicyclo[2.2.2]oct-3(R)-yl Ester.
- Diastereomer 2 2(S)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic Acid 1-aza Bicyclo[2.2.2]oct-3(R)-yl Ester.
- Oxalyl chloride (1.34 ml, 0.0154 mol) was added to a solution of oxothien-2-yl-acetic acid (2 g, 0,0128 mol) and dimethylformamide (one drop) in 30 ml of chloroform (etanol free) at 01C. The mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHCl3 (30 ml) and a solution of 3(R)-quinuclidinol (1.95 g, 0.0154 mol) in CHCl3 (30 ml) was added to this at 01C.
- compositions which comprise, as the active ingredient, at least one quinuclidine derivative of general formula (I) in association with a pharmaceutically acceptable carrier or diluent.
- a pharmaceutically acceptable carrier or diluent Preferably the composition is made up in a form suitable for oral administration.
- composition of this invention The pharmaceutically acceptable carrier or diluents which are mixed with the active compound or compounds, to form the composition of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administration of the composition.
- compositions of this invention are preferably adapted for oral administration.
- the composition for oral administration may take the form of tablets, film-coated tablets, liquid inhalant, powder inhalant and inhalation aerosol; all containing one or more compounds of the invention; such preparations may be made by methods well-known in the art.
- the diluents which may be used in the preparations of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents, if desired.
- Tablets or film-coated tablets may conveniently contain between 500 and 1 mg, preferably from 5 to 300 mg of active ingredient.
- the inhalant compositions may contain between 1 ⁇ g and 1,000 ⁇ g, preferably from 10 to 800 ⁇ g of active ingredient.
- the dose of the compound of general formula (I) depend on the desired effect and duration of treatment; adult doses are generally between 3 mg and 300 mg per day as tablets and 10 ⁇ g and 800 ⁇ g per day as inhalant composition.
- membrane preparations were suspended in DPBS to a final concentration of 89 ⁇ g/ml for the Hm3 subtype.
- the membrane suspension was incubated with the tritiated compound for 60 min. After incubation the membrane fraction was separated by filtration and the bound radioactivity determined. Non specific binding was determined by addition of 10 ⁇ 4 M atropine. At least six concentrations were assayed in duplicate to generate individual displacement curves.
- the compounds of the invention preferably have high affinities for muscarinic M 3 receptors (HM3), preferably human muscarinic receptors. Affinity levels can typically be measured by in vitro assays, for example, as described above.
- HM3 muscarinic M 3 receptors
- Preferred compounds of the invention have an IC 50 (nM) value for M 3 receptors of less than 35, preferably less than 25,20 or 15, more preferably less than 10, 8 or 5.
- the compounds of the present invention inhibited the bronchospasm response to acetylcholine with high potency and a long duration of action.
- the compounds of the present invention have excellent antimuscarinic activity (M 3 ) and thus are useful for the treatment of diseases in which the muscarinic M 3 receptor is implicated, including respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis, urinary diseases such as urinary incontinence and pollakinuria in neuripenia pollakinuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm and chronic cystitis and gastrointestinal diseases such as irritable bowel syndrome, spastic colitis and diverticulitis.
- respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis
- urinary diseases such as urinary incontinence and pollakinuria in neuripenia pollakinuria
- neurogenic bladder nocturnal enuresis
- cystospasm irritable bowel syndrome
- spastic colitis and diverticulitis irritable bowel syndrome, spa
- the present invention further provides a compound of formula (I) or a pharmaceutically acceptable composition comprising a compound of formula(I) for use in a method of treatment of the human or animal body by therapy, in particular for the treatment of respiratory, urinary or gastrointestinal disease.
- the present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable composition comprising a compound of formula (I) for the manufacture of a medicament for the treatment of respiratory, urinary or gastrointestinal disease.
- the compounds of formula (I) and pharmaceutical compositions comprising a compound of formula (I) can be used in a method of treating respiratory, urinary or gastrointestinal disease, which method comprises administering to a human or animal patient in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I).
- the Examples 160 to 164 illustrate pharmaceutical compositions according to the present invention and procedure for their preparation.
- a pharmaceutical composition tablets
- Compound of the present invention 5.0 mg Lactose 113.6 mg Microcrystalline cellulose 28.4 mg Light silicic anhydride 1.5 mg Magnesium stearate 1.5 mg
- 15 g of the compound of the present invention was mixed with 340.8 g of lactose and 85.2 g of microcrystalline cellulose.
- the mixture was subjected to compression moulding using a roller compactor to give a flake-like compressed material.
- the flake-like compressed material was pulverized using a hammer mill, and the pulverized material was screened through a 20 mesh screen.
- a 4.5 g portion of light silicic anhydride and 4.5 g of magnesium stearate were added to the screened material and mixed.
- the mixer product was subjected to a tablets making machine equipped with a die/punch system of 7.5 mm in diameter, thereby obtaining 3,000 tablets each having 150 mg in weight.
- a pharmaceutical composition tablets coated Formulation: Compound of the present invention 5.0 mg Lactose 95.2 mg Corn starch 40.8 mg Polyvinylpyrrolidone K25 7.5 mg Magnesium stearate 1.5 mg Hydroxypropylcellulose 2.3 mg Polyethylene glycol 6000 0.4 mg Titanium dioxide 1.1 mg Purified talc 0.7 mg Using a fluidized bed granulating machine, 15 g of the compound of the present invention was mixed with 285.6 g of lactose and 122.4 g of corn starch. Separately, 22.5 g of polyinylpyrrolidone was dissolved in 127.5 g of water to prepare a binding solution.
- the binding solution was sprayed on the above mixture to give granulates.
- a 4.5 g portion of magnesium stearate was added to the obtained granulates and mixed.
- the obtained mixture was subjected to a tablet making machine equipped with a die/punch biconcave system of 6.5 mm in diameter, thereby obtaining 3,000 tablets, each having 150 mg in weight.
- a coating solution was prepared by suspending 6.9 g of hydroxypropylmethylcellulose 2910, 1.2 g of polyethylene glycol 6000, 3.3 g of titanium dioxide and 2.1 g of purified talc in 72.6 g of water. Using a High Coated, the 3,000 tablets prepared above were coated with the coating solution to give film-coated tablets, each having 154.5 mg in weight.
- liquid inhalant Formulation Compound of the present invention 400 ⁇ g Physiological saline 1 ml
- a 40 mg portion of the compound of the present invention was dissolved in 90 ml of physiological saline, and the solution was adjusted to a total volume of 100 ml with the same saline solution, dispensed in 1 ml portions into 1 ml capacity ampoule and then sterilized at 1151 for 30 minutes to give liquid inhalant.
- a 20 g portion of the compound of the present invention was uniformly mixed with 400 g of lactose, and a 200 mg portion of the mixture was packed in a powder inhaler for exclusive use to produce a powder inhalant.
- the active ingredient concentrate is prepared by dissolving 0.0480 g of the compound of the present invention in 2.0160 g of ethyl alcohol. The concentrate is added to an appropriate filling apparatus. The active ingredient concentrate is dispensed into aerosol container, the headspace of the container is purged with Nitrogen or HFC-134A vapor (purging ingredients should not contain more than 1 ppm oxygen) and is sealed with valve. 11.2344 g of HFC-134A propellant is then pressure filled into the sealed container.
Abstract
Description
This application claims priority from Spain application No. 9901580 filed Jul. 14, 1999 and PCT application No. PCT/EP00/06469 filed Jul. 7, 2000, the contents of each are incorporated herein by reference.
This invention relates to new therapeutically useful quinuclidine derivatives, to some processes for their preparation and to pharmaceutical compositions containing them.
The novel structures according to the invention are antimuscarinic agents with a potent and long lasting effect. In particular, these compounds show high affinity for muscarinic M3 receptors(Hm3).
In accordance with their nature as M3 antagonists, the new compounds are suitable for treating the following diseases: respiratory disorders such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, bronchial hyperreactivity, asthma and rhinitis; urological disorders such as urinary incontinence, pollakinuria in neuripenia pollakinuria, neurogenic or unstable bladder, cystospasm and chronic cystitis; and gastrointestinal disorders such as irritable bowel syndrome, spastic colitis, diverticulitis and peptic ulceration.
The compounds claimed are also useful for the treatment of the respiratory diseases detailed above in association with β2 agonists, steroids, antiallergic drugs or phosphodiesterase IV inhibitors.
Compounds of the present invention may also be expected to have anti-tussive properties.
Depending on their nature the new compounds may be suitable for treating vagally induced sinus bradycardia.
Compounds with related structures have been described as anti-spasmodics and anti-cholinergic agents in several patents.
For example, in patent FR 2012964 are described quinuclidinol derivatives of the formula:
in which R is H, OH or an alkyl group having 1 to 4 carbon atoms; R1 is a phenyl or thienyl group; and R2 is a cyclohexyl, cyclopentyl or thienyl group, or, when R is H, R1 and R2 together with the carbon atom to which they are attached, form a tricyclic group of the formula:
EP-418716 describes thienyl carboxylate esters of formula
- m and n=1 or 2
- Q is a —CH2—CH2—, —CH2—CH2—CH2—, —CH═CH—, group
- Q′ is a ═NR or NRR═ group; R1 is a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl group, optionally substituted; R2 is H, OH, C1-C4 alkoxy or C1-C4 alkyl and Ra is H, F, Cl, CH3— or —NR.
U.S. Pat. No. 5,654,314 describes compounds of formula:
wherein R is an optionally halo- or hydroxy-substituted C1-4 alkyl group; R is a C1-4 alkyl group; or R and R═ together form a C4-6 alkylene group; X− is an anion; and R1 is H, OH, —CH2OH, C1-4 alkyl or C1-4 alkoxy.
The present invention provides new quinuclidine derivatives with potent antagonist activity at muscarinic M3 receptors which have the chemical structure described in formula (I):
- © is a phenyl ring, a C4 to C9 heteroaromatic group containing one or more heteroatoms (preferably selected from nitrogen, oxygen and sulphur atoms), 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 alkoxy 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—, —CR6R7—, —CO—, —O—, —S—, —S—(O)—, SO2 or —NR6— group, wherein R6 and R7 each independently represent a hydrogen atom, straight or branched lower alkyl group, or R6 and R7 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
- 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.
In the quaternary ammonium compounds of the present invention represented by formula (I) an equivalent of an anion (X−)is associated with the positive charge of the N atom. X− may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate, and organic acids such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. X− is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate or succinate. More preferably X− is chloride, bromide or trifluoroacetate.
The compounds of the present invention represented by the formula (I) described above, which may have one or more assymetric carbons, include all the possible stereoisomers. The single isomers and mixtures of the isomers fall within the scope of the present invention.
If any of R1 to R7 or R11 represents an alkyl group, it is preferred that said alkyl group contains 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms. In particular it is preferred that any alkyl group is represented by a methyl, ethyl, propyl, including i-propyl, butyl including a n-butyl, sec-butyl and tert-butyl.
The alicyclic and heterocyclic rings mentioned in relation to formula (I) preferably comprise from 3 to 10, preferably from 5 to 7 members. The aromatic rings mentioned in relation to formula (I) above preferably contain from 6 to 14, preferably 6 or 10 members.
Preferred compounds of formula (I) are those wherein © represents a phenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl or benzothiazolyl group, in particular a phenyl, pyrrolyl, or thienyl group; R1, R2 and R3 each independently represent a hydrogen or halogen atom, or a hydroxyl, methyl, tert-butyl, —CH2OH, 3-hydroxypropyl, —OMe, —NMe2, —NHCOMe, —CONH2, —CN, —NO2, —COOMe or —CF3 group, in particular a hydrogen atom, a hydroxy group or a halogen atom, wherein the halogen atom is preferably fluorine; n=0 or 1; m is an integer from 1 to 6, particularly 1, 2 or 3; A represents a —CH2—, —CH═CH—, —CO—, —NH—, —NMe—, —O— or —S— group, in particular a —CH2—, —CH═CH— or —O— group.
It is also preferred that p=2 and the substituent group —OC(O)B attached to the azoniabicyclo[2.2.2]octane is at the 3 position, preferably having the (R) configuration.
Further preferred compounds of formula I are those wherein B is a group of formula i) or ii) as defined above wherein, if B is a group of formula (i), R8 and R9 each independently represent a phenyl, 2-thienyl, 3-thienyl, 2-furyl or 3-furyl group, wherein R11 is hydrogen atom; and, if B is a group of formula (Ii), Q represents a single bond, —CH2—, —CH2—CH2—, —O— or —S— group, in particular a single bond, —CH2—, —CH2—CH2— or —O— group, most preferably a single bond or —O— group; and in any case R10 is a hydrogen atom or a hydroxy or methyl group; and when i) or ii) contain a chiral centre they may represent either the (R) or the (S) configuration.
Most preferably the —OC(O)B group in formula (I) is diphenylacetoxy, 2-hydroxy-2,2-diphenyl-acetoxy, 2,2-diphenylpropionyloxy, -hydroxy-2-phenyl-2-thien-2-yl-acetoxy, 2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2,2-dithien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-3-ylacetoxy, 9-hydroxy-9[H]-fluorene-9-carbonyloxy, 9-methyl-9[H]-fluorene-9-carbonyloxy, 9[H]-xanthene-9-carbonyloxy, 9-hydroxy-9[H]-xanthene-9-carbonyloxy, 9-methyl-9[H]-xanthene-9-carbonyloxy, 2,2-bis(4-fluorophenyl)-2-hydroxyacetoxy, 2-hydroxy-2,2-di-p-tolylacetoxy, 2,2-difuran-2-yl-2-hydroxy acetoxy, 2,2-dithien-2-ylpropionyloxy, 9,10-dihydroanthracene-9-carbonyloxy, 9 [H]-thioxanthene-9-carbonyloxy, or 5[H]-dibenzo[a,d]cycloheptene-5-carbonyloxy. Especially preferred compounds are those wherein the —OC(O)B group in formula (I) is diphenylacetoxy, 2-hydroxy-2,2-diphenyl-acetoxy, 2,2-diphenylpropionyloxy, 2-hydroxy-2-phenyl-2-thien-2-yl-acetoxy, 2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2,2-dithien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-3-ylacetoxy, 9-hydroxy-9[H]-fluorene-9-carbonyloxy, 9-methyl-9[H]-fluorene-9-carbonyloxy, 9[H]-xanthene-9-carbonyloxy, 9-hydroxy-9[H]-xanthene-9-carbonyloxy or 9-methyl-9[H]-xanthene-9-carbonyloxy.
The most preferred compounds of formula (I) are those wherein the azoniabicyclo group is substituted on the nitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 4-phenylbutyl, 3-phenylpropyl, 3-[2-hydroxyphenoxy]propyl, 3-[4-fluorophenoxy]propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl, 3-thien-2-ylpropyl, 3-phenylaminopropyl, 3(methylphenylamino)propyl, 3-phenylsulfanylpropyl, 3-o-tolyloxypropyl, 3-(2,4,6-trimethylphenoxy)propyl, 3-(2-tert-butyl-6-methylphenoxy)propyl, 3-(biphenyl-4-yloxy)propyl, 3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-propyl, 3-(naphthalen-2-yloxy) propyl, 3-(naphthalen-1-yloxy) propyl, 3-(2-chlorophenoxy)propyl, 3-(2,4-difluorophenoxy)propyl, 3-(3-trifluoromethyl phenoxy)propyl, 3-(3-cyanophenoxy)propyl, 3-(4-cyanophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(4-methoxyphenoxy)propyl, 3-(benzo[1,3]dioxol-5-yloxy) propyl, 3-(2-carbamoylphenoxy)propyl, 3-(3-dimethylaminophenoxy)propyl, 3-(4-nitrophenoxy)propyl, 3-(3-nitrophenoxy)propyl, 3-(4-acetylaminophenoxy) propyl, 3-(3-methoxycarbonylphenoxy)propyl, 3-[4-(3-hydroxypropyl) phenoxy]propyl, 3-(2-hydroxymethylphenoxy)propyl, 3-(3-hydroxymethylphenoxy)propyl, 3-(4-hydroxymethylphenoxy)propyl, 3-(2-hydroxyphenoxy)propyl, 3-(4-hydroxyphenoxy)propyl, 3-(3-hydroxyphenoxy)propyl, 4-oxo-4-thien-2-ylbutyl, 3-(1-methyl-[1H]-imidazol-2-ylsulfanyl)propyl, 3-(benzothiazol-2-yloxy)propyl, 3-benzyloxypropyl, 6-(4-phenylbutoxy)hexyl, 4-phenoxybutyl, or 2-benzyloxyethyl group. Especially preferred compounds are those wherein the azoniabicyclo group is substituted on the nitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 4-phenylbutyl, 3-phenylpropyl, 3-[2-hydroxyphenoxy]propyl, 3-[4-fluorophenoxy]propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl or 3-thien-2-ylpropyl group.
The following compounds are intended to illustrate but not to limit the scope of the present invention.
- 3(R)-Diphenylacetoxy-1-(3-phenoxy-propyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(2-Hydroxy-2-phenyl-2-thien-2-yl-acetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane; bromide
- 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane; bromide
- 3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane; bromide
- 1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; chloride
- 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; trifluoroacetate
- 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azonia-bicyclo[2.2.2]octane; trifluoroacetate
- 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate
- 3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 1-(3-phenylallyl)-3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 1-(4-Phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; bromide
- 1-(2-Phenoxyethyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; bromide
- 1-(3-Phenoxypropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; bromide
- 1-Phenethyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; bromide
- 3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane; bromide
The present invention also provides processes for preparing compounds of formula (I).
The quaternary ammonium derivatives of general Formula I, may be prepared by reaction of an alkylating agent of general Formula II with compounds of general Formula III. In Formulas I, II and III, R1, R2, R3, ©, A, X, B, n, m and p are as defined above.
This alkylation reaction may be carried out by two different experimental procedures, a) and b) which are described below. In particular method b) provides a new experimental process, using solid phase extraction methodologies, that allows the parallel preparation of several compounds. Methods a) and b) are described in the experimental section. Compounds of general Formula II which are not commercially available have been prepared by synthesis according to standard methods. For example, compounds wherein n=0 and A=—O—, —S— or —NR6 1 wherein R6 is as defined above, were obtained by reaction of the corresponding aromatic derivative or its potassium salt with an alkylating agent of general formula Y—(CH2)m-X, wherein X may be a halogen and Y may be a halogen or a sulphonate ester. In other examples, compounds of general Formula II, where n>=1 were synthesised from the corresponding alcohol derivative of general Formula IV by known methods.
Compounds of general Formula III may be prepared by three different methods c, d and e illustrated in the following scheme and detailed in the experimental section.
Some compounds of general formula III where B is a group of formula i), R8 and R9 are as described above and R10 is a hydroxy group, may also be prepared from the glyoxalate esters of general formula VII by reaction with the corresponding organometallic derivative.
Compounds of general formula VII may be prepared from the corresponding glyoxylic acids following the standard methods c, d and e described above and detailed in the experimental section. The glyoxalate derivatives of formula VII where R8 is a 2-thienyl or 2-furyl group have not been described before.
The following compounds are examples of compounds of general formula III and VII which have not been described before:
- 9-Methyl-9[H]-fluorene-9-carboxylic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-1c);
- 9-Methyl-9[H]-xanthene-9-carboxylic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-1d);
- 2-Hydroxydithien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-4-yl ester (intermediate I-4a).
- Oxothien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-4-yl ester (intermediate I-4b).
- Oxothien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4 g).
- Oxofuran-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4e).
- 2-Hydroxy-2,2-difuran-2-yl-acetic acid
- 1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4d).
Compounds of Formula V could be:
- 4-hydroxy-1-azabicyclo[2.2.1]heptane, described in WO150080
- 4-hydroxy-1-azabicyclo[2.2.2]octane, described in Grob, C. A. et. al. Helv. Chim. Acta (1958), 41, 1184-1190
- 3(R)-hydroxy-1-azabicyclo[2.2.2]octane or 3(S)-hydroxy-1-azabicyclo[2.2.2]octane, described in Ringdahl, R. Acta Pharm Suec. (1979), 16, 281-283 and commercially available from CU Chemie Uetikon GmbH.
The following examples are intended to illustrate, but not to limit, the experimental procedures that have been described above.
The structures of the prepared compounds were confirmed by 1H-NMR and MS. The NMR were recorded using a Varian 300 MHz instrument and chemical shifts are expressed as parts per million (δ) from the internal reference tetramethyl silane. Their purity was determined by HPLC, using reverse phase chromatrography on a Waters instrument, with values greater than 95% being obtained. Molecular ions were obtained by electrospray ionization mass spectometry on a Hewlett Packard instrument.
Method-a
200 mg of (Furan-2-yl)-hydroxy-phenylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester (0.6 mmol) were suspended in 4 ml of CH3CN and 6 ml of CHCl3. To this suspension were added 0.48 ml (3 mmol) of 3-phenoxypropyl bromide. After stirring for 72 h at room temperature in inert atmosphere, solvents were evaporated. Ether was added and the mixture stirred. The solid obtained was filtered and washed several times with ether. The yield was 0.27 g (83%) of title compound as a mixture of diastereomers.
1H-NMR (DMSO-d6): δ 1.50-2.20 (m, 6H), 2.25 (m, 1H), 3.10 (m, 1H), 3.20-3.60 (m, 6H), 3.95 (m, 1H), 4.05 (m, 2H), 5.20 (m, 1H), 6.25-6.35 (double dd, 1H), 6.45 (m, 1H), 6.95 (m, 4H), 7.30-7.50 (m, 7H), 7.70 (m, 1H); MS [M-Br]+: 462; mp 166° C.
Method-b
60 mg (0.17 mmols) of hydroxy-dithien-2-yl-acetic acid 1-aza-bicyclo[2.2.2]oct-3(R)-yl ester were dissolved in 1 ml of dmso. To this solution 188 mg (0.85 mmol) of 3-(naphthalen-1-yloxy)-propyl chloride were added. After stirring overnight at room temperature, the mixture was purified by solid phase extraction with a cation exchange Mega Bond Elut cartridge, previously conditioned at pH=7.5 with 0.1 M NaH2PO4 buffer. The reaction mixture was applied to the cartridge and washed first with 2 ml of DMSO and then three times with 5 ml of CH3CN, rinsing away all starting materials. The ammonium derivative was eluted with 5 ml of 0.03 M TFA solution in CH3CN:CHCl3 (2:1). This solution was neutralized with 300 mg of poly(4-vinylpyridine), filtered and evaporated to dryness.
The yield was 17 mg (15%) of title compound. 1H-NMR (DMSO-d6): δ 1.7-2.1 (m, 4H), 2.2-2.4 (m, 3H), 3.2-3.6 (m, 7H), 4.0 (m, 1H), 4.2 (t, 2H), 5.25 (m, 1H), 7.0 (m 3H), 7.2 (m, 2H), 7.4-7.6 (m, 7H), 7.85 (d, 1H), 8.2 (d, 1H); MS [M-CF3COO]+: 534.
Method-c
Methyl ester derivatives of general Formula VI were prepared by standard methods of esterification from the corresponding carboxylic acid or following the procedures described in examples I-1e, I-1f and I-1g or according to procedures described in literature: FR 2012964; Larsson. L et al. Acta Pharm. Suec. (1974), 11(3), 304-308; Nyberg, K. et. al. Acta Chem. Scand. (1970), 24, 1590-1596; and Cohen, V. I. et. al. J. Pharm. Sciences (1992), 81, 326-329.
3.24 g (0.014 mols) of (Furan-2-yl)-hydroxy-phenylacetic acid methyl ester were dissolved in 85 ml of toluene. To this solution were added 2.08 g (0.016 mols) of 3-(R)-hydroxy-1-azabicyclo[2.2.2]octane and 0.224 g (5.6 mmols) of HNa (60% dispersion in mineral oil). The mixture was refluxed with continuous removal of distillate and when necessary replacement with fresh toluene for 1.5 hours. The cooled mixture was extracted with 2N HCl acid, the aqueous layer washed with ethyl acetate, basified with K2CO3 and extracted with CHCl3. The organic layer was dried over Na2SO4 and evaporated. The oil obtained (3.47 g) crystallised after cooling at room temperature. This solid was suspended in hexane and filtered. The yield was 2.5 g (54%) of a mixture of diasteroisomers, mp: 140-142° C.; GC/MS [M]+: 327; 1H-NMR (CDCl3): δ 1.20-1.70 (m, 4H), 1.90-2.10 (m, 1H), 2.45-2.80 (m, 5H), 3.10-3.30 (m, 1H), 4.8 (bs, OH), 4.90-5.0 (m, 1H), 6.20 (m, 1H), 6.35 (m, 1H), 7.30-7.50 (m, 4H), 7.60-7.70 (m, 2H).
After four crystallizations of 0.5 g of this mixture from boiling acetonitrile, 0.110 g of a pure diastereomer(I) were obtained. From the mother liquors of crystallization was obtained the other diastereomer (2). (*:configuration not assigned). Diastereomer 1 was hydrolysed to yield (+)-2-hydroxy-2-phenyl-2-furan-2-ylacetic acid as a pure enantiomer, [α]25 D=+5.6 (c=2, EtOH). Diastereomer 2 was hydrolysed to yield (−)-2-hydroxy-2-phenyl-2-furan-2-ylacetic acid as a pure enantiomer, [γ]25 D=−5.7 (c=2, EtOH).
Diastereomer 1: 2(*)—(Furan-2-yl)hydroxyphenylacetic Acid 1-azabicyclo[2.2.2]oct-3(R)-yl Ester.
1H-NMR (CDCl3): δ 1.20-1.70 (m, 4H), 1.90 (m, 1H), 2.45-2.50 (m, 1H), 2.50-2.80 (m, 4H), 3.10-3.20 (m, 1H), 4.8 (bs, OH), 4.90-5.0 (m, 1H), 6.20 (m, 1H), 6.35 (m, 1H), 7.30-7.50 (m, 4H), 7.60-7.70 (m, 2H).
Diastereomer 2: 2(*)—(Furan-2-yl)hydroxyphenylacetic Acid 1-azabicyclo[2.2.2]oct-3(R)-yl Ester.
1H-NMR (CDCl3): δ 1.20-1.70 (m, 4H), 2.10 (m, 1H), 2.50-2.80 (m, 5H), 3.20-3.30 (m, 1H), 4.8 (bs, OH), 4.90-5.0 (m, 1H), 6.20 (m, 1H), 6.35 (m, 1H), 7.30-7.50 (m, 4H), 7.60-7.70 (m, 2H).
Prepared as in example I-1a. The yield was 3.06 g (64.3%) of a mixture of diastereoisomers, mp: 1721C; GC/MS [M]+: 333; 1H-NMR (DMSO-d6): δ 1.21-1.27 (m, 1H), 1.41-1.60 (m, 3H), 1.87 (m, 1H), 2.36-2.69 (m, 5H), 3.02-3.14 (m, 1H), 4.75-4.82 (m, 1H), 6.24-6.25 (m, 1H), 6.42-6.45 (m, 1H), 7.01-7.06 (m, 1H), 7.11-7.14 (m, 2H), 7.51-7.54 (m, 1H), 7.66-7.69 (m, 1H).
EXAMPLE I-1c
Prepared as in example I-1a. The yield was 3.34 g of an oil (80%). This product was solidified by formation of the oxalate salt (1:1), mp: 1861C. MS [M free base+1]+: 334.
Oxalate salt, 1H-NMR (DMSO-d6): δ 1.43-1.55 (m, 2H), 1.68-1.78 (m, 2H), 1.75 (s, 3H), 2.02 (m, 1H), 2.70-2.90 (m, 1H), 2.92-3.15 (m, 4H), 3.50-3.57 (m, 1H), 4.88 (m, 1H), 7.35-7.47 (m, 4H), 7.62-7.70 (m, 2H), 7.89-7.91 (m, 2H).
Prepared as in example I-1a. The yield was 1.91 g of an oil (53%). This product was solidified by formation of the oxalate salt (1:1), mp: 1521C. MS [M free base+1]+: 350.
Oxalate salt, 1H-NMR (DMSO-d6): δ 1.20-1.30 (m, 1H), 1.40-1.52 (m, 1H), 1.64-1.81 (m, 2H), 1.90 (s, 3H), 2.0 (m, 1H), 2.53-2.66 (m, 1H), 2.71-2.76 (m, 1H), 2.97-3.10 (m, 3H), 3.44-3.52 (m, 1H), 4.90-4.92 (m, 1H), 7.12-7.18 (m, 4H), 7.32-7.38 (m, 2H), 7.43-7.48 (m, 2H), 8.0-9.8 (bs, 1H, H+).
Lithium diisopropylamide (26.7 ml of a 2M solution in heptane/tetrahydrofurane/ethylbenzene, 0.053 mol) was added to a stirred solution of 9[H]-fluorene-9-carboxylic acid (5 g, 0.0237 mol) in THF (70 ml) at between 0 and 51C in N2 atmosphere. The mixture was warmed to room temperature and refluxed 1.5 hours. The reaction mixture was cooled to room temperature and a solution of CH3I (1.85 ml, 0.03 mol) in THF (1.85 ml) was added. The mixture was stirred overnight at room temperature and evaporated. To the residue in MeOH (70 ml) was added concentrated sulfuric acid (3.9 ml) in MeOH (25 ml), the mixture was refluxed for 2 hours and evaporated. The residue was partitioned between chloroform and saturated K2CO3 solution. The aqueous layer was extracted again with chloroform and the organic layers were combined, washed with water, dried over sodium sulphate and evaporated to dryness to obtain 5.73 g of a brown oil. This product was purified by column chromatography (silica gel, hexane/ethyl acetate 95:5) to yield 4.43 g (78.5%) of a pure product, structure confirmed by 1H-NMR.
1H-NMR (CDCl3): δ 1.80 (s, 3H), 3.60 (s, 3H), 7.50-7.65 (m, 4H), 7.75 (m, 2H), 8.0 (m, 2H).
Prepared as in example I-1e. The yield was 2.65 g (47.2%). 1H-NMR (CDCl3): δ 1.90 (s, 3H), 3.6 (s, 3H), 7.05-7.35 (m, 8H).
Lithium diisopropylamide (20.3 ml of a 2M solution in heptane/tetrahydrofurane/ethylbenzene, 0.041 mol) was added to a stirred solution of 7 g (0.029 mol) of 9[H]-xantene-9-carboxylic acid methyl ester (prepared by a standard method) in THF (70 ml) at between 0 and 51C in N2 atmosphere. The mixture was stirred 1 h at this temperature and then was added by N2 pressure to a dry solution of oxygen in ether at 01C. After 30 min, an equal volum of NaHSO3, 40% aqueous solution, was added, and the reaction mixture was warmed to room temperature and stirred for 30 min. The two layers were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, treated with NaHSO3 (40% aqueous solution), washed with water, dried over sodium sulphate and evaporated to dryness to obtain 8.89 g of a brown solid.
This procedure was repeated with 5 g of starting material yielding 6.049 of the same brown solid. The products were combined and purified by column chromatography (silica gel, hexane/ethyl acetate 90:10) to yield 7.60 g (global Rt: 59.4%) of a pure product, structure confirmed by 1H-NMR.
1H-NMR (DMSO-d6): δ 3.5 (s, 3H), 7.0 (s, 1H, OH), 7.2 (m, 4H), 7.4 (m, 2H), 7.55 (m, 2H).
