WO2012146515A1 - Alkaloid ester and carbamate derivatives and medicinal compositions thereof - Google Patents

Alkaloid ester and carbamate derivatives and medicinal compositions thereof Download PDF

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Publication number
WO2012146515A1
WO2012146515A1 PCT/EP2012/057062 EP2012057062W WO2012146515A1 WO 2012146515 A1 WO2012146515 A1 WO 2012146515A1 EP 2012057062 W EP2012057062 W EP 2012057062W WO 2012146515 A1 WO2012146515 A1 WO 2012146515A1
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Prior art keywords
azoniabicyclo
group
octanyl
oxo
formula
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PCT/EP2012/057062
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French (fr)
Inventor
Gabriele Amari
Mauro Riccaboni
Daniele DE ZANI
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Chiesi Farmaceutici S.P.A.
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Priority to BR112013025682A priority Critical patent/BR112013025682A2/en
Priority to CA2834467A priority patent/CA2834467A1/en
Priority to CN201280020912.4A priority patent/CN103502213B/en
Priority to KR1020137028023A priority patent/KR20140019409A/en
Priority to EP12719303.5A priority patent/EP2702041A1/en
Priority to RU2013148009A priority patent/RU2611627C2/en
Publication of WO2012146515A1 publication Critical patent/WO2012146515A1/en

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    • 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
    • C07D409/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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

Definitions

  • the present invention relates to compounds acting as muscarinic receptor antagonists, to methods of preparing such derivatives, to compositions comprising them and therapeutic use thereof.
  • Quaternary ammonium salts acting as muscarinic (M) receptor antagonist drugs are currently used in therapy to induce bronchodilation for the treatment of respiratory diseases.
  • M receptor antagonists are for instance represented by ipratropium bromide and tiotropium bromide.
  • Some chemical classes acting as selective M3 receptor antagonist drugs have been developed for the treatment of inflammatory or obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Quinuclidine carbamate derivatives and their use as M3 antagonists are for instance disclosed in WO 02/051841, WO 03/053966 and WO 2008/012290.
  • WO 2010/015324 describes carbonate derivatives and their use as M3 antagonists.
  • the compounds of the present invention are characterized by a good activity as M3 antagonists and by an improved pulmonary stability.
  • the present invention relates to compounds of general formula (I), acting as muscarinic receptor antagonists, to processes for their preparation, to compositions comprising them, to therapeutic uses and combinations with other pharmaceutical active ingredients among which are, for instance, those currently used in the treatment of respiratory disorders, e.g. beta2-agonists, corticosteroids, P38 MAP kinase inhibitors, IKK2, HNE inhibitors, PDE4 inhibitor, leukotriene modulators, NSAIDs and mucus regulators.
  • other pharmaceutical active ingredients among which are, for instance, those currently used in the treatment of respiratory disorders, e.g. beta2-agonists, corticosteroids, P38 MAP kinase inhibitors, IKK2, HNE inhibitors, PDE4 inhibitor, leukotriene modulators, NSAIDs and mucus regulators.
  • X may be O or S
  • X' may be O or S
  • Y may be NH or absent
  • Ri is selected from the group consisting of aryl, heteroaryl,
  • R 3 and R 4 are the same or different and may be independently H or are selected from the group consisting of (C 3 -C 8 )cycloalkyl, aryl,
  • R 2 is a group of formula (c) or (d):
  • n 1, 2 or 3 ;
  • n 1, 2 or 3 ;
  • a " is a physiologically acceptable
  • R 5 is a group of formula (e):
  • p is 0 or an integer from 1 to 4;
  • q is 0 or an integer from 1 to 4.
  • the present invention is also directed to compounds of general formula
  • R 7 is selected from the group consisting of (C 1 -C 6 )alkyl and aryl(C 1 -C 6 )alkyl, and Ri, X, X', n, m and Y have the above reported meanings in formula (I).
  • halogen atoms as used herein includes fluorine, chlorine, bromine, and iodine.
  • (C 1 -C 6 )alkyl refers to straight-chained or branched alkyl groups wherein the number of carbon atoms is from 1 to 6. Examples of groups are methyl, ethyl, n-propyl, isopropyl, t-butyl, pentyl, hexyl and the like.
  • (C 1 -C 6 )alkoxy refers to alkyl-oxy (e.g. alkoxy) groups, being the alkyl portion as above defined. Examples of said groups may thus comprise methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy and the like.
  • (C 1 -C 6 )alkylsulfanyl refers respectively to alkyl-S-, alkyl-SO- and alkyl-SO 2 - groups.
  • (C 2 -C 6 )alkenyl refers to straight or branched carbon chains with one or more double bonds. Examples of said groups may thus comprise ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
  • (C 2 -C 6 )alkynyl refers to straight or branched carbon chains with one or more triple bonds. Examples of said groups may thus comprise ethinyl, propinyl, butinyl, pentinyl, hexinyl and the like.
  • (C 3 -C 8 )cycloalkyr' refers to mono or bi-cycloaliphatic hydrocarbon groups with from 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2. l]hept-2-yl and the like.
  • (C 3 -C 8 )heterocycloalkyl refers to (C 3 -C 8 )cycloalkyl groups, in which at least one ring carbon atom is replaced by a heteroatom or heteroaromatic group (e.g. N, NH, S or O). Examples include quinuclidinyl, pyrrolidinyl, piperidinyl and the like.
  • aryl refers to mono, bi- or tricyclic ring systems having 5 to 20, preferably from 5 to 15, ring atoms, and wherein at least one ring is aromatic.
  • heteroaryl refers to mono, bi- or tri-cyclic ring systems with 5 to 20 ring atoms, preferably from 5 to 15, in which at least one ring is aromatic and in which at least one carbon ring atom is a heteroatom or heteroaromatic group (e.g. N, NH, S or O).
  • Suitable aryl or heteroaryl monocyclic systems include, for instance, thiophene, benzene, pyrrole, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, pyridine, imidazolidine, furan radicals and the like.
  • Suitable aryl or heteroaryl bicyclic systems include naphthalene, biphenylene, purine, pteridine, benzotriazole, quinoline, isoquinoline, indole, isoindole, benzothiophene, dihydrobenzo dioxin, dihydrobenzo dioxepin, benzo oxazine radicals and the like.
  • Suitable aryl or heteroaryl tricyclic systems include fluorene radicals as well as benzocondensed derivatives of the aforementioned heteroaryl bicyclic systems.
  • aryl(C 1 -C 6 )alkyl and “heteroaryl(C 1 -C 6 )alkyl” refer to a “(C 1 -C 6 )alkyl” respectively substituted by one or more aryl or heteroaryl groups as defined above.
  • physiologically acceptable anions A include those selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methane sulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, and p-toluene sulfonate, preferably chloride, bromide and trifluoroacetate.
  • R 3 and R 4 are independently selected from aryl or heteroaryl groups
  • the said groups may be linked to each other through a (CH 2 ) r group, so as to form a tricyclic ring system.
  • R 2 and Q groups being represented trough groups (c), (d) and (f), (g), the asterisks in these latter represent their point of attachment with the rest of the molecule.
  • the active compounds of formula (I) and (IV) show at least one chiral center, which is represented by the carbon atom being comprised in Q or R 2 and which is directly linked to group Y.
  • the carbon atom of R 2 group being linked to Y is in the form of (S)-enantiomer when R 2 is a group of formula (c).
  • the carbon atom of R 2 group being linked to Y is in the form of (R)-enantiomer when R 2 is a group of formula (c).
  • the carbon atom of Q group being linked to Y is in the form of (S)-enantiomer when Q is a group of formula (f), or a group of formula (g), in this latter case obviously except when m is 2 and n is 1, m is 3 and n is 2.
  • the carbon atom of Q group being linked to Y is in the form of (R)-enantiomer when Q is a group of formula (f), or a group of formula (g), in this latter case obviously except when m is 2 and n is 1, m is 3 and n is 2.
  • Rx represents a group of formula (b)
  • R 3 is bound to the carbon atom bearing a double bond in any of the possible (Z) or (E) configurations and presently identified through the symbol
  • a first preferred group of compounds is that of general formula (IVA)
  • Rx is a group of formula (a)
  • R 3 and R 4 are the same or different and are H or selected from the group consisting of aryl and heteroaryl, which may be optionally substituted by one or more substituents selected from the group consisting of halogen atoms, (C 1 -C 6 )alkoxy of formula (f) or (g)
  • Rx is selected from bis(3-fluorophenyl)methyl, benzhydryl, (4-methoxyphenyl)(phenyl)methyl, (2-fluorophenyl)(4- fluorophenyl)methyl, (2-fluorophenyl)(3-fluorophenyl)methyl, ((3,4-difluorophenyl)(phenyl)methyl, 4-(trifluoromethyl)phenyl)methyl, (2-chlorophenyl)(4-chlorophenyl)methyl and thiophen-2-ylmethyl and Q is selected from quinuclidinyl and benzylpyrrolidinyl.
  • a second preferred group of compounds is that of general formula (IA)
  • Rx is a group of formula (a)
  • R 3 and R 4 are the same or different and are H or selected from the group consisting of aryl and heteroaryl, which may be optionally substituted by one or more substituents selected from the group consisting of halogen atoms, (C 1 -C 6 )alkoxy of formula (c) or (d)
  • R 5 is a group of formula (e) wherein p is 0, 1, 2 or 3, P is absent or is selected from the group consisting of -O-, -CO and -CONH, q is 0, 1 or 2 and W is selected from the group consisting of (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, aryl and heteroaryl optionally substituted by one or more substituents selected from the group consisting of halogen atoms, OH, CN, (Ci-C 6 )alkyl and (C 1 -C 6 )alkoxy.
  • Rx is selected from bis(3-fluorophenyl)methyl, benzhydryl, bis(4-fluorophenyl)methyl, (4-methoxyphenyl)(phenyl)methyl, (2-fluorophenyl)(4-fluorophenyl)methyl), (3,4-difluorophenyl)-(phenyl)- methyl, (4-(trifluoromethyl)phenyl)methyl, (2-chlorophenyl)-(4- chlorophenyl)-methyl and thiophen-2-ylmethyl and R 2 is selected from (2- oxo-2-(thiophen-3-yl)ethyl)-l-azoniabicyclo[2.2.2]octanyl, (2-(4- chlorophenyl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octanyl, (2-oxo
  • a third preferred group of compounds is that of general formula (IVB)
  • Rx is aryl or a group of formula (a)
  • Q is a group of formula (f) or (g)
  • a fourth preferred group of compounds is that of general formula (IB)
  • Rx is aryl or a group of formula (a) or (b)
  • n l or 2
  • Rx is selected from bis(3-fluorophenyl)methyl, 1,2-diphenylethyl, bis(4-chlorophenyl)methyl, bis(4-fluorophenyl)methyl, (4-methoxyphenyl)(phenyl)methyl, 3 -fluorobenzyl, 1 ,2-diphenylvinyl, 3-fluorobenzyl, benzyl, (3,4-difluorophenyl)(phenyl)methyl, fluorenyl and diphenylvinyl and R 2 is selected from 2-oxo-2-phenylethyl- l- azoniabicyclo[2.2.2]octanyl, 2-oxo-2-(thiophen-2-yl)ethyl- l-azoniabicyclo- [2.2.2]octanyl, 2-oxo-2-(thiophen-3-yl)ethy
  • a fifth preferred group of compounds is that of general formula (IC)
  • Rx is a group of formula (a) wherein R 3 and R 4 are independently aryl groups, which may be optionally substituted by one or more halogen atoms, R 2 is a group of formula (c)
  • a sixth preferred group of compounds is that of general formula (IVC)
  • Rx is a group of formula (a) wherein R 3 and R 4 are independently aryl groups, optionally substituted by one or more halogen atoms, Q is a group of formula (f)
  • a seventh preferred group of compounds is that of general formula (ID)
  • R x is a group of formula (a) wherein R 3 and R 4 are independently aryl groups, which may be optionally substituted by one or more halogen atoms, R 2 is a group of formula (c)
  • R x is a group of formula (a) wherein R 3 and R 4 are independently aryl groups, optionally substituted by one or more halogen atoms, Q is a group of formula (f)
  • the present invention also provides pharmaceutical compositions of compounds of formula (I) or (IV) alone or in combination with or in admixture with one or more pharmaceutically acceptable carriers and/or excipients.
  • the present invention also provides the use of compounds of formula (I) or (IV) for preparing a medicament.
  • the invention provides the use of compounds of formula (I) or (IV) for the prevention and/or treatment of any broncho-obstructive or inflammatory disease, preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD).
  • any broncho-obstructive or inflammatory disease preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the invention provides the use of compounds of formula (I) or (IV) for the manufacture of a medicament for the prevention and/or treatment of any broncho-obstructive or inflammatory disease, preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD).
  • any broncho-obstructive or inflammatory disease preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention further provides a method for prevention and/or treatment of any broncho-obstructive or inflammatory disease, preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD), which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of general formula (I) or (IV).
  • any broncho-obstructive or inflammatory disease preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD)
  • COPD chronic obstructive pulmonary disease
  • the present invention also provides pharmaceutical compositions suitable for administration by inhalation.
  • Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.
  • the invention is also directed to a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler and a soft mist nebulizer comprising the compounds of formula (I) or (IV).
  • the invention is also directed to a kit comprising the pharmaceutical compositions of compounds of formula (I) or (IV) alone or in combination with or in admixture with one or more pharmaceutically acceptable carriers and/or excipients and a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler and a soft mist nebulizer comprising the compounds of general formula (I) or (IV).
  • the present invention is also directed to a process for the preparation of compounds of general formula (IV) and (I), which process comprises:
  • the present invention provides the compounds reported below:
  • Ri, R 2 , Q, R 5 , X, X', Y and A are as defined above. It is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (Green T.W. and Wuts P.G.M. (1991) Protecting Groups in Organic Synthesis, John Wiley et Sons).
  • the coupling between compounds of general formula (II) and (III) may be promoted using standard amidation and peptide coupling conditions.
  • the operative conditions are chosen on the basis of the reactivity of the acid (II) over alcohol/thioalcohol (III) and of the compatibility of other groups being present in both compounds (for a general reference on the above reaction and operative conditions thereof see, for instance, Carey, F.A. and Sundeberg, R.J. Advanced Organic Chemistry, Third Edition (1990), Plenum Press, New York and London, pg 145).
  • the said conditions include, for instance, activating acid (II) by means of one or more equivalents of a commercially available condensing agent such as a carbodiimide (e.g. l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and the like) for example in the presence of N-hydroxybenzotriazole (HOBt) followed by reaction of the activated intermediate with alcohol or thioalcohol (III).
  • An organic base such as triethylamine and the like may be also present in the reaction mixture.
  • the activated intermediate may be either isolated, or pre-formed or generated in situ, and then properly reacted with compounds of formula (III).
  • Suitable solvents for the coupling reaction include, but are not limited to, halocarbon solvents (e.g. dichloromethane (DCM)), tetrahydrofuran (THF), dioxane, dimethylformamide (DMF) and acetonitrile.
  • DCM dichloromethane
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • acetonitrile e.g. dichloromethane
  • the reaction proceeds at temperature ranging from about 0°C up to about 170°C, for a time period in the range of about 1 hour up to about 96 hours.
  • the reaction may be carried out under conventional heating (using an oil bath) or under microwave irradiation.
  • the reaction may be conducted either in an open vessel or in a sealed tube.
  • This activation may be affected according to one of the several standard procedures reported in the literature. They comprise, for instance, treatment of acid (II) with one or more equivalents of oxalyl chloride or thionyl chloride.
  • This reaction may be conducted in the presence of a catalytic amount of dimethylformamide (DMF) in a suitable solvent (e.g. dichloromethane) or neat, at temperature ranging from about 0°C to about 120°C.
  • DMF dimethylformamide
  • suitable solvent e.g. dichloromethane
  • the activated intermediate may be either isolated, or pre-formed or generated in situ.
  • This intermediate can then be reacted with alcohol or thioalcohol (III), using known methods in order to obtain compounds of formula (IV).
  • the reaction may be promoted by a base such as triethylamine, pyridine and 4-dimethylaminopyridine, and carried out in a suitable solvent (e.g. dichloromethane) or neat.
  • a suitable solvent e.g. dichloromethane
  • This reaction is performed in a temperature range from about 0°C to about 140°C over a period of about 1 hour to about 74 hours.
  • the reaction may be conducted under conventional heating (using an oil bath) or under microwave heating.
  • the reaction may be carried out in an open vessel or in a sealed tube.
  • thioesters may be converted into di-thioester by treatment with Lawessons's reagent (Cohen, O. et al. Tetrahedron, 2010, 66/20, 3579 - 3582).
  • Lawessons's reagent Cohen, O. et al. Tetrahedron, 2010, 66/20, 3579 - 3582.
  • compound of general formula (II) may be coupled with compound of general formula (III) to afford carbamate, thiocarbamate or dithiocarbamate of general formula (IV).
  • This coupling may be effected according to one of the standard procedures broadly reported in the literature (a survey of the suitable reactions is given by Chaturvedi, D. Current Organic Synthesis, 2007, 3, 308 or by Smith, M.B. and March, J., March's Advanced Organic Chemistry, Fifth Edition (2001), John Wiley & Sons, Inc., New York, appendix B, 1660).
  • the amine (II) could be treated with a suitable activating reagent that could be selected from, but are not limited to, ⁇ , -carbonyldiimidazole, ⁇ , -thiocarbonyldiimidazole, diphosgene, triphosgene or /7-nitrophenylchloroformate.
  • the reaction may be promoted by a base selected from the group consisting of triethylamine, pyridine, 4-dimethylaminopyridine and the like, in a suitable solvent (e.g. dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DCM)).
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • DCM dichloromethane
  • the activated amine is reacted with an alcohol or thioalcohol of formula (III), most conveniently dissolved in the same solvent used for the activation of compound (II).
  • the alcohol or thioalcohol is preliminary treated with a base advantageously selected from NaH, BuLi (butyl lithium) and lithium diisopropylamide (LDA).
  • reaction is largely described in literature under several different conditions.
  • the reaction may be performed neat or in a suitable solvent selected from the group consisting of acetonitrile, ethyl acetate, DMF and tetrahydrofuran.
  • the reaction typically proceeds at temperature range from about 0°C up to about 170°C, for a time in the range of few minutes up to about 72 hours.
  • the reaction may be carried out under conventional heating (using an oil bath) or under microwave irradiation.
  • the reaction may be conducted either in an open vessel or in a sealed tube.
  • the optional salification of the compounds of formula (I) may be carried out by properly converting any of the free acidic groups (e.g. carboxylic) or free amino groups into the corresponding pharmaceutically acceptable salts.
  • the invention also includes any of the optical stereoisomers, diastereoisomers and mixtures thereof, in any proportion.
  • the invention also provides pharmaceutical compositions of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carriers, for example those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.
  • Administration of the compounds of the present invention may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and by ocular administration.
  • solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.
  • the compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
  • Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.
  • liquid oral dosage forms can also be used for administering compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
  • dosage forms can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention.
  • the compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.
  • Suppositories for rectal administration of the compounds of the invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
  • Formulations for vaginal administration can be in the form of cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such as suitable carriers, are also known.
  • the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches.
  • the compounds according to the invention are preferably administered by inhalation.
  • Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.
  • the powder may be filled in gelatine, plastic or other capsules, cartridges or blister packs or in a reservoir.
  • a diluent or carrier generally non-toxic and chemically inert to the compounds of the invention, e.g. lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention.
  • Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form.
  • the propellant- driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.
  • the propellant-free inhalable formulations comprising the compounds of the invention may be in form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by known jet or ultrasonic nebulizers or by soft-mist nebulizers such as Respimat ® .
  • the compounds of the invention may be administered as the sole active agent or in combination with other pharmaceutical active ingredients including those currently used in the treatment of respiratory disorders, e.g. beta 2 -agonists, corticosteroids and anticholinergic or antimuscarinic agents.
  • the dosages of the compounds of the invention depend upon a variety of factors including the particular disease to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, and pharmacokinetic profile of the compound.
  • the compounds of formula (I) can be administered for example, at a dosage comprised between 0.001 and 1000 mg/day, preferably between 0.1 and 500 mg/day.
  • the compounds of formula (I) are administered by inhalation route, they are preferably given at a dosage comprised between 0.001 and 500 mg/day, preferably between 0.1 and 200 mg/day.
  • the compounds of formula (I) may be administered for the prevention and/or treatment of broncho-obstructive or inflammatory diseases, such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), bronchial hyperreactivity, cough, emphysema or rhinitis; urological disorders such as urinary incontinence, pollakiuria, cystospasm, chronic cystitis and overactive bladder (OAB); gastrointestinal disorders such as bowel syndrome, spastic colitis, diverticulitis, peptic ulceration, gastrointestinal motility or gastric acid secretion; dry mouth; mydriasis, tachycardia; ophthalmic interventions cardiovascular disorders such as vagally induced sinus bradycardia.
  • broncho-obstructive or inflammatory diseases such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), bronchial hyperreactivity, cough, emphysema or rhinit
  • diphenylmethanol (0.18 g, 1.00 mmol) was dissolved in dry DMF (5 ml) and treated portionwise with NaH (40.0 mg, 1.00 mmol) at 0°C. The reaction was stirred at room temperature for 20 minutes and then poured into the first flask.
  • phenyl(4-(trifluoromethyl)phenyl)methanol (0.25 g, 1.00 mmol) was dissolved in dry DMF (3 ml) and sodium hydride (60% dispersion in mineral oil, 24.0 mg, 1.00 mmol) was added portionwise at 0°C. The reaction was stirred at room temperature for 15 minutes and then was poured into the first flask.