Method-d
2.15 g of 10,11-Dihydro-5[H]-dibenzo[a,d]cycloheptane-5-carboxylic acid (9.0 mmol) were dissolved in 40 ml of CHCl3 (ethanol free). The solution was cooled at 0° C. and 0.86 ml of oxalyl chloride (9.9 mmols) and a drop of DMF were added. The mixture was stirred and allowed warm to room temperature. After an hour at this temperature the solvents were evaporated and the residue was dissolved in CHCl3 and evaporated again. This procedure was repeated two times. The obtained oil was dissolved in 20 ml of toluene and added to a solution of 1.26 g (9.9 mmol) of 3-(R)-hydroxy-1-azabicyclo[2.2.2]octane in 40 ml of hot toluene. The reaction mixture was refluxed for 2 hours. After cooling the mixture was extracted with 2N HCl acid. The aqueous layer was basified with K2CO3 and extracted with CHCl3. The organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography (silica gel, CHCl3:MeOH:NH40H, 95:5:0.5). The yield was 1.5 g (48%); mp: 112-113° C.; CG/MS [M]+: 347; 1H-NMR (CDCl3): δ 1.10-1.35 (m, 2H), 1.40-1.52 (m, 1H), 1.52-1.68 (m, 1H), 1.90 (m, 1H), 2.40-2.60 (m, 2H), 2.60-2.77 (m, 3H), 2.83-2.96 (m, 2H), 3.07-3.19 (m, 1H), 3.25-3.40 (m, 2H), 4.80 (m, 2H), 7.10-7.30 (m, 8H). 10,11-Dihydro-5[H]-dibenzo[a,d]cycloheptane-5-carboxylic acid was prepared as described in Kumazawa T. et al., J. Med. Chem., (1994), 37, 804-810.
Prepared as in example I-2a. The yield was 3.12 g (71%); mp 1291C; MS [M+1]+: 346; 1H-NMR (DMSO-d6): δ 0.90-1.10 (m, 2H), 1.30-1.50 (m, 2H), 1.58 (m, 1H), 2.21-2.26 (m, 2H), 2.47-2.50 (m, 3H), 2.86-2.94 (m, 1H), 4.48-4.51 (m, 1H), 5.33 (s, 1H), 7.0 (m, 2H), 7.29-7.43 (m, 6H), 7.49-7.51 (m, 2H).
5[H]-Dibenzo[a,d]cycloheptene-5-carboxylic acid was prepared as described in M. A. Davis et al; J. Med. Chem., (1964), Vol 7, 88-94.
Prepared as in example I-2a. The yield was 0.77 g (62.6%); mp 1391C; MS [M+1]+: 334; 1H-NMR (DMSO-d6): δ 1.1-1.2 (m, 1H), 1.25-1.40 (m, 2H), 1.40-1.55 (m, 1H), 1.73 (m, 1H), 2.20 (m, 1H), 2.35-2.65 (m, 4H), 2.90-2.98 (m, 1H), 3.93-4.14 (dd, 2H, J=1.8 Hz, J=4.3 Hz), 4.56 (m, 1H), 5.14 (s, 1H), 7.25-7.35 (m, 4H), 7.35-7.50 (m, 4H).
9,10-Dihydro-anthracene-9-carboxylic acid was prepared as described in E. L. May and E. Mossettig; J. Am. Chem. Soc., (1948), Vol 70, 1077-9.
Method-e
1.1 g (4.8 mmol) of 2,2-diphenylpropionic acid were dissolved in 20 ml of THF. To this solution were added 0.87 g (5.3 mmol) of 1,1=-carbonyldiimidazole and the mixture was refluxed for an hour. The reaction was monitored by TLC following the formation of the imidazolide. When the reaction was completed part of the solvent was evaporated and 0.67 g (5.3 mmol) of 3-(R)-hydroxy-1-azabicyclo[2.2.2]octane were added. The reaction mixture was refluxed for 16 h, cooled, diluted with ether and washed with water. The organic layer was extracted with HCl 2N, the acid solution basified with K2CO3 and extracted with CHCl3. The organic solution was dried over Na2SO4 and evaporated to dryness to yield 1.21 g (75.2%) of an oil that was identified as the title ester.
0.64 g (1.9 mmol) of 2,2-Diphenylpropionic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester were dissolved in 6 ml of ketone and 0.085 g(0.95 mmol) of oxalic acid were added. After slow addition of ether a white solid was formed. The yield was 0.33 g (45.6%) of oxalate of 2,2-Diphenylpropionic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester; mp: 1461C; MS [M free base+1]+: 336.
Oxalate salt, 1H-NMR (CDCl3): δ 1.40-1.64 (m, 2H), 1.90 (s, 3H), 1.80-2.0 (m, 2H), 2.31 (m, 1H), 2.73-2.85 (m, 1H), 3.0-3.10 (m, 1H), 3.10-3.32 (m, 3H), 3.53-3.70 (m, 1H), 5.13 (m, 1H), 7.14-7.40 (m, 10H), 9.25 (broad band, 2H, H+).
Method-f
A solution of 2-thienylmagnesium bromide was prepared from 220 mg (9 mmols)of Magnesium and 0.86 ml (9 mmols) of 2-bromothiophene in 15 ml of THF. This solution was added to 1.95 g (7 mmols) of oxothien-2-yl -acetic acid 1-azabicyclo[2.2.2]oct-4-yl ester (intermediate I-4b) dissolved in 20 ml of THF. The mixture was stirred at room temperature for 1 hour, refluxed for 1 hour, cooled, treated with a saturated solution of ammonium chloride and extracted with ether. After removal of the solvent the solid obtained was recrystallised from acetonitrile to yield 1.45 g, of a white solid (56%). 1H-NMR (DMSO-d6): δ 1.80-2.0 (m, 6H), 2.80-3.0 (m, 6H), 7.0 (m, 2H), 7.13 (m, 2H), 7.18 (s, 1H), 7.51 (m, 2H); MS [M+1]: 350; mp 174° C.
Oxalyl chloride (1.5 ml, 0.017 mol) was added to a solution of oxothien-2-yl-acetic acid (2.24 g, 0,014 mol) and dimethylformamide (one drop) in 30 ml of chloroform (etanol free) at 01C. The mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHCl3 (30 ml) and added to a suspension of 1.1 g (0.009 mols) of 4-hydroxy-1-azabicyclo[2.2.2]octane, 1.8 ml of triethylamine (0,013 mols), 0.6 g (0.9 mmols) of N-(methylpolystyrene)-4-(methylamino) pyridine at 70° C. The mixture was refluxed for 1 hour, cooled, filtered and washed with water. The title product was extracted with a solution of diluted HCl, washed with CHCl3, basified with K2CO3 and extracted again with CHCl3. After removal of the solvent 1.47 g (45%) of a solid was obtained. 1H-NMR (dmso): δ 2.0 (m, 6H), 2.9 (m, 6H), 7.35 (m, 1H), 8.05 (m, 1H), 8.3 (m, 1H).
Phenylmagnesium bromide, 0.0057 mol (5.7 ml of a solution 1M in THF), was added to a solution of 1.3 g (0.0052 mol) of oxofuran-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4e-) dissolved in 15 ml of THF, at −701C in N2 atmosphere. The mixture was stirred at this temperature for 10 minuts, and then warmed to room temperature. After 1 hour, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted three times with ethyl acetate The organic phases were combined, washed with water and dried over Na2SO4. After removal of the solvent, the solid obtained was treated with ether and filtered to yield 0.67 g (40%) of a product whose structure was confirmed by 1H-NMR. This compound was also prepared as is described in Example I-1a (Method c). The diastereomers were separated by crystallization from acetonitrile and distinguished by 1H-NMR.
The title compound was synthesised as in example I-4c from intermediate I-4e—and 2-furanyl lithium which was prepared with furane and butyl lithium following a standard method. The yield was 380 mg (8%). 1H-NMR (CDCl3): δ 1.2-1.4 (m, 1H), 1.4-1.8 (m, 3H), 2.0 (m, 1H), 2.6-2.85 (m, 5H), 3.2 (m, 1H), 5.0 (m, 1H), 6.4 (m, 3H), 7.3 (m, 1H), 7.5 (m, 2H). MS [M+1]+: 318.
Oxalyl chloride (9.75 ml, 0.112 mol) was added to a solution of oxofuran-2-ylacetic acid (10 g, 0.071 mol) and dimethylformamide (one drop) in 150 ml of chloroform (etanol free) at 01C. The mixture was stirred and allowed to warm at room temperature. After five hours the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHCl3 (150 ml) and a solution of 3(R)-quinuclidinol (10.90 g, 0.086 mol) in CHCl3 (150 ml) was added to this at 01C. The mixture was stirred and allowed to warm at room temperature. After 15 h at r.t., the mixture was washed with 10% aqueous potassium carbonate, then with water, dried over Na2SO4 and evaporated to give 9.34 g (52.5%) of the title compound as a dark oil. Estructure confirmed by NMR.
1H-NMR (CDCl3): δ 1.40-1.60 (m, 1H), 1.60-1.80 (m, 2H), 1.80-2.05 (m, 1H), 2.20 (m, 1H), 2.70-3.10 (m, 5H), 3.30-3.45 (m, 1H), 5.10 (m, 1H), 6.7 (m, 1H), 7.7 (m, 1H), 7.8 (m, 1H).
The title compound was prepared as described in example I-4c from intermediate I-4 g. The yield was 3 g (33%) as a mixture of diastereomers. After five crystallizations of 1.5 g of this mixture from boiling isopropanol, 0.200 g of a pure diastereomer(1) were obtained. The mother liquors from first crystallization were enriched with the other diastereomer (2). Diastereomer 1 was hidrolysed to yield (+)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid as a pure enantiomer, [α]25 D=+25.4 (c=2, EtOH). This value was assigned to the R configuration provided that in literature (A. I. Meyers et. al. J. Org. Chem.(1980), 45(14), 2913) the 2(S) enantiomer has been described whith [α]25D=−20 (c=2, EtOH).
Diastereomer 1: 2(R)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic Acid 1-azabicyclo[2.2.2]oct-3(R)-yl Ester.
1H-NMR (DMSO-d6): δ 1.1-1.25 (m, 1H), 1.3-1.6 (m, 3H), 1.83 (m, 1H), 2.4-2.7 (m, 5H), 3.1 (m, 1H), 4.8 (m, 1H), 7.0 (m, 2H), 7.05 (m, 1H), 7.3-7.4 (m, 3H), 7.4-7.45 (m, 2H), 7.5 (m, 1H).
Diastereomer 2: 2(S)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic Acid 1-aza Bicyclo[2.2.2]oct-3(R)-yl Ester.
1H-NMR (DMSO-d6): δ 1.1-1.25 (m, 1H), 1.4-1.6 (m, 3H), 1.9 (m, 1H), 2.3-2.7 (m, 5H), 3.05 (m, 1H), 4.8 (m, 1H), 7.0 (m, 2H), 7.05 (m, 1H), 7.3-7.4 (m, 3H), 7.4-7.45 (m, 2H), 7.5 (m, 1H).
EXAMPLE I-4g
Preparation of Oxothien-2-yl-acetic Acid 1-azabicyclo[2.2.2]oct-3(R)-yl Ester
Oxalyl chloride (1.34 ml, 0.0154 mol) was added to a solution of oxothien-2-yl-acetic acid (2 g, 0,0128 mol) and dimethylformamide (one drop) in 30 ml of chloroform (etanol free) at 01C. The mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHCl3 (30 ml) and a solution of 3(R)-quinuclidinol (1.95 g, 0.0154 mol) in CHCl3 (30 ml) was added to this at 01C. The mixture was stirred and allowed to warm at room temperature. After 1.5 h at r.t., the mixture was washed with 10% aqueous potassium carbonate, then with water, dried over Na2SO4 and evaporated to give 3.14 g (92.6%) of the title compound as a yellow oil. 1H-NMR (CDCl3): δ 1.40-1.50 (m, 1H), 1.50-1.70 (m, 1H), 1.70-1.80 (m, 1H), 1.90-2.0 (m, 1H), 2.15 (m, 1H), 2.70-3.05 (m, 5H), 3.30-3.40 (m, 1H), 5.05 (m, 1H), 7.20 (m, 1H), 7.85 (m, 1H), 8.10 (m, 1H).
Other carboxylic acids of Formula B—C(O)OH, whose preparation (or the syntheses of their derivatives methyl ester, chloride or imidazolide) have not been described in methods c, d, e or in the Examples I-1e, 1-1f and I-1g, and that are not commercially available, could be prepared as is described in the following references:
- FR 2012964
- M. A. Davis et al; J. Med. Chem. (1963), 6, 513-516.
- T. Kumazawa et al; J. Med. Chem, (1994), 37(6), 804-810.
- M. A. Davis et al; J. Med. Chem., (1964), Vol (7), 88-94.
- Sestanj, K; Can. J. Chem., (1971), 49, 664-665.
- Burtner, R.; J. Am. Chem. Soc., (1943), 65, 1582-1585
- Heacock R. A. et al.; Ann. Appl. Biol., (1958), 46(3), 352-365.
- Rigaudy J. et. al.; Bull. Soc. Chim. France, (1959), 638-43.
- Ueda I. et al.; Bull. Chem. Soc. Jpn; (1975), 48 (8), 2306-2309.
- E. L. May et. al.; J. Am. Chem. Soc., (1948), 70, 1077-9.
Also included within the scope of the present invention are pharmaceutical composition which comprise, as the active ingredient, at least one quinuclidine derivative of general formula (I) in association with a pharmaceutically acceptable carrier or diluent. Preferably the composition is made up in a form suitable for oral administration.
The pharmaceutically acceptable carrier or diluents which are mixed with the active compound or compounds, to form the composition of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administration of the composition.
Compositions of this invention are preferably adapted for oral administration. In this case, the composition for oral administration may take the form of tablets, film-coated tablets, liquid inhalant, powder inhalant and inhalation aerosol; all containing one or more compounds of the invention; such preparations may be made by methods well-known in the art.
The diluents which may be used in the preparations of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents, if desired. Tablets or film-coated tablets may conveniently contain between 500 and 1 mg, preferably from 5 to 300 mg of active ingredient. The inhalant compositions may contain between 1Φg and 1,000 Φg, preferably from 10 to 800 Φg of active ingredient. In human therapy, the dose of the compound of general formula (I) depend on the desired effect and duration of treatment; adult doses are generally between 3 mg and 300 mg per day as tablets and 10 Φg and 800 Φg per day as inhalant composition.
Pharmacological Action
The following examples demonstrate the excellent pharmacological activities of the compounds of the present invention. The results on human muscarinic receptors binding and in the test on bronchospasm in guinea pig, were obtained as described below.
Human Muscarinic Receptor Studies.
The binding of [3H]-NMS to human muscarinic receptors was performed according to Waelbroek et al (1990) (1). Assays were carried out at 25° C. Membrane preparations from stably transfected chinese hamster ovary-K1 cells (CHO) expressing the genes for the human muscarinic receptors Hm3 were used.
For determination of IC50, membrane preparations were suspended in DPBS to a final concentration of 89 μg/ml for the Hm3 subtype. The membrane suspension was incubated with the tritiated compound for 60 min. After incubation the membrane fraction was separated by filtration and the bound radioactivity determined. Non specific binding was determined by addition of 10−4 M atropine. At least six concentrations were assayed in duplicate to generate individual displacement curves.
COMPOUNDS | BINDING TO RECEPTOR | ||
No | M3 (IC50 nM) | ||
ATROPINE | 3.2 | ||
IPRATROPIUM | 3.0 | ||
1 | 31 | ||
2 | 15 | ||
7 | 22 | ||
8 | 4.8 | ||
17 | 14 | ||
18 | 6.6 | ||
20 | 6.8 | ||
35 | 13 | ||
36 | 2.7 | ||
39 | 3.8 | ||
44 | 4.4 | ||
53 | 5.6 | ||
71 | 8.2 | ||
74 | 16 | ||
77 | 3.1 | ||
78 | 5 | ||
84 | 9.9 | ||
89 | 5.4 | ||
99 | 31 | ||
100 | 14 | ||
101 | 7.6 | ||
109 | 31 | ||
114 | 14 | ||
116 | 23 | ||
126 | 13 | ||
127 | 16 | ||
128 | 8.8 | ||
129 | 6.3 | ||
136 | 11 | ||
137 | 6.9 | ||
138 | 19 | ||
146 | 13 | ||
- (1) M. Waelbroek, M. Tastenoy, J. Camus, J Christophe. Binding of selective antagonists to four muscarinic receptors (M1 to M4) in rat forebrain. Mol. Pharmacol. (1990) 38: 267-273.
Our results show that the compounds of the present invention have affinities for the M3 receptors which are very similar to the reference compounds.
The compounds of the invention preferably have high affinities for muscarinic M3 receptors (HM3), preferably human muscarinic receptors. Affinity levels can typically be measured by in vitro assays, for example, as described above.
Preferred compounds of the invention have an IC50 (nM) value for M3 receptors of less than 35, preferably less than 25,20 or 15, more preferably less than 10, 8 or 5.
Test on Bronchospasm in Guinea Pig
The studies were performed according to Konzett and Rössler (2). Aqueous solutions of the agents to be tested were nebulized and inhaled by anaesthetized ventilated male guinea pigs (Dunkin-Hartley). The bronchial response to intravenous acetylcholine challenge was determined before and after drug administration and the percent change in pulmonary resistance at several time-points.
- 2. Konzett H., Roössler F. Versuchsanordnung zu Untersuchungen ander bronchialmuskulatur. Arch. Exp. Path. Pharmacol. 195: 71-74 (1940)
The compounds of the present invention inhibited the bronchospasm response to acetylcholine with high potency and a long duration of action.
From the above described results one of ordinary skill in the art can readily understand that the compounds of the present invention have excellent antimuscarinic activity (M3) and thus are useful for the treatment of diseases in which the muscarinic M3 receptor is implicated, including respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis, urinary diseases such as urinary incontinence and pollakinuria in neuripenia pollakinuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm and chronic cystitis and gastrointestinal diseases such as irritable bowel syndrome, spastic colitis and diverticulitis.
The present invention further provides a compound of formula (I) or a pharmaceutically acceptable composition comprising a compound of formula(I) for use in a method of treatment of the human or animal body by therapy, in particular for the treatment of respiratory, urinary or gastrointestinal disease.
The present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable composition comprising a compound of formula (I) for the manufacture of a medicament for the treatment of respiratory, urinary or gastrointestinal disease.
Further, the compounds of formula (I) and pharmaceutical compositions comprising a compound of formula (I) can be used in a method of treating respiratory, urinary or gastrointestinal disease, which method comprises administering to a human or animal patient in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I).
The present invention will be further illustrated by the following examples. The examples are given by way of illustration only and are not to be construed as limiting.
3(R)-Diphenylacetoxy-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a. The yield of final step was 500 mg, 81%. 1H-NMR (CDCl3): δ 1.72-2.18 (m, 6H), 2.35 (m, 1H), 3.0 (m, 1H), 3.23 (m, 1H), 3.59-3.88 (m, 5H), 4.0 (m, 2H), 4.30 (m, 1H), 5.1 (s, 1H), 5.25 (m, 1H), 6.8-6.9 (m, 2H), 6.9-7.0 (m, 1H), 7.2-7.4 (m, 12H); MS [M-Br]+: 456; mp 129° C.
3(R)-(2-Hydroxy-2,2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 280 mg,42%. 1H-NMR (DMSO-d6): δ 1.5-1.7 (m, 2H), 1.9-2.1 (m, 4H), 2.3 (m, 1H), 3.1 (m, 1H), 3.2-3.5 (m, 6H), 3.9-4.1 (m, 3H), 5.25 (m, 1H), 6.8 (bs, OH), 6.95 (m, 3H), 7.2-7.5 (m, 12H); MS [M-Br]+: 472; mp 199° C.
3(R)-[2,2-Bis(4-fluorophenyl)-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 400 mg,85%. 1H-NMR (DMSO-d6): δ 1.5-1.65 (m, 1H), 1.7-1.8 (m, 1H), 1.85-2.0 (m, 2H), 2.05-2.2 (m, 2H), 2.3 (m, 1H), 3.1-3.2 (m, 1H), 3.3-3.5 (m,6H), 3.95 (m, 1H), 4.05 (m, 2H), 5.25 (m, 1H), 6.9-7.0 (m, 4H), 7.1-7.5 (m, 10H); MS [M-Br]+: 508; mp 253° C.
3(R)-[2,2-Bis(4-fluorophenyl)-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 300 mg,67%. 1H-NMR (DMSO-d6): δ 1.5-1.65 (m, 1H), 1.7-1.85 (m, 1H), 1.85-2.1 (m, 2H), 2.3 (m, 1H), 2.9-3.1 (m, 2H), 3.15-3.25 (m, 1H), 3.3-3.6 (m, 6H), 3.95-4.05 (m, 1H), 5.25 (m, 1H), 6.95 (s, OH), 7.1-7.5 (m, 13H); MS [M-Br]+: 478; mp 182° C.
3(R)-(2-Hydroxy-2,2-di-p-tolylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 500 mg, 54%. 1H-NMR (DMSO-d6): δ 1.55-1.8 (m, 2H), 1.85-2.0 (m, 2H), 2.05-1.15 (m, 2H), 2.3 (s, 7H), 3.05-3.15 (m, 1H), 3.25-3.5 (m, 6H), 3.95 (m, 1H), 4.05 (t, 2H), 5.2 (m, 1H), 6.8 (s, OH), 6.95 (m, 3H), 7.1-7.2 (m, 4H), 7.2-7.35 (m, 6H); MS [M-Br]+: 500; mp 183° C.
3(R)-(2-Hydroxy-2,2-di-p-tolylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 650 mg, 74%. 1H-NMR (DMSO-d6): δ 1.55-1.8 (m, 2H), 1.85-2.05 (m, 2H), 2.25 (s, 7H), 2.9-3.05 (m, 2H), 3.1-3.25 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 5.25 (m, 1H), 6.8 (s, OH), 7.1-7.2 (m, 4H), 7.2-7.35 (m, 9H); MS [M-Br]+: 470; mp 144° C.
3(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods e and a. The yield of final step was 250 mg, 61%. 1H-NMR (CDCl3): δ 1.47-1.60 (m, 1H), 1.8-2.0 (m, 1H), 2.0 (s, 3H), 2.0-2.15 (m, 4H), 2.39 (s, 1H), 2.6 (m, 1H), 2.92 (d, 1H), 3.6 (m, 1H), 3.7-3.9 (m, 4H), 4.0 (m, 2H), 4.3 (m, 1H), 5.25 (m, 1H), 6.85 (m, 2H), 7.0 (m, 1H), 7.3 (m, 12H); MS [M-Br]+: 470; mp 186° C.
3(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised as a mixture of diastereomers according to methods c and a. The yield of final step was 520 mg, 62%.1H-NMR (DMSO-d6): δ 1.5-1.95 (m, 4H), 2.1 (m, 2H), 2.3 (m, 1H), 3.1 (m, 1H), 3.3-3.5 (m, 6H), 3.9 (m, 1H), 4.05 (t, 2H), 5.2 (m, 1H), 7.0 (m, 4H), 7.15 (m, 2H), 7.35 (m, 5H), 7.5 (m, 3H); MS [M-Br]+: 478; mp 220° C.
3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b from intermediate I-4f, diastereomer 1. The yield of final step was 10 mg, 23%. 1H-NMR (DMSO-d6): δ 1.5-1.6 (m, 1H), 1.65-1.75 (m, 1H), 1.8-2.0 (m, 2H), 2.05-2.1 (m, 2H), 2.3 (m, 1H), 3.05-3.2 (m, 1H), 3.25-3.55 (m, 6H), 3.85-3.95 (m, 1H), 4.0 (t, 2H), 5.2 (m, 1H), 6.95 (m, 3H), 7.03 (m, 1H), 7.15 (dd, 1H), 7.2 (s, OH), 7.3-7.5 (m, 5H), 7.45-7.55 (m, 3H); MS [M-CF3COO]+: 478.
3(R)-[2(S)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenoxy propyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b from intermediate I-4f, diastereomer 2. The yield of final step was 3 mg, 11%. 1H-NMR (DMSO-d6): δ 1.6-1.75 (m, 2H), 1.8-2.0 (m, 4H), 2.25 (m, 1H), 2.8 (t, 2H), 2.95-3.1 (m, 1H), 3.15-3.5 (m, 6H), 3.8-3.95 (m, 1H), 5.2 (m, 1H), 6.92 (m, 1H), 6.96-7.03 (m, 2H), 7.1 (dd, 1H), 7.18 (s, OH), 7.3-7.4 (m, 4H), 7.43-7.5 (m, 2H), 7.51 (dd, 1H); MS [M-CF3COO]+: 478.
3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b from intermediate I-4f, diastereomer 1. The yield of final step was 9 mg, 22%. 1H-NMR (DMSO-d6): δ 1.45-1.55 (m, 1H), 1.65-1.75 (m, 1H), 1.85-2.05 (m, 2H), 2.3 (m, 1H), 2.9-3.1 (m, 2H), 3.1-3.25 (m, 1H), 3.25-3.55 (m, 6H), 3.9-4.0 (m, 1H), 5.25 (m, 1H), 7.05 (m, 1H), 7.15 (m, 1H), 7.2 (m, 1H), 7.25-7.4 (m, 8H), 7.45 (m, 2H, 7.55 (m, 1H); MS [M-CF3COO]+: 448.
3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b from intermediate I-4f, diastereomer 1. The yield of final step was 11 mg, 26%. 1H-NMR (DMSO-d6): δ 1.45-1.55 (m, 1H), 1.6-1.75 (m, 1H), 1.8-2.0 (m, 4H), 2.25 (m, 1H), 2.55 (t, 2H), 3.0-3.1 (m, 1H), 3.15-3.55 (m, 6H), 3.8-3.9 (m, 1H), 5.2 (m, 1H), 7.0 (m, 1H), 7.1 (m, 1H), 7.15-7.4 (m, 9H), 7.45 (m, 2H), 7.5 (m, 1H); MS [M-CF3COO]+: 462.
3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b from intermediate I-4f, diastereomer 1. The yield of final step was 10 mg, 24%. 1H-NMR (DMSO-d6): δ 1.45-1.55 (m, 1H), 1.65-1.75 (m, 1H), 1.8-2.0 (m, 2H), 2.3 (m, 1H), 3.1-3.6 (m, 9H), 3.9-4.0 (m, 1H), 5.25 (m, 1H), 7.0 (m, 3H), 7.15 (dd, 1H), 7.2 (s, OH), 7.3-7.4 (m, 3H), 7.45-7.55 (m, 4H); MS [M-CF3COO]+: 454.
3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b from intermediate I-4f, diastereomer 1. The yield of final step was 8 mg, 19%. 1H-NMR (DMSO-d6): δ 1.45-1.6 (m, 1H), 1.65-1.75 (m, 1H), 1.8-2.05 (m, 4H), 2.25 (m, 1H), 2.8 (t, 2H), 3.0-3.15 (m, 1H), 3.2-3.5 (m, 6H), 3.8-3.95 (m, 1H), 5.2 (m, 1H), 6.92 (m, 1H), 6.96-7.03 (m, 2H), 7.13 (dd, 1H), 7.2 (s, OH), 7.3-7.4 (m, 4H), 7.45-7.5 (m, 2H), 7.52 (dd, 1H); MS [M-CF3COO]+: 468.
3(R)-[2(S)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b from intermediate I-4f, diastereomer 2. The yield of final step was 7 mg, 26%. 1H-NMR (DMSO-d6): δ 1.6-1.75 (m, 2H), 1.8-2.0 (m, 4H), 2.25 (m, 1H), 2.8 (t, 2H), 2.95-3.1 (m, 1H), 3.15-3.5 (m, 6H), 3.8-3.95 (m, 1H), 5.2 (m, 1H), 6.92 (m, 1H), 6.96-7.03 (m, 2H), 7.1 (dd, 1H), 7.18 (s, OH), 7.3-7.4 (m, 4H), 7.43-7.5 (m, 2H), 7.51 (dd, 1H); MS [M-CF3COO]+: 468.
3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(2-phenoxy ethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b from intermediate I-4f, diastereomer 1. The yield of final step was 11 mg, 26%. 1H-NMR (DMSO-d6): δ 1.5-1.6 (m, 1H), 1.65-1.75 (m, 1H), 1.8-2.0 (m, 2H), 2.25 (m, 1H), 3.15-3.6 (m, 5H), 3.7 (m, 2H), 4.0 (m, 2H), 4.4 (m, 2H), 5.25 (m, 1H), 6.95-7.03 (m, 4H), 7.12 (dd, 1H), 7.2 (s, OH), 7.3-7.4 (m, 5H), 7.4-7.5 (m, 3H); MS [M-CF3COO]+: 464.
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised as a mixture of diastereomers according to methods c and a. The yield of final step was 240 mg, 77%. 1H-NMR (DMSO-d6): δ 1.55-2.0 (m, 4H), 2.27 (m, 1H), 3.05-3.55 (m, 5H), 3.88-3.98 (m, 1H), 4.0-4.10 (m, 2H), 5.21 (m, 1H), 6.23-6.31 (doble dd, 1H), 6.36-6.48 (m, 2H), 6.83-6.90 (dd, 1H), 6.95 (d, OH), 7.26-7.66 (m, 11H); MS [M-Br]+: 444; mp 99° C.
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised as a mixture of diastereomers according to methods c and a. The yield of final step was 210 mg, 66%. 1H-NMR (DMSO-d6): δ 1.50-2.05 (m, 4H), 2.27 (m, 1H), 3.20 (m, 1H), 3.37-3.65 (m, 4H), 3.65-3.75 (m, 2H), 4.04 (m, 1H), 4.40 (m, 2H), 5.21 (m, 1H), 6.23-6.32 (doble dd, 1H), 6.44 (m, 1H), 6.94-7.04 (m, 4H), 7.33-7.50 (m, 7H), 7.64 (m, 1H); MS [M-Br]+: 448; mp 163° C.
3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(2-phenoxy ethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b from intermediate I-la, diastereomer 1. The yield of final step was 11 mg, 23%. 1H-NMR (DMSO-d6): δ 1.65-1.80 (m, 2H), 1.80-2.10 (m, 2H), 2.27 (m, 1H), 3.15-3.65 (m, 5H), 3.68 (m, 2H), 4.0 (m, 1H), 4.40 (t, 2H), 5.20 (m, 1H), 6.23 (d, 1H), 6.42 (m, 1H), 6.92-7.04 (m, 4H), 7.30-7.38 (m, 5H), 7.44-7.50 (m, 2H), 7.64 (m, 1H); MS [M-CF3COO]+: 448.
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound has been described in method-a-.
3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-phenoxy propyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a from intermediate I-1a, diastereomer 1. The yield of final step was 1.15 g 99%. 1H-NMR (DMSO-d6): δ 1.60-2.20 (m, 6H), 2.25 (m, 1H), 3.10 (m, 1H), 3.20-3.60 (m, 6H), 3.95 (m, 1H), 4.05 (m, 2H), 5.20 (m, 1H), 6.25 (dd, 1H), 6.45 (m, 1H), 6.95 (m, 4H), 7.30-7.50 (m, 7H), 7.70 (m, 1H); MS [M-Br]+: 462; mp 156° C.
3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-phenoxy propyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b from intermediate I-la, diastereomer 2. The yield of final step was 10 mg, 20%. 1H-NMR (DMSO-d6): δ 1.50-2.20 (m, 6H), 2.25 (m, 1H), 3.10 (m, 1H), 3.20-3.60 (m, 6H), 3.95 (m, 1H), 4.05 (m, 2H), 5.20 (m, 1H), 6.35 (dd, 1H), 6.45 (m, 1H), 6.95 (m, 4H), 7.30-7.50 (m, 7H), 7.70 (m, 1H); MS [M-CF3COO]+: 462.
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised as a mixture of diastereomers according to methods c and b. The yield of final step was 12 mg, 13%. 1H-NMR (DMSO-d6): δ 1.5 (m, 1H), 1.7 (m, 1H), 1.9-2.05 (m, 2H), 2.3 (m, 1H), 2.95 (m, 2H), 3.15 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H), 5.25 (m, 1H), 6.3 (d, 1H), 6.45 (m, 1H), 6.95 (d, 1H), 7.25-7.45 (m, 8H), 7.5 (m, 2H), 7.7 (m, 1H); MS [M-CF3COO]+: 432.
3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b from intermediate I-1a, diastereomer 1. The yield of final step was 16 mg, 40%. 1H-NMR (DMSO-d6): δ 1.65-1.80 (m, 2H), 1.90-2.05 (m, 2H), 2.3 (m, 1H), 2.95 (m, 2H), 3.15 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H), 5.25 (m, 1H), 6.26 (dd, 1H), 6.46 (m, 1H), 6.95 (s, 1H, OH), 7.25-7.45 (m, 8H), 7.5 (m, 2H), 7.7 (m, 1H); MS [M-CF3COO]+: 432.
3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b from intermediate I-la, diastereomer 2. The yield of final step was 14 mg, 35% 1H-NMR (DMSO-d6): δ 1.50-1.80 (m, 2H), 1.90-2.05 (m, 2H), 2.3 (m, 1H), 2.95 (m, 2H), 3.15 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H), 5.25 (m, 1H), 6.32 (dd, 1H), 6.46 (m, 1H), 6.95 (s, 1H, OH), 7.25-7.45 (m, 8H), 7.5 (m, 2H), 7.7 (m, 1H) MS [M-CF3COO]+: 432.
3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b from intermediate I-la, diastereomer 1. The yield of final step was 10 mg, 21%. 1H-NMR (DMSO-d6): δ 1.60-1.75 (m, 2H), 1.80-2.0 (m, 4H), 2.25 (m, 1H), 2.50-2.60 (m, 2H), 3.0 (m, 1H), 3.10-3.50 (m, 6H), 3.83 (m, 1H), 5.17 (m, 1H), 6.25 (d, 1H), 6.45 (m, 1H), 6.95 (s, 1H), 7.20-7.40 (m, 8H), 7.46-7.48 (m, 2H), 7.66 (m, 1H); MS [M-CF3COO]+: 446.
3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b from intermediate I-la, diastereomer 1. The yield of final step was 9 mg, 19%. 1H-NMR (DMSO-d6): δ 1.65-1.80 (m, 2H), 1.85-2.05 (m, 2H), 2.30 (m, 1H), 3.10-3.40 (m, 3H), 3.40-3.60 (m, 6H), 3.95 (m, 1H), 5.24 (m, 1H), 6.27 (d, 1H), 6.47 (m, 1H), 6.96 (s, 1H), 7.0-7.04 (m 2H), 7.36-7.48 (m, 4H), 7.49-7.54 (m, 2H), 7.70 (m, 1H).; MS [M-CF3COO]+: 438.
3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesized according to methods c and b from intermediate I-1a, diastereomer 1. The yield of final step was 9 mg, 19%. 1H-NMR (DMSO-d6): δ 1.60-1.75 (m, 2H), 1.80-2.05 (m, 4H), 2.26 (m, 1H), 2.81 (t, 2H), 3.02 (m, 1H), 3.10-3.45 (m, 6H), 3.85 (m, 1H), 5.18 (m, 1H), 6.25 (d, 1H), 6.45 (m, 1H), 6.90-7.0 (m, 3H), 7.32-7.42 (m, 4H), 7.45-7.51 (m, 2H), 7.66 (m, 1H); MS [M-CF3COO]+: 452.
3(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised as a mixture of diastereomers according to methods c and b. The yield of final step was 18 mg, 20%. 1H-NMR (DMSO-d6): δ 1.65-2.05 (m, 4H), 2.3 (m, 1H), 3.0 (m, 2H), 3.15-3.6 (m, 7H), 3.95 (m, 1H), 5.25 (m, 1H), 6.35 (dd, 1H), 6.45 (m, 1H), 7.05 (m, 1H), 7.2 (dd, 1H), 7.25-7.5 (m, 6H), 7.55 (m, 1H), 7.65 (m, 1H); MS [M-CF3COO]+: 438.
3(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy)-1 -(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised as a mixture of diastereomers according to methods c and b. The yield of final step was 22 mg, 23%. 1H-NMR (DMSO-d6): δ 2.65-2.05 (m, 4H), 2.3 (m, 1H), 3.15-3.65 (m, 7H), 4.05 (m, 1H), 4.4 (m, 2H), 5.15 (m, 1H), 6.35 (dd, 1H), 6.45 (m, 1H), 6.95-7.05 (m, 4H), 7.15 (d, 1H), 7.3-7.4 (m, 3H), 7.5 (dd, 1H), 7.65 (d, 1H); MS [M-CF3COO]+: 454.
3(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised as a mixture of diastereomers according to methods c and b. The yield of final step was 15.4 mg, 15%. 1H-NMR (DMSO-d6): δ 1.65-2.1 (m, 6H), 7.05-7.55 (m, 9H), 3.95 (m, 1H), 5.1 (m, 1H), 6.35 (dd, 1H), 6.5 (m, 1H), 7.05 (m, 1H), 7.15 (m, 1H), 7.3 (d, 1H), 7.55 (m, 3H), 7.7 (dd, 2H), 8.0 (d, 2H); MS [M-CF3COO]+: 480.
1-(3-phenoxypropyl)-3(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-yl-acetoxy)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised as a mixture of diastereomers according to methods c and a. The yield of final step was 100 mg, 41%. 1H-NMR (DMSO-d6): δ 1.65-2.05 (m, 4H), 2.1-2.0 (m, 2H), 2.3 (m, 1H), 3.15 (m, 1H), 3.25-3.6 (6H), 3.9-4.1 (m, 3H), 5.1 (m, 1H), 6.35 (d, 1H), 6.45 (s, 1H), 6.95 (m, 3H), 7.05 (m, 1H), 7.2 (d, 1H), 7.3 (m, 3H), 7.55 (d, 1H), 7.7 (s, 1H); MS [M-Br]+: 520; mp 173° C.
1-(3-phenoxypropyl)-3(R)-(2,2-difuran-2-yl-2-hydroxy acetoxy)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods f and a. The yield of final step was 200 mg, 60%. 1H-NMR (DMSO-d6): δ 1.6-2.20 (m, 6H), 2.3 (m, 1H), 2.95-3.65 (m, 7H), 3.80-4.10 (m, 3H), 5.2 (m, 1H), 6.3-6.6 (m, 4H), 6.8-7.0 (m, 3H), 7.1 (s, OH), 7.3 (m, 2H), 7.7 (m, 2H); MS [M-Br]+: 452.
3(R)-(2,2-Dithien-2-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 240 mg, 60%. 1H-NMR (DMSO-d6): δ 1.85-2.10 (m, 4H), 2.30 (s, 1H), 3.40 (m, 1H), 3.44-3.80 (m, 6H), 4.10 (m, 1H), 4.45 (m, 2H), 5.20 (m, 1H), 5.90 (s, 1H), 6.95-7.05 (m, 5H), 7.05-7.15 (m, 2H), 7.30-7.40 (m, 2H), 7.45 (m, 2H); MS [M-Br]+: 454; mp 98° C.
3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 280 mg, 83%. 1H-NMR (DMSO-d6): δ 1.80-2.06 (m, 4H), 2.06-2.20 (m, 2H), 2.20-2.30 (m, 1H), 3.20-3.65 (m, 7H), 3.90-4.10 (m, 3H), 5.20 (m, 1H), 5.90 (s, 1H), 6.95-7.05 (m, 5H), 7.05-7.20 (m, 2H), 7.30-7.35 (m, 2H), 7.50 (m, 2H); MS [M-Br]+: 468; mp 148° C.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 180 mg, 59%. 1H-NMR (DMSO-d6): δ 1.65-2.0 (4H, m), 2.35 (m, 1H), 3.0 (m, 2H), 3.2-3.6 (m, 7H), 3.95 (m, 1H), 5.25 (m, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.35 (m, 5H), 7.55 (m, 3H); MS [M-Br]+: 454; mp 216° C.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 450 mg, 58%. 1H-NMR (CDCl3): δ 1.8-2.1 (m, 6H), 2.4 (m, 1H), 2.6 (m, 2H), 3.4-3.8 (m, 7H), 4.2 (m, 1H), 5.25 (m, 1H), 6.1 (bs, OH), 6.9 (m, 2H), 7.1-7.3 (m, 9H); MS [M-Br]+: 468; mp 64° C.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 260 mg, 34%. 1H-NMR (CDCl3): δ 1.8-2.05 (m, 4H), 2.4 (m, 1H), 3.55-3.95 (m, 5H), 4.15-4.5 (m, 3H), 5.25 (m, 1H), 5.9 (s, OH), 6.15 (m, 1H), 6.85 (t, 1H), 6.9-7.05 (m, 3H), 7.15 (m, 1H), 7.2-7.45 (m, 7H); MS [M-Br]+: 466; mp 124° C.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 320 mg, 40%. 1H-NMR (CDCl3): δ 1.6-2.0 (m, 8H), 2.4 (m, 1H), 2.6 (m, 2H), 3.4-3.8 (m, 7H), 4.2 (m, 1H), 5.25 (m, 1H), 6.05 (bs, OH), 6.95 (m, 2H), 7.1-7.3 (m, 9H); MS [M-Br]+: 482; mp 64° C.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 16 mg, 15%. 1H-NMR (DMSO-d6): δ 1.7-2.0 (m, 6H), 2.15 (m, 1H), 3.1 (t, 2H), 3.15-3.55 (m, 7H), 3.95 (m, 1H), 5.25 (m, 1H), 7.0 (d, 2H), 7.15 (d, 2H), 7.55 (m, 5H), 7.65 (t, 1H), 8.0 (d, 2H); MS[M-CF3COO]+: 496.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylaminopropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 14 mg, 14%. 1H-NMR (DMSO-d6): δ 1.7-2.0 (m, 5H), 2.3 (m, 1H), 3.0-3.5 (m, 9H), 3.9 (m, 1H), 5.25 (m, 1H), 5.65 (t, 1H), 6.55 (m, 3H), 7.0 (d, 2H), 7.1 (t, 2H), 7.15 (m, 2H), 7.5 (m, 3H); MS[M-CF3COO]+: 483.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(methylphenylamino)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 20 mg, 19%. 1H-NMR (DMSO-d6): δ 1.65-2.0 (m, 6H), 2.9 (s, 3H), 3.1 (m, 1H), 3.2-3.45 (m, 8H), 3.95 (m, 1H), 5.2 (m, 1H), 6.65 (t, 1H), 6.75 (d, 2H), 7.0 (m, 2H), 7, 2 (m, 4H), 7.5 (m, 3H); MS [M-CF3COO]+: 497.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 800 mg, 83%. 1H-NMR (DMSO-d6): δ 1.6-1.9 (m, 6H), 2.3 (m, 1H), 2.95 (t, 2H), 3.05 (m, 1H), 3.2-3.5 (m, 6H), 3.9 (m, 1H), 5.2 (m, 1H), 7.0 (m, 2H), 7.15 (m, 2H), 7.2 (m, 1H), 7.35 (m, 4H), 7.5 (m, 2H); MS [M-Br]+: 500.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 490 mg, 90%. 1H-NMR (DMSO-d6): δ 1.7 (m, 2H), 1.95 (m, 2H), 2.1 (m, 2H), 2.3 (m, 1H), 3.2 (m, 1H), 3.45 (m, 6H), 4.0 (m, 3H), 5.15 (m, 1H), 6.9 (m, 3H), 7.0 (m, 2H), 7.2 (m, 2H), 7.3 (t, 2H), 7.5 (m, 3H); MS [M-Br]+: 484; mp 227° C.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-otolyloxypropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b The yield of final step was 19 mg, 18%. 1H-NMR (DMSO-d6): δ 1.7-2.0 (m, 4H), 2.1-2.2 (m, 5H), 2.3 (m, 1H), 3.15-3.5 (m, 7H), 3.9-4.05 (m, 3H), 5.05 (m, 1H), 6.85 (t, 1H), 6.9 (d, 1H), 7.0 (m, 2H), 7.15 (m, 4H), 7.5 (m, 3H); MS [M-CF3COO]+: 498.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2,4,6-trimethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 22 mg, 20%. 1H-NMR (DMSO-d6): δ 1.7 (m, 2H), 1.95 (m, 2H), 2.1 (m, 2H), 2.2 (s, 9H), 2.35 (m, 1H), 3.2-3.5 (m, 7H), 3.7 (t, 2H), 3.95 (m, 1H), 5.25 (m, 1H), 6.8 (s, 2H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (m, 3H); MS [M-CF3COO]+: 526.
1-[3-(2-tert-Butyl-6-methylphenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 18 mg, 16%. 1H-NMR (DMSO-d6): δ 1.3 (s, 9H), 2.7 (m, 2H), 2.9 (m, 2H), 2.1 (m, 2H), 2.2 (s, 3H), 2.3 (m, 1H), 3.2-3.5 (m, 7H), 3.8 (t, 2H), 5 3.95 (m, 1H), 5.2 (m, 1H), 6.9-7.15 (m, 7H), 7.5 (m, 3H); MS [M-CF3COO]+: 554.
1-[3-(Biphenyl-4-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]-octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 22 mg, 19%. 1H-NMR (DMSO-d6): δ 1.7 (m, 2H), 1.9 (m, 2H), 2.15 (m, 2H), 2.3 (m, 1H), 3.2-3.5 (m, 7H), 3.95 (m, 1H), 4.1 (t, 2H), 5.25 (m, 1H), 7.0 (m, 4H), 7.2 (m, 2H), 7.3 (t, 1H), 7.45 (t, 2H), 7.5 (m, 3H), 7.6 (m, 4H); MS [M-CF3COO]+: 560.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 23 mg, 21%. 1H-NMR (DMSO-d6): δ 1.7 (m, 6H), 1.9-2.1 (m, 4H), 2.3 (m, 1H), 2.65 (m, 4H), 3.15-3.5 (m, 7H), 3.95 (m, 2H), 5.25 (m, 1H), 6.65 (m, 2H), 6.95 (d, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (m, 3H); MS [M-CF3COO]+: 538.
The title compound was synthesised according to methods c and b. The yield of final step was 17 mg, 15%. 1H-NMR (DMSO-d6): δ 1.7-2.0 (m, 4H), 2.1 (m, 1H), 2.35 (m, 1H), 3.15-3.35 (m, 7H), 3.95 (m, 1H), 4.17 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.15 (m, 3H), 7.35 (m, 2H), 7.5 (m, 4H), 7.85 (m, 3H); MS [M-CF3COO]+: 534.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound has been described in method-b-.
1-[3-(2-Chlorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 20 mg, 18%. 1H-NMR (DMSO-d6): δ 1.65-2.0 (m, 6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t, 2H), 5.25 (m, 2H), 7.0 (m, 3H), 7.2 (m, 3H), 7.35 (t, 1H), 7.45 (d, 1H), 7.55 (m, 3H); MS [M-CF3COO]+: 519.
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Chloride
The title compound was synthesised according to methods c and a. The yield of final step was 180 mg, 59%. 1H-NMR (DMSO-d6): δ 1.65-2.15 (m, 6H), 2.25 (m, 1H), 3.2 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 2H), 4.0 (t, 2H), 5.25 (m, 1H), 7.0 (m, 4H), 7.15 (m, 4H), 7.55 (m, 3H); MS [M-Cl]+: 502; mp 160° C.
1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 14 mg, 13%. 1H-NMR (DMSO-d6): δ 1.65-2.0 (m, 4H), 2.15 (m, 2H), 2.35 (m, 1H), 3.2 (m, 1H), 3.25-3.35 (m, 6H), 3.95 (m, 1H), 4.1 (t, 2H), 5.15 (m, 1H),! 7.05 (m, 3H), 7.2 (d, 2H), 7.25-7.35 (m, 2H), 7.55 (m, 3H); MS [M-CF3COO]+: 520.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-trifluoromethyl phenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 17%. 1H-NMR (DMSO-d6): δ 1.65-2.1 (m, 6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.25-7.35 (m, 3H), 7.5-7.6 (m, 4H); MS [M-CF3COO]+: 552.
1-[3-(3-Cyanophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 18 mg, 17%. 1H-NMR (DMSO-d6): δ 1.65-2.1 (m, 6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7, 18 (m, 2H), 7.3 (d, 1H), 7.45 (m, 2H), 7.55 (m, 4H); MS [M-CF3COO]+: 509.
1-[3-(4-Cyanophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 180 mg, 53%. 1H-NMR (DMSO-d6): δ 1.65-2.2 (m, 6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.1 (d, 2H), 7.15 (m, 2H), 7.5 (m, 2H), 7.8 (d, 2H); MS [M-Br]+: 509; mp 158° C.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 18%. 1H-NMR (DMSO-d6): δ 1.65-2.15 (m, 6H), 2.15 (m, 1H), 3.2 (m, 1H), 3.3-3.5 (m, 6H), 3.75 (s, 3H), 3.95 (m, 1H), 4.0 (t, 2H), 5.25 (m, 1H), 6.55 (m, 3H), 7.0 (m, 2H), 7.2 (m, 3H), 7.55 (m, 3H); MS [M-CF3COO]+: 514.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 14 mg, 13%. 1H-NMR (DMSO-d6): δ 1.65-2.15 (m, 6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.7 (s, 3H), 3.9-4.0 (m, 3H), 5.25 (m, 1H), 6.9 (s, 4H), 7.0 (m, 2H), 7.15 (m, 2H), 7.5 (m, 3H); MS [M-CF3COO]+: 514.
1-[3-(Benzo[1,3]dioxol-5-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo [2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 17%. 1H-NMR (DMSO-d6): δ 1.65-2.15 (m, 7H), 2.3 (m, 1H), 3.15 (m, 1H), 3.25-3.5 (m, 6H), 3.9-4.0 (m, 3H), 5.25 (m, 1H), 5.95 (s, 2H), 6.4 (d, 1H), 6.65 (s, 1H), 6.85 (d, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (m, 3H); MS [M-CF3COO]+: 528.
1-[3-(2-Carbamoylphenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 18 mg, 16%.1H-NMR (DMSO-d6): δ 1.65-2.0 (m, 4H), 2.2 (m, 2H), 2.3 (m, 1H), 3.15 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t, 2H), 5.25 (m, 1H), 7.0-7.2 (m, 6H), 7.4-7.6 (m, 6H), 7.7 (d, 1H); MS [M-CF3COO]+: 527.
1-[3-(3-Dimethylaminophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 17%. 1H-NMR (DMSO-d6): δ 1.65-2.15 (m, 6H), 2.3 (m, 1H), 2.85 (s, 6H), 3.1-3.5 (m, 7H), 3.85-4.0 (m, 3H), 5.25 (m, 1H), 6.2 (m, 1H), 6.25 (d, 1H), 6.35 (d, 1H), 7.0 (m, 2H), 7.1 (t, 1H), 7.2 (m, 2H), 7.5 (m, 3H); MS [M-CF3COO]+: 527.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 22 mg, 20%. 1H-NMR (DMSO-d6): δ 1.65-2.0 (m, 4H), 2.2 (m, 2H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3 3.5 (m, 6H), 3.95 (m, 1H), 4.2 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.15 (m, 4H), 7.5 (m, 3H), 8.15 (d, 2H); MS [M-CF3COO]+: 529.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 18 mg, 16%. 1H-NMR (DMSO-d6): δ 1.65-2.2 (m, 6H), 2.3 (m, 1H), 3.15-3.55 (m, 7H), 3.95 (m, 1H), 4.2 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.45 (dd, 1H), 7.55 (m, 3H), 7.6 (t, 1H), 7.75 (s, 1H), 7.85 (d, 1H); MS [M-CF3COO]+: 529.
1-[3-(4-Acetylaminophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 17%. 1H-NMR (DMSO-d6): δ 1.65-2.15 (m, 6H), 2.0 (s, 3H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.9-4.0 (m, 3H), 5.25 (m, 1H), 6.85 (d, 2H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (m, 5H), 9.8 (s, 1H); MS [M-CF3COO]+: 541.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-methoxycarbonylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 18 mg, 16%. 1H-NMR (DMSO-d6): δ 1.65-2.2 (m, 6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.5 (m, 6H), 3.85 (s, 3H), 3.95 (m, 1H), 4.1 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.15 (m, 2H), 7.25 (dd, 1H), 7.45-7.6 (m, 6H); MS [M-CF3COO]+: 542.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-{3-[4-(3-hydroxypropyl)phenoxy]propyl}-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 14 mg, 13%. 1H-NMR (DMSO-d6): δ 1.6-2.15 (m, 8H), 2.3 (m, 1H), 2.55 (t, 2H), 3.2 (m, 1H), 3.25-3.55 (m, 9H), 3.85-4.0 (m, 3H), 4.45 (t, OH), 5.25 (m, 1H), 7.85 (d, 2H), 7.0 (m, 2H), 7.1 (d, 2H), 7.15 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO]+: 542.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 16 mg, 15%. 1H-NMR (DMSO-d6): δ 1.7-2.2 (m, 6H), 2.35 (m, 1H), 3.1-3.5 (m, 7H), 3.9-4.05 (m, 3H), 4.5 (m, 2H), 5.0 (t, OH), 5.15 (m, 1H), 6.9-7.05 (m, 4H), 7.2 (m, 2H), 7.4 (d, 1H), 7.5 (m, 3H); MS [M-CF3COO]+: 514.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 16 mg, 15%. 1H-NMR (DMSO-d6): δ 1.7-2.2 (m, 6H), 2.35 (m, 1H), 3.15-3.5 (m, 7H), 3.9 (m, 1H), 4.05 (t, 2H), 4.45 (d, 2H), 5, 25 (m, 2H), 6.8 (d, 1H), 6.9 (m, 2H), 7.2 (m, 2H), 7.25 (t, 1H), 7.5 (m, 3H); MS [M-CF3COO]+: 514.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 17 mg, 16%. 1H-NMR (DMSO-d6): δ 1.65-2.2 (m, 6H), 2.3 (m, 1H), 3.15-3.55 (m, 7H), 3.9-4.05 (m, 3H), 4.4 (d, 2H), 5.1 (t, OH), 5.25 (t, 1H), 6.9 (d, 2H), 7.0 (m, 2H), 7.2 (m, 2H), 7.25 (d, 2H), 7.5 (m, 3H); MS [M-CF3COO]+: 514.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 24 mg, 19%. 1H-NMR (DMSO-d6): δ 1.65-2.15 (m, 6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H), 4.0 (t, 2H), 5.25 (m, 1H), 6.7-6.85 (m, 3H), 6.95 (d, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (m, 3H), 8.85 (s, OH); MS [M-CF3COO]+: 500.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 16 mg, 15%. 1H-NMR (DMSO-d6): δ 1.65-2.1 (m, 6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.25-3.5 (m, 6H), 3.95 (m, 3H), 5.25 (m, 1H), 6.7 (d, 2H), 6.75 (d, 2H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (t, 3H), 9.0 (s, OH); MS [M-CF3COO]+: 500.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 16 mg, 15%. 1H-NMR (DMSO-d6): δ 1.65-2.15 (m, 6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.9-4.0 (m, 3H), 5.25 (m, 1H), 6.9-6.0 (m, 3H), 7.0-7.1 (m, 3H), 7.2 (m, 2H), 7.5 (m, 3H), 9.45 (s, OH); MS [M-CF3COO]+: 500.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 21 mg, 22%. 1H-NMR (DMSO-d6): δ 1.65-1.8 (m, 2H), 1.8-2.0 (m, 2H), 2.0-2.15 (m, 2H), 2.3 (m, 1H), 3.05-3.2 (m, 3H), 3.2-3.5 (m, 4H), 3.8-3.95 (m, 3H), 5.2 (m, 1H), 6.05 (t, 2H), 6.75 (t, 2H), 7.0 (t, 2H), 7.15 (d, 2H), 7.55 (m, 3H);MS [M-CF3COO]+: 457.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-oxo-4-thien-2-ylbutyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 18 mg, 17%. 1H-NMR (DMSO-d6): δ 1.7-1.85 (m, 2H), 1.9-2.1 (m, 4H), 2.3 (m, 1H), 3.1 (t, 2H), 3.15-3.55 (m, 7H), 3.95 (m, 1H), 5.25 (m, 1H), 7.0 (t, 2H), 7.4 (d, 2H), 7.25 (t, 1H), 7.55 (m, 3H), 7.95 (d, 1H), 8.05 (d, 1H); MS [M-CF3COO]+: 502.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(1-methyl[1H]-imidazol-2-ylsulfanyl)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 26 mg, 25%. 1H-NMR (DMSO-d6): δ 1.7 (m, 2H), 1.85-2.05 (m, 4H), 2.3 (m, 1H), 3.25-3.5 (m, 7H), 3.6 (s, 3H), 3.9 (m, 1H), 4.2 (t, 2H), 5.2 (m, 1H), 7.0 (m, 3H), 7.15 (m, 2H), 7.3 (m, 1H), 7.5 (m, 3H); MS [M-CF3COO]+: 504.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 430 mg, 54%. 1H-NMR (DMSO-d6): δ 1.6-1.8 (m, 2H), 2.3 (m, 1H), 3.15-3.3 (m, 4H), 3.35-3.55 (m, 5H), 3.95 (m, 1H), 5.25 (m, 1H), 7,0 (m, 4H), 7,15 (m, 2H), 7.4-7.5 (m, 4H); MS [M-Br]+: 460; mp 206° C.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 600 mg, 77%. 1H-NMR (DMSO-d6): δ 1.6-1.8 (m, 2H), 1.85-2.1 (m, 4H), 2.3 (m, 1H), 2.8 (t, 2H), 3.1-3.5 (m, 7H), 3.9 (m, 1H), 5.2 (m, 1H), 6.9-7.05 (m, 4H), 7.15 (m, 2H), 7.4 (d, 1H), 7.5 (m, 3H); MS [M-Br]+: 474; mp 138° C.
1-[3-(Benzothiazol-2-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesized according to methods c and b. The yield of final step was 23 mg, 21%. 1H-NMR (DMSO-d6): δ 1.65-2.1 (m, 6H), 2.3 (m, 1H), 3.15 (m, 1H), 3.25-3.5 (m, 6H), 3.85 (m, 1H), 4.0 (t, 2H), 5.2 (m, 1H), 7.0 (t, 2H), 7.15 (m, 2H), 7.25 (m, 1H), 7.45 (m, 5H), 7.7 (d, 1H); MS [M-CF3COO]+: 541.
1-(3-Benzyloxypropyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 16 mg, 15%. 1H-NMR (DMSO-d6): δ 1.65 (m, 2H), 1.9 (m, 4H), 2.3 (m, 1H), 3.1-3.4 (m, 7H), 3.5 (t, 2H), 3.9 (m, 1H), 3.9 (s, 2H), 5.2 (m, 1H), 7.0 (m, 2H), 7.15 (m, 2H), 7.35 (m, 5H), 7.5 (m, 3H); MS [M-CF3COO]+: 498.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[6-(4-phenylbutoxy)hexyl]-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 560 mg, 60%. 1H-NMR (CDCl3): δ 1.2-1.75 (m, 16H), 1.8-2.1 (m, 4H), 2.4 (m, 1H), 2.6 (t, 2H), 3.3-3.75 (m, 11H), 4.2 (m, 1H), 5.3 (m, 1H), 6.0 (bs, OH), 6.95 (m, 2H), 7.15-7.3 (m, 9H); MS [M-Br]+: 582.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 240 mg, 30%. 1H-NMR (DMSO-d6/CDCl3): δ 1.8-1.95 (m, 6H), 2.1 (m, 2H), 2.45 (m, 1H), 3.18 (m, 1H), 3.5-3.8 (m, 6H), 4.0 (t, 2H), 4.15 (m, 1H) 5.15 (m, 1H), 6.7 (s, OH), 6.9 (m, 5H), 7.15 (d, 1H), 7.25 (m, 5H); MS [M-Br]+: 498; mp 161° C.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 380 mg, 50%. 1H-NMR (DMSO-d6): δ 1-85 (m, 2H), 2.05 (m, 2H), 2.4 (m, 1H), 3.6-4.1 (m, 7H), 4.35 (m, 3H), 5.25 (m, 1H), 6.0 (bs, OH), 6.9 (m, 4H), 7.0 (t, 1H), 7.1 (dd, 2H), 7.2 (dd, 2H), 7.3 (t, 2H); MS [M-Br]+: 470; mp 48° C.
1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 17 mg, 17%. 1H-NMR (DMSO-d6): δ 1.65-2.0 (m, 4H), 2.3 (m, 1H), 3.2-3.55 (m, 7H), 3.85 (m, 2H), 4.5 (s, 2H), 5.25 (m, 1H), 7.0 (t, 2H), 7.15 (t, 2H), 7.3-7.4 (m, 4H), 7.5 (m, 3H); MS [M-CF3COO]+: 484.
3(S)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 600 mg, 54%. 1H-NMR (DMSO-d6/CDCl3): δ 1.85-2.3 (m, 6H), 2.5 (m, 1H), 3.3 (m, 1H), 3.4 (d, 1H), 3.5-3.7 (m, 5H), 4.05 (t, 2H), 4.2 (m, 1H), 5.25 (m, 1H), 6.85 (d, 2H), 7.0 (m, 3H), 7.15 (m, 2H), 7.2 (d, 1H), 7.3 (m, 4H); MS [M-Br]+: 484; mp 230° C.
4-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods f and a. The yield of final step was 290 mg, 60%. 1H-NMR (DMSO-d6): δ 2.15 (m, 2H), 2.35 (m, 6H), 3.35 (m, 2H), 3.65 (m, 6H), 4.05 (t, 2H), 6.9-7.05 (m, 5H), 7.1 (m, 2H), 7.3 (m, 3H), 7.55 (m, 2H); MS [M-Br]+: 484; mp 1681C.
4-(2-Hydroxy-2,2-dithien-2-yl-acetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods f and a. The yield of final step was 260 mg, 57%. 1H-NMR (DMSO-d6): δ 2.35 (m, 6H), 3.0 (m, 2H), 3.4 (m, 2H), 3.75 (m, 6H), 7.0 (m, 2H), 7.3-7.5 (m, 6H), 7.55 (m, 2H); MS [M-Br]+: 454; mp 1951C.
1-(3-phenoxypropyl)-3(R)-(2,2-dithien-2-ylpropionyloxy)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 390 mg, 92%. 1H-NMR (DMSO-d6): δ 1.65-2.20 (m, 6H), 2.10 (s, 3H), 2.30 (bs, 1H), 3.10 (m, 1H), 3.30-3.60 (m, 6H), 3.95-4.10 (m, 3H), 5.20 (m, 1H), 6.90-7.05 (m, 5H), 7.05-7.10 (m, 2H), 7.25-7.35 (m, 2H), 7.50 (m, 2H); MS [M-Br]+: 482; mp 170° C.
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 300 mg, 76%. 1H-NMR (DMSO-d6): δ 1.6 (m, 1H), 1.75 (m, 1H), 1.8-2.0 (m, 2H), 2.0-2.2 (m, 2H), 2.3 (m, 1H), 3.15 (m, 1H), 3.3-3.6 (m, 6H), 3.9 (m, 1H), 4.05 (t, 2H), 5.2 (m, 1H), 6.75 (s, OH), 6.95 (m, 3H), 7.15 (m, 2H), 7.3 (t, 2H), 7.4-7.5 (m, 4H); MS [M-Br]+: 484; mp 2191C.
3(R)-(2-Hydroxy-2,2-dithienyl-3-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 300 mg, 77%. 1H-NMR (DMSO-d6): δ 1.5-1.6 (m, 1H), 1.6-1.75 (m, 1H), 1.8-2.1 (m, 4H), 2.25 (m, 1H), 2.8 (t, 2H), 3.05-3.5 (m, 7H), 3.8-3.95 (m, 1H), 5,15 (m, 1H), 6.75 (s, OH), 6.9-7.0 (m, 2H), 7.1 (m, 2H), 7.35-7.55 (m, 5H); MS [M-Br]+: 474; mp 1921C.