  • Phenyl(4-(trifluoromethyl)phenyl)methyl (R)-quinuclidin-3- ylcarbamate (56.0 mg, 0.14 mmol) was dissolved in ethyl acetate (1 ml) and acetonitrile (0.5 ml). The resulting solution was treated with 2-chloro- l- (thiophen-2-yl)ethanone (24.0 mg, 0.15 mmol) and stirred at room temperature overnight.
  • thiophen-2-ylmethanol (1 14 mg, 1.00 mmol) was dissolved in dry DMF (3 ml) and treated with sodium hydride (60% dispersion in mineral oil, 40.0 mg, 1.00 mmol) at 0°C. Ice-bath was removed and the reaction was stirred at room temperature for 20 minutes and then it was poured into the first flask.
  • 1,2-Diphenylethyl quinuclidine-3-carboxylate (68 mg, 0.20 mmol, prepared as in example 5) and 2-chloro- l-(thiophen-2-yl)ethanone (35.8 mg, 0.22 mmol) were dissolved in acetonitrile (4 ml) and stirred at room temperature for 64h.
  • quinuclidine-3-carboxylic acid hydrochloride (43.5 mg, 0.23 mmol), EDC (43.5 mg, 0.23 mmol), HOBT (34.8 mg, 0.23 mmol) and DIPEA (79 ⁇ , 0.45 mmol) were added again and stirring was continued for 4 days.
  • Oxalyl dichloride (236 ⁇ , 2.78 mmol) was added dropwise to a solution of l-methylpiperidine-4-carboxylic acid hydrochloride (500 mg, 2.78 mmol) in DCM (30 ml) and few drops of DMF (catalytic amount). The reaction was stirred at room temperature for 2 hours. The volatiles were removed under vacuum and the crude was taken up with pyridine (40 ml). 1,2-Diphenylethanone (546 mg, 2.78 mmol) was added and the resulting suspension was heated under microwave irradiation at 140°C for lh.
  • the interaction with M3 muscarinic receptors can be estimated by the results of in vitro studies which evaluated the M3/M2 binding assays, the potency of the test compounds and the offset of the inhibitory activity produced after washout of the antagonists in isolated guinea pig trachea and by the in vivo duration of action against acetylcholine-induced bronchospasm in the guinea pig.
  • CHO-K1 clone cells expressing the human M2 or M3- receptors were harvested in Ca ++ /Mg ++ free phosphate-buffered saline and collected by centrifugation at 1500 rpm for 3 min.
  • the pellets were resuspended in ice cold buffer A (15 mM Tris-HCl pH 7.4, 2 mM MgCl 2 , 0.3 mM EDTA, 1 mM EGTA) and homogenized by a PBI politron (setting 5 for 15 s).
  • the crude membrane fraction was collected by two consecutive centrifugation steps at 40000 g for 20 min at 4°C, separated by a washing step in buffer A.
  • the pellets obtained were finally resuspended in buffer B (75 mM Tris HC1 pH 7.4, 12.5mM MgCl 2 , 0.3 mM EDTA, 1 mM EGTA, 250 mM sucrose), and aliquots were stored at - 80°C.
  • the reaction was terminated by rapid filtration through GF/B Unifilter plates and two washes (0.75 ml) with cold buffer C using a Packard Filtermate Harvester. Radioactivity on the filters was measured by a microplate scintillation counter TriCarb 2500 (PerkinElmer).
  • inhibitory M3 activity tested on compounds are comprised between 0.265 and 1514 nM.
  • a cumulative concentration-response curve to test antagonists was constructed on preparations precontracted by carbachol, until a complete inhibition of smooth muscle tone was achieved.
  • the concentration of antagonist producing a 50% reversal of carbachol-induced tonic contraction (IC 50 ) was taken as a measure of its potency in this bioassay.
  • the inhibitory effects of the compounds of the invention were expressed as percentage of the recovery of the contracting response to carbachol.
  • the percentage of recovery four hours after the washout was lower than 50%.
  • the bronchodilator activity of the tested compounds persisted unchanged up to 24 hours after the administration.
  • Lung stability is calculated as percentage remaining after 1 and 5 hours by dividing the peak area at 1 or 5 hours by the area of the peak at time 0.

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Abstract

The present invention relates to compounds acting as muscarinic receptor antagonists, to methods of preparing such derivatives, to compositions comprising them and therapeutic use thereof.

Description

ALKALOID ESTER AND CARBAMATE DERIVATIVES AND
MEDICINAL COMPOSITIONS THEREOF
FIELD OF THE INVENTION
The present invention relates to compounds acting as muscarinic receptor antagonists, to methods of preparing such derivatives, to compositions comprising them and therapeutic use thereof.
BACKGROUND OF THE INVENTION
Quaternary ammonium salts acting as muscarinic (M) receptor antagonist drugs are currently used in therapy to induce bronchodilation for the treatment of respiratory diseases. Examples of well known M receptor antagonists are for instance represented by ipratropium bromide and tiotropium bromide.
Some chemical classes acting as selective M3 receptor antagonist drugs have been developed for the treatment of inflammatory or obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD).
Quinuclidine carbamate derivatives and their use as M3 antagonists are for instance disclosed in WO 02/051841, WO 03/053966 and WO 2008/012290.
WO 2010/015324 describes carbonate derivatives and their use as M3 antagonists.
The compounds of the present invention are characterized by a good activity as M3 antagonists and by an improved pulmonary stability.
SUMMARY OF THE INVENTION
The present invention relates to compounds of general formula (I), acting as muscarinic receptor antagonists, to processes for their preparation, to compositions comprising them, to therapeutic uses and combinations with other pharmaceutical active ingredients among which are, for instance, those currently used in the treatment of respiratory disorders, e.g. beta2-agonists, corticosteroids, P38 MAP kinase inhibitors, IKK2, HNE inhibitors, PDE4 inhibitor, leukotriene modulators, NSAIDs and mucus regulators.
DETAILED DESCRIPTION OF THE INVENTION
In particular, the invention is directed to compounds of general formula
(I)
Figure imgf000003_0001
(I)
wherein:
X may be O or S;
X' may be O or S;
Y may be NH or absent;
Ri is selected from the group consisting of aryl, heteroaryl,
Figure imgf000003_0002
alkyl, heteroaryl(C1-C6)alkyl and a group of formula (a) or (b)
Figure imgf000003_0003
(a) (b)
Wherein
R3 and R4 are the same or different and may be independently H or are selected from the group consisting of (C3-C8)cycloalkyl, aryl,
Figure imgf000003_0004
alkyl, heteroaryl and heteroaryl(C1-C6)alkyl, which may be optionally substituted by one or more substituents selected from the group consisting of halogen atoms, -OH,
Figure imgf000003_0005
(C1-C6)alkoxy, oxo (=O), -SH, -NO2, -CN, -CONH2, -COOH, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulfanyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl and (C1-C6)alkyl or, when R3 and R4 are both independently aryl or heteroaryl they may be linked to each other through a (CH2)r with r =0-2, to form a tricyclic ring system wherein any of the methylene (CH2)r groups may be optionally replaced by a heteroatom or heteroaromatic group selected from O, S, N and NH, and with the proviso that R3 and R4 are not simultaneously H;
R2 is a group of formula (c) or (d):
Figure imgf000004_0001
(c) (d)
wherein
m = 1, 2 or 3 ;
n = 1, 2 or 3 ;
A" is a physiologically acceptable
R5 is a group of formula (e):
-(CH2)p-P- (CH2)q-W
(e)
wherein
p is 0 or an integer from 1 to 4;
q is 0 or an integer from 1 to 4;
P is absent or is selected from the group consisting of -O-, -S-, -S(O)-, -S(O2)-, -C(O)-, -CO(O)-, -N(R6)-, -CH=CH-, -N(R6)(SO2)-, -N(R6)CO(O)-, -N(R6)C(O)-, -SO2N(R6)-, -CO(O)N(R6)- and -C(O)N(R6)-;
W is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl and heteroaryl, optionally substituted by one or more substituents selected from the group consisting of halogen atoms, -OH, oxo (=O), -SH, -NO2, -N(R6)2, -CN, -CON(R6)2, -COOH, -NHCOR6, -CO2R6, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulfanyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C!-C6)alkyl, (C1-C6)alkoxy, aryl and heteroaryl;
R6 is, independently in each occurrence, H or is selected from the group consisting of (C1-C6)alkyl,
Figure imgf000005_0001
(C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, heteroaryl and aryl, optionally substituted by one or more substituents selected from the group consisting of halogen atoms, -OH, oxo (=O), -SH, -NO2, -CN, -CONH2, -COOH, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulfanyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl,
(C3-C8)cycloalkyl, (C!-C6)alkyl and (C1-C6)alkoxy;
and pharmaceutically acceptable salts thereof.
The present invention is also directed to compounds of general formula
(IV)
Figure imgf000005_0002
(IV)
wherein Q represents a group of formula (f) or (g)
Figure imgf000005_0003
(f) (g)
R7 is selected from the group consisting of (C1-C6)alkyl and aryl(C1-C6)alkyl, and Ri, X, X', n, m and Y have the above reported meanings in formula (I).
The term "halogen atoms" as used herein includes fluorine, chlorine, bromine, and iodine.
The expression "(C1-C6)alkyl" refers to straight-chained or branched alkyl groups wherein the number of carbon atoms is from 1 to 6. Examples of groups are methyl, ethyl, n-propyl, isopropyl, t-butyl, pentyl, hexyl and the like.
The term "(C1-C6)alkoxy" refers to alkyl-oxy (e.g. alkoxy) groups, being the alkyl portion as above defined. Examples of said groups may thus comprise methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy and the like.
The derived expression "(C1-C6)alkoxycarbonyl", refer to alkoxy-CO- groups wherein alkoxy is as defined above.
The expressions
Figure imgf000006_0001
refer to the above "(C1-C6)alkyl" and "(C1-C6)alkoxy" groups wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which can be the same or different from each other.
The expressions "(C1-C6)alkylsulfanyl", "(C1-C6)alkylsulfinyl" and "(C1-C6)alkylsulfonyl" refer respectively to alkyl-S-, alkyl-SO- and alkyl-SO2- groups.
The expression "(C2-C6)alkenyl" refers to straight or branched carbon chains with one or more double bonds. Examples of said groups may thus comprise ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
The expression "(C2-C6)alkynyl" refers to straight or branched carbon chains with one or more triple bonds. Examples of said groups may thus comprise ethinyl, propinyl, butinyl, pentinyl, hexinyl and the like.
The expression "(C3-C8)cycloalkyr' refers to mono or bi-cycloaliphatic hydrocarbon groups with from 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2. l]hept-2-yl and the like.
The derived expression "(C3-C8)heterocycloalkyl" refers to (C3-C8)cycloalkyl groups, in which at least one ring carbon atom is replaced by a heteroatom or heteroaromatic group (e.g. N, NH, S or O). Examples include quinuclidinyl, pyrrolidinyl, piperidinyl and the like.
The expression "aryl" refers to mono, bi- or tricyclic ring systems having 5 to 20, preferably from 5 to 15, ring atoms, and wherein at least one ring is aromatic.
The expression "heteroaryl" refers to mono, bi- or tri-cyclic ring systems with 5 to 20 ring atoms, preferably from 5 to 15, in which at least one ring is aromatic and in which at least one carbon ring atom is a heteroatom or heteroaromatic group (e.g. N, NH, S or O).
Examples of suitable aryl or heteroaryl monocyclic systems include, for instance, thiophene, benzene, pyrrole, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, pyridine, imidazolidine, furan radicals and the like.
Examples of suitable aryl or heteroaryl bicyclic systems include naphthalene, biphenylene, purine, pteridine, benzotriazole, quinoline, isoquinoline, indole, isoindole, benzothiophene, dihydrobenzo dioxin, dihydrobenzo dioxepin, benzo oxazine radicals and the like.
Examples of suitable aryl or heteroaryl tricyclic systems include fluorene radicals as well as benzocondensed derivatives of the aforementioned heteroaryl bicyclic systems.
The expressions "aryl(C1-C6)alkyl" and "heteroaryl(C1-C6)alkyl" refer to a "(C1-C6)alkyl" respectively substituted by one or more aryl or heteroaryl groups as defined above.
Advantageously, the physiologically acceptable anions A" include those selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methane sulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, and p-toluene sulfonate, preferably chloride, bromide and trifluoroacetate.
Besides the presence of A" anion, whenever further basic amino groups are present in the compounds of formula (I), additional physiological acceptable anions, among those formerly indicated, may be present. Likewise, in the presence of acidic groups such as COOH groups, corresponding physiological cation salts may be present as well, for instance including alkaline or alkaline earth metal ions.
In the present description, and unless otherwise provided, within formula (I) or (IV), Y may represent a divalent NH group or, whenever, absent, it clearly represents a single bond so as to provide compounds R!-X-C(=X')R2 or R1-X-C(=X')Q
Furthermore, when both R3 and R4 are independently selected from aryl or heteroaryl groups, the said groups may be linked to each other through a (CH2)r group, so as to form a tricyclic ring system.
From all the above, it is clear to the skilled person that, when r is 0, the said R3 and R4 groups are linked to each other through a bond.
Unless otherwise provided, within formula (I) and (IV), R2 and Q groups being represented trough groups (c), (d) and (f), (g), the asterisks in these latter represent their point of attachment with the rest of the molecule.
As an example, the following groups can be highlighted:
Figure imgf000008_0001
(f1 ) (f2) (f3)
It will be apparent that the compounds of general formula (I) and (IV) may contain asymmetric centers. Therefore the invention also includes the optical stereoisomers and mixtures thereof.
Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
More in particular, the active compounds of formula (I) and (IV) show at least one chiral center, which is represented by the carbon atom being comprised in Q or R2 and which is directly linked to group Y.
Therefore, according to a specific embodiment, in compound (I), the carbon atom of R2 group being linked to Y is in the form of (S)-enantiomer when R2 is a group of formula (c).
According to a preferred embodiment, in compound (I), the carbon atom of R2 group being linked to Y is in the form of (R)-enantiomer when R2 is a group of formula (c).
According to another embodiment, in compound (IV), the carbon atom of Q group being linked to Y is in the form of (S)-enantiomer when Q is a group of formula (f), or a group of formula (g), in this latter case obviously except when m is 2 and n is 1, m is 3 and n is 2.
According to a preferred embodiment, in compound (IV), the carbon atom of Q group being linked to Y is in the form of (R)-enantiomer when Q is a group of formula (f), or a group of formula (g), in this latter case obviously except when m is 2 and n is 1, m is 3 and n is 2.
In the compounds of general formula (I) of the present invention, when R2 is a group of formula (a) and R3 and R4 have different meanings, the carbon atom bearing R3 and R4 is a chiral center.
Moreover, within the compounds of formula (I), when Rx represents a group of formula (b), R3 is bound to the carbon atom bearing a double bond in any of the possible (Z) or (E) configurations and presently identified through the symbol
A first preferred group of compounds is that of general formula (IVA)
Figure imgf000010_0001
(IVA)
wherein Rx is a group of formula (a)
-R,
\
(a)
wherein R3 and R4 are the same or different and are H or selected from the group consisting of aryl and heteroaryl, which may be optionally substituted by one or more substituents selected from the group consisting of halogen atoms, (C1-C6)alkoxy of formula (f) or (g)
Figure imgf000010_0002
(f) (g)
wherein n=m= 1 and R5 is a group of formula (e)
— (CH2)p— P— (CH2)q— W
(e)
wherein p=0,
Figure imgf000010_0003
is absent, q= l and W is aryl.
Still more preferred, within this class, are the compounds of general formula (IVA) wherein Rx is selected from bis(3-fluorophenyl)methyl, benzhydryl, (4-methoxyphenyl)(phenyl)methyl, (2-fluorophenyl)(4- fluorophenyl)methyl, (2-fluorophenyl)(3-fluorophenyl)methyl, ((3,4-difluorophenyl)(phenyl)methyl, 4-(trifluoromethyl)phenyl)methyl, (2-chlorophenyl)(4-chlorophenyl)methyl and thiophen-2-ylmethyl and Q is selected from quinuclidinyl and benzylpyrrolidinyl.
A second preferred group of compounds is that of general formula (IA)
Figure imgf000011_0001
(IA)
wherein Rx is a group of formula (a)
-ΟΗ'"»
\
R4
(a)
wherein R3 and R4 are the same or different and are H or selected from the group consisting of aryl and heteroaryl, which may be optionally substituted by one or more substituents selected from the group consisting of halogen atoms, (C1-C6)alkoxy of formula (c) or (d)
Figure imgf000011_0002
(c) (d)
wherein n=m=l and R5 is a group of formula (e) wherein p is 0, 1, 2 or 3, P is absent or is selected from the group consisting of -O-, -CO and -CONH, q is 0, 1 or 2 and W is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, aryl and heteroaryl optionally substituted by one or more substituents selected from the group consisting of halogen atoms, OH, CN, (Ci-C6)alkyl and (C1-C6)alkoxy.
Still more preferred, within this class, are the compounds of general formula (IA) wherein Rx is selected from bis(3-fluorophenyl)methyl, benzhydryl, bis(4-fluorophenyl)methyl, (4-methoxyphenyl)(phenyl)methyl, (2-fluorophenyl)(4-fluorophenyl)methyl), (3,4-difluorophenyl)-(phenyl)- methyl, (4-(trifluoromethyl)phenyl)methyl, (2-chlorophenyl)-(4- chlorophenyl)-methyl and thiophen-2-ylmethyl and R2 is selected from (2- oxo-2-(thiophen-3-yl)ethyl)-l-azoniabicyclo[2.2.2]octanyl, (2-(4- chlorophenyl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octanyl, (2-oxo-2-p- tolylethyl)-l-azoniabicyclo[2.2.2]-octanyl, (2-(4-fluorophenyl)-2-oxoethyl)-l- azoniabicyclo[2.2.2]octanyl, (2-(3-fluorophenyl)-2-oxoethyl)-l-azoniabicyclo- [2.2.2]octanyl, (2-(2-fluorophenyl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octanyl, (2-(4-methoxyphenyl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octanyl, (2-(4- hydroxyphenyl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octanyl, (bis(3- fluorophenyl)methoxy)carbonylamino)- l-azoniabicyclo[2.2.2]octanyl, (2-(5- chlorothiophen-2-yl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octanyl, (2-oxo-2- (thiazol-2-yl)ethyl)- l-azoniabicyclo-[2.2.2]octanyl, (2-oxopropyl)-l- azoniabicyclo[2.2.2]octanyl, (3-methylbut-2-enyl)-l-azoniabicyclo- [2.2.2] octanyl, benzyl- 1 -azoniabicyclo [2.2.2] octanyl, (3 -phenoxypropyl)- 1 - azoniabicyclo[2.2.2]octanyl, (2-(5-cyanothiophen-2-yl)-2-oxoethyl)-l- azoniabicyclo[2.2.2]octanyl, (2-oxo-2-(pyridin-2-yl)ethyl)-l-azoniabicyclo- [2.2.2] octanyl, (2-(isoxazol-3-ylamino)-2-oxoethyl)- l-azoniabicyclo[2.2.2]- octanyl, (2-oxo-2-(thiophen-2-yl)ethyl)- l-azoniabicyclo-[2.2.2]octanyl, (2- oxo-2-phenylethyl)-l-azoniabicyclo[2.2.2]octanyl,
(2-phenoxyethyl)- 1 -azoniabicyclo [2.2.2] octanyl, (2,3-dihydrobenzofuran-5- yl)ethyl)-l-azoniabicyclo[2.2.2]octanyl, (4-fluorophenethyl)- l-azoniabicyclo- [2.2.2]octanyl and benzyl-methylpyrrolidinyl.
A third preferred group of compounds is that of general formula (IVB)
Figure imgf000013_0001
(IVB)
wherein Rx is aryl or a group of formula (a)
-ΟΗ'"»
\
4
(a)
R3 and R4 are the same or different and are H or are selected from the group consisting of aryl, aryl(C1-C6)alkyl and heteroaryl, which may be optionally substituted by one or more substituents selected from the group consisting of halogen atoms, (C1-C6)alkoxy and
Figure imgf000013_0002
or when R3 and R4 are both independently aryl or heteroaryl they may be linked to each other through a (CH2)r with r =0-2, to form a tricyclic ring system wherein any of the methylene (CH2)r groups may be a heteroatom or heteroaromatic group selected from O, S, N and NH, and with the proviso that R3 and R4 are not simultaneously H; Q is a group of formula (f) or (g)
Figure imgf000013_0003
(f) (g)
wherein n is 1, m is 2 and R7 is a group of formula (f) wherein p=0, P is absent, q is 0 or 1 and W is (C1-C6)alkyl.
Still more preferred, within this class, are the compounds of general formula (IVB) wherein Rx is selected from
(3,4-difluorophenyl)(phenyl)methyl, bis(3-fluorophenyl)methyl, 1,2-diphenylethyl, bis(4-chlorophenyl)methyl, bis(4-fluorophenyl)methyl, benzhydryl, (4-methoxyphenyl)(phenyl)methyl, (2-chlorophenyl)(4- chlorophenyl)methyl, 1,2-diphenylvinyl, 3-fluorobenzyl, benzyl, fluorenyl, and Q is selected from quinuclidin-3-yl and methylpiperidinyl.