3(R)-(2-Hydroxy-2,2-dithien-3-yl-acetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 63 mg, 48%. 1H-NMR (DMSO-d6): δ 1.5-1.7 (m, 1H), 1.7-1.85 (m, 1H), 1.9-2.1 (m, 2H), 2.3 (m, 1H), 2.9-3.1 (m, 2H), 3.15-3.6 (m, 7H), 3.9-4.0 (m, 1H), 5.2 (m, 1H), 6.8 (s, OH), 7.1 (m, 2H), 7.25-7,35 (m, 5H), 7.4 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO]+: 454.
3(R)-(2-Hydroxy-2,2-dithien-3-yl-acetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 75 mg, 55%. 1H-NMR (DMSO-d6): δ 1.5-2.0 (m, 6H), 2.25 (m, 1H), 2.5-2.6 (m, 2H), 3.05-3.6 (m, 8H), 3.8-3.9 (m,1H), 5.15 (m,1H), 6.75 (s, OH), 7.1 (d, 2H), 7.2-7,35 (m, 5H), 7.4 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO]+: 468.
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 68 mg, 48%. 1H-NMR (DMSO-d6): δ 1.5-1.8 (m, 6H), 1.8-2.0 (m, 2H), 2.25 (m, 1H), 2.6 (m, 2H), 3.05 (m,1H), 3.15-3.45 (m, 6H), 3.85 (m, 1H), 5.15 (m, 1H), 6.75 (s, OH), 7.1 (d, 2H), 7.2 (m, 2H), 7,3 (m, 3H), 7.4 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO]+: 482.
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 65 mg, 49%. 1H-NMR (DMSO-d6): δ 1.5-1.65 (m, 1H), 1.65-1.78 (m, 1H), 1.85-2.05 (m, 2H), 2.3 (m, 1H), 3.1-3.6 (m, 9H), 3.95 (m, 1H), 5,2 (m, 1H), 6.75 (s, OH), 7.0 (m, 2H), 7.15 (m, 2H), 7.45 (m, 3H), 7,5 (m, 2H); MS [M-CF3COO]+: 460.
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 63 mg, 43%. 1H-NMR (DMSO-d6): δ 1.5-2.0 (m, 8H), 2.3 (m, 1H), 3.1 (m, 1H), 3.2-3.5 (m, 6H), 3.85 (m, 1H), 4.0 (m, 2H), 5.2 (m, 1H), 6.75 (s, OH), 6.95 (m, 3H), 7.1 (d, 2H), 7.2 (m, 2H), 7,3 (t, 2H), 7.45 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO]+: 498.
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 72 mg, 52%. 1H-NMR (DMSO-d6): δ 1.55-1.65 (m, 1H), 1.7-1.8 (m, 1H), 1.85-2.05 (m, 2H), 2.3 (m, 1H), 3.2-3.6 (m, 5H), 3.7 (m, 2H), 4.05 (m, 1H), 4.4 (m, 2H), 5.2 (m, 1H), 6.75 (s, OH), 6.95-7.05 (m, 3H), 7.1 (d, 2H), 7.3-7.5 (m, 6H); MS [M-CF3COO]+: 470.
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-3-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 79 mg, 54%. 1H-NMR (DMSO-d6): δ 1.55-1.65 (m, 1H), 1.7-1.8 (m, 1H), 1.85-2.0 (m, 2H), 2.05-2.2 (m, 2H), 2.3 (m, 1H), 3.1-3.2 (m, 1H), 3.25-3.55 (m, 6H), 3.85-3.95 (m, 1H), 4.0 (t, 2H), 5.2 (m, 1H), 6.75 (s, OH), 6.95 (m, 2H), 7.15 (m, 4H), 7.4 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO]+: 502.
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 24 mg, 17%. 1H-NMR (DMSO-d6): δ 1.8-2.05 (m, 4H), 2.3 (m, 1H), 3.15 (m, 1H), 3.3-3.5 (m, 4H), 3.9 (m, 1H), 4.05 (m 2H), 5.25 (m, 1H), 6.35 (m,1H), 6.75 (s, OH), 6.85 (t, 1H), 7.1 (m, 2H), 7.3-7.5 (m, 5H), 7.55 (m, 4H); MS [M-CF3COO]+: 502.
1-(3-phenylallyl)-3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 400 mg, 93%. 1H-NMR (DMSO-d6): δ 1.35-1.50 (m, 1H), 1.60-1.75 (m, 1H), 10 1.75-1.95 (m, 2H), 2.10 (m, 1H), 2.85 (m, 1H), 3.10 (d, 1H), 3.20-3.50 (m, 3H), 3.85 (m,1H), 4.0 (dd, 2H), 5.05 (m,1H), 6.40 (dd, 1H), 6.80-6.90 (d, 1H), 6.85 (s, OH), 7.20-7.50 (m, 7H), 7.60 (m, 4H), 7.80 (m, 2H); MS [M-Br]+: 452; mp 146° C.
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxy-propyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 690 mg, 83%. 1H-NMR (DMSO-d6): δ 1.47 (m, 1H), 1.68 (m, 1H), 1.87 (m, 2H), 2.1 (m, 3H), 2.89 (m, 1H), 3.15 (d, 1H), 3.4 (m, 5H), 3.9 (m, 1H), 4.0 (m, 2H), 5.04 (m,1H), 6.85 (s, OH), 6.97 (m, 3H), 7.35 (m, 4H), 7.45 (m, 2H), 7.65 (m, 2H), 7.85 (m, 2H); MS [M-Br]+: 470; mp 108° C.
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 170 mg, 74%. 1H-NMR (DMSO-d6): δ 1.45 (m, 1H), 1.65 (m, 1H), 1.85 (m, 2H), 2.1 (m, 1H), 2.9 (m, 3H), 3.15 (m, 1H), 3.3-3.5 (m, 5H), 3.85 (m,1H), 5.05 (m,1H), 6.85 (s, OH), 7.2-7.4 (m, 7H), 7.45 (t, 2H), 7.55 (d, 1H), 7.65 (d, 1H), 7.85 (d, 2H); MS
[M-Br]+: 440; mp 118° C.
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 460 mg, 96%. 1H-NMR (DMSO-d6): δ 1.42 (m, 1H), 1.66 (m, 1H), 1.80-1.88 (m, 2H), 2.08 (m, 1H), 2.93 (m, 1H), 3.25-3.60 (m, 4H), 3.65 (m, 2H), 3.95 (m, 1H), 4.35 (m 2H), 5.02 (m,1H), 6.85 (s, 1H, OH), 6.97 (d, 2H), 7.04 (t, 1H), 7.20-7.45 (m, 6H), 7.55-7.60 (t, 2H), 7.80 (d, 2H); MS [M-Br]+: 456; mp 140° C.
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 15 mg, 15%. 1H-NMR (DMSO-d6): δ 1.45 (m, 1H), 1.65 (m, 1H), 1.7-2.0 (m, 4H), 2.1 (m, 1H), 2.75 (m, 1H), 3.0-3.2 (m 4H), 3.25-3.4 (m, 4H), 3.85 (m,1H), 5.05 (m, 1H), 6.85 (s, OH), 7.35 (t, 2H), 7.45 (t, 2H), 7.55-7.7 (m, 5H), 7.85 (d, 2H), 8.0 (d, 2H); MS [M-CF3COO]+: 482.
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Chloride
The title compound was synthesised according to methods c and a. The yield of final step was 440 mg, 94%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.65 (m, 2H), 1.7-1.95 (m, 2H), 2.0-2.1 (m, 3H), 2.8 (m, 1H), 3.1 (d, 1H), 3.2-3.4 (m, 5H), 3.8 (m, 1H), 4.0 (t, 2H), 5.0 (m, 1H), 6.85 (s, OH), 6.95 (m, 2H), 7.15 (t, 2H), 7.35 (t, 2H), 7.45 (t, 2H), 7.55 (d, 1H), 7.65 (d, 1H), 7.85 (d, 2H); MS [M-Br]+: 488; mp 142° C.
1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 14 mg, 13%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.6-1.9 (m, 3H), 2.1 (m, 3H), 2.8 (m, 1H), 3.1 (d, 1H), 3.2-3.4 (m, 5H), 3.85 (m, 1H), 4.05 (t, 2H), 5.0 (m, 1H), 6.85 (s, OH), 7.05 (t, 1H), 7.15-7.4 (m, 4H), 7.45 (t, 2H), 7.55 (d, 1H), 7.65 (d, 1H), 7.85 (d, 2H); MS [M-CF3COO]+: 506.
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylaminopropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 14 mg, 15%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.6 (m, 1H), 1.8 (m, 4H), 2.05 (m, 1H), 2.7 (m, 1H), 3, 0 (m, 3H), 3.2-3.4 (m, 6H), 3.8 (m, 1H), 5.0 (m, 1H), 5.6 (t, NH), 6.55 (m, 3H), 6.85 (s, OH), 7.1 (t, 2H), 7.35 (dd, 2H), 7.45 (dd, 2H), 7.55 (dd, 2H), 7.8 (d, 2H); MS [M-CF3COO]+: 469.
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-[3-(4-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 15 mg, 15%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.6 (m, 1H), 1.7-1.9 (m, 2H), 1.95-2.05 (m, 2H), 2.1 (m, 1H), 2.8 (m, 1H), 3.1 (d, 1H) 3.25-3.4 (m, 5H), 3.8-3.9 (m, 3H), 5.0 (m, 1H), 6.7 (d, 2H), 6.75 (d, 2H), 6.85 (s, OH), 7.35 (t, 2H), 7.45 (t, 2H), 7.55 (d, 1H), 7.65 (d, 1H), 7.85 (d, 2H), 9.0 (s, OH); MS [M-CF3COO]+: 486.
1-(2-Benzyloxyethyl)-3(R)-(9-hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 470 mg, 96%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.65 (m, 1H), 1.7-1.9 (m, 2H), 2.1 (m, 1H), 2.9 (m, 1H), 3.15-3.5 (m, 6H), 3.75 (m, 2H), 3.85 (m, 1H), 4.5 (s, 2H), 5.0 (m, 1H), 6.85 (s, OH), 7.3-7.5 (m, 9H), 7.55 (m, 2H), 7.8 (d, 2H); MS [M-Br]+: 470; mp 86° C.
3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(3-thienyl-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 180 mg, 70%. 1H-NMR (DMSO-d6): δ 1.37 (m, 1H), 1.62 (m, 1H), 1.75-1.95 (m, 4H), 2.06 (m, 1H), 2.72 (m, 1H), 2.80 (m, 2H), 3.02-3.06 (m, 1H), 3.15-3.20 (m, 2H), 3.25-3.40 (m, 3H), 3.80 (m, 1H), 5.0 (m, 1H), 6.85 (s, 1H, OH), 6.95-7.0 (m, 2H), 7.25-7.50 (m, 5H), 7.55-7.65 (m, 2H), 7.85 (d, 2H); MS [M-Br]+: 460; mp 140° C.
3(R)— (9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 80 mg, 40%. 1H-NMR (DMSO-d6): δ 1.35 (m, 1H), 1.6 (m, 1H), 1.7-1.90 (m, 2H), 2.05 (m, 1H), 2.5 (m, 2H), 2.7 (m, 1H), 3.0 (m, 1H), 3.15 (m, 2H), 3.2-3.4 (m, 3H), 3.75 (m, 1H), 5.0 (m, 1H), 6.85 (s, OH), 7.20-7.50 (m, 9H), 7.55 (dd, 2H), 7.85 (d, 2H); MS [M-CF3COO]+: 454.
3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 74 mg, 35%. 1H-NMR (DMSO-d6): δ 1.35 (m, 1H), 1.45-1.65 (m, 5H), 1.7-1.90 (m, 2H), 2.05 (m, 1H), 2.55-2.75 (m, 3H), 3.0 (m, 1H), 3.15-3.45 (m, 5H), 3.75 (m, 1H), 5.0 (m, 1H), 6.85 (s, OH), 7.20 (m, 3H), 7.25-7.35 (m, 4H), 7.45-7.5 (m, 2H), 7.55-7.6 (dd, 2H), 7.85 (d, 2H); MS [M-CF3COO]+: 468.
3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy-1-(2-thienyl-2-ylethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 79 mg, 39%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.65 (m, 1H), 1.8-1.95 (m, 2H), 2.1 (m, 1H), 2.9 (m, 1H), 3.1-3.25 (m, 4H), 3.15-3.45 (m, 5H), 3.85 (m, 1H), 5.05 (m, 1H), 6.85 (s, OH), 7.0 (m, 2H), 7.35 (t, 2H), 7.45-7.5 (m, 3H), 7.55 (d, 1H), 7.65 (d, 1H), 7.85 (d, 2H); MS[M-CF3COO]+: 446.
3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 72 mg, 33%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.55-1.9 (m, 7H), 2.05 (m, 1H), 2.7 (m, 1H), 3.0 (m, 1H), 3.15-3.5 (m, 7H), 3.8 (m, 1H), 4.0 (m, 2H), 5.05 (m, 1H), 6.85 (s, OH), 6.95 (m, 3H), 7.25-7.35 (m, 4H), 7.4-7.45 (m, 2H), 7.6 (dd, 2H), 7.85 (d, 2H); MS [M-CF3COO]+: 484.
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 200 mg, 76%. 1H-NMR (DMSO-d6): δ 1.54 (m, 1H), 1.70-1.86 (m, 3H), 1.76 (s, 3H), 2.13 (m, 1H), 3.06 (m, 1H), 3.20-3.50 (m, 4H), 3.86 (m, 1H), 4.05 (dd, 2H), 5.02 (m, 1H), 6.43 (dd, 1H), 6.86 (d, 1H), 7.26-7.46 (m, 7H), 7.58-7.65 (m, 3H), 7.70-7.72 (m, 1H), 7.87-7.90 (m, 2H); MS [M-Br]+: 450; mp 234° C.
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 210 mg, 66%. 1H-NMR (DMSO-d6): δ 1.55 (m, 1H), 1.60-2.0 (m, 3H), 1.76 (s, 3H), 2.12 (m, 1H), 3.10-3.25 (m, 1H), 3.40-3.80 (m, 6H), 4.0 (m, 1H), 4.41 (m, 2H), 4.98 (m, 1H), 6.98-7.05 (m, 3H), 7.27-7.46 (m, 6H), 7.63-7.71 (m, 2H), 7.87-7.90 (m, 2H); MS [M-Br]+: 454; mp 202° C.
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 210 mg, 61%. 1H-NMR (DMSO-d6): δ 1.55 (m, 1H), 1.60-2.0 (m, 3H), 1.78 (s, 3H), 2.0-2.20 (m, 3H), 3.0-3.10 (m, 1H), 3.25-3.53 (m, 6H), 3.86 (m, 1H), 4.03 (m, 2H), 4.98 (m, 1H), 6.95-7.0 (m, 3H), 7.30-7.48 (m, 6H), 7.65-7.92 m, 4H); MS [M-Br]+: 468; mp 204° C.
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 18 mg, 19%. 1H-NMR (DMSO-d6): δ 1.55 (m, 1H), 1.65-1.95 (m, 3H), 1.75 (s, 3H), 2.15 (m, 1H), 2.9-3.1 (m, 4H), 3.25-3.55 (m, 5H), 3.85 (m, 1H), 5.05 (m, 1H), 7.25-7.55 (m, 9H), 7.65 (d, 1H), 7.75 (d, 1H), 7.95 (d, 2H); MS [M-CF3COO]+: 438.
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 19%. 1H-NMR (DMSO-d6): δ 1.55 (m, 1H), 1.65-2.05 (m, 5H), 1.75 (s, 3H), 2.1 (m, 1H) 3.0 (m, 1H), 3.1-3.5 (m, 8H), 3.85 (m, 1H), 7.35-7.5 (m, 4H), 7.55 (t, 2H), 7.65 (t, 2H), 7.7 (d, 1H), 7.9 (d, 2H), 8.0 (d, 2H); MS [M-CF3COO]+: 480.
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 23 mg, 23%. 1H-NMR (DMSO-d6): δ 1.55 (m, 1H), 1.65-1.95 (m, 3H), 1.75 (s, 3H), 2.05-2.15 (m, 3H), 3.0 (m, 1H), 3.25-3.5 (m, 6H), 3.85 (m, 1H), 4.0 (t, 2H), 5.0 (m, 1H), 6.95 (m, 2H), 7.15 (t, 2H), 7.35-7.5 (m, 4H), 7.65 (d, 1H), 7.75 (d, 1H), 7.9 (d, 2H); MS [M-CF3COO]+: 486.
1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-methyl-9H-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 20 mg, 19%. 1H-NMR (DMSO-d6): δ 1.55 (m, 1H), 1.65-1.95 (m, 3H), 1.75 (s, 3H), 2.05-2.2 (m, 3H), 3.0 (m, 1H), 3.25-3.55 (m, 6H), 3.85 (m, 1H), 4.1 (t, 2H), 5.0 (m, 1H), 7.05 (t, 1H), 7.2-7.5 (m, 6H), 7.65 (d, 1H), 7.75/d, 1H), 7.9 (d, 2H); MS [M-CF3COO]+: 504.
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylaminopropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 19%. 1H-NMR (DMSO-d6): δ 1.55 (m, 1H), 1.65-1.95 (m, 5H), 1.75 (s, 3H), 2.1 (m, 1H), 2.95 (m, 1H), 3.05 (m, 2H), 3.15-3.45 (m, 6H), 3.8 (m, 1H), 5.0 (m, 1H), 5.65 (t, NH), 6.6 (m, 3H), 7.1 (t, 2H), 7.35-7.55 (m, 4H), 7.65 (d, 1H), 7.75 (d, 1H), 7.9 (d, 2H); MS [M-CF3COO]+: 467.
1-[3-(4-Hydroxyphenoxy)propyl]-3(R)-(9-methyl-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 22 mg, 22%. 1H-NMR (DMSO-d6): δ 1.55 (m, 1H), 1.65-1.9 (m, 3H), 1.75 (s, 3H), 2.0-2.15 (m, 3H), 3.0 (m, 1H), 3.25-3.5 (m, 6H), 3.8-3.95 (m, 3H), 5.0 (m, 1H), 6.7 (d, 1H), 6.75 (d, 1H), 7.35-7.45 (m, 4H), 7.65 (d, 1H), 7.75 (d, 1H), 7.9 (d, 2H), 9.0 (s, OH); MS [M-CF3COO]+: 484.
1-(2-Benzyloxyethyl)-3(R)-(9-methyl-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 17 mg, 17%. 1H-NMR (DMSO-d6): δ 1.55 (m, 1H), 1.65-1.95 (m, 4H), 1.75 (s, 3H), 2.15 (m, 1H), 3.1 (m, 1H), 3.3-3.55 (m, 6H), 3.8-3.95 (m, 3H), 4.5 (s, 2H), 5.0 (m, 1H), 7.3-7.5 (m, 9H), 7.6-7.7 (m, 2H), 7.9 (d, 2H); MS [M-CF3COO]+: 468.
3(R)-(9,10-Dihydroanthracene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a. The yield of final step was 420 mg, 89%. 1H-NMR (DMSO-d6): δ 1.55 (m, 1H), 1.65-1.95 (m, 3H), 2.15 (m, 1H), 2.95 (m, 2H), 3.15 (m, 1H), 3.25-3.60 (m, 6H), 3.85 (m, 1H), 3.95-4.15 (dd, 2H, J1=1.8 Hz, J2=4.2 Hz), 5.02 (m, 1H), 5.25 (s, 1H), 7.25-7.43 (m, 11H), 7.48-7.55 (m, 2H); MS [M-Br]+: 438; mp 216° C.
3(R)-(9,10-Dihydroanthracene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a. The yield of final step was 450 mg, 82%. 1H-NMR (DMSO-d6): δ 1.56 (m, 1H), 1.65-1.95 (m, 3H), 2.05-2.15 (m, 3H), 3.10 (m, 1H), 3.20-3.50 (m, 6H), 3.80 (m, 1H), 3.94-4.14 (m, 4H), 5.0 (m, 1H), 5.22 (s, 1H), 6.94-7.0 (m, 3H), 7.25-7.35 (m, 6H), 7.40 (m, 2H), 7.54-7.47 (m, 2H); MS [M-Br]+: 468; mp 157° C.
1-(4-Phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a. The yield of final step was 83 mg, 21%. 1H-NMR (DMSO-d6): δ 1.50-2.0 (m, 8H), 2.15 (m, 1H), 2.65 (m, 2H), 3.05-3.65 (m, 7H), 3.80 (m, 1H), 5.0 (m, 1H), 5.30 (s, 1H), 7.10-7.45 (m, 11H), 7.45-7.60 (m, 2H); MS [M-Br]+: 468; mp 95° C.
1-(2-Phenoxyethyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a. The yield of final step was 300 mg, 73%. 1H-NMR (DMSO-d6): δ 1.70-2.0 (m, 4H), 2.2 (m, 1H), 3.20-3.80 (m, 7H), 4.0 (m, 1H), 4.40 (m, 2H), 5.05 (m, 1H), 5.30 (s, 1H), 7.0-7.10 (m, 7H), 7.30-7.45 (m, 4H), 7.45-7.55 (m, 2H); MS [M-Br]+: 456; mp 200° C.
1-(3-Phenoxypropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a. The yield of final step was 350 mg, 83%. 1H-NMR (DMSO-d6): δ 1.70-2.0 (m, 4H), 2.0-2.25 (m, 3H), 3.15-3.65 (m, 7H), 3.85-3.95 (m, 1H), 3.95-4.10 (m, 2H), 5.0 (m, 1H), 5.30 (s, 1H), 6.90-7.0 (m, 3H), 7.10-7.25 (m, 4H), 7.25-7.40 (m, 4H), 7.40-7.60 (m, 2H); MS [M-Br]+: 470; mp 184° C.
1-Phenethyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo [2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a. The yield of final step was 100 mg, 44%. 1H-NMR (DMSO-d6): δ 1.65-2.0 (m, 4H), 2.1 (m, 1H), 2.9-3.05 (m, 2H), 3.15-3.6 (m, 7H), 3.85 (m, 1H), 5.05 (m, 1H), 5.3 (s, 1H)), 7.15-7.55 (m, 13H); MS [M-Br]+: 440.
1-(4-Oxo-4-phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods d and b. The yield of final step was 16 mg, 15%. 1H-NMR (DMSO-d6): δ 1.65-2.05 (m, 6H), 2.1 (m, 1H), 3.1-3.55 (m, 9H), 3.8 (m, 1H), 5.05 (m, 1H), 5.25 (s, 1H), 7.1-7.3 (m, 4H), 7.35 (t, 2H), 7.45-7.6 (m, 4H), 7.7 (d, 1H), 8.0 (d, 1H); MS [M-CF3COO]+: 482.
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane, Trifluoroacetate
The title compound was synthesised according to methods d and b. The yield of final step was 18 mg, 18%. 1H-NMR (DMSO-d6): δ 1.7-2.1 (m, 6H), 2.15 (m, 1H), 3.1-3.5 (m, 7H), 3.8 (m, 1H), 4.0 (t, 2H), 5.0 (m, 1H), 5.3 (s, 1H), 6.95 (m, 2H), 7.1-7.3 (m, 6H), 7.4 (t, 2H), 7.5 (dd, 2H); MS [M-CF3COO]+: 488.
1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods d and b. The yield of final step was 14 mg, 14%. 1H-NMR (DMSO-d6): δ 1.65-1.95 (m, 4H), 2.05-2.2 (m, 3H), 3.1-3.55 (m, 7H), 3.8 (m, 1H), 4.05 (t, 2H), 5.0 (m, 1H), 5.3 (s, 1H), 7.05 (t, 1H), 7.1-7.55 (m, 10H); MS [M-CF3COO]+: 506.
1-(3-Phenylaminopropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods d and b. The yield of final step was 17 mg, 17%. 1H-NMR (DMSO-d6): δ 1.65-2.0 (m, 6H), 2.15 (m, 1H), 3.0-3.5 (m, 9H), 1.75 (m, 1H), 5.0 (m, 1H), 5.3 (s, 1H), 6.65 (t, NH), 6.55 (m, 3H), 0.05-7.3 (m, 6H), 7.35-7.55 (m, 4H); MS [M-CF3COO]+: 469.
1-[3-(4-Hydroxyphenoxy)propyl]-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods d and b. The yield of final step was 21 mg, 20%. 1H-NMR (DMSO-d6): δ 1.7-2.1 (m, 6H), 2.15 (m, 1H), 3.1-3.5 (m, 7H), 3.7-3.95 (m, 3H), 5.0 (m, 1H), 5.3 (s, 1H), 6.7 (d, 2H), 6.75 (d, 2H), 7.1-7.3 (m, 4H), 7.35-7.55 (m, 4H), 9.0 (s, OH); MS [M-CF3COO]+: 486.
1-(2-Benzyloxyethyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods d and b. The yield of final step was 16 mg, 16%. 1H-NMR (DMSO-d6): δ 1.65-1.95 (m, 4H), 2.1 (m, 1H), 3.1-3.9 (m, 10H), 4.5 (s, 2H), 5.0 (m, 1H), 5.3 (s, 1H), 7.15 (m, 4H), 7.3-7.5 (m, 7H), 7.55 (t, 2H); MS [M-CF3COO]+: 470.
3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 340 mg, 71%. 1H-NMR (DMSO-d6): δ 1.30 (m, 1H), 1.65 (m, 1H), 1.70-1.95 (m, 2H), 1.95-2.10 (m, 3H), 2.70 (m, 1H), 2.90 (m, 1H), 3.2-3.5 (m, 5H), 3.80 (m, 1H), 4.0 (t, 2H), 5.05 (m, 1H), 6.90-7.0 (m, 3H), 7.20-7.35 (m, 7H), 7.40-7.46 (m, 2H), 7.65-7.70 (m, 2H); MS [M-Br]+: 486; mp 219° C.
3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 290 mg, 64%. 1H-NMR (DMSO-d6): δ 1.32 (m, 1H), 1.65 (m, 1H), 1.70-1.95 (m, 2H), 2.1 (m, 1H), 2.75-2.90 (m, 3H), 3.05 (m, 1H), 3.30-3.50 (m, 5H), 3.82 (m, 1H), 5.05 (m, 1H), 7.20-7.40 (m, 10H), 7.40-7.50 (m, 2H), 7.65-7.70 (m, 2H); MS [M-Br]+: 456; mp 221° C.
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 310 mg, 97%. 1H-NMR (DMSO-d6): δ 1.30 (m, 1H), 1.62 (m, 1H), 1.70-1.90 (m, 4H), 2.05 (m, 1H), 2.60 (m, 1H), 2.75-2.85 (m, 4H), 3.15 (m, 2H), 3.25-3.40 (m, 2H), 3.75 (m, 1H), 5.0 (m, 1H), 6.93 (m, 1H), 7.0 (m, 1H), 7.14-7.26 (m, 5H), 7.36-7.45 (m, 3H), 7.63-7.67 (m, 2H); MS [M-Br]+: 476; mp 111° C.
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 85 mg, 41%. 1H-NMR (DMSO-d6): δ 1.30 (m, 1H), 1.65 (m, 1H), 1.70-1.95 (m, 2H), 2.05 (m, 1H), 2.5-2.6 (m, 2H), 2.80 (m, 1H), 3.05-3.75 (m, 7H), 5.05 (m, 1H), 7.1-7.45 (m, 12H), 7.65-7.70 (m, 2H); MS [M-CF3COO]+: 470.
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 84 mg, 38%. 1H-NMR (DMSO-d6): δ 1.30 (m, 1H), 1.4-1.85 (m, 7H), 2.05 (m, 1H), 2.5-2.6 (m, 2H), 2.80 (m, 1H), 3.05-3.4 (m, 6H), 3.7 (m, 1H), 5.05 (m, 1H), 7.15-7.35 (m, 10H), 7.4 (m, 1H), 7.65 (m, 2H); MS [M-CF3COO]+: 484.
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 81 mg, 39%. 1H-NMR (DMSO-d6): δ 1.30 (m, 1H), 1.6 (m, 1H), 1.7-1.9 (m, 2H), 2.05 (m, 1H), 2.75 (m, 1H), 3.0 (m, 1H), 3.1-3.2 (m, 2H), 3.3-3.6 (m, 5H), 3.8 (m, 1H), 5.05 (m, 1H), 6.95-7.0 (m, 2H), 7.15-7.3 (m, 5H), 7.45 (m, 3H), 7.65 (m, 2H); MS [M-CF3COO]+: 462.
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 83 mg, 37%. 1H-NMR (DMSO-d6): δ 1.3 (m, 1H), 1.5-1.9 (m, 7H), 2.05 (m, 1H), 2.6 (m, 1H), 2,8 (m, 1H), 3.1-3.45 (m, 7H), 3.75 (m, 1H), 4.0 (m, 2H), 5.05 (m,1H), 6.95-7.0 (m, 3H), 7.15-7.45 (m, 9H), 7.65 (m, 2H); MS [M-CF3COO]+: 500.
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 102 mg, 48%. 1H-NMR (DMSO-d6): δ 1.3 (m, 1H), 1.55-1.95 (m, 3H), 2.05 (m, 1H), 2,8 (m, 1H), 3.1 (m, 1H), 3.35-3.65 (m, 5H), 3.9 (m, 1H), 4.35 (m, 2H), 5.05 (m, 1H), 6.95 (d, 2H), 7.0-7.1 (m, 2H), 7.2 (m, 4H), 7.3-7.45 (m, 4H), 7.6 (t, 2H); MS [M-CF3COO]+: 472.
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-hydroxy-9H-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 99 mg, 44%. 1H-NMR (DMSO-d6): δ 1.3 (m, 1H), 1.6 (m, 1H), 1.7-2.0 (m, 4H), 2.05 (m, 1H), 2.7 (m, 1H), 2.9 (m, 1H), 3.2-3.5 (m, 5H), 3.75-3.85 (m,1H), 3.95 (m, 2H), 5.0 (m,1H), 6.95 (m, 2H), 7.1-7.3 (m, 7H), 7.45 (t, 2H), 7.65 (t, 2H); MS [M-CF3COO]+: 504.
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 25 mg, 12%. 1H-NMR (DMSO-d6): δ 1.25-1.30 (m, 1H), 1.55-1.95 (m, 3H), 2.10 (m, 1H), 2.65-2.75 (m, 1H), 2.9 (m, 1H), 3.25-3.50 (m, 2H), 3.75-3.8 (m,1H), 3.95 (m, 2H), 4.2 (d, 1H), 5.0 (m, 1H), 6.35 (m, 1H), 6.80 (d, 1H), 7.05-7.50 (m, 8H), 7.60 (m, 4H); MS [M-CF3COO]+: 468.
3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a. The yield of final step was 110 mg. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H), 2.05-2.15 (m, 3H), 1.8 (m, 1H), 3.15 (m, 2H), 3.25-3.5 (m, 5H), 3.85 (m, 1H), 4.0 (t, 2H), 5.05 (m, 1H), 6.95-7.0 (m, 3H), 7.15-7.2 (m, 4H), 7.3-7.4 (m, 4H), 7.45 (d, 1H), 7.55 (d, 1H); MS [M-Br]+: 484; mp 195° C.
3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 20%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.65 (m, 1H), 1.8-1.95 (m, 2H), 1.9 (s, 3H), 2.15 (m, 1H), 2.8-2.95 (m, 3H), 3.15 (d, 1H), 3.3-3.5 (m, 5H), 4.9 (m, 1H), 5.1 (m, 1H), 7.15 (m, 4H), 7.25-7.4 (m, 7H), 7.45 (d, 1H), 7.55 (d, 1H); MS [M-CF3COO]+: 454.
3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 24 mg, 24%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.65 (m, 1H), 1.8-1.95 (m, 2H), 1.9 (s, 3H), 2.15 (m, 1H), 2.95 (m, 1H), 3.25 (m, 1H), 3.4-3.65 (m, 5H), 3.85 (m, 1H), 4.35 (t, 2H), 5.05 (m, 1H), 6.95 (d, 2H), 7.05 (t, 2H), 7.15 (m, 3H), 7.25-7.45 (m, 6H); MS [M-CF3COO]+: 470.
3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 19%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.65 (m, 1H), 1.75-1.95 (m, 7H), 2.15 (m, 1H), 2.8 (m, 1H), 3.05-3.25 (m, 4H), 3.3-3.5 (m, 4H), 3.85 (m, 1H), 5.05 (m, 1H), 7.15 (m, 4H), 7.35 (t, 2H), 7.45-7.6 (m, 4H), 7.7 (t, 1H), 8.0 (d, 2H); MS [M-CF3COO]+: 496.
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 25 mg, 24%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H), 1-95-2.1 (m, 2H), 2.15 (m, 1H), 2.8 (m, 1H), 3.1 (d, 1H), 3.25-3.5 (m, 5H), 3.8 (m, 1H), 4.0 (t, 2H), 5.05 (m, 1H), 6.95 (m, 2H), 7.15 (m, 6H), 7.35 (t, 2H), 7.5 (dd, 2H); MS [M-CF3COO]+: 502.
1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 16 mg, 15%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H), 2.0-2.15 (m, 3H), 2.8 (m, 1H), 3.1 (d, 1H), 7.05 (t, 1H), 7.1-7.4 (m, 8H), 7.5 (dd, 2H); MS [M-CF3COO]+: 520.
3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenylaminopropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 16 mg, 15%. 1H-NMR (DMSO-d6): δ 1.35 (m, 1H), 1.6 (m, 1H), 1.7-1.9 (m, 4H), 1.9 (s, 3H), 2.1 (m, 1H), 2.7 (m, 1H), 2.95-3.05 (m, 3H), 3.1-3.4 (m, 6H), 3.75 (m, 1H), 5.0 (m, 1H), 5.6 (m, 1H), 6.55 (m, 3H), 7.05-7.15 (m, 6H), 7.3 (m, 2H), 7.45 (t, 2H); MS [M-CF3COO]+: 483.
1-[3-(4-Hydroxyphenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 18%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.65 (m, 1H), 2.75-2.05 (m, 4H), 1.9 (s, 3H), 2.15 (m, 1H), 2.8 (m, 1H), 3.1 (d, 1H), 3.25-3.5 (m, 5H), 3.8-3.95 (m, 3H), 5.05 (m, 1H), 6.65-6.8 (m, 4H), 7.2 (m, 4H), 7.35 (t, 2H), 7.5 (m, 2H), 9.0 (s, OH); MS [M-CF3COO]+: 500.
1-(2-Benzyloxyethyl)-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b. The yield of final step was 14 mg, 14%. 1H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H), 2.1 (m, 1H), 2.9 (m, 1H), 3.2-3.5 (m, 6H), 3.75-3.95 (m, 3H), 4.5 (s, 2H), 5.05 (m, 1H), 7.15 (m, 4H), 7.3-7.5 (m, 9H); MS [M-CF3COO]+: 484.
1-(3-Phenoxypropyl)-3(R)-(9[H]-thioxanthene-9-carbonyloxy)-1-azonia-bicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a. The yield of final step was 323 mg, 50%. 1H-NMR (DMSO-d6): δ 1.35 (m, 1H), 1.65 (m, 1H), 1.70-1.95 (m, 2H), 2.0-2.2 (m, 3H), 2.75-2.90 (m, 1H), 3,12 (m, 1H), 3.25-3.50 (m, 5H), 3.80 (m, 1H), 4.0 (t, 2H), 5.0 (m, 1H), 5.6 (s, 1H), 6.94-7.0 (m, 3H), 7.22-7.41 (m, 6H), 7.45-7.64 (m, 4H); MS [M-Br]+: 486; mp 157° C.
1-(3-phenylallyl)-3(R)-(10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a. The yield of final step was 250 mg, 94%. 1H-NMR (CDCl3): δ 1.50-1.60 (m, 1H), 1.60-1.80 (m, 1H), 1.90 (m, 2H), 2.30 (m, 1H), 2.65-2.80 (m, 2H), 2.90-3.20 (m, 3H), 3.50 (d, 1H), 3.60-3.90 (m, 3H), 4.20 (m, 1H), 4.35-4.60 (doble dd, 2H), 5.10 (m, 1H), 5.15 (s, 1H), 6.05 (dd, 1H), 6.90-7.0 (m, 2H), 7.0-7.5 (m, 11H); MS [M-Br]+: 464; mp 132° C.
1-(3-phenoxypropyl)-3(R)-(10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a. The yield of final step was 290 mg, 94%. 1H-NMR (CDCl3): δ 1.45-1.60 (m, 1H), 1.65-1.80 (m, 1H), 1.80-2.0 (m, 2H), 2.0-2.20 (m, 3H), 2.80-3.0 (m, 3H), 3.15-3.30 (m, 2H), 3.30-3.45 (d, 1H), 3.45-3.80 (m, 5H), 3.85-4.0 (m, 2H), 4.20 (m, 1H), 5.10 (m, 1H), 5.20 (s, 1H), 6.80-6.90 (d, 2H), 6.90-7.0 (t, 1H), 7.10-7.30 (m, 8H), 7.40 (m, 2H); MS [M-Br]+: 482; mp 182° C.
3(R)-(5[H]-Dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a. The yield of final step was 180 mg, 56%. 1H-NMR (DMSO-d6): δ 1.2 (m, 1H), 1.6 (m, 1H), 1.7-1.9 (m, 2H), 1.95 (m, 1H), 2.1 (m, 2H), 2.8 (m, 1H), 2.95 (d, 1H), 3.25-3.45 (m, 5H), 3.8 (m, 1H), 4.05 (t, 2H), 4.9 (m, 1H), 5.45 (s, 1H), 6.9-7.1 (m, 5H), 7.3-7.5 (m, 9H), 7.55 (d, 2H); MS [M-Br]+: 480; mp 1111C.
3(R)-(5[H]-Dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a. The yield of final step was 210 mg, 68%. 1H-NMR (DMSO-d6): δ 1.2 (m, 1H), 1.7-1.9 (m, 2H), 2.0 (m, 1H), 2.85-3.1 (m, 4H), 3.3-3.5 (m, 5H), 3.85 (m, 1H), 4.95 (m, 1H), 5.45 (s, 1H), 7.05 (m, 2H), 7.25-7.5 (m, 11H), 7.55 (m, 2H); MS [M-Br]+: 450; mp 2481C.
The Examples 160 to 164 illustrate pharmaceutical compositions according to the present invention and procedure for their preparation.
Preparation of a pharmaceutical composition: tablets |
Formulation: | |||
Compound of the present invention | 5.0 | mg | ||
Lactose | 113.6 | mg | ||
Microcrystalline cellulose | 28.4 | mg | ||
Light silicic anhydride | 1.5 | mg | ||
Magnesium stearate | 1.5 | mg | ||
Using a mixer machine, 15 g of the compound of the present invention was mixed with 340.8 g of lactose and 85.2 g of microcrystalline cellulose. The mixture was subjected to compression moulding using a roller compactor to give a flake-like compressed material. The flake-like compressed material was pulverized using a hammer mill, and the pulverized material was screened through a 20 mesh screen. A 4.5 g portion of light silicic anhydride and 4.5 g of magnesium stearate were added to the screened material and mixed. The mixer product was subjected to a tablets making machine equipped with a die/punch system of 7.5 mm in diameter, thereby obtaining 3,000 tablets each having 150 mg in weight.
Preparation of a pharmaceutical composition: tablets coated |
Formulation: | |||
Compound of the present invention | 5.0 | mg | ||
Lactose | 95.2 | mg | ||
Corn starch | 40.8 | mg | ||
Polyvinylpyrrolidone K25 | 7.5 | mg | ||
Magnesium stearate | 1.5 | mg | ||
Hydroxypropylcellulose | 2.3 | mg | ||
Polyethylene glycol 6000 | 0.4 | mg | ||
Titanium dioxide | 1.1 | mg | ||
Purified talc | 0.7 | mg | ||
Using a fluidized bed granulating machine, 15 g of the compound of the present invention was mixed with 285.6 g of lactose and 122.4 g of corn starch. Separately, 22.5 g of polyinylpyrrolidone was dissolved in 127.5 g of water to prepare a binding solution. Using a fluidized bed granulating machine, the binding solution was sprayed on the above mixture to give granulates. A 4.5 g portion of magnesium stearate was added to the obtained granulates and mixed. The obtained mixture was subjected to a tablet making machine equipped with a die/punch biconcave system of 6.5 mm in diameter, thereby obtaining 3,000 tablets, each having 150 mg in weight.
Separately, a coating solution was prepared by suspending 6.9 g of hydroxypropylmethylcellulose 2910, 1.2 g of polyethylene glycol 6000, 3.3 g of titanium dioxide and 2.1 g of purified talc in 72.6 g of water. Using a High Coated, the 3,000 tablets prepared above were coated with the coating solution to give film-coated tablets, each having 154.5 mg in weight.
Preparation of a pharmaceutical composition: liquid inhalant |
Formulation: | |
Compound of the present invention | 400 | Φg |
Physiological saline | 1 | ml |
A 40 mg portion of the compound of the present invention was dissolved in 90 ml of physiological saline, and the solution was adjusted to a total volume of 100 ml with the same saline solution, dispensed in 1 ml portions into 1 ml capacity ampoule and then sterilized at 1151 for 30 minutes to give liquid inhalant.
Preparation of a pharmaceutical composition: powder inhalant |
Formulation: | |
Compound of the present invention | 200 | Φg |
Lactose | 4,000 | Φg |
A 20 g portion of the compound of the present invention was uniformly mixed with 400 g of lactose, and a 200 mg portion of the mixture was packed in a powder inhaler for exclusive use to produce a powder inhalant.
Preparation of a pharmaceutical composition: inhalation aerosol. |
Formulation: | |||
Compound of the present invention | 200 | Φg | ||
Dehydrated (Absolute) ethyl alcohol USP | 8,400 | Φg | ||
1,1,1,2-Tetrafluoroethane (HFC-134A) | 46,810 | Φg | ||
The active ingredient concentrate is prepared by dissolving 0.0480 g of the compound of the present invention in 2.0160 g of ethyl alcohol. The concentrate is added to an appropriate filling apparatus. The active ingredient concentrate is dispensed into aerosol container, the headspace of the container is purged with Nitrogen or HFC-134A vapor (purging ingredients should not contain more than 1 ppm oxygen) and is sealed with valve. 11.2344 g of HFC-134A propellant is then pressure filled into the sealed container.
Claims (30)
1. A compound according to formula (I)
wherein:
© is a phenyl ring, a C4 to C9 heteroaromatic group 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 atom 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 C1 to C4 alkyl group which may optionally be substituted, for example, with a hydroxy or alkoxy group, wherein R4 and R5 each independently represent a hydrogen atom, straight or branched lower C1 to C4 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—, —CR6R7—, —CO—, —O—, —S—, —S(O)—, SO2 or —NR6— group, wherein R6 and R7 each independently represent a hydrogen atom, straight or branched lower C1 to C4 alkyl group or R6 and R7 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):
wherein R10 represents a hydrogen atom, a hydroxy or methyl group; and R8 and R9 each independently represent
2. A compound according to claim 1 , wherein any alkyl group present as R1 to R7 or R11 contains from 1 to 4 carbon atoms.
3. A compound according to claim 1 wherein p=2.
4. A compound according to claim 1 wherein © represents a phenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl or benzothiazolyl group.
5. A compound according to claim 4 , wherein © represents a phenyl, pyrrolyl or thienyl group.
6. A compound according to claim 1 wherein R1, R2 and R3 each independently represent a hydrogen or halogen atom or a hydroxy, methyl, tert-butyl, —CH2OH, 3-hydroxypropyl, —OMe, —NMe2, —NHCOMe, —CONH2, —CN, —NO2 —NO2, —COOMe or —CF3 group.
7. A compound according to claim 6 wherein R1, R2 and R3 each independently represent a hydrogen or halogen atom or a hydroxy group.
8. A compound according to claim 7 , wherein the halogen atom is fluorine.
9. A compound according to claim 1 wherein A represents a —CH2—, —CH═CH—, —CO—, —NH—, —NMe—, —O— or —S— group; n is 0 or 1; and m is an integer from 1 to 6.
10. A compound according to claim 9 , wherein A represents a —CH2—, 13 CH═CH— or —O— group and m is 1, 2 or 3.
11. A compound according to claim 1 wherein the azoniabicyclo group is substituted on the nitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 3-(2-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl or 3-thien-2-ylpropyl group.
12. A compound according to claim 1 wherein B represents a group of formula (i) and R8 and R9 each independently represent a phenyl, 2-thienyl, 3-thienyl, 2-furyl, or 3-furyl group and R11 represents a hydrogen atom.
13. A compound according to claim 1 wherein X X− represents a bromide, chloride or trifluoroacetate anion.
14. A compound according to claim 1 wherein the azoniabicyclo group is substituted in the 3-position.
15. A compound according to claim 14 , wherein the substituent in the 3 position has (R) configuration.
16. A compound according to claim 15 , wherein R8 is different from R9 in group i), and the asymmetric carbon to which R8 and R9 are bonded has the (R) configuration.
17. A compound according to claim 15 , wherein R8 is different from R9 in group i), and the asymmetric carbon to which R8 and R9 are bonded has the (S) configuration.
18. A compound according to claim 1 which is a single stereoisomer.
19. A compound according to claim 1 which is
3(R)-Diphenylacetoxy-1-(3-phenoxy-propyl)-1azoniabicyclo[2.2.2]octane; bromide,
3(R)-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide,
3(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide,
3(R)-(2-Hydroxy-2-phenyl-2-thien-2-yl-acetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo [2.2.2]octane; bromide,
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo [2.2.2]octane; bromide,
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo [2.2.2]octane; bromide,
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo [2.2.2]octane; bromide,
3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide,
3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; bromide3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; bromide,
3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; bromide3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; bromide,
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane; bromide,
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo [2.2.2]octane; chloride,
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-azoniabicyclo [2.2.2]octane; Trifluoroacetate,
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azonia-bicyclo[2.2.2]octane; trifluoroacetate,
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane; bromide,
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; bromide,
1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate, or
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide.
20. A compound according to claim 1 characterised in that it has an IC50 value for muscarinic M3 receptors (Hm3) of less than 35 nM.
22. A process according to claim 21 characterised in that the resulting reaction mixture is purified by solid phase extraction.
23. A pharmaceutical composition comprising a compound according to claim 1 in admixture with a pharmaceutically acceptable carrier or diluent.
24. A method for treating respiratory, urinary and/or gastrointestinal disease which method comprises administering to a human or animal patient in need of such treatment an effective amount of a compound according to any one of claims claim 1 to 12, 13 to 20 or of a pharmaceutical composition according to claim 23 .
25. A method for treating COPD, chronic bronchitis, asthma and/or ehinitis rhinitis which method comprises administering to a human or animal patient in need of such treatment an effective amount of a compound according to any one of claims claim 1 to 12, 13 to 20 or of a pharmaceutical composition according to claim 23 .
26. A compound chosen from
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; X−
or
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; X−,
wherein X− represents a pharmaceutically acceptable anion of a mono or polyvalent acid.
27. A compound chosen from
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; X−
or
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; X−,
wherein X− represents chloride, bromide, iodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, or p-toluenesulfonate.
28. A compound according to claim 27, wherein X− represents chloride, bromide, iodide, sulfate, nitrate, acetate, trifluoroacetate, maleate, oxalate, or succinate.
29. A compound according to claim 27, wherein X− represents chloride, bromide, or trifluoroacetate.
30. A compound chosen from
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide
or
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; bromide.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/019,009 USRE46417E1 (en) | 1999-07-14 | 2016-02-09 | Quinuclidine derivatives and their use as muscarinic M3 receptor ligands |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES9901580 | 1999-07-14 | ||
ES009901580A ES2165768B1 (en) | 1999-07-14 | 1999-07-14 | NEW DERIVATIVES OF QUINUCLIDINE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
PCT/EP2000/006469 WO2001004118A2 (en) | 1999-07-14 | 2000-07-07 | Quinuclidine derivatives and their use as muscarinic m3 receptor ligands |
US10/047,464 US6750226B2 (en) | 1999-07-14 | 2002-01-14 | Quinuclidine derivatives and their use as muscarinic M3 receptor ligands |
US15/019,009 USRE46417E1 (en) | 1999-07-14 | 2016-02-09 | Quinuclidine derivatives and their use as muscarinic M3 receptor ligands |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/047,464 Reissue US6750226B2 (en) | 1999-07-14 | 2002-01-14 | Quinuclidine derivatives and their use as muscarinic M3 receptor ligands |
Publications (1)
Publication Number | Publication Date |
---|---|
USRE46417E1 true USRE46417E1 (en) | 2017-05-30 |
Family
ID=8309225
Family Applications (16)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/047,464 Expired - Lifetime US6750226B2 (en) | 1999-07-14 | 2002-01-14 | Quinuclidine derivatives and their use as muscarinic M3 receptor ligands |
US10/740,264 Expired - Fee Related US7109210B2 (en) | 1999-07-14 | 2003-12-17 | Quinuclidine derivatives and medicinal compositions containing the same |
US11/116,777 Expired - Lifetime US7078412B2 (en) | 1999-07-14 | 2005-04-28 | Quinuclidine derivatives and medicinal compositions containing the same |
US11/325,059 Expired - Lifetime US7196098B2 (en) | 1999-07-14 | 2006-01-03 | Quinuclidine derivatives and medicinal compositions containing the same |
US11/636,181 Expired - Fee Related US7358260B2 (en) | 1999-07-14 | 2006-12-08 | Quinuclidine derivatives and medicinal compositions containing the same |
US12/074,929 Expired - Fee Related US7750023B2 (en) | 1999-07-14 | 2008-03-07 | Quinuclidine derivatives and medicinal compositions containing the same |
US12/787,772 Expired - Fee Related US7897617B2 (en) | 1999-07-14 | 2010-05-26 | Quinuclidine derivatives and medicinal compositions containing the same |
US13/011,131 Expired - Fee Related US8129405B2 (en) | 1999-07-14 | 2011-01-21 | Quinuclidine derivatives and medicinal compositions containing the same |
US13/354,873 Expired - Fee Related US8513279B2 (en) | 1999-07-14 | 2012-01-20 | Quinuclidine derivatives and medicinal compositions containing the same |
US13/939,742 Expired - Fee Related US8802699B2 (en) | 1999-07-14 | 2013-07-11 | Quinuclidine derivatives and medicinal compositions containing the same |
US14/311,102 Expired - Fee Related US9056100B2 (en) | 1999-07-14 | 2014-06-20 | Quinuclidine derivatives and medicinal compositions containing the same |
US14/712,866 Expired - Lifetime US9333195B2 (en) | 1999-07-14 | 2015-05-14 | Quinuclidine derivatives and medicinal compositions containing the same |
US15/019,009 Active 2025-04-11 USRE46417E1 (en) | 1999-07-14 | 2016-02-09 | Quinuclidine derivatives and their use as muscarinic M3 receptor ligands |
US15/095,036 Expired - Fee Related US9687478B2 (en) | 1999-07-14 | 2016-04-09 | Quinuclidine derivatives and medicinal compositions containing the same |
US15/599,646 Expired - Fee Related US10034867B2 (en) | 1999-07-14 | 2017-05-19 | Quinuclidine derivatives and medicinal compositions containing the same |
US16/045,333 Expired - Lifetime US10588895B2 (en) | 1999-07-14 | 2018-07-25 | Quinuclidine derivatives and medicinal compositions containing the same |
Family Applications Before (12)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/047,464 Expired - Lifetime US6750226B2 (en) | 1999-07-14 | 2002-01-14 | Quinuclidine derivatives and their use as muscarinic M3 receptor ligands |
US10/740,264 Expired - Fee Related US7109210B2 (en) | 1999-07-14 | 2003-12-17 | Quinuclidine derivatives and medicinal compositions containing the same |
US11/116,777 Expired - Lifetime US7078412B2 (en) | 1999-07-14 | 2005-04-28 | Quinuclidine derivatives and medicinal compositions containing the same |
US11/325,059 Expired - Lifetime US7196098B2 (en) | 1999-07-14 | 2006-01-03 | Quinuclidine derivatives and medicinal compositions containing the same |
US11/636,181 Expired - Fee Related US7358260B2 (en) | 1999-07-14 | 2006-12-08 | Quinuclidine derivatives and medicinal compositions containing the same |
US12/074,929 Expired - Fee Related US7750023B2 (en) | 1999-07-14 | 2008-03-07 | Quinuclidine derivatives and medicinal compositions containing the same |
US12/787,772 Expired - Fee Related US7897617B2 (en) | 1999-07-14 | 2010-05-26 | Quinuclidine derivatives and medicinal compositions containing the same |
US13/011,131 Expired - Fee Related US8129405B2 (en) | 1999-07-14 | 2011-01-21 | Quinuclidine derivatives and medicinal compositions containing the same |
US13/354,873 Expired - Fee Related US8513279B2 (en) | 1999-07-14 | 2012-01-20 | Quinuclidine derivatives and medicinal compositions containing the same |
US13/939,742 Expired - Fee Related US8802699B2 (en) | 1999-07-14 | 2013-07-11 | Quinuclidine derivatives and medicinal compositions containing the same |
US14/311,102 Expired - Fee Related US9056100B2 (en) | 1999-07-14 | 2014-06-20 | Quinuclidine derivatives and medicinal compositions containing the same |
US14/712,866 Expired - Lifetime US9333195B2 (en) | 1999-07-14 | 2015-05-14 | Quinuclidine derivatives and medicinal compositions containing the same |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/095,036 Expired - Fee Related US9687478B2 (en) | 1999-07-14 | 2016-04-09 | Quinuclidine derivatives and medicinal compositions containing the same |
US15/599,646 Expired - Fee Related US10034867B2 (en) | 1999-07-14 | 2017-05-19 | Quinuclidine derivatives and medicinal compositions containing the same |
US16/045,333 Expired - Lifetime US10588895B2 (en) | 1999-07-14 | 2018-07-25 | Quinuclidine derivatives and medicinal compositions containing the same |
Country Status (39)
Country | Link |
---|---|
US (16) | US6750226B2 (en) |
EP (1) | EP1200431B3 (en) |
JP (2) | JP4030040B2 (en) |
KR (3) | KR100854315B1 (en) |
CN (2) | CN1272334C (en) |
AR (1) | AR029760A1 (en) |
AT (1) | ATE235492T1 (en) |
AU (1) | AU2005202144B2 (en) |
BE (1) | BE2013C001I2 (en) |
BG (1) | BG65565B1 (en) |
BR (1) | BRPI0012434B8 (en) |
CA (1) | CA2381165C (en) |
CO (1) | CO5200759A1 (en) |
CY (1) | CY2013001I1 (en) |
CZ (1) | CZ304292B6 (en) |
DE (2) | DE60001840D1 (en) |
DK (1) | DK1200431T6 (en) |
EE (1) | EE04915B3 (en) |
EG (1) | EG24066A (en) |
ES (2) | ES2165768B1 (en) |
FR (1) | FR13C0001I2 (en) |
HK (1) | HK1042487B (en) |
HU (1) | HU228594B1 (en) |
IL (1) | IL147533A0 (en) |
LU (1) | LU92132I2 (en) |
MY (1) | MY126959A (en) |
NO (2) | NO329484B3 (en) |
PE (1) | PE20010397A1 (en) |
PL (1) | PL204024B1 (en) |
PT (1) | PT1200431E (en) |
RU (2) | RU2264401C3 (en) |
SI (1) | SI1200431T1 (en) |
SK (1) | SK287480B6 (en) |
TR (1) | TR200200768T2 (en) |
TW (1) | TWI284644B (en) |
UA (1) | UA73509C2 (en) |
UY (2) | UY26244A1 (en) |
WO (1) | WO2001004118A2 (en) |
ZA (1) | ZA200200232B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10034867B2 (en) | 1999-07-14 | 2018-07-31 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
US10085974B2 (en) | 2008-03-13 | 2018-10-02 | Almirall, S.A. | Dosage and formulation |
Families Citing this family (217)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7214687B2 (en) | 1999-07-14 | 2007-05-08 | Almirall Ag | Quinuclidine derivatives and medicinal compositions containing the same |
AR028948A1 (en) * | 2000-06-20 | 2003-05-28 | Astrazeneca Ab | NEW COMPOUNDS |
US20040077605A1 (en) * | 2001-06-20 | 2004-04-22 | Salvati Mark E. | Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function |
US6787532B2 (en) | 2000-08-05 | 2004-09-07 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivatives |
US6759398B2 (en) | 2000-08-05 | 2004-07-06 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative |
US6858596B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivative |
US6858593B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
US6777399B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
GB0019172D0 (en) | 2000-08-05 | 2000-09-27 | Glaxo Group Ltd | Novel compounds |
US6750210B2 (en) | 2000-08-05 | 2004-06-15 | Smithkline Beecham Corporation | Formulation containing novel anti-inflammatory androstane derivative |
US6777400B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
IL156499A0 (en) * | 2000-12-22 | 2004-01-04 | Almirall Prodesfarma Ag | Quinuclidine carbamate derivatives and their use as m3 antagonists |
JP4295985B2 (en) | 2000-12-28 | 2009-07-15 | ラボラトリオス・アルミラル・ソシエダッド・アノニマ | Novel quinuclidine derivative and pharmaceutical composition containing the same |
UA77656C2 (en) | 2001-04-07 | 2007-01-15 | Glaxo Group Ltd | S-fluoromethyl ester of 6-alpha, 9-alpha-difluoro-17-alpha-[(2-furanylcarbonyl)oxy]-11-beta-hydroxy-16- alpha-methyl-3-oxoandrosta-1,4-dien-17-beta-carbothioacid as anti-inflammatory agent |
KR100912324B1 (en) | 2001-09-14 | 2009-08-14 | 글락소 그룹 리미티드 | Phenethanolamine derivatives for treatment of respiratory diseases |
IL162596A0 (en) * | 2001-12-20 | 2005-11-20 | S A L V A T Lab Sa | 1-Alkyl-1-azoniabicyclo Ä2.2.2Ü octane carbamate derivatives and their use as muscarinic receptor ntagonists |
DE10203753A1 (en) * | 2002-01-31 | 2003-08-14 | Boehringer Ingelheim Pharma | New xanthene carboxylic acid esters, processes for their preparation and their use as medicines |
US7405224B2 (en) | 2002-01-31 | 2008-07-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthenecarboxylates, processes for preparing them, and their use as pharmaceutical compositions |
GB0202635D0 (en) * | 2002-02-05 | 2002-03-20 | Glaxo Wellcome Mfg Pte Ltd | Formulation containing novel anti-inflammatory androstane derivative |
ES2206021B1 (en) * | 2002-04-16 | 2005-08-01 | Almirall Prodesfarma, S.A. | NEW DERIVATIVES OF PIRROLIDINIO. |
GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
ES2203327B1 (en) * | 2002-06-21 | 2005-06-16 | Almirall Prodesfarma, S.A. | NEW QUINUCLIDINE CARBAMATES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
ES2204295B1 (en) * | 2002-07-02 | 2005-08-01 | Almirall Prodesfarma, S.A. | NEW DERIVATIVES OF QUINUCLIDINE-AMIDE. |
UY27927A1 (en) * | 2002-08-06 | 2003-12-31 | Glaxo Group Ltd | ACETILCOLINE M3 MUSCARINIC RECEIVER ANTAGONISTS |
TW200800953A (en) | 2002-10-30 | 2008-01-01 | Theravance Inc | Intermediates for preparing substituted 4-amino-1-(pyridylmethyl) piperidine |
AU2002356369A1 (en) * | 2002-12-23 | 2004-07-14 | Ranbaxy Laboratories Limited | Xanthine derivatives as muscarinic receptor antagonists |
GB0303396D0 (en) | 2003-02-14 | 2003-03-19 | Glaxo Group Ltd | Medicinal compounds |
AR044519A1 (en) | 2003-05-02 | 2005-09-14 | Novartis Ag | DERIVATIVES OF PIRIDIN-TIAZOL AMINA AND PIRIMIDIN-TIAZOL AMINA |
CN100445281C (en) * | 2003-05-02 | 2008-12-24 | 诺瓦提斯公司 | Quinuclidine derivatives binding to mucarinic M3 receptors |
AR044134A1 (en) | 2003-05-02 | 2005-08-24 | Novartis Ag | DERIVATIVES OF QUINUCLIDINE, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS. |
DE602004021921D1 (en) | 2003-05-28 | 2009-08-20 | Theravance Inc | AZABICYCLOALKAN COMPOUNDS AS MUSCARIN RECEPTOR ANTAGONISTS |
GB0316290D0 (en) | 2003-07-11 | 2003-08-13 | Glaxo Group Ltd | Novel compounds |
JP2007524641A (en) | 2003-07-11 | 2007-08-30 | セラヴァンス, インコーポレーテッド | Substituted 4-amino-1-benzylpiperidine compounds |
UY28417A1 (en) * | 2003-07-17 | 2005-02-28 | Glaxo Group Ltd | ANTAGONISTS OF ACETILCOLINE MUSCARINIC RECEPTORS |
AR045914A1 (en) * | 2003-07-17 | 2005-11-16 | Glaxo Group Ltd | TERTIARY ALCOHOLIC COMPOUND OF 8-AZONIABICICLO [3.2.1] OCTOBER, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE TO PREPARE THIS LAST |