A fourth preferred group of compounds is that of general formula (IB)
Figure imgf000014_0001
(IB)
wherein Rx is aryl or a group of formula (a) or (b)
Figure imgf000014_0002
(a) (b)
wherein R3 and R4 are the same or different and are H or selected from the group consisting of aryl, aryl(C1-C6)alkyl and heteroaryl, which may be optionally substituted by one or more substituents selected from the group consisting of halogen atoms, (C1-C6)alkoxy and
Figure imgf000014_0003
or when R3 and R4 are both independently aryl or heteroaryl they may be linked to each other through a (CH2)r with r =0-2, wherein when n=0, to form a tricyclic ring system wherein any of the methylene (CH2)r may be a heteroatom or heteroaromatic group selected from O, S, N and NH, and with the proviso that R3 and R4 are not simultaneousl H R is a rou of formula (c) or (d)
Figure imgf000014_0004
(c) (d)
wherein n=l or 2, m=l and R5 is a group of formula (e), wherein p=l or 3, P is absent or is selected from the group consisting of O, CO and CO(O), q=l and W is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, aryl, heteroaryl optionally substituted by one or more substituents selected from the group consisting of halogen atoms, OH, CN, (C1-C6)alkyl, (C1-C6)alkoxycarbonyl and (C1-C6)alkoxy.
Still more preferred, within this class, are the compounds of general formula (IB), wherein Rx is selected from bis(3-fluorophenyl)methyl, 1,2-diphenylethyl, bis(4-chlorophenyl)methyl, bis(4-fluorophenyl)methyl, (4-methoxyphenyl)(phenyl)methyl, 3 -fluorobenzyl, 1 ,2-diphenylvinyl, 3-fluorobenzyl, benzyl, (3,4-difluorophenyl)(phenyl)methyl, fluorenyl and diphenylvinyl and R2 is selected from 2-oxo-2-phenylethyl- l- azoniabicyclo[2.2.2]octanyl, 2-oxo-2-(thiophen-2-yl)ethyl- l-azoniabicyclo- [2.2.2]octanyl, 2-oxo-2-(thiophen-3-yl)ethyl-l-azoniabicyclo[2.2.2]octanyl, 2- (4-methoxyphenyl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octanyl, 2-(4- fluorophenyl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octanyl, 2-oxo-2-p- tolylethyl)-l-azoniabicyclo[2.2.2]octanyl, 2-(5-chlorothiophen-2-yl)-2- oxoethyl)-l-azoniabicyclo[2.2.2]octanyl, 2-(4-chlorophenyl)-2-oxoethyl- l- azoniabicyclo[2.2.2]octanyl, l-(2-oxopropyl)- l-azoniabicyclo[2.2.2]octanyl, l-(2-tert-butoxy-2-oxoethyl)-l-azoniabicyclo[2.2.2]octanyl, l-(2-oxo-2- (pyridin-2-yl)ethyl)- l-azoniabicyclo[2.2.]octanyl, l-(2-(3-(ethoxycarbonyl)- isoxazol-5-yl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octanyl, l-(2-(4- hydroxyphenyl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octanyl, l-(2- (benzothiophen-5-yl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octanyl, 1 -benzyl- 1- azoniabicyclo[2.2.2]octanyl, l-(2-oxo-2-(thiophen-2-yl)ethyl)-l- azoniabicyclo[2.2.2]octanyl and 1 -methyl- l-(2-oxo-2-(thiophen-2- yl)ethyl)piperidinyl.
A fifth preferred group of compounds is that of general formula (IC)
Figure imgf000016_0001
(IC)
wherein Rx is a group of formula (a) wherein R3 and R4 are independently aryl groups, which may be optionally substituted by one or more halogen atoms, R2 is a group of formula (c)
Figure imgf000016_0002
(c)
wherein R5 is a group of formula (e) with p=l, P is CO, q is 0 and W is heteroaryl.
Still more preferred, within this class, are the compounds of general formula (IC) wherein Rx is bis(3-fluorophenyl)methyl and R2 is (2-oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octanyl.
A sixth preferred group of compounds is that of general formula (IVC)
Figure imgf000016_0003
(IVC)
wherein Rx is a group of formula (a) wherein R3 and R4 are independently aryl groups, optionally substituted by one or more halogen atoms, Q is a group of formula (f)
Figure imgf000016_0004
(f) Still more preferred, within this class, are the compounds of general formula (IVC) wherein Rx is bis(3-fluorophenyl)methyl and Q is quinuclidin- 3-yl.
A seventh preferred group of compounds is that of general formula (ID)
Figure imgf000017_0001
(ID)
wherein Rx is a group of formula (a) wherein R3 and R4 are independently aryl groups, which may be optionally substituted by one or more halogen atoms, R2 is a group of formula (c)
A
Figure imgf000017_0002
(c)
wherein R5 is a group of formula (e) with p=l, P is CO, q is 0 and W is heteroaryl.
Still more preferred, within this class, are the compounds of general formula (ID) wherein Rx is benzyl and R2 is (2-oxo-2-(thiophen-2-yl)ethyl)- l- azoniabicy clo [2.2.2] octanyl .
An eighth preferred group of compounds is that of general formula (IVD)
Figure imgf000017_0003
(IVD)
wherein Rx is a group of formula (a) wherein R3 and R4 are independently aryl groups, optionally substituted by one or more halogen atoms, Q is a group of formula (f)
Figure imgf000018_0001
Still more preferred, within this class, are the compounds of general formula (IVC) wherein Rx is benzyl and Q is quinuclidinyl.
The present invention also provides pharmaceutical compositions of compounds of formula (I) or (IV) alone or in combination with or in admixture with one or more pharmaceutically acceptable carriers and/or excipients.
The present invention also provides the use of compounds of formula (I) or (IV) for preparing a medicament.
In a further aspect, the invention provides the use of compounds of formula (I) or (IV) for the prevention and/or treatment of any broncho-obstructive or inflammatory disease, preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD).
In a further aspect, the invention provides the use of compounds of formula (I) or (IV) for the manufacture of a medicament for the prevention and/or treatment of any broncho-obstructive or inflammatory disease, preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD).
The present invention further provides a method for prevention and/or treatment of any broncho-obstructive or inflammatory disease, preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD), which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of general formula (I) or (IV).
The present invention also provides pharmaceutical compositions suitable for administration by inhalation.
Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.
The invention is also directed to a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler and a soft mist nebulizer comprising the compounds of formula (I) or (IV).
The invention is also directed to a kit comprising the pharmaceutical compositions of compounds of formula (I) or (IV) alone or in combination with or in admixture with one or more pharmaceutically acceptable carriers and/or excipients and a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler and a soft mist nebulizer comprising the compounds of general formula (I) or (IV).
The present invention is also directed to a process for the preparation of compounds of general formula (IV) and (I), which process comprises:
(a) reacting a compound of general formula (II)
(II)
wherein z is a carboxyl group or its corresponding acyl chloride derivative, or an amino group and Q is as defined above, with a compound of general formula (III)
Ri ^x-L
(III) wherein L is H or an alkaline or alkaline earth metal, Ri and X are as defined above, to obtain a compound of general formula (IV)
X'
1 ^γ^
(IV) wherein Χ', Q and Y are as described above, the said reaction being carried out in the presence of suitable amounts of condensing agents; and optionally, (b) the alkylation of compounds of general formula (IV) with an agent of general formula (VI)
R5-A
(VI)
wherein R5 and A are as described above, to give compounds of general formula (I)
Figure imgf000020_0001
(I)
According to specific embodiments, the present invention provides the compounds reported below:
Compound Chemical name
1 (R)-bis(3-f uorophenyl)methyl quinuclidin-3-ylcarbamate
2 (R)-benzhydryl quinuclidin-3 -ylcarbamate
3 (R)-bis(4-f uorophenyl)methyl quinuclidin-3 -ylcarbamate
(4-methoxyphenyl)(phenyl)methyl (R)-quinuclidin-3-
4
ylcarbamate
(2-f uorophenyl)(4-f uorophenyl)methyl (R)-quinuclidin-3 -
5
ylcarbamate
(2-f uorophenyl)(3-f uorophenyl)methyl (R)-quinuclidin-3-
6
ylcarbamate
(3,4-dif uorophenyl)(phenyl)methyl (R)-quinuclidin-3-
7
ylcarbamate
8 bis(3-f uorophenyl)methyl quinuclidine-3-carboxylate
9 1,2-diphenylethyl quinuclidine-3-carboxylate
10 bis(4-chlorophenyl)methyl quinuclidine-3-carboxylate
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-
11 oxo-2-(thiophen-3-yl)ethyl)-l-azoniabicyclo[2.2.2]octane
bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-
12 (4-chlorophenyl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-
13
oxo-2-p-tolylethyl)-l-azoniabicyclo[2.2.2]octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-
14 (4-f uorophenyl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-
15 (3-f uorophenyl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-
16 (2-f uorophenyl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-
17 (4-methoxyphenyl)-2-oxoethyl)- l- azoniabicy clo [2.2.2] octane bromide
(continued) (R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-(4- hydroxyphenyl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octane bromide
(R)- l-(2-(benzo[b]thiophen-5-yl)-2-oxoethyl)-3-((bis(3- f uorophenyl)methoxy)carbonylamino)- 1 - azoniabicy clo [2.2.2] octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-(5- chlorothiophen-2-yl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-oxo- 2-(thiazol-2-yl)ethyl)-l -azoniabicy clo [2.2.2] octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2- oxopropyl)- l-azoniabicyclo[2.2.2]octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(3- methylbut-2-enyl)- 1 -azoniabicyclo [2.2.2] octane bromide
(R)- l-benzyl-3-((bis(3-f uorophenyl)methoxy)carbonylamino)- 1 -azoniabicyclo [2.2.2] octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(3- phenoxypropyl)- 1 -azoniabicyclo [2.2.2] octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-(5- cyanothiophen-2-yl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-oxo- 2-(pyridin-2-yl)ethyl)-l -azoniabicy clo [2.2.2] octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-
(isoxazol-3-ylamino)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octane chloride
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-oxo- 2-(thiophen-2-yl)ethyl)- l-azoniabicyclo[2.2.2]octane chloride
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-oxo- 2-phenylethyl)- 1 -azoniabicy clo [2.2.2] octane chloride
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2- phenoxyethyl)- l-azoniabicyclo[2.2.2]octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(2-(2,3- dihydrobenzofuran-5-yl)ethyl)- l-azoniabicyclo[2.2.2]octane bromide
(R)-3-((bis(3-f uorophenyl)methoxy)carbonylamino)-l-(4- f uorophenethyl)- l-azoniabicyclo[2.2.2]octane bromide
(continued) (R)-3-(benzhydryloxycarbonylamino)-l-(2-oxo-2-phenylethyl)- l-azoniabicyclo[2.2.2]octane chloride
(R)-3-((bis(4-f uorophenyl)methoxy)carbonylamino)-l-(2-oxo- 2-phenylethyl)- 1 -azoniabicy clo [2.2.2] octane chloride
(3R)-3-(((4-methoxyphenyl)(phenyl)methoxy)carbonylamino)- l-(2-oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride
(3R)-3-(((2-f uorophenyl)(4-f uorophenyl)methoxy)- carbonylamino)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-l- azoniabicy clo [2.2.2] octane chloride
(3R)-3-(((2-f uorophenyl)(3-f uorophenyl)methoxy)- carbonylamino)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-l- azoniabicy clo [2.2.2] octane chloride
(3R)-3-(((3,4-dif uorophenyl)(phenyl)methoxy)carbonylamino)- l-(2-oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride
phenyl(4-(trifluoromethyl)phenyl)methyl (R)-quinuclidin-3- ylcarbamate
(3R)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-3-((phenyl(4- (trif uoromethyl)phenyl)methoxy)carbonylamino)- 1 - azoniabicy clo [2.2.2] octane chloride
(2-chlorophenyl)(4-chlorophenyl)methyl (R)-quinuclidin-3 - ylcarbamate
(3R)-3-(((2-chlorophenyl)(4-chlorophenyl)methoxy)- carbonylamino)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-l- azoniabicy clo [2.2.2] octane chloride
(R)-thiophen-2-ylmethyl quinuclidin-3 -ylcarbamate
(R)- l-(2-oxo-2-(thiophen-2-yl)ethyl)-3-((thiophen-2- ylmethoxy)carbonylamino)- 1 -azoniabicy clo [2.2.2] octane chloride
(R)-O-bis(3-f uorophenyl)methyl quinuclidin-3 - ylcarbamothioate
(R)-3-((bis(3-f uorophenyl)methoxy)carbonothioylamino)- l-(2- oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride
(R)-bis(3-f uorophenyl)methyl l-benzylpyrrolidin-3- ylcarbamate
(continued) (3R)-l-benzyl-3-((bis(3-f uorophenyl)methoxy)carbonylamino)- 1-methylpyrrolidinium iodide
3 -((bis(3-f uorophenyl)methoxy)carbonyl)-l -(2-0X0-2- phenylethyl)-l-azoniabicyclo[2.2.2]octane bromide
3 -((bis(3-f uorophenyl)methoxy)carbonyl)-l -(2-0X0-2- (thiophen-2 -yl)ethyl) - 1 - azoniabicy clo [2.2.2] o ctane chloride
3-((bis(3-f uorophenyl)methoxy)carbonyl)-l-(2-(4- methoxyphenyl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octane bromide
3-((bis(3-f uorophenyl)methoxy)carbonyl)-l-(2-(4- f uorophenyl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octane
bromide
3-((bis(3-f uorophenyl)methoxy)carbonyl)-l-(2-oxo-2-p- tolylethyl)- 1 -azoniabicy clo [2.2.2] octane bromide
3-((bis(3-f uorophenyl)methoxy)carbonyl)-l-(2-(5- chlorothiophen-2-yl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octane bromide
3-((bis(3-f uorophenyl)methoxy)carbonyl)-l-(2-(4- chlorophenyl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octane
bromide
3-((bis(3-f uorophenyl)methoxy)carbonyl)-l-(2-(3- f uorophenyl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octane
bromide
3-((bis(3-f uorophenyl)methoxy)carbonyl)-l-(2-oxopropyl)-l- azoniabicyclo[2.2.2]octane chloride
3-((bis(3-f uorophenyl)methoxy)carbonyl)-l-(2-tert-butoxy-2- oxoethyl)-l-azoniabicyclo[2.2.2]octane chloride
3-((bis(3-f uorophenyl)methoxy)carbonyl)-l-(2-oxo-2-(pyridin- 2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate
3-((bis(3-fluorophenyl)methoxy)carbonyl)-l-(2-(3- (ethoxycarbonyl)isoxazol-5-yl)-2-oxoethyl)- l- azoniabicy clo [2.2.2] octane bromide
3-((bis(3-fluorophenyl)methoxy)carbonyl)-l-(2-(2- fluorophenyl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octane
bromide
3 -((bis(3-fluorophenyl)methoxy)carbonyl)-l -(2-0X0-2- (thiophen-3 -yl)ethyl)- 1 -azoniabicy clo [2.2.2] octane bromide
(continued) 3-((bis(3-fluorophenyl)methoxy)carbonyl)-l-(2-(4- hydroxyphenyl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octane bromide
l-(2-(benzo[b]thiophen-5-yl)-2-oxoethyl)-3-((bis(3- f uorophenyl)methoxy) carb ony 1) - 1 - azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate
1 -benzyl-3 -((bis(3 -fluorophenyl)methoxy)carbonyl)- 1 - azoniabicy clo [2.2.2] octane bromide
3-((l,2-diphenylethoxy)carbonyl)-l-(2-oxo-2-(thiophen-2- yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate
3-((bis(4-chlorophenyl)methoxy)carbonyl)- 1 -(2-0X0-2- (thiophen-2 -yl)ethyl) - 1 - azoniabicy clo [2.2.2] o ctane chloride bis(4-fluorophenyl)methyl quinuclidine-3-carboxylate
3 -((bis(4-fluorophenyl)methoxy)carbonyl)-l -(2-0X0-2- (thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2- trifluoroacetate
benzhydryl quinuclidine-3 -carboxylate
3-(benzhydryloxycarbonyl)-l-(2-oxo-2-(thiophen-2- yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate
(4-methoxyphenyl)(phenyl)methyl quinuclidine-3 - carboxylate
3-(((4-methoxyphenyl)(phenyl)methoxy)carbonyl)- l-(2-oxo-
2-(thiophen-2-yl)ethyl)- l-azoniabicyclo[2.2.2]octane chloride
(2-chlorophenyl)(4-chlorophenyl)methyl quinuclidine-3 - carboxylate
3-(((2-chlorophenyl)(4-chlorophenyl)methoxy)carbonyl)-l-
(2-oxo-2-(thiophen-3-yl)ethyl)-l-azoniabicyclo[2.2.2]octane
2,2,2-trifluoroacetate
(3,4-difluorophenyl)(phenyl)methyl quinuclidine-3 - carboxylate
3-(((3,4-difluorophenyl)(phenyl)methoxy)carbonyl)- l-(2- oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride
3 -fluorobenzyl quinuclidine-3 -carboxylate
3-((3-fluorobenzyloxy)carbonyl)-l-(2-oxo-2-(thiophen-2- yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (continued)
Figure imgf000026_0002
Compounds of general formula (I) and (IV) may be prepared according following synthetic Scheme 1.
Figure imgf000026_0001
I) (IV) (I)
Scheme 1
Unless otherwise noted, Ri, R2, Q, R5, X, X', Y and A are as defined above. It is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (Green T.W. and Wuts P.G.M. (1991) Protecting Groups in Organic Synthesis, John Wiley et Sons).
General procedure for the preparation of compounds of formula (I) and (IV)
Compounds of general formula (IV), reported in the present invention, may be prepared starting from compounds of general formula (II), in which z may be either a carboxyl or an amino group and Q may be a group of general formula (f) or (g):
(f) (g)
wherein m, n and R5 are as described above.
These compounds (II) can be reacted with compounds of general formula (III), in which Rx and X are as described above and L can be H or an alkaline or alkaline earth metal (i.e. potassium, lithium, sodium, calcium and so on).
Starting materials of general formula (II) and (III) are commercially available or may be conveniently prepared according to standard procedures extensively reported in literature.
- In case z is a carboxyl group, the coupling between compounds of general formula (II) and (III) may be promoted using standard amidation and peptide coupling conditions. The operative conditions are chosen on the basis of the reactivity of the acid (II) over alcohol/thioalcohol (III) and of the compatibility of other groups being present in both compounds (for a general reference on the above reaction and operative conditions thereof see, for instance, Carey, F.A. and Sundeberg, R.J. Advanced Organic Chemistry, Third Edition (1990), Plenum Press, New York and London, pg 145).
The said conditions include, for instance, activating acid (II) by means of one or more equivalents of a commercially available condensing agent such as a carbodiimide (e.g. l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and the like) for example in the presence of N-hydroxybenzotriazole (HOBt) followed by reaction of the activated intermediate with alcohol or thioalcohol (III). An organic base such as triethylamine and the like may be also present in the reaction mixture. The activated intermediate may be either isolated, or pre-formed or generated in situ, and then properly reacted with compounds of formula (III). Suitable solvents for the coupling reaction include, but are not limited to, halocarbon solvents (e.g. dichloromethane (DCM)), tetrahydrofuran (THF), dioxane, dimethylformamide (DMF) and acetonitrile. The reaction proceeds at temperature ranging from about 0°C up to about 170°C, for a time period in the range of about 1 hour up to about 96 hours. The reaction may be carried out under conventional heating (using an oil bath) or under microwave irradiation. The reaction may be conducted either in an open vessel or in a sealed tube.
In some embodiments of the invention, acid (II) can be most conveniently activated as acyl halide such as acyl chloride (z=COCl). This activation may be affected according to one of the several standard procedures reported in the literature. They comprise, for instance, treatment of acid (II) with one or more equivalents of oxalyl chloride or thionyl chloride. This reaction may be conducted in the presence of a catalytic amount of dimethylformamide (DMF) in a suitable solvent (e.g. dichloromethane) or neat, at temperature ranging from about 0°C to about 120°C. The activated intermediate may be either isolated, or pre-formed or generated in situ. This intermediate can then be reacted with alcohol or thioalcohol (III), using known methods in order to obtain compounds of formula (IV). The reaction may be promoted by a base such as triethylamine, pyridine and 4-dimethylaminopyridine, and carried out in a suitable solvent (e.g. dichloromethane) or neat. This reaction is performed in a temperature range from about 0°C to about 140°C over a period of about 1 hour to about 74 hours. The reaction may be conducted under conventional heating (using an oil bath) or under microwave heating. The reaction may be carried out in an open vessel or in a sealed tube.
The resulting esters (X, X'=0) and thioesters (X=S; X'=0) of general formula (IV) can be then alkylated to obtain compounds of general formula (I). Alternatively, they can be first transformed into the corresponding thienoester (X=0; X'=S) or di-thioester (X, X'=S) of general formula (IV). This conversion can be effected according to one of the known standard procedures. For instance, esters (IV) can be treated with Lawessons's reagent (Nicolaou, K. C. et al. Journal of the American Chemical Society, 1990, 12/17, 6263 - 6276) or with tetraphosphorus decasulfide (Cho, D. et al. Tetrahedron, 2010, 66/30, 5583 - 5588) to achieve the corresponding thienoester (IV). Likewise, thioesters may be converted into di-thioester by treatment with Lawessons's reagent (Cohen, O. et al. Tetrahedron, 2010, 66/20, 3579 - 3582). The resulting thienoester (X=0; X'=S) or di-thioester (X, X'=S) of general formula (IV) can then be alkylated to obtain compounds of general formula (I).
- In case z is an amino group, compound of general formula (II) may be coupled with compound of general formula (III) to afford carbamate, thiocarbamate or dithiocarbamate of general formula (IV). This coupling may be effected according to one of the standard procedures broadly reported in the literature (a survey of the suitable reactions is given by Chaturvedi, D. Current Organic Synthesis, 2007, 3, 308 or by Smith, M.B. and March, J., March's Advanced Organic Chemistry, Fifth Edition (2001), John Wiley & Sons, Inc., New York, appendix B, 1660). For instance, the amine (II) could be treated with a suitable activating reagent that could be selected from, but are not limited to, Ι, -carbonyldiimidazole, Ι, -thiocarbonyldiimidazole, diphosgene, triphosgene or /7-nitrophenylchloroformate. The reaction may be promoted by a base selected from the group consisting of triethylamine, pyridine, 4-dimethylaminopyridine and the like, in a suitable solvent (e.g. dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DCM)). The activated intermediate is generally pre-formed but it may be either generated in situ or isolated. Then, the activated amine is reacted with an alcohol or thioalcohol of formula (III), most conveniently dissolved in the same solvent used for the activation of compound (II). Preferably, the alcohol or thioalcohol is preliminary treated with a base advantageously selected from NaH, BuLi (butyl lithium) and lithium diisopropylamide (LDA).
The compounds of general formula (IV) wherein Q is a group of formula (f) or (g), are eventually alkylated with an agent of general formula (VI) to give compounds of general formula (I), wherein R2 is a group with the above described meanings.
This kind of reaction is largely described in literature under several different conditions. For instance, the reaction may be performed neat or in a suitable solvent selected from the group consisting of acetonitrile, ethyl acetate, DMF and tetrahydrofuran. The reaction typically proceeds at temperature range from about 0°C up to about 170°C, for a time in the range of few minutes up to about 72 hours. The reaction may be carried out under conventional heating (using an oil bath) or under microwave irradiation. The reaction may be conducted either in an open vessel or in a sealed tube.
Compounds of general formula (I) can be either considered as final products or can be further reacted to prepare other compounds of general formula (I). Thus, any suitable moiety of Ri or R2 group in general formula (I) could undergo a variety of reactions, to afford other final compounds of general formula (I).
Likewise, the optional salification of the compounds of formula (I) may be carried out by properly converting any of the free acidic groups (e.g. carboxylic) or free amino groups into the corresponding pharmaceutically acceptable salts.
In this case too, the operative conditions used for the optional salification of the compounds of the invention are conventional
Further, depending from any of the meanings provided to Ri and R2, among those formerly reported, it will be clear to the skilled person that asymmetric centers may be present within the compounds of formula (I). Therefore, the invention also includes any of the optical stereoisomers, diastereoisomers and mixtures thereof, in any proportion.
The invention also provides pharmaceutical compositions of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carriers, for example those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.
Administration of the compounds of the present invention may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and by ocular administration.
Various solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.
Various liquid oral dosage forms can also be used for administering compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.
Suppositories for rectal administration of the compounds of the invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
Formulations for vaginal administration can be in the form of cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such as suitable carriers, are also known.
For topical administration the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches.
For the treatment of the diseases of the respiratory tract, the compounds according to the invention are preferably administered by inhalation.
Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.
For administration as a dry powder, known single- or multi-dose inhalers may be utilized. In that case the powder may be filled in gelatine, plastic or other capsules, cartridges or blister packs or in a reservoir.
A diluent or carrier, generally non-toxic and chemically inert to the compounds of the invention, e.g. lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention.
Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form. The propellant- driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.
The propellant-free inhalable formulations comprising the compounds of the invention may be in form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by known jet or ultrasonic nebulizers or by soft-mist nebulizers such as Respimat®.
The compounds of the invention may be administered as the sole active agent or in combination with other pharmaceutical active ingredients including those currently used in the treatment of respiratory disorders, e.g. beta2-agonists, corticosteroids and anticholinergic or antimuscarinic agents.
The dosages of the compounds of the invention depend upon a variety of factors including the particular disease to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, and pharmacokinetic profile of the compound.
Advantageously, the compounds of formula (I) can be administered for example, at a dosage comprised between 0.001 and 1000 mg/day, preferably between 0.1 and 500 mg/day.
When the compounds of formula (I) are administered by inhalation route, they are preferably given at a dosage comprised between 0.001 and 500 mg/day, preferably between 0.1 and 200 mg/day.
The compounds of formula (I) may be administered for the prevention and/or treatment of broncho-obstructive or inflammatory diseases, such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), bronchial hyperreactivity, cough, emphysema or rhinitis; urological disorders such as urinary incontinence, pollakiuria, cystospasm, chronic cystitis and overactive bladder (OAB); gastrointestinal disorders such as bowel syndrome, spastic colitis, diverticulitis, peptic ulceration, gastrointestinal motility or gastric acid secretion; dry mouth; mydriasis, tachycardia; ophthalmic interventions cardiovascular disorders such as vagally induced sinus bradycardia.
The present invention will now be further described by way of the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without any further purification; all reactions are conducted under an inert atmosphere and in dry solvents.
EXAMPLE 1
Preparation of (R)-bis(3-fluorophenyl)methyl quinuclidin-3- ylcarbamate (compound 1)
Figure imgf000034_0001
In a first flask, (R)-quinuclidin-3 -amine dihydro chloride (500 mg, 2.51 mmol) was dissolved in MeOH (25 ml) and water (2.50 ml). Sodium bicarbonate (211 mg, 2.51 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was then evaporated to dryness. The residue was dissolved in dry DMF (25.0 ml) and CDI (407 mg, 2.51 mmol) was added. The reaction was stirred at room temperature for 16 hours.
In a second flask, bis(3-fluorophenyl)methanol (1.11 g, 5.02 mmol) was dissolved in dry DMF (25 ml) and treated portionwise with sodium hydride (60% dispersion in mineral oil, 201 mg, 5.02 mmol) at 0°C. This second reaction was stirred at room temperature for 30 min and then poured into the first flask.
The resulting reaction was stirred at room temperature for 2 days. Then the reaction was portioned between Et2O and water. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/l to DCM/MeOH=75/25 + 0.5% TEA) to obtain (R)-bis(3-fluorophenyl)methyl quinuclidin-3-ylcarbamate (419 mg).
1H NMR (300 MHz, DMSO-<¾) δ ppm 7.63 (d, 1 H), 7.35 - 7.49 (m, 2 H), 7.19 - 7.32 (m, 4 H), 7.04 - 7.18 (m, 2 H), 6.68 (s, 1 H), 3.42 - 3.58 (m, 1 H), 2.93 - 3.15 (m, 1 H), 2.71 - 2.85 (m, 1 H), 2.55 - 2.70 (m, 3 H), 2.41 - 2.47 (m, 1 H), 1.65 - 1.83 (m, 2 H), 1.36 - 1.64 (m, 2 H), 1.09 - 1.35 (m, 1 H).
EXAMPLE 2
Preparation of (R)-benzhydryl quinuclidin-3-ylcarbamate (compound 2)
Figure imgf000035_0001
In a first flask, (R)-quinuclidin-3 -amine dihydro chloride (0.10 g,
0.50 mmol) was dissolved in MeOH (5 ml) and water (0.5 ml). Sodium bicarbonate (84.0 mg, 1.00 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was then evaporated to dryness. The solid was dissolved in dry DMF (5 ml) and CDI (81.0 mg, 0.50 mmol) was added. The reaction was stirred at room temperature for 7 hours.
In a second flask, diphenylmethanol (0.18 g, 1.00 mmol) was dissolved in dry DMF (5 ml) and treated portionwise with NaH (40.0 mg, 1.00 mmol) at 0°C. The reaction was stirred at room temperature for 20 minutes and then poured into the first flask.
The resulting reaction was stirred at room temperature overnight. Reaction was portioned between Et2O and water. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/l to DCM/MeOH=75/25 + 0.5% TEA) to obtain (R)-benzhydryl quinuclidin-3 - ylcarbamate (105 mg).
1H NMR (300 MHz, DMSO-d6) δ ppm 7.57 (d, 1 H) 7.18 - 7.46 (m, 10 H) 6.66 (s, 1 H) 3.40 - 3.59 (m, 1 H) 2.96 - 3.13 (m, 1 H) 2.56 - 2.89 (m, 4 H) 2.40 - 2.48 (m, 1 H) 1.67 - 1.81 (m, 2 H) 1.37 - 1.64 (m, 2 H) 1.12 - 1.35 (m, 1 H).
EXAMPLE 3
Preparation of (R)-bis(4-fluorophenyl)methyl quinuclidin-3- ylcarbamate (compound 3)
Figure imgf000036_0001
In a first flask, (R)-quinuclidin-3 -amine dihydrochloride (50.0 mg, 0.25 mmol) was dissolved in MeOH (2.5 ml) and water (0.25 ml). Sodium bicarbonate (42.0 mg, 0.50 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was then evaporated to dryness. The solid was dissolved in dry DMF (2.50 ml) and CDI (40.5 mg, 0.25 mmol) was added. The reaction was stirred at room temperature for 7 hours.
In a second flask, bis(4-fluorophenyl)methanol (1 11 mg, 0.50 mmol) was dissolved in dry DMF (5 ml) and sodium hydride (20.0 mg, 0.50 mmol) was added portionwise at 0°C. The reaction was stirred at 0°C for 5 minutes and then poured into the first flask, cooled at 0°C.
The resulting reaction was stirred at room temperature overnight. The reaction was then portioned between Et2O and water. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/l to DCM/MeOH=75/25 + 0.5% TEA) to obtain (R)-bis(4-fluorophenyl)methyl quinuclidin-3-ylcarbamate (37.0 mg).
1H NMR (300 MHz, DMSO-d6) δ ppm 7.60 (d, 1 H) 7.40 (dd, 4 H) 7.03 - 7.30 (m, 4 H) 6.68 (s, 1 H) 3.37 - 3.60 (m, 1 H) 2.95 - 3.16 (m, 1 H) 2.74 - 2.89 (m, 1 H) 2.55 - 2.70 (m, 3 H) 2.45 (d, 1 H) 1.65 - 1.84 (m, 2 H) 1.36 - 1.64 (m, 2 H) 1.21 - 1.36 (m, 1 H).
The following compounds were prepared following the route described in Example 3, using the suitable alcohols instead of bis(4- fluorophenyl)methanol. These compounds were achieved as a mixture of diastereoisomers.
Table 1
Figure imgf000038_0002
EXAMPLE 4
Preparation of bis(3-fluorophenyl)methyl quinuclidine-3- carboxylate (compound 8)
Figure imgf000038_0001
Quinuclidine-3-carboxylic acid hydrochloride (817 mg, 4.26 mmol), EDC (1.23 g, 6.39 mmol), and HOBT (979 mg, 6.39 mmol) were dissolved in dry DMF (40 ml). DIPEA (2.61 ml, 14.9 mmol) and bis(3- fluorophenyl)methanol (1.03 mg, 4.69 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted several times with Et2O. The organic phases were collected and washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography (DCM/MeOH= 9/1) to obtain bis(3- fluorophenyl)methyl quinuclidine-3-carboxylate (874 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 7.42 (td, 2 H), 7.22 - 7.34 (m, 4
H), 7.05 - 7.19 (m, 2 H), 6.85 (s, 1 H), 2.99 - 3.12 (m, 1 H), 2.86 - 2.99 (m, 1 H), 2.59 - 2.83 (m, 5 H), 2.13 - 2.24 (m, 1 H), 1.41 - 1.72 (m, 2 H), 1.15 - 1.40 (m, 2 H).
EXAMPLE 5
Preparation of 1,2-diphenylethyl quinuclidine-3-carboxylate
(compound 9)
Figure imgf000039_0001
Quinuclidine-3-carboxylic acid hydrochloride (160 mg, 0.83 mmol), EDC (290 mg, 1.51 mmol), and HOBT (232 mg, 1.51 mmol) were dissolved in dry DMF (8 ml). 1,2-Diphenylethanol (150 mg, 0.76 mmol) and TEA (0.32 ml, 2.27 mmol) were added and the resulting mixture was stirred at room temperature overnight. Then quinuclidine-3-carboxylic acid hydrochloride (72.5 mg, 0.38 mmol), EDC (87 mg, 0.45 mmol), and HOBT (57.9 mg, 0.38 mmol) were added followed by TEA (0.16 ml, 1.13 mmol) and the mixture was stirred for additional 32 hours. The mixture was diluted with water and extracted three times with Et2O. The organic phases were collected, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude residue was purified by flash chromatography (DCM/MeOH=9/l) to obtain 1,2-diphenylethyl quinuclidine-3-carboxylate (136 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 6.83 - 7.61 (m, 10 H), 5.68 - 6.17 (m, 1 H), 3.01 - 3.25 (m, 2 H), 2.54 - 2.98 (m, 7 H), 1.76 - 1.90 (m, 1 H), 1.32 - 1.64 (m, 2 H), 0.80 - 1.22 (m, 2 H).
EXAMPLE 6
Preparation of bis(4-chlorophenyl)methyl quinuclidine-3- carboxylate (compound 10)
Figure imgf000040_0001
Quinuclidine-3-carboxylic acid hydrochloride (150 mg, 0.78 mmol), EDC (225 mg, 1.17 mmol) and HOBT (180 mg, 1.17 mmol) were dissolved in dry THF (7.5 ml). Bis(4-chlorophenyl)methanol (218 mg, 0.86 mmol) was added followed by TEA (382 μΐ, 2.74 mmol). The resulting reaction was stirred at room temperature overnight. THF was removed under vacuum and the crude was partitioned between EtOAc and water. The organic phase was washed with sat. NaHCO3, dried over sodium sulphate, filtered and evaporated to dryness. The crude was purified by flash chromatography (EtOAc/MeOH=8/2 to 7:3+1% of NH4OH) to obtain bis(4- chlorophenyl)methyl quinuclidine-3-carboxylate (85.0 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 7.30 - 7.54 (m, 8 H) 6.89 (s, 1 H) 3.33 - 3.55 (m, 2 H) 2.94 - 3.26 (m, 5 H) 2.54 - 2.65 (m, 1 H) 1.78 - 2.10 (m, 2 H) 1.59 - 1.78 (m, 1 H) 1.31 - 1.55 (m, 1 H).
EXAMPLE 7
Preparation of (R)-3-((bis(3-fluorophenyl)methoxy)carbonylamino)- l-(2-oxo-2-(thiophen-3-yl)ethyl)-l-azoniabicyclo[2.2.2]octane bromide (compound 11)
Figure imgf000041_0001
2-Bromo-l-(thiophen-3-yl)ethanone (27.5 mg, 0.13 mmol) was added to a solution of (R)-bis(3-fluorophenyl)methyl quinuclidin-3-ylcarbamate (50 mg, 0.13 mmol, prepared as in example 1) in ethyl acetate (2 ml). The reaction was stirred at room temperature overnight. Et2O (2 ml) was added and the precipitate was collected by suction filtration and dried under vacuum at 40°C over a week-end to obtain (R)-3-((bis(3-fluorophenyl)methoxy)- carbonylamino)-l-(2-oxo-2-(thiophen-3-yl)ethyl)-l-azoniabicyclo[2.2.2]- octane bromide (66.3 mg).
1H NMR (300 MHz, DMSO-<¾) δ ppm 8.63 (dd, 1 H) 8.09 - 8.25 (m, 1 H) 7.74 (dd, 1 H) 7.51 - 7.62 (m, 1 H) 7.35 - 7.50 (m, 2 H) 7.20 - 7.35 (m, 4 H) 7.07 - 7.20 (m, 2 H) 6.73 (s, 1 H) 4.97 (dd, 2 H) 3.92 - 4.25 (m, 2 H) 3.46 - 3.83 (m, 5 H) 1.81 - 2.25 (m, 5 H);
LC-MS (ESI POS): 496.99 (M+).
The following compounds were prepared following the route described in Example 7, using the suitable alkylating agents instead of 2-bromo- l- (thiophen-3-yl)ethanone. Table 2
Figure imgf000042_0001
(continued)
Figure imgf000043_0001
(continued)
Figure imgf000044_0001
(continued)
Figure imgf000045_0001
(continued)
Figure imgf000046_0001
(continued)
Figure imgf000047_0001
(continued)
Figure imgf000048_0001
EXAMPLE 8
Preparation of (R)-3-((bis(3-fluorophenyl)methoxy)carbonylamin l-(2-(5-cyanothiophen-2-yl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octane bromide (compound 26)
Figure imgf000049_0001
5-(2-Bromoacetyl)thiophene-2-carbonitrile (33.4 mg, 0.14 mmol) was added to a solution of (R)-bis(3-fluorophenyl)methyl quinuclidin-3- ylcarbamate (54 mg, 0.14 mmol, prepared as in example 1) in ethyl acetate (2 ml). The resulting solution was stirred at room temperature for two days, then 5-(2-bromoacetyl)thiophene-2-carbonitrile (3.4 mg, 0.015 mmol) was added and the stirring was kept for additional 16 hours. Et2O was added and the precipitate was recovered by filtration to afford (R)-3-((bis(3- fluorophenyl)methoxy)carbonylamino)- l-(2-(5-cyanothiophen-2-yl)-2- oxoethyl)-l-azoniabicyclo[2.2.2]octane bromide (68 mg).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.08 - 8.22 (m, 3 H), 7.34 - 7.58 (m, 2 H), 7.20 - 7.34 (m, 4 H), 7.04 - 7.20 (m, 2 H), 6.73 (s, 1 H), 5.06 (br. s., 2 H), 3.86 - 4.24 (m, 2 H), 3.56 - 3.86 (m, 3 H), 3.40 - 3.56 (m, 2 H), 2.10 - 2.26 (m, 2 H), 1.84 - 2.08 (m, 3 H);
LC-MS (ESI POS): 522.14 (M+). EXAMPLE 9
Preparation of (R)-3-((bis(3-fluorophenyl)methoxy)carbonylamino)- l-(2-oxo-2-(pyridin-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane bromide (compound 27).
Figure imgf000050_0001
2-Bromo-l-(pyridin-2-yl)ethanone hydrobromide (39.2 mg, 0.14 mmol) was added to a solution of (R)-bis(3-fluorophenyl)methyl quinuclidin-3- ylcarbamate (52 mg, 0.14 mmol, prepared as in example 1) in ethyl acetate (2 ml). The reaction was stirred at room temperature for 16 hours then Et2O (1 mL) was added and the precipitate was collected by suction filtration and dried under vacuum at 40°C overnight. The product was further purified by preparative HPLC to obtain (R)-3-((bis(3-fluorophenyl)methoxy)- carbonylamino)-l-(2-oxo-2-(pyridin-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane bromide (16.5 mg).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.76 (dt, 1 H) 8.15 - 8.24 (m, 1 H) 8.01 - 8.15 (m, 2 H) 7.78 (ddd, 1 H) 7.43 (td, 2 H) 7.19 - 7.36 (m, 4 H) 7.07 - 7.19 (m, 2 H) 6.73 (s, 1 H) 5.22 (s, 2 H) 3.94 - 4.19 (m, 2 H) 3.44 - 3.90 (m, 5 H) 2.17 - 2.38 (m, 1 H) 1.78 - 2.17 (m, 4 H);
LC-MS (ESI POS): 492.20 (M+).
The following compound was prepared following the route described in Example 9 using the suitable alkylating agents instead of 2-bromo-l-(pyridin- 2-yl)ethanone hydrobromide. Table 3
Figure imgf000051_0002
EXAMPLE 10
Preparation of (R)-3-((bis(3-fluorophenyl)methoxy)carbonylamino)- l-(2-oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo [2.2.2] octane chloride (compound 29)
Figure imgf000051_0001
(R)-Bis(3-fluorophenyl)methyl quinuclidin-3-ylcarbamate (35 mg, 0.09 mmol, prepared as in example 1) and 2-chloro- l-(thiophen-2-yl)ethanone (16.6 mg, 0.10 mmol) were dissolved in acetonitrile (2 ml) and stirred at room temperature for 16 hours. Acetonitrile was evaporated and the crude was purified by flash chromatography (DCM/MeOH=9/l) to obtain (R)-3-((bis(3- fluorophenyl)methoxy)carbonylamino)- l-(2-oxo-2-(thiophen-2-yl)ethyl)-l- azoniabicyclo[2.2.2]octane chloride (50.1 mg).
1H NMR (300 MHz, DMSO- 6) δ ppm 8.20 (dd, 2 H), 8.10 (dd, 1 H), 7.38 - 7.54 (m, 2 H), 7.29 - 7.38 (m, 2 H), 7.25 (br. s., 3 H), 6.95 - 7.21 (m, 2 H), 6.73 (s, 1 H), 5.03 (s, 2 H), 3.85 - 4.23 (m, 2 H), 3.48 - 3.80 (m, 5 H), 1.95 - 2.32 (m, 4 H), 1.91 (br. s., 1 H);
LC-MS (ESI POS): 497.33 (M+).
EXAMPLE 11
Preparation of (R)-3-((bis(3-fluorophenyl)methoxy)carbonylamino)- l-(2-oxo-2-phenylethyl)-l-azoniabicyclo [2.2.2] octane chloride (compound
30)
Figure imgf000052_0001
2-Chloro-l-phenylethanone (20.8 mg, 0.13 mmol) was added to a solution of (R)-bis(3-fluorophenyl)methyl quinuclidin-3-ylcarbamate (50 mg, 0.13 mmol, prepared as in example 1) in ethyl acetate (2 ml). The reaction was stirred at room temperature overnight then the solvent was evaporated under vacuum. The residue was treated with Et2O (4 ml) and sonicated to obtain a solid, which was collected by suction filtration and purified by flash chromatography (DCM/MeOH=95/5), to obtain (R)-3-((bis(3- fluorophenyl)methoxy)carbonylamino)- l-(2-oxo-2-phenylethyl)- 1- azoniabicyclo[2.2.2]octane chloride (37.2 mg).