PE20050711A1 (en) * | 2003-07-17 | 2005-09-10 | Glaxo Group Ltd | 8-AZONIABICYCLE COMPOUNDS [3.2.1] OCTANS AS ANTAGONISTS OF MUSCARINIC ACETYLCHOLINE RECEPTORS |
GB0317374D0 (en) | 2003-07-24 | 2003-08-27 | Glaxo Group Ltd | Medicament dispenser |
US20050026948A1 (en) * | 2003-07-29 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a betamimetic |
US20050026886A1 (en) * | 2003-07-29 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a PDE IV inhibitor |
US20050026887A1 (en) * | 2003-07-29 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a steroid |
DE602004005462T2 (en) * | 2003-07-29 | 2007-07-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | MEDICAMENTS FOR INHALATION WITH BETAMIMETICS AND ANTICHOLINERGICUM |
CA2534125A1 (en) * | 2003-07-29 | 2005-02-17 | Boehringer Ingelheim International Gmbh | Medicaments comprising pde iv inhibitors and an anticholinergic for treating respiratory disorders |
RU2361586C2 (en) * | 2003-07-29 | 2009-07-20 | Берингер Ингельхайм Интернациональ Гмбх | Combination from anticholinergic and steroid and its application for treatment of diseases of respiratory tracts by inhalation |
WO2005013994A1 (en) * | 2003-07-31 | 2005-02-17 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising anticholinergics and a betamimetic |
US20050025718A1 (en) * | 2003-07-31 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a betamimetic |
AP2007004238A0 (en) * | 2003-10-14 | 2007-12-31 | Glaxo Group Ltd | Muscarinic acetycholine receptor antagonists |
TW200528448A (en) * | 2003-10-17 | 2005-09-01 | Glaxo Group Ltd | Muscarinic acetylcholine receptor antagonists |
PE20050489A1 (en) * | 2003-11-04 | 2005-09-02 | Glaxo Group Ltd | ANTAGONISTS OF MUSCARINE ACETYLCHOLINE RECEPTORS |
GB0329182D0 (en) | 2003-12-17 | 2004-01-21 | Glaxo Group Ltd | Chemical compounds |
GB0401334D0 (en) | 2004-01-21 | 2004-02-25 | Novartis Ag | Organic compounds |
EP1725236A4 (en) * | 2004-03-11 | 2009-05-13 | Glaxo Group Ltd | Novel m3 muscarinic acetylcholine receptor antagonists |
ES2239546B1 (en) * | 2004-03-15 | 2006-12-01 | Almirall Prodesfarma, S.A. | NEW QUATERNIZED QUINUCLIDINE ESTERS. |
EP1725564A4 (en) | 2004-03-17 | 2007-09-12 | Glaxo Group Ltd | M3 muscarinic acetylcholine receptor antagonists |
MY144753A (en) | 2004-04-27 | 2011-10-31 | Glaxo Group Ltd | Muscarinic acetylcholine receptor antagonists |
EP1747219A4 (en) * | 2004-05-13 | 2010-05-26 | Glaxo Group Ltd | Muscarinic acetylcholine receptor antagonists field of the invention |
PE20060272A1 (en) | 2004-05-24 | 2006-05-22 | Glaxo Group Ltd | (2R, 3R, 4S, 5R, 2'R, 3'R, 4'S, 5'S) -2.2 '- {TRANS-1,4-CYCLOHEXANODIYLBIS- [IMINO (2 - {[2- (1-METHYL- 1H-IMIDAZOL-4-IL) ETHYL] AMINO} -9H-PURIN-6,9-DIYL)]} BIS [5- (2-ETHYL-2H-TETRAZOLE-5-IL) TETRAHYDRO-3,4-FURANODIOL] AS AN A2A AGONIST |
DE602005018969D1 (en) * | 2004-05-31 | 2010-03-04 | Almirall Sa | Compositions with antimuscarinic agents and corticosteroids |
ES2257152B1 (en) * | 2004-05-31 | 2007-07-01 | Laboratorios Almirall S.A. | COMBINATIONS THAT INCLUDE ANTIMUSCARINIC AGENTS AND BETA-ADRENERGIC AGONISTS. |
DE602004018844D1 (en) * | 2004-06-16 | 2009-02-12 | Ranbaxy Lab Ltd | XANTHINE DERIVATIVES SUITABLE AS ANTAGONISTS OF THE MUSCARIN RECEPTOR |
TWI307630B (en) | 2004-07-01 | 2009-03-21 | Glaxo Group Ltd | Immunoglobulins |
GB0418045D0 (en) | 2004-08-12 | 2004-09-15 | Glaxo Group Ltd | Compounds |
GB0418278D0 (en) | 2004-08-16 | 2004-09-15 | Glaxo Group Ltd | Medicament dispenser |
GT200500281A (en) | 2004-10-22 | 2006-04-24 | Novartis Ag | ORGANIC COMPOUNDS. |
GB0424284D0 (en) | 2004-11-02 | 2004-12-01 | Novartis Ag | Organic compounds |
GB0426164D0 (en) | 2004-11-29 | 2004-12-29 | Novartis Ag | Organic compounds |
JP5281291B2 (en) | 2005-01-10 | 2013-09-04 | グラクソ グループ リミテッド | New compounds |
JP2008532973A (en) * | 2005-03-09 | 2008-08-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Novel pharmaceutical composition based on anticholinergic and PDE5-inhibitor |
AR053346A1 (en) | 2005-03-25 | 2007-05-02 | Glaxo Group Ltd | COMPOSITE DERIVED FROM 8H -PIRIDO (2,3-D) PIRIMIDIN -7 ONA 2,4,8- TRISUSTITUTED PHARMACEUTICAL COMPOSITION AND USE TO PREPARE A COMPOSITION FOR TREATMENT AND PROFILXIS OF A DISEASE MEDIATED BY KINASE CSBP / RK / P38 |
WO2006105401A2 (en) | 2005-03-30 | 2006-10-05 | Schering Corporation | Medicaments and methods combining an anticholinergic, a corticosteroid, and a long acting beta agonist |
GB0507577D0 (en) | 2005-04-14 | 2005-05-18 | Novartis Ag | Organic compounds |
GB0510390D0 (en) | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
GB0514809D0 (en) | 2005-07-19 | 2005-08-24 | Glaxo Group Ltd | Compounds |
JP2009503099A (en) * | 2005-08-02 | 2009-01-29 | グラクソ グループ リミテッド | M3 muscarinic acetylcholine receptor antagonist |
EP1937230A4 (en) * | 2005-08-02 | 2009-08-26 | Glaxo Group Ltd | M3 muscarinic acetylcholine receptor antagonists |
TW200738634A (en) * | 2005-08-02 | 2007-10-16 | Astrazeneca Ab | New salt |
JP2009504624A (en) * | 2005-08-08 | 2009-02-05 | アージェンタ ディスカバリー リミテッド | Bicyclo [2.2.1] hept-7-ylamine derivatives and uses thereof |
WO2007022351A2 (en) * | 2005-08-18 | 2007-02-22 | Glaxo Group Limited | Muscarinic acetylcholine receptor antagonists |
TW200744612A (en) * | 2005-08-26 | 2007-12-16 | Astrazeneca Ab | New combination |
EP2532679B1 (en) | 2005-10-21 | 2017-04-12 | Novartis AG | Human antibodies against il13 and therapeutic uses |
AR058109A1 (en) | 2005-12-20 | 2008-01-23 | Glaxo Group Ltd | ACID 3 - (4 - {[4 - (4 - {[3 - (3, 3 - DIMETILE - 1 - PIPERIDINIL) PROPIL] OXI} PHENYL) - 1 - PIPERIDINIL] CARBONIL} - 1 - NAFTALENIL) PROPANOIC AS ANTAGONISTS OF THE RECEIVERS OF HISTAMINE H1 / H3, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND THEIR USE IN THE PREPARATION OF MEDICINES FOR THE TREATMENT |
WO2007077164A1 (en) * | 2006-01-06 | 2007-07-12 | Boehringer Ingelheim International Gmbh | New pharmaceutical compositions based on anticholinergics and andolast |
GB0601951D0 (en) | 2006-01-31 | 2006-03-15 | Novartis Ag | Organic compounds |
PE20071227A1 (en) | 2006-04-20 | 2008-02-18 | Glaxo Group Ltd | INDAZOLE-DERIVED COMPOUNDS AS GLUCOCORTICOID RECEPTOR MODULATORS |
AR060607A1 (en) | 2006-04-21 | 2008-07-02 | Novartis Ag | PURINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, PREPARATION METHOD AND USES IN OBSTRUCTIVE OR INFLAMMATORY DISEASES OF RESPIRATORY ROADS. |
GB0611587D0 (en) | 2006-06-12 | 2006-07-19 | Glaxo Group Ltd | Novel compounds |
US20090250058A1 (en) * | 2006-07-14 | 2009-10-08 | Astrazeneca Ab | Inhalation System and Delivery Device for the Administration of a Drug in the Form of Dry Powder |
CN101553493B (en) | 2006-07-19 | 2012-07-04 | 阿斯利康(瑞典)有限公司 | Novel tricyclic spiropiperidine compounds, their synthesis and their uses as modulators of chemokine receptor activity |
ES2298049B1 (en) * | 2006-07-21 | 2009-10-20 | Laboratorios Almirall S.A. | PROCEDURE FOR MANUFACTURING BROMIDE OF 3 (R) - (2-HIDROXI-2,2-DITIEN-2-ILACETOXI) -1- (3-PHENOXIPROPIL) -1-AZONIABICICLO (2.2.2) OCTANO. |
EP2081933B1 (en) | 2006-09-29 | 2011-03-23 | Novartis AG | Pyrazolopyrimidines as pi3k lipid kinase inhibitors |
TW200825084A (en) | 2006-11-14 | 2008-06-16 | Astrazeneca Ab | New compounds 521 |
GB0622827D0 (en) | 2006-11-15 | 2006-12-27 | Glaxo Group Ltd | Sheet driver for use in a drug dispenser |
EP2114972A2 (en) * | 2006-12-13 | 2009-11-11 | Gilead Sciences, Inc. | Monophosphates as mutual prodrugs of muscarinic receptor antagonists and beta-agonists for the treatment of copd and chronic bronchitis |
BRPI0720799A2 (en) | 2007-01-10 | 2014-03-11 | Irm Llc | COMPOUNDS AND COMPOSITIONS AS CHANNEL ACTIVATION PROTEASE INHIBITORS. |
GB0702456D0 (en) | 2007-02-08 | 2007-03-21 | Astrazeneca Ab | New combination |
US20110243924A1 (en) * | 2007-02-21 | 2011-10-06 | Jorge Beleta Supervia | Novel methods |
PE20081889A1 (en) | 2007-03-23 | 2009-03-05 | Smithkline Beecham Corp | INDOL CARBOXAMIDES AS INHIBITORS OF IKK2 |
BRPI0811562A2 (en) | 2007-05-07 | 2014-12-09 | Novartis Ag | ORGANIC COMPOUNDS |
KR101517574B1 (en) * | 2007-09-07 | 2015-05-07 | 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 | Guanidine-containing compounds useful as muscarinic receptor antagonists |
CA2608561A1 (en) * | 2007-10-29 | 2009-04-29 | Carl Paluszkiewicz | Motorcycle wind deflector accessory support |
CA2707857C (en) | 2007-12-10 | 2016-09-13 | Novartis Ag | Spirocyclic amiloride analogues |
JP2011506477A (en) | 2007-12-14 | 2011-03-03 | セラヴァンス, インコーポレーテッド | Amidine-containing compounds useful as muscarinic receptor antagonists |
AU2009203693B2 (en) | 2008-01-11 | 2012-06-07 | Novartis Ag | Pyrimidines as kinase inhibitors |
EP2080508A1 (en) * | 2008-01-15 | 2009-07-22 | CHIESI FARMACEUTICI S.p.A. | Dry powder formulation comprising an anticholinergic drug |
US20100055045A1 (en) | 2008-02-26 | 2010-03-04 | William Gerhart | Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations |
EP2257172A4 (en) * | 2008-02-26 | 2013-07-03 | Elevation Pharmaceuticals Inc | Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations |
EP2100598A1 (en) * | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
US8268834B2 (en) | 2008-03-19 | 2012-09-18 | Novartis Ag | Pyrazine derivatives that inhibit phosphatidylinositol 3-kinase enzyme |
GB0808707D0 (en) * | 2008-05-13 | 2008-06-18 | Argenta Discovery Ltd | New compounds 275 |
US8329729B2 (en) | 2008-05-13 | 2012-12-11 | Astrazeneca Ab | Quinuclidine derivatives as muscarinic M3 receptor antagonists |
CA2724726C (en) | 2008-05-23 | 2018-02-27 | Amira Pharmaceuticals, Inc. | 5-lipoxygenase-activating protein inhibitor |
RU2509077C2 (en) | 2008-05-27 | 2014-03-10 | Астразенека Аб | Phenoxypyridinylamide derivatives, and their use in treatment of pde4-mediated disease states |
US20090326004A1 (en) | 2008-06-03 | 2009-12-31 | Ranbaxy Laboratories Limited | Muscarinic receptor antagonists |
JP5502858B2 (en) | 2008-06-05 | 2014-05-28 | グラクソ グループ リミテッド | 4-Carboxamide indazole derivatives useful as inhibitors of PI3 kinase |
BRPI0915018A2 (en) | 2008-06-10 | 2015-10-27 | Novartis Ag | organic compounds |
US8263623B2 (en) | 2008-07-11 | 2012-09-11 | Pfizer Inc. | Triazol derivatives useful for the treatment of diseases |
EP2154136A1 (en) | 2008-08-08 | 2010-02-17 | CHIESI FARMACEUTICI S.p.A. | Quinuclidine carbonate derivatives and medicinal compositions thereof |
PL2391366T3 (en) | 2009-01-29 | 2013-04-30 | Novartis Ag | Substituted benzimidazoles for the treatment of astrocytomas |
WO2010094643A1 (en) | 2009-02-17 | 2010-08-26 | Glaxo Group Limited | Quinoline derivatives and their uses for rhinitis and urticaria |
ES2542551T3 (en) | 2009-03-09 | 2015-08-06 | Glaxo Group Limited | 4-Oxadiazol-2-yl-indazoles as inhibitors of PI3 kinases |
WO2010102968A1 (en) | 2009-03-10 | 2010-09-16 | Glaxo Group Limited | Indole derivatives as ikk2 inhibitors |
JP2012520845A (en) | 2009-03-17 | 2012-09-10 | グラクソ グループ リミテッド | Pyrimidine derivatives used as Itk inhibitors |
MX2011009724A (en) | 2009-03-19 | 2011-10-14 | Merck Sharp & Dohme | RNA INTERFERENCE MEDIATED INHIBITION OF BTB AND CNC HOMOLOGY 1, BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR 1 (BACH 1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) SEQUENCE LISTING. |
WO2010107957A2 (en) | 2009-03-19 | 2010-09-23 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF GATA BINDING PROTEIN 3 (GATA3) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
US20120010272A1 (en) | 2009-03-27 | 2012-01-12 | Merck Sharp & Dohme Corp. | RNA Interference Mediated Inhibition of Apoptosis Signal-Regulating Kinase 1 (ASK1) Gene Expression Using Short Interfering Nucleic Acid (siNA) |
EP2411018A2 (en) | 2009-03-27 | 2012-02-01 | Merck Sharp&Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF THE NERVE GROWTH FACTOR BETA CHAIN (NGFß) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (SINA) |
KR20110138223A (en) | 2009-03-27 | 2011-12-26 | 머크 샤프 앤드 돔 코포레이션 | Rna interference mediated inhibition of the intercellular adhesion molecule 1 (icam-1) gene expression using short interfering nucleic acid (sina) |
RU2554878C2 (en) | 2009-04-09 | 2015-06-27 | Новартис Аг | Method of producing pyrrolidinium salts |
UY32571A (en) | 2009-04-24 | 2010-11-30 | Glaxo Group Ltd | COMPOUNDS DERIVED FROM PIRAZOL AMIDA |
WO2010122088A1 (en) | 2009-04-24 | 2010-10-28 | Glaxo Group Limited | Pyrazole and triazole carboxamides as crac channel inhibitors |
ES2876933T3 (en) | 2009-04-30 | 2021-11-15 | Glaxo Group Ltd | Oxazole-substituted indazoles as PI3-kinase inhibitors |
US8815258B2 (en) | 2009-05-29 | 2014-08-26 | Pearl Therapeutics, Inc. | Compositions, methods and systems for respiratory delivery of two or more active agents |
KR101976107B1 (en) | 2009-05-29 | 2019-05-09 | 펄 테라퓨틱스 인코포레이티드 | Respiratory delivery of active agents |
GB0910537D0 (en) | 2009-06-18 | 2009-07-29 | Ivax Pharmaceuticals Ireland | Inhaler |
US8389526B2 (en) | 2009-08-07 | 2013-03-05 | Novartis Ag | 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives |
AU2010283806A1 (en) | 2009-08-12 | 2012-03-01 | Novartis Ag | Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation |
EP2467141B1 (en) | 2009-08-17 | 2018-10-31 | Intellikine, LLC | Heterocyclic compounds and uses thereof |
AU2010284972A1 (en) | 2009-08-20 | 2012-03-08 | Novartis Ag | Heterocyclic oxime compounds |
WO2011050325A1 (en) | 2009-10-22 | 2011-04-28 | Vertex Pharmaceuticals Incorporated | Compositions for treatment of cystic fibrosis and other chronic diseases |
GB0919465D0 (en) | 2009-11-06 | 2009-12-23 | Norton Healthcare Ltd | Airflow adaptor for a breath-actuated dry powder inhaler |
JP2013512879A (en) | 2009-12-03 | 2013-04-18 | グラクソ グループ リミテッド | Benzpyrazole derivatives as inhibitors of PI3 kinase |
EP2507231A1 (en) | 2009-12-03 | 2012-10-10 | Glaxo Group Limited | Indazole derivatives as pi 3 - kinase inhibitors |
EP2507226A1 (en) | 2009-12-03 | 2012-10-10 | Glaxo Group Limited | Novel compounds |
WO2011073662A1 (en) | 2009-12-17 | 2011-06-23 | Astrazeneca Ab | Combination of a benzoxazinone and a further agent for treating respiratory diseases |
WO2011110575A1 (en) | 2010-03-11 | 2011-09-15 | Glaxo Group Limited | Derivatives of 2-[2-(benzo- or pyrido-) thiazolylamino]-6-aminopyridine, useful in the treatment of respiratoric, allergic or inflammatory diseases |
US8247436B2 (en) | 2010-03-19 | 2012-08-21 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF |
GB201007203D0 (en) | 2010-04-29 | 2010-06-16 | Glaxo Group Ltd | Novel compounds |
PT2614058E (en) | 2010-09-08 | 2015-10-27 | Glaxosmithkline Ip Dev Ltd | Polymorphs and salts of n-[5-[4-(5-{[(2r,6s)-2,6-dimethyl-4-morpholinyl]methyl}-& xa;1,3-oxazol-2-yl)-1h-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide |
UY33597A (en) | 2010-09-09 | 2012-04-30 | Irm Llc | COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF THE TRK |
WO2012034095A1 (en) | 2010-09-09 | 2012-03-15 | Irm Llc | Compounds and compositions as trk inhibitors |
WO2012035055A1 (en) | 2010-09-17 | 2012-03-22 | Glaxo Group Limited | Novel compounds |
US8372845B2 (en) | 2010-09-17 | 2013-02-12 | Novartis Ag | Pyrazine derivatives as enac blockers |
GB201016912D0 (en) | 2010-10-07 | 2010-11-24 | Astrazeneca Ab | Novel combination |
JP2013544794A (en) | 2010-10-21 | 2013-12-19 | グラクソ グループ リミテッド | Pyrazole compounds acting on allergic disorders, inflammatory disorders and immune disorders |
US9156791B2 (en) | 2010-10-21 | 2015-10-13 | Glaxo Group Limited | Pyrazole compounds acting against allergic, immune and inflammatory conditions |
GB201018124D0 (en) | 2010-10-27 | 2010-12-08 | Glaxo Group Ltd | Polymorphs and salts |
US20130324526A1 (en) | 2011-02-10 | 2013-12-05 | Novartis Ag | [1,2,4] triazolo [4,3-b] pyridazine compounds as inhibitors of the c-met tyrosine kinase |
EP2678016B1 (en) | 2011-02-23 | 2016-08-10 | Intellikine, LLC | Heterocyclic compounds and uses thereof |
KR20140014184A (en) | 2011-02-25 | 2014-02-05 | 아이알엠 엘엘씨 | Compounds and compositions as trk inhibitors |
JP2014507458A (en) | 2011-03-11 | 2014-03-27 | グラクソ グループ リミテッド | Pyrido [3,4-B] pyrazine derivatives as Syk inhibitors |
GB201104153D0 (en) | 2011-03-11 | 2011-04-27 | Glaxo Group Ltd | Novel compounds |
EP2510928A1 (en) | 2011-04-15 | 2012-10-17 | Almirall, S.A. | Aclidinium for use in improving the quality of sleep in respiratory patients |
UY34305A (en) | 2011-09-01 | 2013-04-30 | Novartis Ag | DERIVATIVES OF BICYCLIC HETEROCICLES FOR THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION |
BR112014006223A8 (en) | 2011-09-15 | 2018-01-09 | Novartis Ag | 6-substituted 3- (quinolin-6-ylthio) - [1,2,4-triazol [4,3-a] pyradines, their uses, pharmaceutical compositions, and combination |
WO2013038373A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
JP6165733B2 (en) | 2011-09-16 | 2017-07-19 | ノバルティス アーゲー | N-substituted heterocyclylcarboxamides |
WO2013038378A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
US9034879B2 (en) | 2011-09-16 | 2015-05-19 | Novartis Ag | Heterocyclic compounds for the treatment of CF |
WO2013038381A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine/pyrazine amide derivatives |
EP2793893A4 (en) | 2011-11-23 | 2015-07-08 | Intellikine Llc | Enhanced treatment regimens using mtor inhibitors |
AU2012352153B2 (en) | 2011-12-13 | 2018-07-26 | Veracyte, Inc. | Cancer diagnostics using non-coding transcripts |
US8809340B2 (en) | 2012-03-19 | 2014-08-19 | Novartis Ag | Crystalline form |
AU2013243097A1 (en) | 2012-04-03 | 2014-10-09 | Novartis Ag | Combination products with tyrosine kinase inhibitors and their use |
EP2666465A1 (en) | 2012-05-25 | 2013-11-27 | Almirall, S.A. | Novel dosage and formulation |
CN104837828B (en) * | 2012-12-05 | 2017-07-18 | 奇斯药制品公司 | It is used as the phenylethyl pyridine derivate of PDE4 inhibitor |
AU2013363837A1 (en) | 2012-12-17 | 2015-06-11 | Almirall, S.A. | New use of aclidinium |
US9073921B2 (en) | 2013-03-01 | 2015-07-07 | Novartis Ag | Salt forms of bicyclic heterocyclic derivatives |
RU2696582C2 (en) | 2013-03-15 | 2019-08-05 | Перл Терапьютикс, Инк. | Methods and systems for conditioning disperse crystalline materials |
JP2016512835A (en) | 2013-03-15 | 2016-05-09 | インテリカイン, エルエルシー | Combinations of kinase inhibitors and their use |
JP6218940B2 (en) * | 2013-07-13 | 2017-10-25 | ベイジン エフエスウェルカム テクノロジー ディベロップメント カンパニー リミテッド | Kinin compounds, optical isomers thereof, production methods thereof, and pharmaceutical uses |
AU2014321419B2 (en) | 2013-09-22 | 2017-06-15 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine compounds and methods of use |
WO2015055690A1 (en) | 2013-10-17 | 2015-04-23 | Glaxosmithkline Intellectual Property Development Limited | Pi3k inhibitor for treatment of respiratory disease |
JP6475707B2 (en) | 2013-10-17 | 2019-02-27 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited | PI3K inhibitors for the treatment of respiratory diseases |
CZ306791B6 (en) | 2013-10-29 | 2017-07-12 | Zentiva, K.S. | An industrially applicable process of preparing aclidinium bromide of high purity |
WO2015084804A1 (en) | 2013-12-03 | 2015-06-11 | Novartis Ag | Combination of mdm2 inhibitor and braf inhibitor and their use |
CN103755699A (en) * | 2014-01-06 | 2014-04-30 | 万特制药(海南)有限公司 | Preparation method of 2-hydroyxl-2,2-dithienyl-2-polyglycolic acid-1-azabicyclo[2, 2, 2] octyl-3(R)-base ester |
CN103755698A (en) * | 2014-01-06 | 2014-04-30 | 万特制药(海南)有限公司 | Technology for preparing aclidinium bromide employing one-pot process |
CZ2014188A3 (en) | 2014-03-26 | 2015-10-07 | Zentiva, K.S. | Novel forms of aclidinium chloride and process for preparing thereof |
US9403801B2 (en) | 2014-03-28 | 2016-08-02 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
MX2016013981A (en) | 2014-04-24 | 2016-11-15 | Novartis Ag | Amino pyridine derivatives as phosphatidylinositol 3-kinase inhibitors. |
JP6433509B2 (en) | 2014-04-24 | 2018-12-05 | ノバルティス アーゲー | Aminopyrazine derivatives as phosphatidylinositol 3-kinase inhibitors |
US9862711B2 (en) | 2014-04-24 | 2018-01-09 | Novartis Ag | Pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors |
TW201625247A (en) | 2014-05-12 | 2016-07-16 | 葛蘭素史密斯克藍智慧財產權有限公司 | Pharmaceutical compositions for treating infectious diseases |
WO2016011658A1 (en) | 2014-07-25 | 2016-01-28 | Novartis Ag | Combination therapy |
ES2831416T3 (en) | 2014-07-31 | 2021-06-08 | Novartis Ag | Combination therapy of a MET inhibitor and an EGFR inhibitor |
WO2016140136A1 (en) * | 2015-03-02 | 2016-09-09 | 株式会社Lttバイオファーマ | Quinuclidine derivative |
PT108370B (en) * | 2015-03-30 | 2018-10-25 | Hovione Farm S A | ACLIDINE BROMETON PREPARATION PROCESS |
WO2016162878A1 (en) * | 2015-04-04 | 2016-10-13 | Harman Finochem Limited | An advantageous process for preparing 1-azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3r)- and its novel crystalline form-i |
CZ2015257A3 (en) | 2015-04-16 | 2016-10-26 | Zentiva, K.S. | Method of reducing particle size of [(3R)-1-(3-phenoxypropyl)chinuclidin-1-ium-3-yl] 2-hydroxy-2,2-bis(2-thienyl)acetate bromide |
CN105085355B (en) * | 2015-06-25 | 2017-11-14 | 御盛隆堂药业有限责任公司 | A kind of substituted pyrrolidine carboxylic acid's ester type compound and its preparation method and application |
WO2017044434A1 (en) | 2015-09-11 | 2017-03-16 | Sunshine Lake Pharma Co., Ltd. | Substituted heteroaryl compounds and methods of use |
GB201602527D0 (en) | 2016-02-12 | 2016-03-30 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
JP2019524792A (en) | 2016-08-08 | 2019-09-05 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited | Compound |
WO2018094392A1 (en) | 2016-11-21 | 2018-05-24 | Lupin Inc. | Medicament dispenser |
GB201700727D0 (en) | 2017-01-16 | 2017-03-01 | Teva Pharma | Inhalers and airflow adaptors therefor |
GB201706102D0 (en) | 2017-04-18 | 2017-05-31 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
GB201712081D0 (en) | 2017-07-27 | 2017-09-13 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
US20190076607A1 (en) | 2017-09-13 | 2019-03-14 | Lupin Atlantis Holdings Sa | Inhaler and mesh for an inhaler |
EP3710006A4 (en) | 2017-11-19 | 2021-09-01 | Sunshine Lake Pharma Co., Ltd. | Substituted heteroaryl compounds and methods of use |
WO2019129801A1 (en) | 2017-12-28 | 2019-07-04 | Linnea S.A. | Process for the purification of methyl-2,2-dithienylglycolate |
EP3740468A4 (en) | 2018-01-20 | 2021-10-06 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine compounds and methods of use |
WO2020058823A1 (en) | 2018-09-17 | 2020-03-26 | Lupin, Inc. | Dose indicator assembly for a medicament dispenser |
AU2020290094B2 (en) | 2019-06-10 | 2024-01-18 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF, COPD, and bronchiectasis |
EP4021572A1 (en) | 2019-08-28 | 2022-07-06 | Novartis AG | Substituted 1,3-phenyl heteroaryl derivatives and their use in the treatment of disease |
TW202140550A (en) | 2020-01-29 | 2021-11-01 | 瑞士商諾華公司 | Methods of treating an inflammatory or obstructive airway disease using anti-tslp antibody |
US20230120431A1 (en) | 2020-03-25 | 2023-04-20 | Lupin Inc. | Multi-Carrier Medicament Dispensers |
WO2021191875A1 (en) | 2020-03-26 | 2021-09-30 | Glaxosmithkline Intellectual Property Development Limited | Cathepsin inhibitors for preventing or treating viral infections |
MX2023000955A (en) | 2020-07-23 | 2023-04-26 | Lupin Inc | Dose counter assemblies for medicament dispensers. |
Citations (69)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2012964A1 (en) | 1968-07-15 | 1970-03-27 | Sogeras | |
EP0003445A1 (en) | 1978-01-10 | 1979-08-08 | Pharmuka Laboratoires | 1-Aza-bicyclo(2,2,2)octanes, process for their preparation and intermediates, and medicines containing them |
GB2041763A (en) | 1979-02-05 | 1980-09-17 | Chiesi P | An inhalor for pulverulent medicinal substances |
US4338931A (en) | 1979-04-27 | 1982-07-13 | Claudio Cavazza | Device for the quick inhalation of drugs in powder form by humans suffering from asthma |
EP0069715A1 (en) | 1981-07-08 | 1983-01-12 | Aktiebolaget Draco | Powder inhalator |
EP0166294A2 (en) | 1984-06-18 | 1986-01-02 | Miles Inc. | Medicament inhalation device |
US4579854A (en) | 1983-12-24 | 1986-04-01 | Tanabe Seiyaku Co., Ltd. | Bronchodilating 8-hydroxy-5-{(1R)-1-hydroxy-2-[N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)-amino]ethyl} carbostyril |
EP0205247A2 (en) | 1985-05-10 | 1986-12-17 | State Of Israel, Represented By Prime Minister's Office, Israel Institute For Biological Research | Derivatives of quinuclidine |
US4644033A (en) | 1983-01-11 | 1987-02-17 | Essilor International | Polyurethane hydrogels and process for their manufacture |
US4675326A (en) * | 1985-05-08 | 1987-06-23 | Gabriel Amitai | Bisquaternary antidotes |
WO1987007502A1 (en) | 1986-06-06 | 1987-12-17 | Phares Pharmaceutical Research N.V. | Composition and method |
EP0302699A2 (en) | 1987-08-03 | 1989-02-08 | Walton S.A. | Improvements relating to n-substituted benzamides |
US4843074A (en) | 1988-05-17 | 1989-06-27 | Marion Laboratories, Inc. | 1-azabicyclo[2.2.2]octan-3-yl 2-aryl-3-azacyclo-2-hydroxypropionates and their quaternary salts |
WO1991002558A1 (en) | 1989-08-17 | 1991-03-07 | Boehringer Ingelheim Kg | Inhalator |
EP0418716A1 (en) | 1989-09-16 | 1991-03-27 | Boehringer Ingelheim Kg | Thienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the compounds |
EP0424021A1 (en) | 1989-10-19 | 1991-04-24 | Pfizer Limited | Antimuscarinic bronchodilators |
EP0424790A2 (en) | 1989-10-27 | 1991-05-02 | Miat S.P.A. | Multi-dose inhaler for medicaments in powder form |
WO1991014468A1 (en) | 1990-03-21 | 1991-10-03 | Dmw (Technology) Limited | Atomising devices and methods |
WO1992000771A1 (en) | 1990-07-13 | 1992-01-23 | Innovata Biomed Limited | Inhaler |
WO1992003175A1 (en) | 1990-08-11 | 1992-03-05 | Fisons Plc | Inhalation device |
WO1992004346A1 (en) | 1990-09-06 | 1992-03-19 | Pfizer Limited | Antimuscarinic bronchodilators |
WO1992004345A1 (en) | 1990-09-12 | 1992-03-19 | Allergan, Inc. | 6- or 7- (2-IMINO-2-IMIDAZOLIDINE)-1,4-BENZOXAZINES AS ALPHA ADRENERGIC AGENTS |
WO1992004068A1 (en) | 1990-08-30 | 1992-03-19 | Boehringer Ingelheim Kg | Inhalator without propeller gas with foreign air stream |
WO1992004928A2 (en) | 1990-09-26 | 1992-04-02 | Pharbita B.V. | Inhaler devices provided with a reservoir for several doses of medium for inhaling, transporting device, whirl chamber |
WO1992009322A1 (en) | 1990-11-29 | 1992-06-11 | Boehringer Ingelheim Kg | Inhalation device |
CA2062854A1 (en) | 1991-03-14 | 1992-09-15 | Manfred Keller | Pharmaceutical aerosol formulations |
EP0505321A2 (en) | 1991-03-21 | 1992-09-23 | Ciba-Geigy Ag | Inhaler |
US5201308A (en) | 1990-02-14 | 1993-04-13 | Newhouse Michael T | Powder inhaler |
US5254330A (en) | 1990-01-24 | 1993-10-19 | British Technology Group Ltd. | Aerosol carriers |
US5290815A (en) | 1989-09-07 | 1994-03-01 | Glaxo Group Limited | Treatment of inflammation and allergy |
US5290539A (en) | 1990-12-21 | 1994-03-01 | Minnesota Mining And Manufacturing Company | Device for delivering an aerosol |