1H NMR (300 MHz, DMSO-<¾) 5 ppm 8.22 (d, 1 H) 7.91 - 8.05 (m, 2 H) 7.68 - 7.85 (m, 1 H) 7.54 - 7.68 (m, 2 H) 7.43 (td, 2 H) 7.21 - 7.36 (m, 4 H) 7.01 - 7.20 (m, 2 H) 6.73 (s, 1 H) 5.15 (s, 2 H) 3.95 - 4.18 (m, 2 H) 3.63 - 3.92 (m, 4 H) 3.47 - 3.63 (m, 1 H) 1.98 - 2.36 (m, 4 H) 1.79 - 1.98 (m, 1 H);
LC-MS (ESI POS): 491.21 (M+).
EXAMPLE 12
Preparation of (R)-3-((bis(3-fluorophenyl)methoxy)carbonylamino)- l-(2-phenoxyethyl)-l-azoniabicyclo[2.2.2]octane bromide (compound 31)
Figure imgf000053_0001
(R)-Bis(3-fluorophenyl)methyl quinuclidin-3-ylcarbamate (50 mg, 0.13 mmol, prepared as in example 1) was added to a solution of (2-bromoethoxy)benzene (27.0 mg, 0.13 mmol) in ethyl acetate (2 ml). The mixture was stirred at room temperature overnight. Then (2-bromoethoxy)benzene (27 mg, 0.13 mmol) was added and the mixture was heated at 100°C for 15 minutes under microwave irradiation. A catalytic amount of potassium iodide was added and the reaction was heated at 120°C for lh under microwave irradiation. The precipitate was collected by filtration and dried to obtain (R)-3-((bis(3-fluorophenyl)methoxy)carbonylamino)- l-(2- phenoxyethyl)- l-azoniabicyclo[2.2.2]octane bromide (17 mg).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.05 (d, 1 H), 7.42 (td, 2 H), 7.29 - 7.37 (m, 2 H), 7.20 - 7.29 (m, 4 H), 7.08 - 7.20 (m, 2 H), 6.90 - 7.06 (m, 3 H), 6.73 (s, 1 H), 4.38 - 4.46 (m, 2 H), 3.95 - 4.11 (m, 1 H), 3.84 - 3.95 (m, 1 H), 3.60 - 3.72 (m, 2 H), 3.44 - 3.61 (m, 4 H), 3.33 - 3.38 (m, 1 H), 2.06 - 2.22 (m, 2 H), 1.73 - 2.05 (m, 3 H);
LC-MS (ESI POS): 493.34 (M+). EXAMPLE 13
Preparation of (R)-3-((bis(3-fluorophenyl)methoxy)carbonylamin l-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-l-azoniabicyclo[2.2.2]octane bromide (compound 32)
Figure imgf000054_0001
To a solution of (R)-bis(3-fluorophenyl)methyl quinuclidin-3- ylcarbamate (53 mg, 0.14 mmol, prepared as in example 1) in ethyl acetate (2 ml), 5-(2-bromoethyl)-2,3-dihydrobenzofuran (32.3 mg, 0.14 mmol) was added. The resulting mixture was stirred at room temperature for 8 days and then the solvent was evaporated and the crude was purified by flash chromatography (DCM/MeOH=95/5) to collect (R)-3-((bis(3-fluorophenyl)- methoxy)carbonylamino)- l-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-l- azoniabicyclo[2.2.2]octane bromide (22.2 mg).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.08 (d, 1 H), 7.36 - 7.51 (m, 2
H), 7.26 (d, 4 H), 7.06 - 7.19 (m, 3 H), 7.00 (d, 1 H), 6.64 - 6.81 (m, 2 H), 4.50 (t, 2 H), 3.92 - 4.13 (m, 1 H), 3.83 (t, 1 H), 3.37 - 3.59 (m, 4 H), 3.33 (d, 2 H), 3.19 - 3.25 (m, 1 H), 3.15 (t, 2 H), 2.90 (m, 2 H), 2.04 - 2.25 (m, 2 H), 1.68 - 2.04 (m, 3 H);
LC-MS (ESI POS): 519.30 (M+). EXAMPLE 14
Preparation of (R)-3-((bis(3-fluorophenyl)methoxy)carbonylamino)- l-(4-fluorophenethyl)-l-azoniabicyclo[2.2.2]octane bromide (compound
33)
Figure imgf000055_0001
(R)-bis(3-Fluorophenyl)methyl quinuclidin-3-ylcarbamate (55 mg, 0.14 mmol, prepared as in example 1) was dissolved in ethyl acetate (2 ml) and 1- (2-bromoethyl)-4-fluorobenzene (21 μΐ, 0.15 mmol) was added. The reaction was stirred at room temperature for 24 hours, then l-(2-bromoethyl)-4- fluorobenzene (6.21 μΐ, 0.04 mmol) was added again. After being stirred at room temperature for 2 days, the reaction was concentrated under vacuum and the crude was first purified by flash chromatography (DCM/MeOH=9/l) and then triturated with DCM/Et2O (1/1) to obtain (R)-3-((bis(3-fluorophenyl)- methoxy)carbonylamino)- l-(4-fluorophenethyl)-l-azoniabicyclo[2.2.2]octane bromide (45 mg).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.09 (d, 1 H), 7.39 - 7.48 (m, 2 H), 7.35 (dd, 2 H), 7.23 - 7.30 (m, 4 H), 7.09 - 7.23 (m, 4 H), 6.74 (s, 1 H), 3.94 - 4.15 (m, 1 H), 3.64 - 3.94 (m, 1 H), 3.41 - 3.59 (m, 4 H), 3.35 (d, 2 H), 3.14 - 3.25 (m, 1 H), 3.00 (dd, 2 H), 2.04 - 2.25 (m, 2 H), 1.69 - 2.04 (m, 3 H);
LC-MS (ESI POS): 495.24 (M+). EXAMPLE 15
Preparation of (R)-3-(benzhydryloxycarbonylamino)-l-(2-oxo-2- phenylethyl)-l-azoniabicyclo[2.2.2]octane chloride (compound 34)
Figure imgf000056_0001
2-Chloro-l-phenylethanone (55.0 mg, 0.36 mmol) was added to a solution of (R)-benzhydryl quinuclidin-3-ylcarbamate (100 mg, 0.30 mmol, prepared as in example 2) in ethyl acetate (4 ml). The reaction was stirred at room temperature overnight. The suspension was decanted, solution was removed and the product was evaporated to dryness. Et2O was added, the suspension was sonicated. The precipitate was collected by suction filtration and dried under vacuum at 40°C to obtain (R)-3- (benzhydryloxycarbonylamino)- 1 -(2-oxo-2-phenylethyl)- 1 -azoniabicyclo- [2.2.2]octane chloride (110 mg)
1H NMR (300 MHz, DMSO-<¾) δ ppm 8.15 (d, 1 H) 7.94 - 8.05 (m, 2
H) 7.69 - 7.81 (m, 1 H) 7.52 - 7.66 (m, 2 H) 7.1 1 - 7.45 (m, 10 H) 6.71 (s, 1 H) 5.15 (s, 2 H) 3.92 - 4.19 (m, 2 H) 3.44 - 3.86 (m, 5 H) 1.96 - 2.32 (m, 4 H) 1.73 - 1.96 (m, 1 H);
LC-MS (ESI POS): 455.21 (M+). EXAMPLE 16
Preparation of (R)-3-((bis(4-fluorophenyl)methoxy)carbonylamino)- l-(2-oxo-2-phenylethyl)-l-azoniabicyclo[2.2.2]octane chloride (compound
Figure imgf000057_0001
2-Chloro-l-phenylethanone (13 mg, 0.09 mmol) was added to a solution of (R)-bis(4-fluorophenyl)methyl quinuclidin-3-ylcarbamate (32.0 mg, 0.09 mmol, prepared as in example 3) in ethyl acetate (2 ml). The reaction was stirred at room temperature overnight. Then other 2-chloro-l-phenylethanone (2.7 mg, 0.02 mmol) was added to the solution and the reaction was stirred for additional 24 hours. The reaction was evaporated to dryness and the residue was triturated in Et2O. Then isopropyl ether was added and the product was sonicated and the precipitate was collected by suction filtration to obtain (R)- 3-((bis(4-fluorophenyl)methoxy)carbonylamino)-l-(2-oxo-2-phenylethyl)-l- azoniabicyclo[2.2.2]octane chloride (32.4 mg)
1H NMR (300 MHz, DMSO-<¾) δ ppm 8.09 - 8.22 (m, 1 H) 7.91 - 8.05 (m, 2 H) 7.69 - 7.81 (m, 1 H) 7.55 - 7.69 (m, 2 H) 7.34 - 7.48 (m, 4 H) 7.09 - 7.31 (m, 4 H) 6.73 (s, 1 H) 5.14 (s, 2 H) 3.86 - 4.20 (m, 2 H) 3.47 - 3.87 (m, 5 H) 1.61 - 2.41 (m, 5 H);
LC-MS (ESI POS): 491.21 (M+). EXAMPLE 17
Preparation of (3R)-3-(((4-methoxyphenyl)(phenyl)-methoxy)- carbonylamino)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo [2.2.2]- octane chloride (compound 36)
Figure imgf000058_0001
2-Chloro-l-(thiophen-2-yl)ethanone (12.0 mg, 0.07 mmol) was added to a solution of (4-methoxyphenyl)(phenyl)methyl (R)-quinuclidin-3- ylcarbamate (22.0 mg, 0.06 mmol, prepared as in example 3) in ethyl acetate (2 ml). The reaction was stirred at room temperature for two days. The reaction was evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=95/5) to obtain (3R)-3-(((4- methoxyphenyl)(phenyl)methoxy)carbonylamino)-l-(2-oxo-2-(thiophen-2- yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride (23 mg, mixture of diastereoisomers).
1H NMR (300 MHz, DMSO-<¾) δ ppm 8.20 (d, 1 H) 8.08 (d, 1 H) 8.04 - 8.13 (m, 1 H) 7.35 (m, 5 H) 7.29 (m, 3 H) 6.74 - 7.04 (m, 2 H) 6.66 (s, 1 H) 5.00 (s, 2 H) 3.88 - 4.19 (m, 2 H) 3.74 (s, 3 H) 3.57 - 3.72 (m, 4 H) 3.42 - 3.57 (m, 1 H) 1.92 - 2.26 (m, 4 H) 1.64 - 1.92 (m, 1 H);
LC-MS (ESI POS): 491.21 (M+).
The following compounds were prepared following the route described in Example 17 using the suitable intermediates (Example 3, Table 1) instead of (4-methoxyphenyl)(phenyl)methyl (R)-quinuclidin-3-ylcarbamate. These compounds were obtained as a mixture of diastereoisomers. Table 4
Figure imgf000059_0001
EXAMPLE 18
Preparation of (3R)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-3-((phenyl(4- (trifluoromethyl)phenyl)methoxy)carbonylamino)-l-azoniabicyclo- [2.2.2]octane chloride (compound 41)
1- Preparation of phenyl(4-(trifluoromethyl)phenyl)methyl (R)- quinuclidin-3-ylcarbamate (compound 40)
Figure imgf000060_0001
In a first flask, (R)-quinuclidin-3 -amine dihydrochloride (100 mg, 0.50 mmol) was dissolved in MeOH (5 ml) and water (0.5 ml). NaHCO3 (84.0 g, 1.00 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction mixture was evaporated and the residue was dissolved in dry DMF (5 ml) and CDI (81.0 mg, 0.50 mmol) was added. The reaction was stirred at room temperature overnight.
In a second flask, phenyl(4-(trifluoromethyl)phenyl)methanol (0.25 g, 1.00 mmol) was dissolved in dry DMF (3 ml) and sodium hydride (60% dispersion in mineral oil, 24.0 mg, 1.00 mmol) was added portionwise at 0°C. The reaction was stirred at room temperature for 15 minutes and then was poured into the first flask.
The resulting mixture was stirred at room temperature overnight, then it was portioned between Et2O and water. The organic phase was washed with brine and dried over sodium sulphate. The solvent was removed in vacuo and the crude was purified by flash chromatography (DCM/MeOH=95/5 to DCM/MeOH/TEA=75/25/0.5) to obtain phenyl(4-(trifluoromethyl)- phenyl)methyl (R)-quinuclidin-3-ylcarbamate (56.0 mg, mixture of diastereoisomers).
2- Preparation of (3R)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-3- ((phenyl(4-(trifluoromethyl)phenyl)methoxy)carbonylamino)-l- azoniabicyclo[2.2.2]octane chloride (compound 41)
Figure imgf000061_0001
Phenyl(4-(trifluoromethyl)phenyl)methyl (R)-quinuclidin-3- ylcarbamate (56.0 mg, 0.14 mmol) was dissolved in ethyl acetate (1 ml) and acetonitrile (0.5 ml). The resulting solution was treated with 2-chloro- l- (thiophen-2-yl)ethanone (24.0 mg, 0.15 mmol) and stirred at room temperature overnight. The solvent was evaporated and the crude was first purified by flash chromatography (DCM/MeOH=95/5) and then by preparative HPLC (CH3CN/H2O) to afford (3R)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-3-((phenyl(4- (trifluoromethyl)phenyl)methoxy)carbonylamino)- 1 -azoniabicy clo [2.2.2]- octane chloride (30.0 mg, mixture of diastereoisomers).
1H NMR (300 MHz, DMSO-<¾) 5 ppm 8.18 - 8.26 (m, 2 H), 8.09 (d, 1 H), 7.69 - 7.79 (m, 2 H), 7.55 - 7.69 (m, 2 H), 7.17 - 7.49 (m, 6 H), 6.80 (s, 1
H), 5.01 (s, 2 H), 3.92 - 4.27 (m, 2 H), 3.44 - 3.88 (m, 5 H), 1.73 - 2.37 (m, 5 H);
LC-MS (ESI POS): 529.13 (M+). EXAMPLE 19
Preparation of (3R)-3-(((2-chlorophenyl)(4-chlorophenyl)methoxy)- carbonylamino)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo- [2.2.2]octane chloride (compound 43)
1- Preparation of (2-chlorophenyl)(4-chlorophenyl)methyl (R)- quinuclidin-3-ylcarbamate (compound 42)
Figure imgf000062_0001
In a first flask, (R)-quinuclidin-3 -amine dihydrochloride (80.0 mg, 0.40 mmol) was dissolved in MeOH (8 ml) and water (0.8 ml). Sodium bicarbonate (67.5 mg, 0.80 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was evaporated to dryness and the solid was dissolved in dry DMF (8 ml). CDI (65.1 mg, 0.40 mmol) was added and the reaction was stirred at room temperature overnight.
In a second flask, (2-chlorophenyl)(4-chlorophenyl)methanol (100 mg, 0.39 mmol) was dissolved in dry DMF (3 ml) and treated with sodium hydride (60% dispersion in mineral oil, 15.8 mg, 0.39 mmol) at 0°C. Ice-bath was removed and the reaction was stirred at room temperature for 20 minutes and then it was added to the first reaction.
The resulting mixture was stirred at room temperature overnight and then it was portioned between Et2O and water. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/l to DCM/MeOH=75/25) to obtain (2-chlorophenyl)(4-chlorophenyl)methyl (R)- quinuclidin-3-ylcarbamate (95 mg, mixture of diastereoisomers).
2- Preparation of (3R)-3-(((2-chlorophenyl)(4- chlorophenyl)methoxy)carbonylamino)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-l- azoniabicyclo[2.2.2]octane chloride (compound 43)
Figure imgf000063_0001
To a solution of (2-chlorophenyl)(4-chlorophenyl)methyl (R)- quinuclidin-3-ylcarbamate (95.0 mg, 0.23 mmol) in ethyl acetate (3 ml), 2- chloro-l-(thiophen-2-yl)ethanone (37.6 mg, 0.23 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was taken up in diethyl ether and filtered. The product was purified by flash chromatography (DCM/MeOH=95/5) to obtain (3R)-3-(((2-chlorophenyl)(4-chlorophenyl)methoxy)carbonylamino)- l-(2-oxo- 2-(thiophen-2-yl)ethyl)- l-azoniabicyclo[2.2.2]octane chloride (45.0 mg, mixture of diastereoisomers).
1H NMR (300 MHz, DMSO-<¾) 5 ppm 8.15 - 8.31 (m, 2 H) 8.02 - 8.15 (m, 1 H) 7.27 - 7.66 (m, 9 H) 6.81 - 7.00 (m, 1 H) 5.03 (s, 2 H) 3.85 - 4.23 (m, 2 H) 3.59 - 3.85 (m, 4 H) 3.46 - 3.59 (m, 1 H) 1.95 - 2.28 (m, 4 H) 1.82 - 1.93 (m, 1 H);
LC-MS (ESI POS): 529.09 (M+).
EXAMPLE 20
Preparation of (R)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-3-((thiophen-2- ylmethoxy)carbonylamino)-l-azoniabicyclo[2.2.2]octane chloride
(compound 45)
1- Preparation of (R)-thiophen-2-ylmethyl quinuclidin-3- ylcarbamate (compound 44)
Figure imgf000064_0001
In a first flask, (R)-quinuclidin-3 -amine dihydro chloride (100 mg, 0.50 mmol) was dissolved in MeOH (10 ml) and water (1 ml). Sodium bicarbonate (84 mg, 1.00 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was evaporated to dryness and the solid was dissolved in dry DMF (10 ml). CDI (81 mg, 0.50 mmol) was added and the reaction was stirred at room temperature overnight.
In a second flask, thiophen-2-ylmethanol (1 14 mg, 1.00 mmol) was dissolved in dry DMF (3 ml) and treated with sodium hydride (60% dispersion in mineral oil, 40.0 mg, 1.00 mmol) at 0°C. Ice-bath was removed and the reaction was stirred at room temperature for 20 minutes and then it was poured into the first flask.
The resulting mixture was stirred at room temperature overnight, then it was portioned between Et2O and water. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/l to 75/25) to obtain (R)- thiophen-2-ylmethyl quinuclidin-3-ylcarbamate (50 mg).
2- Preparation of (R)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-3-((thiophen-
2-ylmethoxy)carbonylamino)-l-azoniabicyclo[2.2.2]octane chloride (compound 45)
Figure imgf000065_0001
2-Chloro-l-(thiophen-2-yl)ethanone (30.2 mg, 0.19 mmol) was added to a solution of (R)-thiophen-2-ylmethyl quinuclidin-3-ylcarbamate (50.0 mg, 0.19 mmol) in EtOAc (3 ml). The reaction was stirred at room temperature overnight. The solvent was removed and the residue was triturated in Et2O, filtered and dried to give (R)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-3-((thiophen-2- ylmethoxy)carbonylamino)-l-azoniabicyclo[2.2.2]octane chloride (60 mg).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.21 (dd, 1 H), 8.12 (dd, 1 H), 7.96 (br. s., 1 H), 7.55 (dd, 1 H), 7.35 (dd, 1 H), 7.16 (dd, 1 H), 7.03 (dd, 1 H), 5.22 (s, 2 H), 5.04 (s, 2 H), 3.90 - 4.19 (m, 2 H), 3.58 - 3.84 (m, 4 H), 3.44 - 3.58 (m, 1 H), 1.72 - 2.24 (m, 5 H);
LC-MS (ESI POS): 391.23 (M+).
EXAMPLE 21
Preparation of (R)-3-((bis(3-fluorophenyl)methoxy)- carbonothioylamino)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-l- azoniabicyclo[2.2.2]octane chloride (compound 47)
1- Preparation of (R)-0-bis(3-fluorophenyl)methyl quinuclidin-3- ylcarbamothioate (compound 46)
Figure imgf000065_0002
In a first flask, (R)-quinuclidin-3 -amine dihydro chloride (500 mg, 2.51 mmol) was dissolved in MeOH (25 ml) and water (2.5 ml). Sodium bicarbonate (211 mg, 2.51 mmol) was added and the reaction was stirred at room temperature for 1 hour. The solvent was evaporated to dryness and the residue was suspended in dry DMF (25 ml) and treated with di(lH-imidazol- l-yl)methanethione (448 mg, 2.51 mmol). The reaction was stirred 4 hours at room temperature.
In a second flask, NaH (60% dispersion in mineral oil, 187 mg, 4.68 mmol) was added portionwise to a solution of bis(3- fluorophenyl)methanol (1.03 g, 4.68 mmol) in dry DMF (25 ml) at 0°C. The reaction was stirred at room temperature for 30 minutes and then it was added to the first flask.
The resulting mixture was stirred at room temperature overnight and then the reaction was portioned between Et2O and water. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/l and then DCM/MeOH= 75/25+0.5% TEA) to obtain (R)-O-bis(3-fluorophenyl)methyl quinuclidin-3- ylcarbamothioate (60 mg).
2- Preparation of (R)-3-((bis(3-fluorophenyl)methoxy)- carbonothioylamino)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-l- azoniabicyclo[2.2.2]octane chloride (compound 47)
Figure imgf000066_0001
To a solution of (R)-O-bis(3-fluorophenyl)methyl quinuclidin-3- ylcarbamothioate (60 mg, 0.15 mmol) in ethyl acetate (1 ml), 2-chloro-l- (thiophen-2-yl)ethanone (27.3 mg, 0.17 mmol) was added. The reaction was stirred at room temperature for 3 days. The solvent was evaporated and the residue was purified by flash chromatography (DCM/MeOH=75/25) to obtain (R)-3-((bis(3-fluorophenyl)methoxy)carbonothioylamino)- 1 -(2-0X0-2- (thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride (20 mg).