EP0603229A1 (en) | 1991-09-14 | 1994-06-29 | Pfizer Limited | Quinuclidine esters process and intermediate for their preparation and pharmaceutical compositions containing them |
WO1994014492A2 (en) | 1992-12-18 | 1994-07-07 | Schering Corporation | Inhaler for powdered medications |
US5435301A (en) | 1992-11-24 | 1995-07-25 | Bayer Aktiengesellschaft | Powder inhaler having dispersing, discharge, and dwell-time chambers, along with an acceleration channel |
WO1995024889A1 (en) | 1994-03-15 | 1995-09-21 | Glaxo Group Limited | Inhalation composition containing lactose pellets |
WO1996004346A1 (en) | 1994-07-29 | 1996-02-15 | Minnesota Mining And Manufacturing Company | Acrylic syrup curable to a crosslinked viscoelastomeric material |
US5507281A (en) | 1990-08-30 | 1996-04-16 | Boehringer Ingelheim Kg | Device for initiating a mechanical switching operation in synchronism with the breathing |
WO1996019968A1 (en) | 1994-12-24 | 1996-07-04 | Glaxo Group Limited | Pharmaceutical aerosol containing at least one sugar |
WO1996032150A1 (en) | 1995-04-14 | 1996-10-17 | Glaxo Wellcome Inc. | Metered dose inhaler for salmeterol |
US5569447A (en) | 1994-04-19 | 1996-10-29 | The United States Of America Represented By The Secretary Department Of Health And Human Services | Stannylated 3-quinuclidinyl benzilates and methods of preparing radiohalogenated derivatives |
EP0747355A1 (en) | 1994-02-10 | 1996-12-11 | Yamanouchi Pharmaceutical Co. Ltd. | Novel carbamate derivative and medicinal composition containing the same |
WO1997000703A1 (en) | 1995-06-21 | 1997-01-09 | Asta Medica Aktiengesellschaft | Pharmaceutical powder cartridge with integrated metering device and inhaler for powdered medicaments |
WO1997001337A1 (en) | 1995-06-29 | 1997-01-16 | Mcneil-Ppc, Inc. | The combination of topical nasal antihistamines and topical nasal steroids |
US5610163A (en) | 1989-09-16 | 1997-03-11 | Boehringer Ingelheim Gmbh | Esters of thienyl carboxylic acids and amino alcohols and their quaternization products |
WO1997012687A1 (en) | 1995-10-04 | 1997-04-10 | Boehringer Ingelheim International Gmbh | Device of miniaturised construction for producing high pressure in a fluid to be atomised |
US5654314A (en) | 1991-03-15 | 1997-08-05 | Boehringer Ingelheim Kg | Esters of bi- and tricyclic amino alcohols and their use in pharmaceutical compositions |
WO1997028801A1 (en) | 1996-02-09 | 1997-08-14 | Mayo Foundation For Medical Education And Research | Colonic delivery of nicotine to treat inflammatory bowel disease |
WO1997034871A1 (en) | 1996-03-22 | 1997-09-25 | Nitromed, Inc. | Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders |
US5676930A (en) | 1992-12-09 | 1997-10-14 | Boehringer Ingelheim Pharmaceuticals, Inc. | Stabilized medicinal aerosol solution formulations |
EP0801067A1 (en) | 1994-12-28 | 1997-10-15 | Yamanouchi Pharmaceutical Co. Ltd. | Novel quinuclidine derivatives and medicinal composition thereof |
WO1998015280A1 (en) | 1996-10-08 | 1998-04-16 | Astra Aktiebolag | New combination |
US5885834A (en) | 1996-09-30 | 1999-03-23 | Epstein; Paul M. | Antisense oligodeoxynucleotide against phosphodiesterase |
US5962505A (en) | 1998-08-31 | 1999-10-05 | Bobrove; Arthur M. | Method for treating hot flashes in humans |
WO1999051205A1 (en) | 1998-04-03 | 1999-10-14 | University College Cardiff Consultants Limited | Aerosol composition |
US6150415A (en) | 1996-08-13 | 2000-11-21 | The Regents Of The University Of California | Epoxide hydrolase complexes and methods therewith |
WO2001050080A2 (en) | 1999-12-29 | 2001-07-12 | Valeo Climatisation | Multichannel tube heat exchanger |
US6299861B1 (en) | 1995-08-01 | 2001-10-09 | Boehringer Ingelheim Kg | Ipratropium bromide enantiomer with prolonged duration of effect |
US6299863B1 (en) | 1992-04-03 | 2001-10-09 | Sepracor Inc. | Aerosol formulations containing micronized optically pure (R,R) formoterol for bronchodilating therapy |
US6423298B2 (en) | 1998-06-18 | 2002-07-23 | Boehringer Ingelheim Pharmaceuticals, Inc. | Pharmaceutical formulations for aerosols with two or more active substances |
US6521260B1 (en) | 1995-01-31 | 2003-02-18 | Vectura Limited | Carrier particles for use in dry powder inhalers |
US6521261B2 (en) | 1995-01-09 | 2003-02-18 | Edward Mendell Co., Inc. | Pharmaceutical excipient having improved compressibility |
US20030085480A1 (en) | 1997-03-20 | 2003-05-08 | Tsong-Toh Yang | Preparation of powder agglomerates |
US6686346B2 (en) | 1996-12-05 | 2004-02-03 | Astra Aktiebolag | Formulation |
US6986346B2 (en) | 1998-10-17 | 2006-01-17 | Boehringer Ingelheim Pharma Kg | Closure-cap and container as a two-chamber cartridge for nebulisers for producing aerosols and active substance formulations, suitable for storage |
US7078412B2 (en) * | 1999-07-14 | 2006-07-18 | Almirall Prodesfarma Ag | Quinuclidine derivatives and medicinal compositions containing the same |
US7214687B2 (en) * | 1999-07-14 | 2007-05-08 | Almirall Ag | Quinuclidine derivatives and medicinal compositions containing the same |
EP2165159A1 (en) | 2007-07-03 | 2010-03-24 | Nxp B.V. | Calibration of an amr sensor |
EP2242134A1 (en) | 2001-10-26 | 2010-10-20 | Valence Technology, Inc. | Alkali/transition metal halo - and hydroxy-phosphates and related electrode active materials |
WO2013175013A1 (en) * | 2012-05-25 | 2013-11-28 | Almirall, S.A. | Novel dosage and formulation |
Family Cites Families (113)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3091570A (en) | 1960-08-08 | 1963-05-28 | Lakeside Lab Inc | Antidepressant: 3-pyrrolidyl glycolates |
FI69963C (en) | 1984-10-04 | 1986-09-12 | Orion Yhtymae Oy | DOSERINGSANORDNING |
GB9004781D0 (en) | 1990-03-02 | 1990-04-25 | Glaxo Group Ltd | Device |
US5263480A (en) | 1991-02-01 | 1993-11-23 | Cyberonics, Inc. | Treatment of eating disorders by nerve stimulation |
CZ300910B6 (en) | 1998-06-18 | 2009-09-09 | Boehringer Ingelheim Pharmaceuticals, Inc. | Pharmaceutical formulation |
ITMI981671A1 (en) | 1998-07-21 | 2000-01-21 | Zambon Spa | PHTHALAZINIC DERIVATIVES INHIBITORS OF PHOSPHODISTERASE 4 |
ES2193726T3 (en) | 1998-08-04 | 2003-11-01 | Jago Res Ag | MEDICINAL AEROSOL FORMULATIONS. |
GB9902689D0 (en) | 1999-02-08 | 1999-03-31 | Novartis Ag | Organic compounds |
DE19921693A1 (en) | 1999-05-12 | 2000-11-16 | Boehringer Ingelheim Pharma | Pharmaceutical composition for treating respiratory disorders, e.g. asthma, comprises combination of anticholinergic and beta-mimetic agents having synergistic bronchospasmolytic activity and reduced side-effects |
US20040002548A1 (en) | 1999-05-12 | 2004-01-01 | Boehringer Ingelheim Pharma Kg | Medicament compositions containing anticholinergically-effective compounds and betamimetics |
SE9902935D0 (en) | 1999-08-18 | 1999-08-18 | Astra Pharma Prod | Pharmaceutical compositions |
GB9928311D0 (en) | 1999-11-30 | 2000-01-26 | Novartis Ag | Organic compounds |
US6410563B1 (en) | 1999-12-22 | 2002-06-25 | Merck Frosst Canada & Co. | Substituted 8-arylquinoline phosphodiesterase-4 inhibitors |
WO2001054728A1 (en) | 2000-01-28 | 2001-08-02 | Asahi Kasei Kabushiki Kaisha | NOVEL REMEDIES WITH THE USE OF β3 AGONIST |
DK1252157T3 (en) | 2000-01-31 | 2004-10-25 | Pfizer Prod Inc | Pyrimidine carboxamides useful as inhibitors of PDE4 isozymes |
WO2001070746A1 (en) | 2000-03-23 | 2001-09-27 | Takeda Chemical Industries, Ltd. | Furoisoquinoline derivatives, process for producing the same and use thereof |
GB0008485D0 (en) | 2000-04-07 | 2000-05-24 | Glaxo Group Ltd | Pharmaceutical compositions |
GB0009606D0 (en) | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Therapeutic combinations |
GB0009605D0 (en) | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Medicaments |
GB0009592D0 (en) | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Respiratory combinations |
GB0009583D0 (en) | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Respiratory formulations |
GB0012261D0 (en) | 2000-05-19 | 2000-07-12 | Astrazeneca Ab | Novel process |
IL152955A0 (en) | 2000-05-22 | 2003-06-24 | Chiesi Farma Spa | Stable pharmaceutical solution formulations for pressurised metered dose inhalers |
US20020052312A1 (en) | 2000-05-30 | 2002-05-02 | Reiss Theodore F. | Combination therapy of chronic obstructive pulmonary disease using muscarinic receptor antagonists |
AR029984A1 (en) | 2000-07-27 | 2003-07-23 | Smithkline Beecham Corp | METHOD FOR REDUCING ASSOCIATED EXCERBATIONS COPD AMBITO |
US6852728B2 (en) | 2000-10-14 | 2005-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Anticholinergics, processes for preparing them, and pharmaceutical compositions containing them |
US6706726B2 (en) | 2000-10-14 | 2004-03-16 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Anticholinergics which may be used as medicaments as well as processes for preparing them |
US20020193393A1 (en) | 2001-03-07 | 2002-12-19 | Michel Pairet | Pharmaceutical compositions based on anticholinergics and PDE-IV inhibitors |
US20020137764A1 (en) | 2000-10-31 | 2002-09-26 | Karin Drechsel | Inhalable formulation of a solution containing a tiotropium salt |
DE10062712A1 (en) | 2000-12-15 | 2002-06-20 | Boehringer Ingelheim Pharma | New drug compositions based on anticholinergics and corticosteroids |
US20020183292A1 (en) | 2000-10-31 | 2002-12-05 | Michel Pairet | Pharmaceutical compositions based on anticholinergics and corticosteroids |
US6608054B2 (en) | 2001-03-20 | 2003-08-19 | Boehringer Ingelheim Pharma Kg | Pharmaceutical compositions based on anticholinergics and endothelin antagonists |
US20020151541A1 (en) | 2000-10-31 | 2002-10-17 | Michel Pairet | Pharmaceutical compositions containing tiotropium salts and antihistamines and their use |
US6620438B2 (en) | 2001-03-08 | 2003-09-16 | Boehringer Ingelheim Pharma Kg | Pharmaceutical compositions based on anticholinergics and NK1-receptor antagonists |
US7776315B2 (en) | 2000-10-31 | 2010-08-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and additional active ingredients |
CA2436540C (en) | 2000-10-31 | 2008-01-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and corticosteroids |
US20030158196A1 (en) | 2002-02-16 | 2003-08-21 | Boehringer Ingelheim Pharma Gmbh Co. Kg | Pharmaceutical compositions based on anticholinergics and EGFR kinase inhibitors |
DE10110772A1 (en) | 2001-03-07 | 2002-09-12 | Boehringer Ingelheim Pharma | New drug compositions based on anticholinergics and PDE-IV inhibitors |
US20020122773A1 (en) | 2000-12-20 | 2002-09-05 | Michel Pairet | Pharmaceutical compositions based on anticholinergics and dopamine agonists |
US20020193392A1 (en) | 2000-11-13 | 2002-12-19 | Christel Schmelzer | Pharmaceutical compositions based on tiotropium salts of salts of salmeterol |
DE10056104A1 (en) | 2000-11-13 | 2002-05-23 | Boehringer Ingelheim Pharma | Drug compositions useful for treatment of respiratory diseases, especially asthma and chronic obstructive pulmonary disease comprises tiotropium salts and salmeterol salts |
US20100310477A1 (en) | 2000-11-28 | 2010-12-09 | Boehringer Ingelheim Pharma Gmbh & Co. Kg. | Pharmaceutical compositions based on anticholingerics and additional active ingredients |
IL156499A0 (en) | 2000-12-22 | 2004-01-04 | Almirall Prodesfarma Ag | Quinuclidine carbamate derivatives and their use as m3 antagonists |
JP4295985B2 (en) | 2000-12-28 | 2009-07-15 | ラボラトリオス・アルミラル・ソシエダッド・アノニマ | Novel quinuclidine derivative and pharmaceutical composition containing the same |
US20020179087A1 (en) | 2001-02-01 | 2002-12-05 | Karl-Heinz Bozung | Pharmaceutical compositions containing an oxitropium salt and a betamimetic |
US20020189610A1 (en) | 2001-02-01 | 2002-12-19 | Karl-Heinz Bozung | Pharmaceutical compositions containing an ipratropium salt and a betamimetic |
DE10104367A1 (en) | 2001-02-01 | 2002-08-08 | Boehringer Ingelheim Pharma | Medicinal compositions containing betamimetics with fewer side effects |
DE10104370A1 (en) | 2001-02-01 | 2002-08-08 | Boehringer Ingelheim Pharma | Medicinal compositions with fewer side effects |
GB0103630D0 (en) | 2001-02-14 | 2001-03-28 | Glaxo Group Ltd | Chemical compounds |
US6667344B2 (en) | 2001-04-17 | 2003-12-23 | Dey, L.P. | Bronchodilating compositions and methods |
US20030216329A1 (en) | 2001-04-24 | 2003-11-20 | Robinson Cynthia B. | Composition, formulations & kit for treatment of respiratory & lung disease with dehydroepiandrosterone(s) steroid & an anti-muscarinic agent(s) |
WO2002096423A2 (en) | 2001-05-25 | 2002-12-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Combination of a pde4 inhibitor and tiotropium or derivate thereof for treating obstructive airways |
KR20040007605A (en) | 2001-05-25 | 2004-01-24 | 화이자 인코포레이티드 | A pde4 inhibitor and an anti-cholinergic agent in combination for treating obstructive airways diseases |
GB0115181D0 (en) | 2001-06-20 | 2001-08-15 | Glaxo Group Ltd | Novel use |
DE10129703A1 (en) | 2001-06-22 | 2003-01-02 | Sofotec Gmbh & Co Kg | Atomizing system for a powder mixture and method for dry powder inhalers |
DE10130371A1 (en) | 2001-06-23 | 2003-01-02 | Boehringer Ingelheim Pharma | New drug compositions based on anticholinergics, corticosteroids and betamimetics |
US20030018019A1 (en) * | 2001-06-23 | 2003-01-23 | Boehringer Ingelheim Pharma Kg | Pharmaceutical compositions based on anticholinergics, corticosteroids and betamimetics |
GB0118373D0 (en) | 2001-07-27 | 2001-09-19 | Glaxo Group Ltd | Novel therapeutic method |
US6680345B2 (en) | 2001-09-14 | 2004-01-20 | Boehringer Ingelheim Pharma Kg | Salicylic acid salts of salmeterol |
US6919325B2 (en) | 2001-09-14 | 2005-07-19 | Boehringer Ingelheim Pharma Kg | Pharmaceutical compositions containing tiotropium salts and low-solubility salmeterol salts |
EP1429768B1 (en) | 2001-09-14 | 2016-11-16 | Boehringer Ingelheim Pharma GmbH & Co.KG | Novel medicaments for inhalation |
WO2003042160A1 (en) | 2001-11-13 | 2003-05-22 | Theravance, Inc. | Aryl aniline beta-2 adrenergic receptor agonists |
US6974803B2 (en) | 2001-12-06 | 2005-12-13 | Pfizer Inc | Pharmaceutical combination |
DE10202940A1 (en) | 2002-01-24 | 2003-07-31 | Sofotec Gmbh & Co Kg | Cartridge for a powder inhaler |
US6790856B2 (en) | 2002-01-31 | 2004-09-14 | Boehringer Ingelheim Pharma Kg | Fluorenecarboxylic acid esters, process for the manufacture thereof, and use thereof as medicaments |
GB0202635D0 (en) | 2002-02-05 | 2002-03-20 | Glaxo Wellcome Mfg Pte Ltd | Formulation containing novel anti-inflammatory androstane derivative |
PT3384931T (en) | 2002-03-01 | 2019-09-26 | Chiesi Farm Spa | Formoterol superfine formulation |
US6756508B2 (en) | 2002-03-04 | 2004-06-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Cinnamic acid salts, processes for their preparation, and their use as medicaments |
DE10216429A1 (en) | 2002-04-12 | 2003-10-23 | Boehringer Ingelheim Pharma | Synergistic medicaments for treating inflammatory or obstructive respiratory tract diseases, containing quaternized scopine ester anticholinergic agent and steroid, e.g. budesonide |
US7094788B2 (en) | 2002-04-13 | 2006-08-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Esters of hydroxyl-substituted nitrogen heterocycles, processes for the preparation thereof as well as the use thereof as pharmaceutical compositions |
DE10216333A1 (en) | 2002-04-13 | 2003-10-30 | Boehringer Ingelheim Pharma | New diarylacetic acid quaternized azabicycloheptyl esters, are anticholinergic agents useful e.g. for treating asthma, chronic obstructive pulmonary disease, arrhythmia or menstrual disorders |
ES2206021B1 (en) | 2002-04-16 | 2005-08-01 | Almirall Prodesfarma, S.A. | NEW DERIVATIVES OF PIRROLIDINIO. |
ES2195785B1 (en) | 2002-05-16 | 2005-03-16 | Almirall Prodesfarma, S.A. | NEW DERIVATIVES OF PIRIDAZIN-3 (2H) -ONA. |
SI1507558T1 (en) | 2002-05-17 | 2011-12-30 | Novartis Pharma Ag | Pharmaceutical composition comprising a renin inhibitor, a calcium channel blocker and a diuretic |
ES2204295B1 (en) | 2002-07-02 | 2005-08-01 | Almirall Prodesfarma, S.A. | NEW DERIVATIVES OF QUINUCLIDINE-AMIDE. |
US20040058950A1 (en) | 2002-07-09 | 2004-03-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and PDE-IV inhibitors |
GB0230045D0 (en) | 2002-12-23 | 2003-01-29 | Glaxo Group Ltd | Compounds |
ES2211315B1 (en) | 2002-11-12 | 2005-10-16 | Almirall Prodesfarma, S.A. | NEW TRICYCLE COMPOUNDS. |
EP1567136A1 (en) | 2002-11-27 | 2005-08-31 | ALTANA Pharma AG | Pde4 and pde3/4 inhibitors for use in the treatment of cachexia |
ES2211344B1 (en) | 2002-12-26 | 2005-10-01 | Almirall Prodesfarma, S.A. | NEW DERIVATIVES OF PIRIDAZIN-3 (2H) -ONA. |
PE20040950A1 (en) | 2003-02-14 | 2005-01-01 | Theravance Inc | BIPHENYL DERIVATIVES AS AGONISTS OF ß2-ADRENERGIC RECEPTORS AND AS ANTAGONISTS OF MUSCARINAL RECEPTORS |
DE10307759B3 (en) | 2003-02-19 | 2004-11-18 | Schering Ag | Trimers of macrocyclically substituted benzene derivatives, their production and use as contrast media and pharmaceutical compositions containing them |
EP1452179A1 (en) | 2003-02-27 | 2004-09-01 | CHIESI FARMACEUTICI S.p.A. | Novel medicament combination of a highly potent long-lasting beta2-agonist and a corticosteroid |
US20040184995A1 (en) | 2003-03-17 | 2004-09-23 | Yamanouchi Pharmaceutical Co., Ltd. | Novel dry powder inhalation for lung-delivery and manufacturing method thereof |
EP1610787B1 (en) | 2003-03-28 | 2008-01-23 | Nycomed GmbH | Synergistic combination comprising roflumilast and an anticholinergic agent selected from tiotropium salts for the treatment of respiratory diseases |
EP1610788A1 (en) | 2003-03-28 | 2006-01-04 | ALTANA Pharma AG | Synergistic combination comprising roflumilast and an anticholinergic agent selected from ipratropium, oxitropium and tiotropium salts for the treatment of respiratory diseases |
US20050026886A1 (en) | 2003-07-29 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a PDE IV inhibitor |
US20050026948A1 (en) | 2003-07-29 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a betamimetic |
RU2361586C2 (en) | 2003-07-29 | 2009-07-20 | Берингер Ингельхайм Интернациональ Гмбх | Combination from anticholinergic and steroid and its application for treatment of diseases of respiratory tracts by inhalation |
DE602004005462T2 (en) | 2003-07-29 | 2007-07-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | MEDICAMENTS FOR INHALATION WITH BETAMIMETICS AND ANTICHOLINERGICUM |
US20050026887A1 (en) | 2003-07-29 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a steroid |
CA2534125A1 (en) | 2003-07-29 | 2005-02-17 | Boehringer Ingelheim International Gmbh | Medicaments comprising pde iv inhibitors and an anticholinergic for treating respiratory disorders |
US20050025718A1 (en) | 2003-07-31 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a betamimetic |
WO2005013994A1 (en) | 2003-07-31 | 2005-02-17 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising anticholinergics and a betamimetic |
DE10347994A1 (en) | 2003-10-15 | 2005-06-16 | Pari GmbH Spezialisten für effektive Inhalation | Aqueous aerosol preparation |
ES2232306B1 (en) | 2003-11-10 | 2006-08-01 | Almirall Prodesfarma, S.A. | NEW DERIVATIVES OF PIRIDAZIN-3 (2H) -ONA. |
NZ548300A (en) | 2004-02-06 | 2010-04-30 | Meda Pharma Gmbh & Co Kg | The combination of anticholinergics and glucocorticoids for the long-term treatment of asthma and COPD |
DK1718336T3 (en) | 2004-02-06 | 2008-10-20 | Meda Pharma Gmbh & Co Kg | New combination of anticholinergic and beta-mimetics for the treatment of respiratory diseases |
EP1713471B1 (en) | 2004-02-06 | 2012-01-18 | MEDA Pharma GmbH & Co. KG | Combination of anticholinergics and inhibitors of phosphodiesterase type 4 for the treatment of respiratory diseases |
US7712077B2 (en) * | 2004-02-27 | 2010-05-04 | International Business Machines Corporation | Method and system for instantiating components conforming to the “COM” specification in custom contexts |
ES2239546B1 (en) | 2004-03-15 | 2006-12-01 | Almirall Prodesfarma, S.A. | NEW QUATERNIZED QUINUCLIDINE ESTERS. |
DE102004016179A1 (en) | 2004-03-30 | 2005-10-20 | Boehringer Ingelheim Pharma | Compounds for the treatment of proliferative processes |
DE602005018969D1 (en) | 2004-05-31 | 2010-03-04 | Almirall Sa | Compositions with antimuscarinic agents and corticosteroids |
ES2257152B1 (en) | 2004-05-31 | 2007-07-01 | Laboratorios Almirall S.A. | COMBINATIONS THAT INCLUDE ANTIMUSCARINIC AGENTS AND BETA-ADRENERGIC AGONISTS. |
WO2006105401A2 (en) | 2005-03-30 | 2006-10-05 | Schering Corporation | Medicaments and methods combining an anticholinergic, a corticosteroid, and a long acting beta agonist |
ES2298049B1 (en) | 2006-07-21 | 2009-10-20 | Laboratorios Almirall S.A. | PROCEDURE FOR MANUFACTURING BROMIDE OF 3 (R) - (2-HIDROXI-2,2-DITIEN-2-ILACETOXI) -1- (3-PHENOXIPROPIL) -1-AZONIABICICLO (2.2.2) OCTANO. |
GB0702457D0 (en) | 2007-02-08 | 2007-03-21 | Astrazeneca Ab | New combination 666 |
PE20081788A1 (en) | 2007-02-19 | 2008-12-18 | Cipla Ltd | PHARMACEUTICAL COMBINATIONS |
US20110243924A1 (en) | 2007-02-21 | 2011-10-06 | Jorge Beleta Supervia | Novel methods |
EP2100599A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
EP2100598A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
EP2510928A1 (en) | 2011-04-15 | 2012-10-17 | Almirall, S.A. | Aclidinium for use in improving the quality of sleep in respiratory patients |
AU2013363837A1 (en) | 2012-12-17 | 2015-06-11 | Almirall, S.A. | New use of aclidinium |
-
1999
- 1999-07-14 ES ES009901580A patent/ES2165768B1/en not_active Expired - Fee Related
-
2000
- 2000-07-07 SK SK43-2002A patent/SK287480B6/en not_active IP Right Cessation
- 2000-07-07 DE DE60001840A patent/DE60001840D1/en not_active Expired - Lifetime
- 2000-07-07 TR TR2002/00768T patent/TR200200768T2/en unknown
- 2000-07-07 UA UA2002010323A patent/UA73509C2/en unknown
- 2000-07-07 RU RU2002103605A patent/RU2264401C3/en active Protection Beyond IP Right Term
- 2000-07-07 CA CA2381165A patent/CA2381165C/en not_active Expired - Lifetime
- 2000-07-07 AT AT00951361T patent/ATE235492T1/en active
- 2000-07-07 HU HU0202100A patent/HU228594B1/en active Protection Beyond IP Right Term
- 2000-07-07 SI SI200030108T patent/SI1200431T1/en unknown
- 2000-07-07 CN CNB008127549A patent/CN1272334C/en not_active Expired - Lifetime
- 2000-07-07 CZ CZ2002-121A patent/CZ304292B6/en unknown
- 2000-07-07 BR BRPI0012434A patent/BRPI0012434B8/en not_active IP Right Cessation
- 2000-07-07 EP EP00951361.5A patent/EP1200431B3/en not_active Expired - Lifetime
- 2000-07-07 PL PL357160A patent/PL204024B1/en not_active IP Right Cessation
- 2000-07-07 IL IL14753300A patent/IL147533A0/en active Protection Beyond IP Right Term
- 2000-07-07 KR KR1020067027730A patent/KR100854315B1/en active Protection Beyond IP Right Term
- 2000-07-07 KR KR1020067027733A patent/KR100854321B1/en not_active IP Right Cessation
- 2000-07-07 ES ES951361T patent/ES2193098T7/en active Active
- 2000-07-07 PT PT00951361T patent/PT1200431E/en unknown
- 2000-07-07 CN CNB2006100068921A patent/CN100451018C/en not_active Expired - Lifetime
- 2000-07-07 KR KR1020027000479A patent/KR100773844B1/en not_active IP Right Cessation
- 2000-07-07 DE DE60001840.7T patent/DE60001840T4/en not_active Expired - Lifetime
- 2000-07-07 WO PCT/EP2000/006469 patent/WO2001004118A2/en active IP Right Grant
- 2000-07-07 DK DK00951361.5T patent/DK1200431T6/en active
- 2000-07-07 EE EEP200200017A patent/EE04915B3/en active Protection Beyond IP Right Term
- 2000-07-07 JP JP2001509727A patent/JP4030040B2/en not_active Expired - Lifetime
- 2000-07-11 PE PE2000000691A patent/PE20010397A1/en not_active IP Right Cessation
- 2000-07-12 EG EG20000907A patent/EG24066A/en active
- 2000-07-12 TW TW089113865A patent/TWI284644B/en active
- 2000-07-12 MY MYPI20003178 patent/MY126959A/en unknown
- 2000-07-13 AR ARP000103613A patent/AR029760A1/en active IP Right Grant
- 2000-07-13 CO CO00052873A patent/CO5200759A1/en active IP Right Grant
- 2000-07-14 UY UY26244A patent/UY26244A1/en unknown
-
2002
- 2002-01-10 ZA ZA200200232A patent/ZA200200232B/en unknown
- 2002-01-14 NO NO20020180A patent/NO329484B3/en not_active IP Right Cessation
- 2002-01-14 BG BG106301A patent/BG65565B1/en unknown
- 2002-01-14 US US10/047,464 patent/US6750226B2/en not_active Expired - Lifetime
- 2002-05-29 HK HK02103992A patent/HK1042487B/en not_active IP Right Cessation
-
2003
- 2003-12-17 US US10/740,264 patent/US7109210B2/en not_active Expired - Fee Related
-
2005
- 2005-04-28 US US11/116,777 patent/US7078412B2/en not_active Expired - Lifetime
- 2005-05-18 AU AU2005202144A patent/AU2005202144B2/en active Active
- 2005-07-06 RU RU2005121162/04A patent/RU2306312C2/en active
- 2005-07-12 JP JP2005203365A patent/JP4951217B2/en not_active Expired - Fee Related
-
2006
- 2006-01-03 US US11/325,059 patent/US7196098B2/en not_active Expired - Lifetime
- 2006-12-08 US US11/636,181 patent/US7358260B2/en not_active Expired - Fee Related
-
2008
- 2008-03-07 US US12/074,929 patent/US7750023B2/en not_active Expired - Fee Related
-
2010
- 2010-05-26 US US12/787,772 patent/US7897617B2/en not_active Expired - Fee Related
-
2011
- 2011-01-21 US US13/011,131 patent/US8129405B2/en not_active Expired - Fee Related
- 2011-07-08 UY UY0001033494A patent/UY33494A/en not_active Application Discontinuation
-
2012
- 2012-01-20 US US13/354,873 patent/US8513279B2/en not_active Expired - Fee Related
-
2013
- 2013-01-03 BE BE2013C001C patent/BE2013C001I2/fr unknown
- 2013-01-07 CY CY2013001C patent/CY2013001I1/en unknown
- 2013-01-08 FR FR13C0001C patent/FR13C0001I2/en active Active
- 2013-01-16 LU LU92132C patent/LU92132I2/en unknown
- 2013-01-18 NO NO2013002C patent/NO2013002I2/en unknown
- 2013-07-11 US US13/939,742 patent/US8802699B2/en not_active Expired - Fee Related
-
2014
- 2014-06-20 US US14/311,102 patent/US9056100B2/en not_active Expired - Fee Related
-
2015
- 2015-05-14 US US14/712,866 patent/US9333195B2/en not_active Expired - Lifetime
-
2016
- 2016-02-09 US US15/019,009 patent/USRE46417E1/en active Active
- 2016-04-09 US US15/095,036 patent/US9687478B2/en not_active Expired - Fee Related
-
2017
- 2017-05-19 US US15/599,646 patent/US10034867B2/en not_active Expired - Fee Related
-
2018
- 2018-07-25 US US16/045,333 patent/US10588895B2/en not_active Expired - Lifetime
Patent Citations (98)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1219606A (en) | 1968-07-15 | 1971-01-20 | Rech S Et D Applic Scient Soge | Quinuclidinol derivatives and preparation thereof |
US3714357A (en) | 1968-07-15 | 1973-01-30 | Rech D Applic Scient Sogeras S | Pharmaceutical compositions comprising quinuclidinol derivatives |
FR2012964A1 (en) | 1968-07-15 | 1970-03-27 | Sogeras | |
EP0003445A1 (en) | 1978-01-10 | 1979-08-08 | Pharmuka Laboratoires | 1-Aza-bicyclo(2,2,2)octanes, process for their preparation and intermediates, and medicines containing them |
US4224332A (en) | 1978-01-10 | 1980-09-23 | Pharmindustrie | 1-Aza-[2,2,2]-bicyclooctanes and anti-depressant and anti-parkinsonian compositions thereof |
GB2041763A (en) | 1979-02-05 | 1980-09-17 | Chiesi P | An inhalor for pulverulent medicinal substances |