1H NMR (300 MHz, DMSO-d6 353K) δ ppm 9.74 (br. s., 1 H), 8.16 (dd, 1 H), 8.07 (dd, 1 H), 7.38 - 7.52 (m, 3 H), 7.33 (dd, 1 H), 7.20 - 7.30 (m, 4 H), 7.04 - 7.20 (m, 2 H), 4.97 (s, 2 H), 4.45 - 4.70 (m, 1 H), 4.13 - 4.35 (m, 1 H), 3.61 - 3.90 (m, 5 H), 2.32 - 2.46 (m, 2 H), 1.87 - 2.26 (m, 3 H);
LC-MS (ESI POS): 513.25 (M+).
EXAMPLE 22
Preparation of (3R)-l-benzyl-3-((bis(3-fluorophenyl)methoxy)- carbonylamino)-l-methylpyrrolidinium iodide (compound 49)
1- Preparation of (R)-bis(3-fluorophenyl)methyl 1-benzylpyrrolidin- 3-ylcarbamate (compound 48)
Figure imgf000067_0001
In a first flask, CDI (184 mg, 1.135 mmol) was added to a solution of (R)- l-benzylpyrrolidin-3 -amine (200 mg, 1.13 mmol) in dry DMF (20 ml) and the reaction was stirred at room temperature overnight.
In a second flask, bis(3-fluorophenyl)methanol (375 mg, 1.70 mmol) was dissolved in dry DMF (9 ml) and treated with sodium hydride (60% dispersion in mineral oil, 68.1 mg, 1.703 mmol) at 0°C. Ice-bath was removed and the reaction was stirred at room temperature for 20 minutes and then it was added to the first flask.
The resulting mixture was stirred at room temperature overnight and then portioned between Et2O and water. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=98/2) to give (R)-bis(3- fluorophenyl)methyl l-benzylpyrrolidin-3-ylcarbamate (300 mg).
2- Preparation of (3R)-l-benzyl-3-((bis(3-fluorophenyl)methoxy)- carbonylamino)-l-methylpyrrolidinium iodide (compound 49)
Figure imgf000068_0001
To a solution of (R)-bis(3-fluorophenyl)methyl l-benzylpyrrolidin-3- ylcarbamate (300 mg, 0.71 mmol) in EtOAc (9 ml), iodomethane (44.2 μΐ, 0.71 mmol) was added and the reaction was stirred at room temperature overnight. The solvent was then removed under vacuum and the residue was triturated with diethyl ether. The product was purified by flash chromatography (DCM/MeOH=99/l) and then by preparative HPLC to give (3R)-l-benzyl-3-((bis(3-fluorophenyl)methoxy)carbonylamino)-l- methylpyrrolidinium iodide (25 mg).
1H NMR (300 MHz, DMSO-<¾) δ ppm 8.08 (d, 1 H), 7.34 - 7.68 (m, 8 H), 7.03 - 7.34 (m, 5 H), 6.71 and 6.74 (s, 1 H), 4.56 and 4.62 (s, 2 H), 4.32 - 4.51 (m, 1 H), 3.33 - 4.05 (m, 4 H), 2.95 and 3.02 (s, 3 H), 2.56 - 2.67 (m, 1 H), 1.98 - 2.25 (m, 1 H);
LC-MS (ESI POS): 437.24 (M+). EXAMPLE 23
Preparation of 3-((bis(3-fluorophenyl)methoxy)carbonyl)-l-(2-oxo- 2-phenylethyl)-l-azoniabicyclo[2.2.2]octane bromide (compound 50)
Figure imgf000069_0001
Bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (95 mg, 0.27 mmol, prepared as in example 4) and 2-bromo-l -phenylethanone (58.2 mg, 0.29 mmol) were dissolved in acetonitrile (5 ml) and stirred at room temperature overnight. The solvent was evaporated and the resulting residue was purified by flash chromatography (DCM/MeOH=95/5 to 9/1) to obtain 3- ((bis(3-fluorophenyl)methoxy)carbonyl)-l-(2-oxo-2-phenylethyl)-l- azoniabicyclo[2.2.2]octane bromide (110 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 7.92 - 8.06 (m, 2 H), 7.71 - 7.82 (m, 1 H), 7.56 - 7.69 (m, 2 H), 7.30 - 7.52 (m, 6 H), 7.10 - 7.22 (m, 2 H), 6.93 (s, 1 H), 5.24 (s, 2 H), 4.03 - 4.21 (m, 1 H), 3.91 (t, 1 H), 3.59 - 3.82 (m, 4 H), 3.45 - 3.59 (m, 1 H), 2.64 - 2.71 (m, 1 H), 2.02 - 2.25 (m, 2 H), 1.83 - 2.02 (m, 1 H), 1.40 - 1.64 (m, 1 H);
LC-MS (ESI POS): 475.97 (M+).
The following compounds were prepared following the route described in Example 23 using the suitable alkylating agents instead of 2-bromo-l phenylethanone. These compounds were obtained as a racemic mixture. Table 5
Figure imgf000070_0001
(continued)
Figure imgf000071_0001
EXAMPLE 24
Preparation of 3-((bis(3-fluorophenyl)methoxy)carbonyl)-l-(2-oxo- 2-p-tolylethyl)-l-azoniabicyclo[2.2.2]octane bromide (compound 54)
Figure imgf000071_0002
Bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (95 mg, 0.27 mmol, prepared as in example 4) and 2-bromo-l-p-tolylethanone (62.3 mg, 0.29 mmol) were dissolved in acetonitrile (10 ml) and stirred at room temperature overnight. The solvent was evaporated and the residue was triturated with Et2O/EtOAc (1/1) and recovered by suction filtration to obtain 3-((bis(3-fluorophenyl)methoxy)carbonyl)-l-(2-oxo-2-p-tolylethyl)- l- azoniabicyclo[2.2.2]octane bromide (117.6 mg, racemic mixture). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82 - 7.97 (m, 2 H), 7.33 - 7.49 (m, 6 H), 7.30 - 7.37 (m, 2 H), 7.10 - 7.23 (m, 2 H), 6.93 (s, 1 H), 5.20 (s, 2 H), 4.13 (dd, 1 H), 3.83 - 3.97 (m, 1 H), 3.59 - 3.78 (m, 4 H), 3.48 - 3.59 (m, 1 H), 2.61 - 2.71 (m, 1 H), 2.42 (s, 3 H), 2.01 - 2.23 (m, 2 H), 1.85 - 2.01 (m, 1 H), 1.43 - 1.65 (m, 1 H);
LC-MS (ESI POS): 490.15 (M+).
The following compounds were prepared following the route described in Example 24 using the suitable alkylating agents instead of 2-bromo-l-p- tolylethanone. These compounds were obtained as a racemic mixture.
Table 6
Figure imgf000072_0001
(continued)
Figure imgf000073_0001
EXAMPLE 25
Preparation of 3-((bis(3-fluorophenyl)methoxy)carbonyl)-l-(2-tert- butoxy-2-oxoethyl)-l-azoniabicyclo[2.2.2]octane chloride (compound 59)
Figure imgf000074_0001
Bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (70 mg, 0.20 mmol, prepared as in example 4) and tert-butyl 2-chloroacetate (31 μΐ, 0.21 mmol) were dissolved in acetonitrile (3 ml) and stirred at room temperature overnight. Tert-butyl 2-chloroacetate (28 μΐ, 0.20 mmol) was added again and mixture was stirred for additional 24 hours. Acetonitrile was evaporated and the resulting crude compound was triturated from Et2O and filtered to obtain 3-((bis(3-fluorophenyl)methoxy)carbonyl)- l-(2-tert-butoxy- 2-oxoethyl)-l-azoniabicyclo[2.2.2]octane chloride (42.4 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 7.26 - 7.56 (m, 6 H), 7.09 - 7.23 (m, 2 H), 6.91 (s, 1 H), 4.3 1 (s, 2 H), 4.03 (dd, 1 H), 3.80 (t, 1 H), 3.38 - 3.71 (m, 5 H), 2.59 - 2.69 (m, 1 H), 1.77 - 2.17 (m, 4 H), 1.48 (s, 9 H);
LC-MS (ESI POS): 472.19 (M+). EXAMPLE 26
Preparation of 3-((bis(3-fluorophenyl)methoxy)carbonyl)-l-(2-oxo- 2-(pyridin-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (compound 60)
Figure imgf000075_0001
Bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (70 mg, 0.20 mmol, prepared as in example 4) and 2-bromo-l-(pyridin-2-yl)ethanone hydrobromide (60.5 mg, 0.21 mmol) were suspended in acetonitrile (5 ml) and stirred at room temperature for 16h. TEA (27 μΐ, 0.20 mmol) was added and the resulting clear solution was stirred at room temperature overnight. The volatiles were evaporated and the residue was first purified by flash chromatography (DCM/MeOH= 9/1) and then by preparative HPLC to obtain 3-((bis(3-fluorophenyl)methoxy)carbonyl)-l-(2-oxo-2-(pyridin-2-yl)ethyl)- l- azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (60.3 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.77 (m, 1 H) 7.99 - 8.21 (m, 2 H) 7.68 - 7.89 (m, 1 H) 7.27 - 7.56 (m, 6 H) 7.04 - 7.25 (m, 2 H) 6.93 (s, 1 H) 5.32 (s, 2 H) 4.17 (m, 1 H) 3.94 (t, 1 H) 3.71 (m, 4 H) 3.54 (t, 1 H) 2.61 - 2.71 (m, 1 H) 2.02 - 2.24 (m, 2 H) 1.83 - 2.01 (m, 1 H) 1.46 - 1.66 (m, 1 H);
LC-MS (ESI POS): 477.08 (M+). EXAMPLE 27
Preparation of 3-((bis(3-fluorophenyl)methoxy)carbonyl)-l-(2-(3- (ethoxycarbonyl)isoxazol-5-yl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octane bromide (compound 61)
Figure imgf000076_0001
Bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (86 mg, 0.24 mmol, prepared as in example 4) and ethyl 5-(2-bromoacetyl)isoxazole- 3-carboxylate (69.4 mg, 0.26 mmol) were dissolved in acetonitrile (3 ml) and stirred at room temperature overnight. The precipitated was recovered by suction filtration to obtain 3-((bis(3-fluorophenyl)methoxy)carbonyl)-l-(2-(3- (ethoxycarbonyl)isoxazol-5-yl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octane bromide (26 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 7.90 (s, 1 H), 7.23 - 7.52 (m, 6 H), 7.16 (td, 2 H), 6.92 (s, 1 H), 5.06 (s, 2 H), 4.43 (q, 2 H), 4.00 - 4.16 (m, 1 H), 3.81 - 3.97 (m, 1 H), 3.48 - 3.80 (m, 5 H), 2.65 - 2.71 (m, 1 H), 2.01 - 2.24 (m, 2 H), 1.78 - 2.01 (m, 1 H), 1.45 - 1.65 (m, 1 H), 1.35 (t, 3 H);
LC-MS (ESI POS): 539.16 (M+). EXAMPLE 28
Preparation of 3-((bis(3-fluorophenyl)methoxy)carbonyl)-l-(2-(2- fluorophenyl)-2-oxoethyl)-l-azoniabicyclo [2.2.2] octane bromide (compound 62)
Figure imgf000077_0001
Bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (90 mg, 0.25 mmol, prepared as in example 4) and 2-bromo- l-(2- fluorophenyl)ethanone (65.6 mg, 0.30 mmol) were dissolved in acetonitrile (4 ml) and stirred at room temperature overnight. Acetonitrile was evaporated and the residue was triturated with Et2O and filtered to obtain 3-((bis(3- fluorophenyl)methoxy)-carbonyl)-l-(2-(2-fluorophenyl)-2-oxoethyl)- l- azoniabicyclo[2.2.2]octane bromide (51.3 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 7.97 (td, 1 H), 7.72 - 7.87 (m, 1 H), 7.30 - 7.55 (m, 8 H), 7.10 - 7.23 (m, 2 H), 6.93 (s, 1 H), 5.06 (d, 2 H), 4.14 (dd, 1 H), 3.92 (t, 1 H), 3.60 - 3.82 (m, 4 H), 3.49 - 3.59 (m, 1 H), 2.64 - 2.71 (m, 1 H), 2.01 - 2.19 (m, 2 H), 1.82 - 2.01 (m, 1 H), 1.41 - 1.70 (m, 1 H);
LC-MS (ESI POS): 494.10 (M+).
The following compounds were prepared following the route described in Example 28 using the suitable alkylating agents instead of 2-bromo-l-(2- fluorophenyl)ethanone. These compounds were obtained as a racemic mixture. Table 7
Figure imgf000078_0001
EXAMPLE 29
Preparation of l-(2-(benzo[b]thiophen-5-yl)-2-oxoethyl)-3-((bis(3- fluorophenyl)methoxy)carbonyl)-l-azoniabicyclo[2.2.2]octane 2,2,2- trifluoroacetate (compound 65)
Figure imgf000079_0001
Bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (86 mg, 0.24 mmol, prepared as in example 4) and l-(benzo[b]thiophen-5-yl)-2- bromoethanone (67.5 mg, 0.26 mmol) were dissolved in acetonitrile (3 ml) and stirred at room temperature overnight. Acetonitrile was evaporated and the crude was first triturated with Et2O and then purified by preparative HPLC to obtain l-(2-(benzo[b]thiophen-5-yl)-2-oxoethyl)-3-((bis(3-fluorophenyl)- methoxy)carbonyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (83 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (d, 1 H), 8.25 (d, 1 H), 7.97 (d, 1 H), 7.93 (dd, 1 H), 7.66 (dd, 1 H), 7.30 - 7.53 (m, 6 H), 7.09 - 7.23 (m, 2 H), 6.94 (s, 1 H), 5.31 (s, 2 H), 4.17 (dd, 1 H), 3.94 (t, 1 H), 3.62 - 3.84 (m, 4 H), 3.47 - 3.62 (m, 1 H), 2.66 - 2.73 (m, 1 H), 2.02 - 2.24 (m, 2 H), 1.88 - 2.04 (m, 1 H), 1.40 - 1.69 (m, 1 H);
LC-MS (ESI POS): 532.09 (M+).
EXAMPLE 30
Preparation of l-benzyl-3-((bis(3-fluorophenyl)methoxy)carbonyl)- l-azoniabicyclo[2.2.2]octane bromide (compound 66)
Figure imgf000079_0002
To a solution of bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (90 mg, 0.25 mmol, prepared as in example 4) in EtOAc (3 ml), (bromomethyl)benzene (30.0 μΐ, 0.25 mmol) was added and the reaction was stirred at room temperature overnight. The solvent was removed and the crude was purified by flash chromatography (DCM/MeOH=95/5) to obtain 1 -benzyl - 3-((bis(3-fluorophenyl)methoxy)carbonyl)-l-azoniabicyclo[2.2.2]octane bromide (50 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 7.52 (s, 5 H), 7.42 (td, 2 H), 7.23 - 7.38 (m, 4 H), 7.08 - 7.19 (m, 2 H), 6.86 (s, 1 H), 4.53 (s, 2 H), 3.68 - 3.83 (m, 1 H), 3.56 - 3.68 (m, 1 H), 3.35 - 3.53 (m, 4 H), 3.13 - 3.27 (m, 1 H), 2.57 - 2.65 (m, 1 H), 1.91 - 2.18 (m, 2 H), 1.68 - 1.91 (m, 1 H), 1.36 - 1.57 (m, 1 H);
LC-MS (ESI POS): 448.23 (M+).
EXAMPLE 31
Preparation of 3-((l,2-diphenylethoxy)carbonyl)-l-(2-oxo-2- (thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (compound 67)
Figure imgf000080_0001
1,2-Diphenylethyl quinuclidine-3-carboxylate (68 mg, 0.20 mmol, prepared as in example 5) and 2-chloro- l-(thiophen-2-yl)ethanone (35.8 mg, 0.22 mmol) were dissolved in acetonitrile (4 ml) and stirred at room temperature for 64h. Acetonitrile was evaporated and the resulting crude was first purified by flash chromatography (DCM/MeOH=9/l) and then by preparative HPLC to obtain 3-((l,2-diphenylethoxy)carbonyl)-l-(2-oxo-2- (thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (44 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.14 - 8.26 (m, 1 H), 7.95 - 8.12 (m, 1 H), 7.10 - 7.59 (m, 11 H), 6.02 and 6.10 (dd, 1 H), 5.03 and 5.05 (s, 2 H), 3.90 - 4.06 (m, 1 H), 3.59 - 3.89 (m, 5 H), 2.98 - 3.33 (m, 3 H), 1.45 - 2.45 (m, 4 H), 0.83 - 1.31 (m, 1 H);
LC-MS (ESI POS): 460.18 (M+).
EXAMPLE 32
Preparation of 3-((bis(4-chlorophenyl)methoxy)carbonyl)-l-(2-oxo- 2-(thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride (compound
Figure imgf000081_0001
To a solution of bis(4-chlorophenyl)methyl quinuclidine-3-carboxylate (45 mg, 0.1 1 mmol, prepared as in example 6) in EtOAc (1.6 ml), 2-chloro-l- (thiophen-2-yl)ethanone (20.0 mg, 0.13 mmol) was added. The reaction was stirred at room temperature for 16h. Solvent was removed and the crude was purified by preparative HPLC to afford 3-((bis(4-chlorophenyl)methoxy)- carbonyl)-l-(2-oxo-2-(thiophen-2-yl)ethyl)- l-azoniabicyclo[2.2.2]octane chloride (16 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.21 (dd, 1 H), 8.09 (dd, 1 H),
7.40 - 7.57 (m, 8 H), 7.35 (dd, 1 H), 6.92 (s, 1 H), 5.09 (s, 2 H), 4.01 - 4.16 (m, 1 H), 3.80 - 4.00 (m, 1 H), 3.54 - 3.78 (m, 3 H), 3.47 - 3.54 (m, 2 H), 2.59 - 2.69 (m, 1 H), 2.01 - 2.21 (m, 2 H), 1.82 - 2.01 (m, 1 H), 1.41 - 1.64 (m, 1 H);
LC-MS (ESI POS): 514.02 (M+). EXAMPLE 33
Preparation of 3-((bis(4-fluorophenyl)methoxy)carbonyl)-l-(2-oxo- 2-(thiophen-2-yl)ethyl)-l-azoniabicyclo [2.2.2] octane 2,2,2-trifluoroacetate (compound 70)
1- Preparation of bis(4-fluorophenyl)methyl quinuclidine-3- carboxylate (compound 69)
Figure imgf000082_0001
Quinuclidine-3-carboxylic acid hydrochloride (96 mg, 0.50 mmol), EDC (131 mg, 0.68 mmol), and HOBT (104 mg, 0.68 mmol) were suspended in dry DMF (5 ml). Bis(4-fluorophenyl)methanol (100 mg, 0.45 mmol) and DIPEA (278 μΐ, 1.59 mmol) were added and the mixture was stirred at room temperature for 24h.
Then, quinuclidine-3-carboxylic acid hydrochloride (43.5 mg, 0.23 mmol), EDC (43.5 mg, 0.23 mmol), HOBT (34.8 mg, 0.23 mmol) and DIPEA (79 μΐ, 0.45 mmol) were added again and stirring was continued for 4 days.
Finally quinuclidine-3-carboxylic acid hydrochloride (43.5 mg, 0.23 mmol), EDC (43.5 mg, 0.23 mmol), and DIPEA (79 μΐ, 0.45 mmol) were added and the suspension was stirred for additional 24h. The reaction was portioned between sat. NaHCO3 and Et2O, the organic layer was separated, washed again with sat. NaHCO3 and then brine. The organic phase was dried over Na2SO4, filtered and evaporated to afford bis(4-fluorophenyl)methyl quinuclidine-3-carboxylate (51 mg, racemic mixture). The compound was used as such in the next step. 2- Preparation of 3-((bis(4-fluorophenyl)methoxy)carbonyl)-l-(2- oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo [2.2.2] octane 2,2,2- trifluoroacetate (compound 70)
Figure imgf000083_0001
To a solution of bis(4-fluorophenyl)methyl quinuclidine-3-carboxylate (51 mg, 0.14 mmol) in acetonitrile (5 ml), 2-bromo- l-(thiophen-2-yl)ethanone (32.2 mg, 0.16 mmol) was added and the reaction was stirred at room temperature for 15h. The solvent was evaporated and the resulting crude was purified by preparative HPLC to obtain 3-((bis(4-fluorophenyl)methoxy)- carbonyl)-l-(2-oxo-2-(thiophen-2-yl)ethyl)- l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (73.4 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.21 (dd, 1 H) 8.08 (dd, 1 H) 7.43 - 7.60 (m, 4 H) 7.35 (dd, 1 H) 7.15 - 7.28 (m, 4 H) 6.93 (s, 1 H) 5.08 (s, 2 H) 3.99 - 4.17 (m, 1 H) 3.79 - 3.94 (m, 1 H) 3.62 - 3.77 (m, 5 H) 2.56 - 2.66 (m, 1 H) 1.77 - 2.20 (m, 3 H) 1.31 - 1.67 (m, 1 H);
LC-MS (ESI POS): 482.17 (M+).
EXAMPLE 34
Preparation of 3-(benzhydryloxycarbonyl)-l-(2-oxo-2-(thiophen-2- yl)ethyl)-l-azoniabicyclo [2.2.2] octane 2,2,2-trifluoroacetate (compound 72)
1- Preparation of benzhydryl quinuclidine-3-carboxylate
(compound 71)
Figure imgf000084_0001
Quinuclidine-3-carboxylic acid hydrochloride (114 mg, 0.60 mmol), EDC (156 mg, 0.81 mmol), and HOBT (125 mg, 0.81 mmol) were suspended in dry DMF (5 ml). Diphenylmethanol (100 mg, 0.54 mmol) and DIPEA (332 μΐ, 1.90 mmol) were added and the mixture was stirred at room temperature for 24h. Quinuclidine-3-carboxylic acid hydrochloride (52.0 mg, 0.27 mmol), EDC (52.0 mg, 0.27 mmol), and HOBT (41.6 mg, 0.27 mmol) followed by DIPEA (95 μΐ, 0.54 mmol) were added again and the mixture was stirred for 4 days. The reaction was then portioned between sat. NaHCO3 and Et2O. The organic layer was separated, washed again with sat. NaHCO3, water and brine, dried over Na2SO4, filtered and evaporated to afford benzhydryl quinuclidine-3-carboxylate (54 mg, racemic mixture). The compound was used as such in the next step.
2- Preparation of 3-(benzhydryloxycarbonyl)-l-(2-oxo-2-(thiophen-
2-yl)ethyl)-l-azoniabicyclo [2.2.2] octane 2,2,2-trifluoroacetate (compound 72)
Figure imgf000084_0002
To a solution of benzhydryl quinuclidine-3-carboxylate (54 mg, 0.17 mmol) in acetonitrile (5 ml), 2-bromo- l-(thiophen-2-yl)ethanone (37.9 mg, 0.18 mmol) was added and the reaction was stirred at room temperature for 15h. The solvent was evaporated and the resulting crude was first purified by preparative HPLC and then by flash chromatography (DCM/MeOH=95/5 to 9/1) to obtain 3-(benzhydryloxycarbonyl)-l-(2-oxo-2- (thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (53.8 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.20 (dd, 1 H) 8.09 (dd, 1 H) 7.23 - 7.52 (m, 1 1 H) 6.90 (s, 1 H) 5.09 (s, 2 H) 4.04 - 4.16 (m, 1 H) 3.79 - 3.95 (m, 1 H) 3.56 - 3.79 (m, 4 H) 3.33 - 3.56 (m, 1 H) 2.57 - 2.70 (m, 1 H) 1.99 - 2.24 (m, 2 H) 1.76 - 1.99 (m, 1 H) 1.40 - 1.68 (m, 1 H);
LC-MS (ESI POS): 446.15 (M+).
EXAMPLE 35
Preparation of 3-(((4-methoxyphenyl)(phenyl)methoxy)carbonyl)-l- (2-oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride (compound 74)
1- Preparation of (4-methoxyphenyl)(phenyl)methyl quinuclidine-3- carboxylate (compound 73)
Figure imgf000085_0001
Quinuclidine-3-carboxylic acid hydrochloride (150 mg, 0.78 mmol), EDC (225 mg, 1.17 mmol) and HOBT (180 mg, 1.17 mmol) were dissolved in dry THF (7.5 ml). (4-Methoxyphenyl)(phenyl)methanol (184 mg, 0.86 mmol) and TEA (382 μΐ, 2.74 mmol) were added, and the resulting reaction was stirred at room temperature for four days. THF was removed under vacuum, and the crude residue was partitioned between EtOAc and water. The organic phase was washed with a sat. NaHCO3, dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (EtOAc/MeOH=8/2 to EtOAc/MeOH=7:3 + 1% NH4OH) to give (4-methoxyphenyl)(phenyl)methyl quinuclidine-3-carboxylate (37 mg, mixture of diastereoisomers). The compound was used as such in the next step.
2- Preparation of 3-(((4-methoxyphenyl)-(phenyl)methoxy)- carbonyl)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride (compound 74)
Figure imgf000086_0001
To a solution of (4-methoxyphenyl)(phenyl)methyl quinuclidine-3- carboxylate (37 mg, 0.10 mmol) in EtOAc (1.5 ml), 2-chloro- l-(thiophen-2- yl)ethanone (19 mg, 0.12 mmol) was added. Acetonitrile was added till complete dissolution and the reaction was stirred at room temperature overnight. The organic solvents were removed under vacuum and the residue was purified by flash chromatography (DCM/MeOH=9/l) to obtain 3-(((4- methoxyphenyl)(phenyl)methoxy)carbonyl)- l-(2-oxo-2-(thiophen-2-yl)ethyl)- l-azoniabicyclo[2.2.2]octane chloride (16 mg, mixture of diastereoisomers).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.21 (dd, 1 H), 8.09 (dd, 1 H), 7.24 - 7.51 (m, 8 H), 6.89 - 6.98 (m, 2 H), 6.86 (s, 1 H), 5.09 (s, 2 H), 4.02 - 4.20 (m, 1 H), 3.80 - 3.94 (m, 1 H), 3.74 (s, 3 H), 3.36 - 3.73 (m, 5 H), 2.56 - 2.66 (m, 1 H), 1.79 - 2.23 (m, 3 H), 1.36 - 1.67 (m, 1 H);
LC-MS (ESI POS): 476.17 (M+). EXAMPLE 36
Preparation of 3-(((2-chlorophenyl)(4-chlorophenyl)methoxy)- carbonyl)-l-(2-oxo-2-(thiophen-3-yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (compound 76)
1- Preparation of (2-chlorophenyl)(4-chlorophenyl)methyl quinuclidine-3-carboxylate (compound 75)
Figure imgf000087_0001
Quinuclidine-3-carboxylic acid hydrochloride (0.1 g, 0.52 mmol), EDC (150 mg, 0.78 mmol) and HOBT (120 mg, 0.78 mmol) were dissolved in dry THF (3 ml). (2-Chlorophenyl)(4-chlorophenyl)methanol (145 mg, 0.57 mmol) was dissolved in dry THF (2ml) and then added to the reaction mixture. Triethylamine (253 μΐ, 1.83 mmol) was added and the resulting reaction was stirred at room temperature overnight. The mixture was evaporated and the crude was taken up with EtOAc and washed with water and brine. The organic phase was separated, dried (sodium sulfate), filtered and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH=95/5) to afford (2-chlorophenyl)(4-chlorophenyl)methyl quinuclidine-3-carboxylate (40 mg, mixture of diastereoisomers). The compound was used as such in the next step. 2- Preparation of 3-(((2-chlorophenyl)(4-chlorophenyl)methoxy)- carbonyl)-l-(2-oxo-2-(thiophen-3-yl)ethyl)-l-azoniabicyclo [2.2.2] octane 2,2,2-trifluoroacetate (compound 76)
Figure imgf000088_0001
To a solution of (2-chlorophenyl)(4-chlorophenyl)methyl quinuclidine-3- carboxylate (40 mg, 0.10 mmol) in EtOAc (1.5 ml), 2-bromo-l-(thiophen-3- yl)ethanone (23 mg, 0.11 mmol) was added. Acetonitrile was added till complete dissolution and the reaction was stirred at room temperature overnight. The organic solvents were evaporated under vacuum, and the crude residue was purified by preparative HPLC to obtain 3-(((2-chlorophenyl)(4- chlorophenyl)methoxy)carbonyl)- 1 -(2-oxo-2-(thiophen-3 -yl)ethyl)- 1 - azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (28.6 mg, mixture of diastereoisomers).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.62 (dd, 1 H) 7.74 (dd, 1 H)
7.56 (dd, 1 H) 7.35 - 7.66 (m, 8 H) 7.12 (s, 1 H) 5.05 (s, 2 H) 4.09 (dd, 1 H) 3.87 (t, 1 H) 3.59 - 3.75 (m, 5 H) 2.54 - 2.64 (m, 1 H) 1.86 - 2.20 (m, 3 H) 1.43 - 1.73 (m, 1 H);
LC-MS (ESI POS): 514.08 (M+).
EXAMPLE 37
Preparation of 3-(((3,4-difluorophenyl)(phenyl)methoxy)carbonyl)- l-(2-oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo [2.2.2] octane chloride (compound 78)
1- Preparation of (3,4-difluorophenyl)(phenyl)methyl quinuclidine- 3-carboxylate (compound 77)
Figure imgf000089_0001
Quinuclidine-3-carboxylic acid hydrochloride (80 mg, 0.42 mmol), EDC (120 mg, 0.62 mmol) and HOBT (96 mg, 0.62 mmol) were dissolved in dry THF (3 ml). (3,4-Dif uorophenyl)(phenyl)methanol (101 mg, 0.46 mmol) was dissolved in dry THF (2 ml) and then added to the reaction mixture. Triethylamine (203 μΐ, 1.46 mmol) was finally added and the resulting reaction was stirred at room temperature overnight. The volatiles were evaporated and the crude was taken up with EtOAc and washed with water and then with sat. NaHCO3. The organic phase was dried over sodium sulfate, filtered and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH=9/l) to obtain (3,4-difluorophenyl)(phenyl)- methyl quinuclidine-3-carboxylate (65 mg, mixture of diastereoisomers).
2- Preparation of 3-(((3,4-difluorophenyl)(phenyl)- methoxy)carbonyl)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo- [2.2.2]octane chloride (compound 78)
Figure imgf000089_0002
To a solution of (3,4-difluorophenyl)(phenyl)methyl quinuclidine-3- carboxylate (65 mg, 0.18 mmol) in ethyl acetate (3 ml), 2-chloro- l-(thiophen- 2-yl)ethanone (29.2 mg, 0.18 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was taken up with diethyl ether and filtered to give 3-(((3,4- difluorophenyl)(phenyl)methoxy)carbonyl)- l-(2-oxo-2-(thiophen-2-yl)ethyl)- l-azoniabicyclo[2.2.2]octane chloride (20 mg, mixture of diastereoisomers).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.21 (d, 1 H), 8.11 (d, 1 H), 7.52
- 7.71 (m, 1 H), 7.18 - 7.52 (m, 8 H), 6.90 (s, 1 H), 5.14 (s, 2 H), 3.98 - 4.19 (m, 1 H), 3.82 - 3.98 (m, 1 H), 3.41 - 3.82 (m, 5 H), 2.59 - 2.69 (m, 1 H), 1.40
- 2.21 (m, 4 H);
LC-MS (ESI POS): 482.17 (M+).
EXAMPLE 38
Preparation of 3-((3-fluorobenzyloxy)carbonyl)-l-(2-oxo-2- (thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (compound 80)
1- Preparation of 3-fluorobenzyl quinuclidine-3-carboxylate
(compound 79)
Figure imgf000090_0001
Quinuclidine-3-carboxylic acid hydrochloride (95 mg, 0.50 mmol), EDC (143 mg, 0.74 mmol), HOBT (114 mg, 0.74 mmol) and triethylamine (242 μΐ, 1.73 mmol) were dissolved in dry THF (5 ml). (3-Fluorophenyl)methanol (68.8 mg, 0.54 mmol) was dissolved in dry THF (2 ml) and added to the reaction mixture. The resulting reaction was stirred at room temperature overnight. The volatiles were evaporated and the crude was taken up with EtOAc and washed with water and then with sat. NaHCO3. The organic phase was separated, dried over sodium sulfate, filtered and evaporated under vacuum to obtain 3-fluorobenzyl quinuclidine-3-carboxylate (120 mg, racemic mixture). The compound was used in the next step without any further purification.
2- Preparation of 3-((3-fluorobenzyloxy)carbonyl)-l-(2-oxo-2- (thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (compound 80)
Figure imgf000091_0001
2-Chloro-l-(thiophen-2-yl)ethanone (67 mg, 0.42 mmol) was added to a solution of 3-fluorobenzyl quinuclidine-3-carboxylate (100 mg, 0.38 mmol) in a mixture of EtOAc (1.2 ml) with some drops of DMF. The reaction was stirred at room temperature overnight. Then a second portion of 2-chloro- l- (thiophen-2-yl)ethanone (67 mg, 0.42 mmol) was added and the reaction stirred at room temperature for 3 hours. The solvent was removed and the residue was dissolved in acetonitrile and heated under microwave irradiation at 100°C for 2 hours. Acetonitrile was evaporated and the crude was triturated with Et2O and then purified by preparative HPLC to obtain 3-((3- fluorobenzyloxy)carbonyl)-l-(2-oxo-2-(thiophen-2-yl)ethyl)- l-azoniabicyclo- [2.2.2]octane 2,2,2-trifluoroacetate (70 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.21 (dd, 1 H), 8.09 (dd, 1 H),
7.45 (td, 1 H), 7.36 (dd, 1 H), 7.24 - 7.30 (m, 2 H), 7.1 1 - 7.23 (m, 1 H), 5.26 (d, 1 H), 5.20 (d, 1 H), 5.10 (s, 2 H), 4.10 (ddd, 1 H), 3.81 - 3.93 (m, 1 H), 3.57 - 3.76 (m, 4 H), 3.31 - 3.49 (m, 1 H), 2.54 - 2.61 (m, 1 H), 1.85 - 2.18 (m, 3 H), 1.63 - 1.85 (m, 1 H);
LC-MS (ESI POS): 388.27 (M+). EXAMPLE 39
Preparation of 3-((9H-fluoren-9-yloxy)carbonyl)-l-(2-oxo-2- (thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (compound 82)
1- Preparation of 9H-fluoren-9-yl quinuclidine-3-carboxylate (compound 81)
Figure imgf000092_0001
Quinuclidine-3-carboxylic acid hydrochloride (95 mg, 0.50 mmol), EDC (143 mg, 0.74 mmol), triethylamine (242 μΐ, 1.73 mmol) and HOBT (114 mg, 0.74 mmol) were dissolved in dry THF (5 ml). 9H-fluoren-9-ol (99 mg, 0.54 mmol) was dissolved in dry THF (2 ml) and then added to the reaction mixture. The resulting suspension was stirred at room temperature overnight. The mixture was evaporated and the crude taken up with EtOAc and washed sequentially with water and sat. NaHCO3. The organic phase was dried over sodium sulfate, filtered and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH=9/l) to afford 9H- fluoren-9-yl quinuclidine-3-carboxylate (102 mg, racemic mixture).
2- Preparation of 3-((9H-fluoren-9-yloxy)carbonyl)-l-(2-oxo-2- (thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (compound 82)
Figure imgf000092_0002
2-Chloro-l-(thiophen-2-yl)ethanone (55 mg, 0.344 mmol) was added to a solution of 9H-fluoren-9-yl quinuclidine-3-carboxylate (100 mg, 0.31 mmol) in acetonitrile (1ml). The reaction was stirred at room temperature overnight. 2-Chloro-l-(thiophen-2-yl)ethanone (55 mg, 0.34 mmol) was added again and the mixture stirred at room temperature for 3 hours. The solvent was removed and the residue was re-dissolved in acetonitrile and heated under microwave irradiation at 100°C for 3 hours. Acetonitrile was removed and the residue was triturated with Et2O and then purified by preparative HPLC to obtain 3-((9H- fluoren-9-yloxy)carbonyl)-l-(2-oxo-2-(thiophen-2-yl)ethyl)-l- azoniabicyclo[2.2.2]octane 2,2,2-trifluoroacetate (46 mg, racemic mixture).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.22 (dd, 1 H), 8.11 (dd, 1 H), 7.87 (d, 2 H), 7.55 - 7.65 (m, 2 H), 7.49 (t, 2 H), 7.3 1 - 7.42 (m, 3 H), 6.85 (s, 1 H), 5.12 (s, 2 H), 4.1 1 - 4.27 (m, 1 H), 3.85 - 3.96 (m, 1 H), 3.59 - 3.78 (m, 4 H), 3.35 - 3.52 (m, 1 H), 2.39 - 2.46 (m, 1 H), 1.82 - 2.13 (m, 4 H);
LC-MS (ESI POS): 444.30 (M+).
EXAMPLE 40
Preparation of 4-((bis(3-fluorophenyl)methoxy)carbonyl)-l-methyl- l-(2-oxo-2-(thiophen-2-yl)ethyl)piperidinium chloride (compound 84)
1- Preparation of bis(3-fluorophenyl)methyl l-methylpiperidine-4- carboxylate (compound 83)
Figure imgf000093_0001
l-Methylpiperidine-4-carboxylic acid hydrochloride (250 mg, 1.39 mmol), EDC (400 mg, 2.09 mmol) and HOBT (320 mg, 2.09 mmol) were dissolved in dry THF (10 ml). Bis(3-fluorophenyl)methanol (337 mg, 1.53 mmol) was dissolved in dry THF (4 ml) and then added to the reaction mixture. Triethylamine (679 μΐ, 4.87 mmol) was finally added and the resulting reaction was stirred at room temperature overnight. The reaction was evaporated and the residue was taken up with EtOAc and washed with water and sat.NaHCO3. The organic phase was dried over sodium sulfate, filtered and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH=9/l) to afford bis(3-fluorophenyl)methyl l-methylpiperidine-4-carboxylate (150 mg).
2- Preparation of 4-((bis(3-fluorophenyl)methoxy)carbonyl)-l-methyl- l-(2-oxo-2-(thiophen-2-yl)ethyl)piperidinium chloride (compound 84)
Figure imgf000094_0001
To a solution of bis(3-fluorophenyl)methyl l-methylpiperidine-4- carboxylate (150 mg, 0.43 mmol) in ethyl acetate (5 ml), 2-chloro-l- (thiophen-2-yl)ethanone (69.8 mg, 0.43 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was taken up in diethyl ether, filtered and purified by flash chromatography (DCM/MeOH=95/5) to obtain 4-((bis(3- fluorophenyl)methoxy)carbonyl)-l -methyl- l-(2-oxo-2-(thiophen-2- yl)ethyl)piperidinium chloride (18 mg).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.20 (d, 1 H), 8.14 (d, 1 H), 7.23 - 7.54 (m, 7 H), 7.04 - 7.23 (m, 2 H), 6.87 (s, 1 H), 5.24 (br. s., 2 H), 3.90 - 4.20 (m, 2 H), 3.44 - 3.60 (m, 2 H), 3.31 (br. s., 3 H), 2.80 - 3.00 (m, 1 H), 1.96 - 2.32 (m, 4 H);
LC-MS (ESI POS): 470.18 (M+).
EXAMPLE 41
Preparation of 4-((bis(3-fluorophenyl)methoxy)carbonyl)-l-methyl- l-(2-oxo-2-(thiophen-3-yl)ethyl)piperidinium bromide (compound 85)
Figure imgf000095_0001
2-Bromo-l-(thiophen-3-yl)ethanone (23.7 mg, 0.12 mmol) was added to a solution of bis(3-fluorophenyl)methyl l-methylpiperidine-4-carboxylate (40 mg, 0.12 mmol, prepared as in example 40) in EtOAc (3 ml). The reaction was stirred at room temperature overnight. The solvent was evaporated and crude was purified by preparative HPLC (eluent: CH3CN/H2O) to obtain 4-((bis(3-fluorophenyl)methoxy)carbonyl)-l -methyl- l-(2-oxo-2-(thiophen-3- yl)ethyl)piperidinium bromide (36.1 mg).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.63 - 8.71 (m, 1 H), 7.67 - 7.83 (m, 1 H), 7.50 - 7.62 (m, 1 H), 7.24 - 7.50 (m, 6 H), 7.01 - 7.24 (m, 2 H), 6.87 and 6.88 (s, 1 H), 5.17 and 5.20 (s, 2 H), 3.73 - 4.07 (m, 2 H), 3.39 - 3.71 (m, 2 H), 3.30 and 3.32 (s, 3 H), 2.79 - 3.05 (m, 1 H), 2.11 - 2.36 (m, 4 H);
LC-MS (ESI POS): 470.24 (M+).
EXAMPLE 42
Preparation of 4-((bis(3-fluorophenyl)methoxy)carbonyl)-l-methyl- l-(2-oxo-2-(thiazol-2-yl)ethyl)piperidinium bromide (compound 86)
Figure imgf000095_0002
To a solution of bis(3-fluorophenyl)methyl l-methylpiperidine-4- carboxylate (106 mg, 0.31 mmol, prepared as in example 40) in EtOAc (3 ml), 2-bromo-l-(thiazol-2-yl)ethanone (63.2 mg, 0.31 mmol) was added. The mixture was stirred at room temperature for 27h. The solvent was evaporated and the crude was triturated with Et2O and collected by filtration. The compound was purified by flash chromatography (DCM/MeOH=95/5 to 9/1) to obtain 4-((bis(3-fluorophenyl)methoxy)carbonyl)-l -methyl- l-(2-oxo-2- (thiazol-2-yl)ethyl)piperidinium bromide (120 mg).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.40 (d, 1 H), 8.26 (d, 1 H), 7.25 - 7.55 (m, 6 H), 7.02 - 7.25 (m, 2 H), 6.87 (s, 1 H), 5.32 and 5.34 (s, 1 H), 3.44 - 4.26 (m, 4 H), 3.32 (s, 3 H), 2.77 - 3.05 (m, 1 H), 2.00 - 2.43 (m, 4 H);
LC-MS (ESI POS): 471.15 (M+).
EXAMPLE 43
Preparation of (l r,4r)-4-((l,2-diphenylethoxy)carbonyl)-l-methyl-l- (2-oxo-2-phenylethyl)piperidinium bromide (compound 88a) and (ls,4s)- 4-((l,2-diphenylethoxy)carbonyl)-l-methyl-l-(2-oxo-2-phenylethyl)- piperidinium bromide (compound 88b).