US4338931A (en) | 1979-04-27 | 1982-07-13 | Claudio Cavazza | Device for the quick inhalation of drugs in powder form by humans suffering from asthma |
EP0069715A1 (en) | 1981-07-08 | 1983-01-12 | Aktiebolaget Draco | Powder inhalator |
US4644033A (en) | 1983-01-11 | 1987-02-17 | Essilor International | Polyurethane hydrogels and process for their manufacture |
US4579854A (en) | 1983-12-24 | 1986-04-01 | Tanabe Seiyaku Co., Ltd. | Bronchodilating 8-hydroxy-5-{(1R)-1-hydroxy-2-[N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)-amino]ethyl} carbostyril |
EP0166294A2 (en) | 1984-06-18 | 1986-01-02 | Miles Inc. | Medicament inhalation device |
US4675326A (en) * | 1985-05-08 | 1987-06-23 | Gabriel Amitai | Bisquaternary antidotes |
US4855290A (en) | 1985-05-10 | 1989-08-08 | State Of Israel, Represented By Prime Minister's Office, Israel Institute For Biological Research | Derivatives of quinuclidine |
EP0205247A2 (en) | 1985-05-10 | 1986-12-17 | State Of Israel, Represented By Prime Minister's Office, Israel Institute For Biological Research | Derivatives of quinuclidine |
WO1987007502A1 (en) | 1986-06-06 | 1987-12-17 | Phares Pharmaceutical Research N.V. | Composition and method |
EP0302699A2 (en) | 1987-08-03 | 1989-02-08 | Walton S.A. | Improvements relating to n-substituted benzamides |
US4843074A (en) | 1988-05-17 | 1989-06-27 | Marion Laboratories, Inc. | 1-azabicyclo[2.2.2]octan-3-yl 2-aryl-3-azacyclo-2-hydroxypropionates and their quaternary salts |
WO1991002558A1 (en) | 1989-08-17 | 1991-03-07 | Boehringer Ingelheim Kg | Inhalator |
US5685294A (en) | 1989-08-17 | 1997-11-11 | Boehringer Ingelheim Kg | Powder inhaler having magazine storage and a hinged mouthpiece |
US5290815A (en) | 1989-09-07 | 1994-03-01 | Glaxo Group Limited | Treatment of inflammation and allergy |
USRE39820E1 (en) | 1989-09-16 | 2007-09-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Esters of thienyl carboxylic acids and amino alcohols and their quaternization products |
US5610163A (en) | 1989-09-16 | 1997-03-11 | Boehringer Ingelheim Gmbh | Esters of thienyl carboxylic acids and amino alcohols and their quaternization products |
EP0418716A1 (en) | 1989-09-16 | 1991-03-27 | Boehringer Ingelheim Kg | Thienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the compounds |
EP0418716B1 (en) | 1989-09-16 | 1994-04-06 | Boehringer Ingelheim Kg | Thienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the compounds |
WO1991004252A1 (en) | 1989-09-16 | 1991-04-04 | Boehringer Ingelheim Kg | New esters of thienyl carboxylic acids and amino alcohols, their quaternization products, and manufacture and use of said compounds |
EP0424021A1 (en) | 1989-10-19 | 1991-04-24 | Pfizer Limited | Antimuscarinic bronchodilators |
EP0424790A2 (en) | 1989-10-27 | 1991-05-02 | Miat S.P.A. | Multi-dose inhaler for medicaments in powder form |
EP0424790B1 (en) | 1989-10-27 | 1993-08-04 | Miat S.P.A. | Multi-dose inhaler for medicaments in powder form |
US5254330A (en) | 1990-01-24 | 1993-10-19 | British Technology Group Ltd. | Aerosol carriers |
US5201308A (en) | 1990-02-14 | 1993-04-13 | Newhouse Michael T | Powder inhaler |
WO1991014468A1 (en) | 1990-03-21 | 1991-10-03 | Dmw (Technology) Limited | Atomising devices and methods |
WO1992000771A1 (en) | 1990-07-13 | 1992-01-23 | Innovata Biomed Limited | Inhaler |
WO1992003175A1 (en) | 1990-08-11 | 1992-03-05 | Fisons Plc | Inhalation device |
WO1992004068A1 (en) | 1990-08-30 | 1992-03-19 | Boehringer Ingelheim Kg | Inhalator without propeller gas with foreign air stream |
US5617845A (en) | 1990-08-30 | 1997-04-08 | Boehringer Ingelheim Kg | Inhalation device free from propellent gas |
US5507281A (en) | 1990-08-30 | 1996-04-16 | Boehringer Ingelheim Kg | Device for initiating a mechanical switching operation in synchronism with the breathing |
WO1992004346A1 (en) | 1990-09-06 | 1992-03-19 | Pfizer Limited | Antimuscarinic bronchodilators |
WO1992004345A1 (en) | 1990-09-12 | 1992-03-19 | Allergan, Inc. | 6- or 7- (2-IMINO-2-IMIDAZOLIDINE)-1,4-BENZOXAZINES AS ALPHA ADRENERGIC AGENTS |
WO1992004928A2 (en) | 1990-09-26 | 1992-04-02 | Pharbita B.V. | Inhaler devices provided with a reservoir for several doses of medium for inhaling, transporting device, whirl chamber |
WO1992009322A1 (en) | 1990-11-29 | 1992-06-11 | Boehringer Ingelheim Kg | Inhalation device |
US5575280A (en) | 1990-11-29 | 1996-11-19 | Boehringer Ingelheim Kg | Powder inhalation device having nozzle to empty dosing chamber |
US5290539A (en) | 1990-12-21 | 1994-03-01 | Minnesota Mining And Manufacturing Company | Device for delivering an aerosol |
CA2062854A1 (en) | 1991-03-14 | 1992-09-15 | Manfred Keller | Pharmaceutical aerosol formulations |
US5654314A (en) | 1991-03-15 | 1997-08-05 | Boehringer Ingelheim Kg | Esters of bi- and tricyclic amino alcohols and their use in pharmaceutical compositions |
EP0505321A2 (en) | 1991-03-21 | 1992-09-23 | Ciba-Geigy Ag | Inhaler |
US5263475A (en) | 1991-03-21 | 1993-11-23 | Ciba-Geigy Corp. | Inhaler |
EP0603229A1 (en) | 1991-09-14 | 1994-06-29 | Pfizer Limited | Quinuclidine esters process and intermediate for their preparation and pharmaceutical compositions containing them |
US6299863B1 (en) | 1992-04-03 | 2001-10-09 | Sepracor Inc. | Aerosol formulations containing micronized optically pure (R,R) formoterol for bronchodilating therapy |
US5435301A (en) | 1992-11-24 | 1995-07-25 | Bayer Aktiengesellschaft | Powder inhaler having dispersing, discharge, and dwell-time chambers, along with an acceleration channel |
US5676930A (en) | 1992-12-09 | 1997-10-14 | Boehringer Ingelheim Pharmaceuticals, Inc. | Stabilized medicinal aerosol solution formulations |
WO1994014492A2 (en) | 1992-12-18 | 1994-07-07 | Schering Corporation | Inhaler for powdered medications |
EP0747355A1 (en) | 1994-02-10 | 1996-12-11 | Yamanouchi Pharmaceutical Co. Ltd. | Novel carbamate derivative and medicinal composition containing the same |
WO1995024889A1 (en) | 1994-03-15 | 1995-09-21 | Glaxo Group Limited | Inhalation composition containing lactose pellets |
US5569447A (en) | 1994-04-19 | 1996-10-29 | The United States Of America Represented By The Secretary Department Of Health And Human Services | Stannylated 3-quinuclidinyl benzilates and methods of preparing radiohalogenated derivatives |
WO1996004346A1 (en) | 1994-07-29 | 1996-02-15 | Minnesota Mining And Manufacturing Company | Acrylic syrup curable to a crosslinked viscoelastomeric material |
WO1996019968A1 (en) | 1994-12-24 | 1996-07-04 | Glaxo Group Limited | Pharmaceutical aerosol containing at least one sugar |
EP0801067A1 (en) | 1994-12-28 | 1997-10-15 | Yamanouchi Pharmaceutical Co. Ltd. | Novel quinuclidine derivatives and medicinal composition thereof |
US6521261B2 (en) | 1995-01-09 | 2003-02-18 | Edward Mendell Co., Inc. | Pharmaceutical excipient having improved compressibility |
US6521260B1 (en) | 1995-01-31 | 2003-02-18 | Vectura Limited | Carrier particles for use in dry powder inhalers |
WO1996032150A1 (en) | 1995-04-14 | 1996-10-17 | Glaxo Wellcome Inc. | Metered dose inhaler for salmeterol |
WO1997000703A1 (en) | 1995-06-21 | 1997-01-09 | Asta Medica Aktiengesellschaft | Pharmaceutical powder cartridge with integrated metering device and inhaler for powdered medicaments |
WO1997001337A1 (en) | 1995-06-29 | 1997-01-16 | Mcneil-Ppc, Inc. | The combination of topical nasal antihistamines and topical nasal steroids |
US6299861B1 (en) | 1995-08-01 | 2001-10-09 | Boehringer Ingelheim Kg | Ipratropium bromide enantiomer with prolonged duration of effect |
US5964416A (en) | 1995-10-04 | 1999-10-12 | Boehringer Ingelheim Gmbh | Device for producing high pressure in a fluid in miniature |
US6402055B1 (en) | 1995-10-04 | 2002-06-11 | Boehringer Ingelheim Gmbh | Device for producing high pressure in a fluid in miniature |
US6918547B2 (en) | 1995-10-04 | 2005-07-19 | Joachim Jaeger | Device for producing high pressure in a fluid in miniature |
US6726124B2 (en) | 1995-10-04 | 2004-04-27 | Boehringer International Gmbh | Device for producing high pressure in a fluid in miniature |
WO1997012687A1 (en) | 1995-10-04 | 1997-04-10 | Boehringer Ingelheim International Gmbh | Device of miniaturised construction for producing high pressure in a fluid to be atomised |
US7104470B2 (en) | 1995-10-04 | 2006-09-12 | Boehringer Ingelheim International Gmbh | Device for producing high pressure in a fluid in miniature |
US6497373B2 (en) | 1995-10-04 | 2002-12-24 | Boehringer International Gmbh | Device for producing high pressure in a fluid in miniature |
WO1997028801A1 (en) | 1996-02-09 | 1997-08-14 | Mayo Foundation For Medical Education And Research | Colonic delivery of nicotine to treat inflammatory bowel disease |
WO1997034871A1 (en) | 1996-03-22 | 1997-09-25 | Nitromed, Inc. | Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders |
US6150415A (en) | 1996-08-13 | 2000-11-21 | The Regents Of The University Of California | Epoxide hydrolase complexes and methods therewith |
US5885834A (en) | 1996-09-30 | 1999-03-23 | Epstein; Paul M. | Antisense oligodeoxynucleotide against phosphodiesterase |
WO1998015280A1 (en) | 1996-10-08 | 1998-04-16 | Astra Aktiebolag | New combination |
US6686346B2 (en) | 1996-12-05 | 2004-02-03 | Astra Aktiebolag | Formulation |
US20030085480A1 (en) | 1997-03-20 | 2003-05-08 | Tsong-Toh Yang | Preparation of powder agglomerates |
WO1999051205A1 (en) | 1998-04-03 | 1999-10-14 | University College Cardiff Consultants Limited | Aerosol composition |
US6423298B2 (en) | 1998-06-18 | 2002-07-23 | Boehringer Ingelheim Pharmaceuticals, Inc. | Pharmaceutical formulations for aerosols with two or more active substances |
US5962505A (en) | 1998-08-31 | 1999-10-05 | Bobrove; Arthur M. | Method for treating hot flashes in humans |
US6986346B2 (en) | 1998-10-17 | 2006-01-17 | Boehringer Ingelheim Pharma Kg | Closure-cap and container as a two-chamber cartridge for nebulisers for producing aerosols and active substance formulations, suitable for storage |
US7040311B2 (en) | 1998-10-17 | 2006-05-09 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Closure-cap and container as a two-chamber cartridge for nebulizers for producing aerosols and active substance formulations, suitable for storage |
US8129405B2 (en) * | 1999-07-14 | 2012-03-06 | Almirall Prodesfarma S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
US7078412B2 (en) * | 1999-07-14 | 2006-07-18 | Almirall Prodesfarma Ag | Quinuclidine derivatives and medicinal compositions containing the same |
US7196098B2 (en) * | 1999-07-14 | 2007-03-27 | Almirall Prodesfarma Ag | Quinuclidine derivatives and medicinal compositions containing the same |
US7214687B2 (en) * | 1999-07-14 | 2007-05-08 | Almirall Ag | Quinuclidine derivatives and medicinal compositions containing the same |
US9333195B2 (en) * | 1999-07-14 | 2016-05-10 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
US7358260B2 (en) * | 1999-07-14 | 2008-04-15 | Laboratories Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
US9056100B2 (en) * | 1999-07-14 | 2015-06-16 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
US7750023B2 (en) * | 1999-07-14 | 2010-07-06 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
US8802699B2 (en) * | 1999-07-14 | 2014-08-12 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
US7897617B2 (en) * | 1999-07-14 | 2011-03-01 | Almirall Prodesfarma S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
US7109210B2 (en) * | 1999-07-14 | 2006-09-19 | Almirall Prodesfarma Ag | Quinuclidine derivatives and medicinal compositions containing the same |
US8513279B2 (en) * | 1999-07-14 | 2013-08-20 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
WO2001050080A2 (en) | 1999-12-29 | 2001-07-12 | Valeo Climatisation | Multichannel tube heat exchanger |
EP2242134A1 (en) | 2001-10-26 | 2010-10-20 | Valence Technology, Inc. | Alkali/transition metal halo - and hydroxy-phosphates and related electrode active materials |
EP2165159A1 (en) | 2007-07-03 | 2010-03-24 | Nxp B.V. | Calibration of an amr sensor |
WO2013175013A1 (en) * | 2012-05-25 | 2013-11-28 | Almirall, S.A. | Novel dosage and formulation |
Non-Patent Citations (89)
Title |
---|
6001 Chemical Abstracts, Columbus, Ohio, US. vol. 104(19). XP-002128290, p. 659. (1 page total). |
Alabaster, V., "Discovery and Development of Selective M3 Antagonists for Clinical Use," Life Sciences, 1997, 60 (13-14), 1053-1060. |
Atrovent® (ipratropium bromide) Inhalation Solution Prescribing Information, Boehringer Ingelheim International GmbH 830885-R, Revised Oct. 1998. |
Auerbach, D. et al., "Routine Nebuilzed Ipratropium and Albuterol Together are Better Than Either Alone in COPD*," The Combivent Inhalation Solution Study Group, Chest, 1997 112,1514-1521. |
Ayres, JG et al. Thorax 52(Supp 1): S1-S21 (1997). |
Banner, K. et al., "The Effect of Selective Phosphodiesterase 3 and 4 Isoenzyme Inhibitors and Established Anti-Asthma Drugs on Inflammatory Cell Activation," British Journal of Pharmacology, 1996, 119, 1255-1261. |
Barnes, P. et al., "The Effect of Platelet Activating Factor on Pulmonary-Adrenoceptors," British Journal of Pharmacology, 1987, 90, 709-715. |
Barnes, P. et al., Eds., Asthma, vol. 2, Lippincott-Raven, Philadelphia, 1997, ISBN 0-397-51682-7, Chapter 142: Compliance by H. Mawhinney et al., pp. 2099-2113. |
Beasley, R. et al., "Withdrawal of Fenoterol and the End of the New Zealand Asthma Mortality Epidemic," International Archives of Allergy and Immunology, 1995, 107, 325-327. |
Berenbaum, M., "Synergy, Additivism and Antagonism in Immunosuppression, A Critical Review," Clinical and Experimental Immunology, 1977, 28, 1-18. |
Berenbaum, M., "What is Synergy?," Pharmacological Reviews, 1989, 41, 93-141 and Errata, p. 422. |
Berkow, R. et al., Eds., The Merck Manual of Diagnosis and Therapy, Sixteenth Edition, 1992, Foreword and Chapter 34, "Airways Obstruction Asthma," pp. 646-657. |
Bone, R. et al., "In Chronic Obstructive Pulmonary Disease, A Combination oflpratropium and Albuterol is More Effective that Either Agent Alone: An 85-Day Multicenter Trial," Combivent Inhalation Aerosol Study Group, Chest, 1994, 105, 1411-1419. |
British Thoracic Society, "BTS Guidelines for the Management of Chronic Obstructive Pulmonary Disease," The COPD Guidelines Group of the Standards of Care Committee of the BTS, Thorax, 1997, 52, Supplement 5, SI-S28. |
Brodde, 0-E., "1- and 2-Adrenoceptors in the Human Heart: Properties, Function, and Alterations in Chronic Heart Failure," Pharmacological Reviews, 1991, 43 (2), 203-242. |
Bryant, D., "Nebulized Ipratropium Bromide in the Treatment of Acute Asthma," Chest Journal, 88(1), 24-29. |
Burtner, R. and Cusic, J. W. (1943). "Antispasmodics, II. Basic Esters of Some Polynuclear Carboxylic Acids," J. Am. Chem. Soc. 65:1582-1585. |
Calverley, P.M.A., Ed., Chronic Obstructive Pulmonary Disease, Chapman and Hall, London, 1995, ISBN 0 412 46450, Chapter 16: Bronchodilators: Basic Pharmacology by P.J. Barnes, pp. 391 and 398-401. |
CHEMICAL ABSTRACTS, vol. 19, no. 104, 12 May 1986, Columbus, Ohio, US; abstract no. 104-168339, GODOVIKOV, N. N. ET AL.: "Synthesis and muscarinolytic activity of quinuclidinyl benzilate alkyl iodides" XP002128290 |
Christensen et al., "1,4-Cyclohexanecarboxylates: Potent and Selective Inhibitors of Phosphodiesterase 4 for the Treatment of Asthma," J. Med. Chem. 41:821-835 (1998). |
Clarkson, E. et al., "Binding and Active Transport of Large Analogues of Acetylcholine by Cholinergic Synaptic Vesicles In Vitro," Journal of Neurochemistry, 1992, 59, 695-700. |
Cohen, V. I. et al. (1992). "Synthesis and Receptor Affinities of New 3-Quinuclidinyl α-Heteroaryl-α-aryl-α-Hydroxyacetates," J. Pharm Sciences 81:326-329. |
Costain, D. et al., "Guidelines for Management of Asthma in Adults: I-Chronic Persistent Asthma," Br. Med. J. 301: 651-653 (1990). |
Davis, M. A. et al. (1963). "New Psychotropic Agents. VI. Basic Esters of 5-Hydroxydibenzo[a,d] cycloheptadiene-5-carboxylic Acid," J. Med. Chem 6:513-516. |
Davis. M. A. et al (1964). "Anticonvulsants. I. Dibenzo[a,d]cycloheptadiene-5-carboxamide and Related Compounds," J. Med. Chem. 7:88-94. |
Dent, et al., "Effectis of a Selective PDE4 Inhibitor, D-22888, on Human Airways and Eosinophils in vitro and Late Phase Allergic Pulmonary Eosinophilia in Guinea Pigs," Pulmonary Pharma & Thera. 11:13-21 (1998). |
Disse, B. et al., "BA 679 BR, A Novel Long-Acting Anticholinergic Bronchodilator," Life Sciences, 1993, 52, 537-544. |
Dompeling, E. et al., "Slowing the Deterioration of Asthma and Chronic Obstructive Pulmonary Disease Observed During Bronchodilator Therapy by Adding Inhaled Corticosteroids," Annals of Internal Medicine, 1993, 118, 770-778. |
Easton, P. et al., "A Comparison of the Bronchodilating Effects of a Beta-2 Andrenergic Agent (Albuterol) and an Anticholinergic Agent (Ipratropium Bromide), Given by Aerosol Alone or in a Sequence,"New England Journal of Medicine, 1986,315 (12), 735-730. |
Eglen, R. et al, "Muscarinic Receptor Subtypes and Smooth Muscle Function," Pharmacological Reviews, 1996, 48 (4), 531-565. |
Eglen, RM et al., "Muscarinic Receptor Subtypes: Pharmacology and Therapeutic Potential," DN & P, 10(8): 462-469 (Oct. 1997). |
Emea, "Note for Guidance on Dose Response Information to Support Drug Registration," ICH Topic E 4. 1994. CPMP/ICH/378/95. |
English Translation of Instructions for Medicine, The Merck Manual, M., "MIR", 1997, vol. 2, p. 693. |
Etzler, F M. et al., "Particle size analysis; a comparative study of various methods", Part. Part. Syst. Charact., vol. 12, Oct. 1995; pp. 217-224. |
Foye, et al., Principles of Medicinal Chemistry, 4th Edition, pp. 338-340 (1995). |
Frith, P. et al., "Oxitropium Bromide, Dose-Response and Time-Response Study of a New Anticholinergic Bronchodilator Drug," Chest, 1986, 89 (2), 249-253. |
Gao, SH et al., Stereochemistry of the heterocyclic alcohols containing piperidine unit, Gaodeng Xuexiao Huaxue Xuebao, vol. 20: p. 232-236 (1999). |
Global Initiative for Asthma, Global Strategy for Asthma Management and Prevention, NIH Publication No. 02-3659, Issued Jan. 1995, revised 2002. |
Godoviko et al., "Synthesis and Muscarinolytic Activity of Quinuclidinyl Benzylate Iodoalkylates," Pharmceutical Chemistry Journal, vol. 19, No. 9, 602-604 (1985). |
Grob, C. A. and Brenneisen, P. (1958). "Die Synthese von 4-Brom-und 4-Hydroxy-Chinuclidin," Helv. Chim. Acta 41:1184-1191. |
Gross, N. et al., "Dose Response to Ipratropium as a Nebulized Solution in Patients with Chronic Obstructive Pulmonary Disease, A Three-Center Study," American Review of Respiratory Disease, 1989, 139, 1188-1191. |
Gross, N. et al., "Inhalation by Nebulization of Albuterol-Ipratropium Combination (Dey Combination) is Superior to Either Agent Alone in the Treatment of Chronic Obstructive Pulmonary Disease," Respiration, 1998, 65, 354-362. |
Gross, N. et al., "Role of the Parasympathetic System in Airway Obstruction Due to Emphysema," New England Journal of Medicine, 1984, 16 311 (7), 421-425. |
Hancox, RJ et al., "Randomised trial of an inhaled B2 agonist, inhaled corticosteroids and their combination in the treatment of asthma," Thorax, 54: 482-487 (1999). |
Hardman, J. et al., Eds., Goodman and Gilman's: The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill, New York, 1996, Chapter 28: Drugs Used in the Treatment of Asthma by W. Serafin, pp. 659-682. |
Heacock, R.A. et al. (1958). "Materials and Methods," The Annals of Applied Biology, Marsh R. W. and Thomas, I, eds, Cambridge at the University Press, vol. 46, pp. 356-365. |
Instructions for Medicine, The Merck Manual, M., "MIR", vol. 2, p. 693. |
Johnson, M., "Salmeterol," Medicinal Research Reviews, 1995, 15 (3), 225-257. |
Konzett, H. and Rössler, R. (1940). "Versuchsanordnung zu Untersuchungnen an der Bronchialmuskulatur," Arch. Exp. Path. Pharmacol. 195:71-74. |
Kumazawa, T. et al. (1994). "Inhibitors of Acyl-CoA:Cholesterol Acyltransferase. 1. Synthesis and Hypocholesterolemic Activity of Dibenz[b,e]oxepin-11carboxanilides," J. Med. Chem. 37(6): 804-810. |
Larsson, L. et al. (1974). "The Hydrogen Bond Condition in Some Anticholinergic Esters of Glycolic Acids. I" Acta Pharm. Suec. 11(3):304-308. |
Le Souef, P, "The meaning of lung dose", Allergy, vol. 54, Mar. 1999, pp. 93-96. |
Lopez-Vidiero, M. et al., "Effect of Atropine on Sputum Production," Thorax, 1975, 30, 543-547. |
Lund, H. et al., "Quaternization Reactions," Acta Chemica Scandinavica, 1973, 27, 383-390. |
Lygo, B. et al., "Asymmetric Approaches to 2-Hydroxymethylquinuclidine Derivatives," Tetrahedron, 1999, 55, 2795-2810. |
Maesen, F.P.V. et al., "Ba 679 Br, A New Long-Acting Antimuscarinic Bronchodilator: A Pilot Dose-Escalation Study in COPD," European Respiratory Journal, 1993, 6, 1031-1036. |
Martin, L. "Drugs for Asthma/COPD—A Medical Primer for Physicians," http://www/lakesidepress.com/pulmonary/Asthma-Rx.html (updated Feb. 1999). |
May, E. L and Mossettig, E. (1948). "Studies in the Anthracene Series. V. A Novel Rearrangement in the Reaction of Halomethyl Ketones with Secondary Amines," J. Am. Chem. Soc. 70: 1077-1079. |
Merck Manual of Diagnosis and Therapy, Robert Berkow ed., 16th Edition, p. 646-657 (1992). |
Mery, P-F. et al., "Muscarinic Regulation of the L-Type Calcium Current in Isolated Cardiac Myocytes," Life Sciences, 1997, 60, (13-14), 1113-1120. |
Meyers, A. I. et al. (1980). "Resolution of α-Substituted Mandelic Acids via Chiral Oxazolines Using Pressurized Chromatography," J. Org. Chem. 45(14): 2912-2914. |
Nishikawa, M. et al., "Effect of Short and Long-Acting 2-Adrenoceptor Agonists on Pulmonary 2-Adrenoceptor Expression in Human Lung," European Journal of Pharmacology, 1996,318, 123-129. |
Nishimura, et al., "Additive effect of oxitropium bromide in combination with inhaled corticosteroids in the treatment of elderly patients with chronic asthma," Allergology International 48: 85-88 (1999). |
Noronha-Blob, L et al., Stereoselective antimuscarininc effects of 3-quinuclidinyl atrolactate and 3-quinuclidinyl xanthene-9-carboxylate, European Journal of Pharmacology 211:97-103 (1992). |
Nyberg, K. et al. (1970). "Investigations of Dithienylglycolic Esters," Acta Chem. Scand. 24:1590-1596. |
Parfitt, K., Ed., Martindale: The Complete Drug Reference, Thirty-Second Edition, 1999, 745-747. |
Rang, H et al., Eds., Pharmacology, Third Edition, 1995, Chapter 17, "The Respiratory System," pp. 351-366. |
Rang, HP et al., "Pharmacology," Churchill Livingston Inc., pp. 358-361 (1995). |
Rees, PJ "Bronchodilators in the therapy of chronic obstructive pulmonary disease," Eur. Respir. Mon. 7:135-149 (1998). |
Rennard, SI, (1998) "Anticholinergics and beta2-agonists: Efficacy, Safety and Combination Therapy in Chronic Obstructive Pulmonary Disease," Chapter 9, Barnes and Bulst (Ed.) The Role of Anticholinergics in Chronic Obstructive Pulmonary Disease and Chronic Asthma, pp. 137-144, Gardiner-Caldwell Communications Limited. |
Rigaudy, J. et al. (1959). "Cétones Derivées du Dibenzo[a,d] cycloheptadiène. La Dibenzo-2-,3-6,7 Cycloheptadiènedione-4,5," Bull. Soc. Chim. France. 638-643. |
Ringdahl, R. et al. (1979). "Facile Preparation of the Enantiomers of 3-Acetoxyquinuclidinol," Acta Pharm Suec. 16:281-283. |
Rzeszotarski, W. et al., "Affinity and Selectivity of the Opitcal Isomers of 3-Quinuclidinyl Benzilate and Related Muscarinic Antagonists," Journal of Medicinal Chemistry, 1988, 31, 1463-1466. |
Schmidt, R. "Dose-Finding Studies in Clinical Drug Development," Eur J Clin Pharmacol, 1988. 34:15-19. |
Serafin, W. "Drugs Used in the Treatment of Asthma," Goodman Gilman's The Pharmacological Basis of Therapeutics, Chapter 28 , Joel G. Hardman et al eds, 9th Edition, pp. 659-682 (1996). |
Sestanj, K. (1971). "A Facile Formation of Dibenzo[a,b] cycloheptenylium Ion by Decarbonylation. Color Reactions of the Cyhemptaminde Metabolites," Can. J. Chem. 49:664-665. |
Sharma, V. et al. "Does Mammalian Heart Contain Only the M2-Muscarinic Receptor Subtype?," Life Sciences, 1997, 60 (13-14), 1023-1029. |
Spitzer, W. et al., "The Use of P-Agonists and the Risk of Death and Near Death from Asthma," New England Journal of Medicine, 1992, 326, 501-506. |
Suissa, S. et al., "Patterns of Increasing P-Agonist Use and the Risk of Fatal or Near-Fatal Asthma," European Respiratory Journal, 1994, 7, 1602-1609. |
Tavakkoli et al., "Drug Treatment of Asthma in the 1990s, Achievements and New Strategies," Drugs, 57(1): 1-8 (1999). |
Teixera et al., "Phosphodiesterase (PDE) 4 inhibitors: anti-inflammatory drugs of the future," TiPS, 18:164 (May 1997). |
The Merck Manual of Diagnosis and Therapy, Seventeenth Edition, 1999, Foreword and Chapter 68, "Chronic Obstructive Airway Disorders," pp. 555-583. |
Theolair™ Prescribing Information, 3M Phamaceuticals, 601000, May 1998, 12 pages. |
Torphy, T. "Phosphodiesterase Isozymes, Molecular Targets for Novel Antiasthma Agents," Am. J. Respit. Crit. Care Med., 157:351-370 (1998). |
Traunecker, W. et al., "Pharmacological Effects of a Combination of Fenoterol Hydrobromide and Ipratropium Bromide," Respiration, 1986, 50 (4), 244-251. |
Ueda, I. (1975). "The Rearrangement of 10-Bromo-10, 11-Dihydrodibenzo[b,f]thiepin-11-one and Related Compounds in an Alkaline Solution," Bulletin of the Chemical Society of Japan 48(8):2306-2309. |
Waelbroek, M. et al. (1990). "Binding of Selective Antagonists to Four Muscarinic Receptors (M1 to M4) in Rat Forebrain," Mol. Pharmacol. 38:267-273. |
Walsh, D. et al., "Synthesis and Antiallergy Activity of 4-(Diarylhydroxymethyl)-1[3-(aryloxy)propyl]piperidines and Structurally Related Compounds," Journal of Medicinal Chemistry, 1989,32, 105-118. |
Zaagsma, J. et al. "Muscarinic Control of Airway Function," Life Sciences, 1997, 60 (13-14), 1061-1068. |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10034867B2 (en) | 1999-07-14 | 2018-07-31 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
US10588895B2 (en) | 1999-07-14 | 2020-03-17 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
US10085974B2 (en) | 2008-03-13 | 2018-10-02 | Almirall, S.A. | Dosage and formulation |
US11000517B2 (en) | 2008-03-13 | 2021-05-11 | Almirall, S.A. | Dosage and formulation |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10588895B2 (en) | Quinuclidine derivatives and medicinal compositions containing the same | |
US20060106055A1 (en) | Novel quinuclidine derivatives and medicinal compositions containing the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FEPP | Fee payment procedure |
Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
CC | Certificate of correction | ||
PTEG | Grant of a patent term extension |
Free format text: PRODUCT NAME: TUDORZA PRESSAIR (ACLIDINIUM BROMIDE INHALATION POWDER) Filing date: 20120919 Expiry date: 20200905 |
|
PTEG | Grant of a patent term extension |
Free format text: PRODUCT NAME: TUDORZA PRESSAIR (ACLIDINIUM BROMIDE INHALATION POWDER) Filing date: 20120919 Expiry date: 20200905 |