Preparation of 1,2-diphenylethyl l-methylpiperidine-4-carboxylate
(compound 87)
Figure imgf000096_0001
Oxalyl dichloride (141 μΐ, 1.67 mmol) was added dropwise to a solution of l-methylpiperidine-4-carboxylic acid hydrochloride (300 mg, 1.67 mmol) in DCM (20 ml) and few drops of DMF (catalytic amount). The reaction was stirred at room temperature for 2 hours. The volatiles were removed under vacuum and the crude was taken up with pyridine (20 ml). 1,2-Diphenylethanol (331 mg, 1.67 mmol) was added and the resulting suspension was heated under microwave irradiation at 140°C for lh. Pyridine was removed under vacuum and the crude was purified by flash chromatography (DCM/MeOH=97/3 to 94/6) to obtain 1,2-diphenylethyl 1- methylpiperidine-4-carboxylate (200 mg).
2- Preparation of (lR,4R)-4-((l,2-diphenylethoxy)carbonyl)-l- methyl-l-(2-oxo-2-phenylethyl)piperidinium bromide (compound 88a) and (lS,4S)-4-((l,2-diphenylethoxy)carbonyl)-l-methyl-l-(2-oxo-2- phenylethyl)piperidinium bromide (compound 88b)
Figure imgf000097_0001
Compound 88a Compound 88b
2-Bromo-l-phenylethanone (61.5 mg, 0.31 mmol) was added to a solution of 1,2-diphenylethyl l-methylpiperidine-4-carboxylate (100 mg, 0.31 mmol) in acetonitrile (5 ml). The reaction was stirred at room temperature overnight. The solvent was evaporated and the crude was purified by flash chromatography (DCM/MeOH=98/2), collecting first (lR,4R)-4- ((l,2-diphenylethoxy)carbonyl)-l -methyl- 1 -(2-0X0-2- phenylethyl)piperidinium bromide (82.3 mg, compound 64a) and then (lS,4S)-4-((l,2-diphenylethoxy)carbonyl)-l-methyl- l-(2-oxo-2- phenylethyl)piperidinium bromide (32.1 mg, compound 64b).
Compound 88a:
1H NMR (300 MHz, DMSO-d6) δ ppm 7.88 - 8.15 (m, 2 H), 7.77 (tt, 1 H), 7.50 - 7.69 (m, 2 H), 7.15 - 7.48 (m, 10 H), 5.98 (t, 1 H), 5.30 (s, 2 H), 3.44 - 3.84 (m, 4 H), 3.27 (s, 3 H), 3.10 - 3.20 (m, 2 H), 2.57 - 2.71 (m, 1 H), 1.89 - 2.18 (m, 4 H);
LC-MS (ESI POS): 442.15 (M+).
Compound 88b: 1H NMR (300 MHz, DMSO-d6) δ ppm 8.01 (m, 2 H), 7.66 - 7.83 (m, 1 H), 7.50 - 7.66 (m, 2 H), 7.12 - 7.36 (m, 10 H), 5.72 - 6.10 (m, 1 H), 5.25 (s, 2 H), 3.89 - 3.95 (m, 1 H), 3.79 - 3.86 (m, 1 H), 3.31 - 3.66 (m, 2 H), 3.26 (s, 3 H), 2.98 - 3.18 (m, 2 H), 2.65 - 2.71 (m, 1 H), 1.97 - 2.13 (m, 4 H);
LC-MS (ESI POS): 442.2 (M+).
EXAMPLE 44
Preparation of (lR,4R)-4-(((E)-l,2-diphenylvinyloxy)carbonyl)-l- methyl-l-(2-oxo-2-phenylethyl)piperidinium bromide (compound 90)
Preparation of (E)-l,2-diphenylvinyl l-methylpiperidine-4- carboxylate (compound 89)
Figure imgf000098_0001
Oxalyl dichloride (236 μΐ, 2.78 mmol) was added dropwise to a solution of l-methylpiperidine-4-carboxylic acid hydrochloride (500 mg, 2.78 mmol) in DCM (30 ml) and few drops of DMF (catalytic amount). The reaction was stirred at room temperature for 2 hours. The volatiles were removed under vacuum and the crude was taken up with pyridine (40 ml). 1,2-Diphenylethanone (546 mg, 2.78 mmol) was added and the resulting suspension was heated under microwave irradiation at 140°C for lh. Pyridine was removed under vacuum and the crude was purified by flash chromatography (DCM/MeOH=95/5) to obtain (E)-l,2-diphenylvinyl l-methylpiperidine-4-carboxylate (62 mg). Preparation of (lR,4R)-4-(((E)-l,2-diphenylvinyloxy)carbonyl)-l- methyl-l-(2-oxo-2-phenylethyl)piperidinium bromide (compound 90)
Figure imgf000099_0001
2-Bromo-l-phenylethanone (57.6 mg, 0.29 mmol) was added to a solution of (E)-l,2-diphenylvinyl l-methylpiperidine-4-carboxylate (62 mg, 0.19 mmol) in acetonitrile (3 ml). The reaction was stirred at room temperature overnight then the solvent was evaporated. The crude was purified by flash chromatography (DCM/MeOH=98/2) and then by flash chromatography (DCM/MeOH=99/l) to obtain (lR,4R)-4-(((E)- l,2- diphenylvinyloxy)carbonyl)- l -methyl- l-(2-oxo-2-phenylethyl)piperidinium bromide (18 mg).
1H NMR (300 MHz, DMSO-d6) δ ppm 7.96 - 8.08 (m, 2 H), 7.73 - 7.84 (m, 1 H), 7.60 - 7.70 (m, 4 H), 7.52 - 7.60 (m, 2 H), 7.38 - 7.50 (m, 5 H), 7.28 - 7.36 (m, 1 H), 7.06 (s, 1 H), 5.36 (s, 2 H), 3.77 - 3.95 (m, 2 H), 3.60 - 3.76 (m, 2 H), 3.36 (s, 3 H), 3.12 (tt, 1 H), 2.10 - 2.42 (m, 4 H);
LC-MS (ESI POS): 440.23 (M+).
EXAMPLE 45
Preparation of 4-((3-fluorobenzyloxy)carbonyl)-l-(2-oxo-2-
(thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride (compound 92) Preparation of 3-fluorobenzyl quinuclidine-4-carboxylate (compound 91)
Figure imgf000100_0001
A mixture of quinuclidine-4-carboxylic acid hydrochloride (100 mg, 0.52 mmol) and thionyl chloride (500 μΐ, 6.85 mmol) was refluxed for 2 hours. The reaction was cooled at room temperature and the solvent was accurately removed. The residue was suspended in dry DCM and treated with (3-fluorophenyl)methanol (65.8 mg, 0.52 mmol). The reaction was stirred at room temperature for 24 hours. The solvent was evaporated, the residue was dissolved in water (1 ml), basified with NaHCO3 and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated to obtain 3-fluorobenzyl quinuclidine-4-carboxylate (41 mg, 29.8 % yield), which was used in the next step without any further purification.
Preparation of 4-((3-fluorobenzyloxy)carbonyl)-l-(2-oxo-2-
(thiophen-2-yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride (compound 92)
Figure imgf000100_0002
To a solution of 3-fluorobenzyl quinuclidine-4-carboxylate (41 mg, 0.16 mmol) dissolved in EtOAc (2 ml), 2-chloro- l-(thiophen-2-yl)ethanone (20.0 mg, 0.12 mmol) was added. The reaction was stirred at room temperature for three days, then the precipitate was collected by suction filtration to obtain 4-((3-fluorobenzyloxy)carbonyl)-l-(2-oxo-2-(thiophen-2- yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride (30 mg, 45.4% yield).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.21 (dd, 1 H), 8.01 - 8.17 (m, 1 H), 7.39 - 7.58 (m, 1 H), 7.35 (dd, 1 H), 7.06 - 7.28 (m, 3 H), 5.18 (s, 2 H), 4.97 - 5.13 (m, 2 H), 3.68 - 3.87 (m, 6 H), 2.04 - 2.30 (m, 6 H);
LC-MS (ESI POS): 388.21 (M+).
EXAMPLE 46
Preparation of 3-(benzylthiocarbonyl)-l-(2-oxo-2-(thiophen-2- yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride (compound 94)
Preparation of S-benzyl quinuclidine-3-carbothioate (compound 93)
Figure imgf000101_0001
Quinuclidine-3-carboxylic acid hydrochloride (55 mg, 0.29 mmol), EDC (83 mg, 0.43 mmol) and HOBT (65.9 mg, 0.43 mmol) were dissolved in dry THF (5 ml) under nitrogen atmosphere. Triethylamine (140 μΐ, 1.00 mmol) and phenylmethanethiol (37.1 μΐ, 0.32 mmol) were dissolved in dry THF (2 ml) and then added to the reaction mixture. The resulting suspension was stirred at room temperature overnight. The mixture was evaporated and the crude partitioned between EtOAc and water. The organic phase was washed with saturated NaHCO3, dried over sodium sulfate, filtered and evaporated under vacuum to obtain S-benzyl quinuclidine-3-carbothioate (110 mg, crude), which was used in the next step without any further purification. 2- Preparation of 3-(benzylthiocarbonyl)-l-(2-oxo-2-(thiophen-2- yl)ethyl)-l-azoniabicyclo[2.2.2]octane chloride (compound 94)
Figure imgf000102_0001
2-Chloro-l-(thiophen-2-yl)ethanone (68.0 mg, 0.42 mmol) was added to a solution of S-benzyl quinuclidine-3-carbothioate (100 mg, 0.38 mmol) in acetonitrile (1 ml). The reaction was stirred at room temperature overnight, then a second portion of 2-chloro- l-(thiophen-2-yl)ethanone (68.0 mg, 0.42 mmol) was added and the reaction was stirred at room temperature for additional 3 hours. The solvent was removed in vacuo and the residue was dissolved in acetonitrile and heated under microwave irradiation at 100°C for 3 hours. Acetonitrile was removed and the residue was triturated with Et2O. The crude was then purified by a preparative HPLC (eluent: CH3CN/H2O) to obtain 3 -(benzylthiocarbonyl)- 1 -(2-oxo-2-(thiophen-2-yl)ethyl)- 1 - azoniabicyclo[2.2.2]octane chloride (8.9 mg, 5.5% yield).
1H NMR (300 MHz, DMSO-d6) δ ppm 8.17 (d, 1 H), 7.81 (d, 1 H), 7.24 - 7.42 (m, 5 H), 7.20 (dd, 1 H), 5.23 (s, 2 H), 4.24 - 4.33 (m, 2 H), 4.25 (d, 1 H), 4.19 (d, 1 H), 3.94 - 4.14 (m, 3 H), 3.71 - 3.87 (m, 1 H), 3.38 - 3.52 (m, 1 H), 2.52 - 2.67 (m, 1 H), 2.07 - 2.36 (m, 2 H), 1.81 - 2.07 (m, 2 H);
LC-MS (ESI POS): 396.29 (M+).
Legend
* NMR
s = singlet
d = doublet
t = triplet
q = quartet dd = doublet of doublets
m = multiplet
br = broad
Biological characterization
The interaction with M3 muscarinic receptors can be estimated by the results of in vitro studies which evaluated the M3/M2 binding assays, the potency of the test compounds and the offset of the inhibitory activity produced after washout of the antagonists in isolated guinea pig trachea and by the in vivo duration of action against acetylcholine-induced bronchospasm in the guinea pig.
EXAMPLE 47
M3/M2 Binding assays
CHO-K1 clone cells expressing the human M2 or M3- receptors (Swissprot P08172, P20309 respectively) were harvested in Ca++/Mg++ free phosphate-buffered saline and collected by centrifugation at 1500 rpm for 3 min. The pellets were resuspended in ice cold buffer A (15 mM Tris-HCl pH 7.4, 2 mM MgCl2, 0.3 mM EDTA, 1 mM EGTA) and homogenized by a PBI politron (setting 5 for 15 s). The crude membrane fraction was collected by two consecutive centrifugation steps at 40000 g for 20 min at 4°C, separated by a washing step in buffer A. The pellets obtained were finally resuspended in buffer B (75 mM Tris HC1 pH 7.4, 12.5mM MgCl2, 0.3 mM EDTA, 1 mM EGTA, 250 mM sucrose), and aliquots were stored at - 80°C.
The day of experiment, frozen membranes were resuspended in buffer C (50 mM Tris-HCl pH 7.4, 2.5 mM MgCl2, 1 mM EDTA). The non selective muscarinic radioligand [3H]-N-methyl scopolamine (Mol. Pharmacol. 45:899-907) was used to label the M2, and M3 binding sites. Binding experiments were performed in duplicate (ten point concentrations curves) in 96 well plates at radioligand concentration of 0.1-0.3 nM. The non specific binding was determined in the presence of cold N-methyl scopolamine 10 μΜ. Samples (final volume 0.75 ml) were incubated at room temperature for 60 min for M2 and 90 min for M3 binding assay. The reaction was terminated by rapid filtration through GF/B Unifilter plates and two washes (0.75 ml) with cold buffer C using a Packard Filtermate Harvester. Radioactivity on the filters was measured by a microplate scintillation counter TriCarb 2500 (PerkinElmer).
The values of inhibitory M3 activity tested on compounds are comprised between 0.265 and 1514 nM.
EXAMPLE 48
In vitro interaction with the M3 receptors
The potency of the antagonist activity in isolated guinea pig trachea was investigated following a method previously described by Haddad EB et al. in Br J Pharmacol 127, 413-420, 1999, with few modifications.
A cumulative concentration-response curve to test antagonists was constructed on preparations precontracted by carbachol, until a complete inhibition of smooth muscle tone was achieved. The concentration of antagonist producing a 50% reversal of carbachol-induced tonic contraction (IC50) was taken as a measure of its potency in this bioassay.
In the experiments aiming at assessing the offset of the inhibitory effects produced by test compounds, the minimal concentration of the test compounds known to produce a maximal inhibitory effect was administered to carbachol-precontracted preparations. As soon as the tonic contraction was completely reversed, the organ bath solution was renewed and preparations were thoroughly washed with fresh Krebs solution. Carbachol (0.3 μΜ) was administered again (at 30 min interval between washout and next administration) during the next 4 hours.
After the administration of carbachol, the inhibitory effects of the compounds of the invention, administered at a concentration of 10 nM, were expressed as percentage of the recovery of the contracting response to carbachol. The percentage of recovery four hours after the washout was lower than 50%.
EXAMPLE 49
In vivo studies
The in vivo tests on acetylcholine-induced bronchospasm in guinea pig were performed according to H. Konzett H and Rossler F Arch Exp Path Pharmacol 195, 71-74, 1940. Aqueous solutions of the test compounds were instilled intratr ache ally in anaesthetised mechanically ventilated guinea pigs. Bronchial response to intravenous acetylcholine challenge was determined before and after drug administration and changes in pulmonary resistance at several time-points were expressed as percent of inhibition of bronchospasm.
The bronchodilator activity of the tested compounds persisted unchanged up to 24 hours after the administration.
EXAMPLE 50
Lung stability
Firstly, fresh rat lungs (previously, washed in saline) are homogenized in Amm. Formiate Buffer 20mM. In order to demonstrate that the compounds are degraded, stability in lung homogenate at 1 and 5 hours was tested for the compound of the invention. Briefly ΙΟμΙ of a stock solution 250 μΜ of the compound in acetonitrile were added to 1ml of lung horn, and samples were incubated at 37°C. Lung 1ιοηι.(50μΕ) was taken after 0, 1 and 5 hours of incubation and added to 200μ1 of acetonitrile with addition of verapamil as internal standard (250ng/ml). Samples were analysed by HPLC-MS/MS analysis.
Lung stability is calculated as percentage remaining after 1 and 5 hours by dividing the peak area at 1 or 5 hours by the area of the peak at time 0.
More than 79% of tested compounds could be still detected after 1 hour of incubation and more than 57% after 5 hours, indicating these compounds are stable in presence of homogenated lung.

Claims

1. A compound of general formula (I)
Figure imgf000106_0001
(I)
wherein:
X may be O or S;
X' may be O or S;
Y may be NH or absent;
Ri is selected from the group consisting of aryl, heteroaryl,
Figure imgf000106_0002
alkyl, heteroaryl(C1-C6)alkyl and a group of formula (a) or (b)
Figure imgf000106_0003
(a) (b)
wherein
R3 and R4 are the same or different and may be independently H or are selected from the group consisting of (C3-C8)cycloalkyl, aryl,
Figure imgf000106_0004
alkyl, heteroaryl and heteroaryl(C1-C6)alkyl, which may be optionally substituted by one or more substituents selected from the group consisting of halogen atoms, OH,
Figure imgf000106_0005
(C1-C6)alkoxy, oxo (=O), -SH, -NO2, -CN, -CONH2, -COOH, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulfanyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl and (C1-C6)alkyl or, when R3 and R4 are both independently aryl or heteroaryl they may be linked to each other through a (CH2)r with r =0-2, to form a tricyclic ring system wherein any of the methylene (CH2)r groups may be optionally replaced by a heteroatom or heteroaromatic group selected from O, S, N and NH, and with the proviso that R3 and R4 are not simultaneously H;
R2 is a group of formula (c) or (d):
Figure imgf000107_0001
(c) (d)
wherein
m = 1, 2 or 3 ;
n = 1, 2 or 3 ;
A" is a physiologically acceptable
R5 is a group of formula (e):
-(CH2)P-P- (CH2)q-W
(e)
wherein
p is 0 or an integer from 1 to 4;
q is 0 or an integer from 1 to 4;
P is absent or is selected from the group consisting of -O-, -S-, -S(O)-, -S(O2)-, -C(O)-, -CO(O)-, -N(R6)-, -CH=CH-, -N(R6)(SO2)-, -N(R6)CO(O)-, -N(R6)C(O)-, -SO2N(R6)-, -CO(O)N(R6)- and -C(O)N(R6)-;
W is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl and heteroaryl, optionally substituted by one or more substituents selected from the group consisting of halogen atoms, -OH, oxo (=O), -SH, -NO2, -N(R6)2, - CN, -CON(R6)2, -COOH, -NHCOR6, -CO2R6, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulfanyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C!-C6)alkyl, (C1-C6)alkoxy, aryl and heteroaryl;
R6 is, independently in each occurrence, H or is selected from the group consisting of (C1-C6)alkyl,
Figure imgf000108_0001
(C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, heteroaryl and aryl, optionally substituted by one or more substituents selected from the group consisting of halogen atoms, -OH, oxo (=O), -SH, -NO2, -CN, -CONH2, -COOH, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulfanyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl,
(C3-C8)cycloalkyl, (C!-C6)alkyl and (C1-C6)alkoxy;
and pharmaceutically acceptable salts thereof.
2. A compound of general formula (IA) according to claim 1
Figure imgf000108_0002
(IA)
wherein Rx is a group of formula (a), wherein R3 and R4 are the same or different and are H or selected from the group consisting of aryl and heteroaryl, which may be optionally substituted by one or more substituents selected from the group consisting of halogen atoms, (C1-C6)alkoxy and (Ci- C6)haloalkyl, R2 is a group of formula (c) or (d)
Figure imgf000108_0003
(c) (d)
wherein n=m= l and R5 is a group of formula (e) wherein p is 0, 1, 2 or 3, P is absent or is selected from the group consisting of -O-, -C(O)- and -CON(H)-, q is 0, 1 or 2 and W is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, aryl and heteroaryl optionally substituted by one or more substituents selected from the group consisting of halogen atoms, OH, CN, (Ci-C6)alkyl and (C1-C6)alkoxy.
3. A compound of general formula (I) or (IA) according to claims 1 or 2, wherein Rx is selected from bis(3-fluorophenyl)methyl, benzhydryl, bis(4- fluorophenyl)methyl, (4-methoxyphenyl)(phenyl)methyl, -(2-fluorophenyl)(4- fluorophenyl)methyl), (3,4-difluorophenyl)(phenyl)-methyl, (4- (trifluoromethyl)phenyl)methyl, (2-chlorophenyl)(4-chlorophenyl)methyl and thiophen-2-ylmethyl and R2 is selected from (2-oxo-2-(thiophen-3-yl)ethyl)- l- azoniabicyclo[2.2.2]octanyl, (2-(4-chlorophenyl)-2-oxoethyl)- l-azonia- bicyclo[2.2.2]octanyl, (2-oxo-2-p-tolylethyl)- l -azoniabicyclo [2.2.2] octanyl, (2-(4-fluorophenyl)-2-oxoethyl)-l-azoniabicyclo[2.2.2]octanyl, (2-(3- fluorophenyl)-2-oxoethyl)- 1 -azoniabicyclo [2.2.2] octanyl, (2-(2-fluorophenyl)- 2-oxoethyl)-l-azoniabicyclo[2.2.2]octanyl, (2-(4-methoxyphenyl)-2- oxoethyl)-l -azoniabicyclo [2.2.2] octanyl, (2-(4-hydroxyphenyl)-2-oxoethyl)-l- azoniabicy clo [2.2.2] octanyl, (bis(3 -fluorophenyl)methoxy)-carbonylamino)- 1 - azoniabicyclo [2.2.2] octanyl, (2-(5-chlorothiophen-2-yl)-2-oxoethyl)-l- azoniabicyclo[2.2.2]octanyl, (2-oxo-2-(thiazol-2-yl)ethyl)-l-azoniabicyclo- [2.2.2] octanyl, (2-oxopropyl)-l-azoniabicyclo-[2.2.2]octanyl, (3-methylbut-2- enyl)-l-azoniabicyclo[2.2.2]octanyl, benzyl- 1 -azoniabicyclo [2.2.2] octanyl, (3-phenoxypropyl)-l-azoniabicyclo-[2.2.2]octanyl, (2-(5-cyanothiophen-2-yl)- 2-oxoethyl)-l-azoniabicyclo-[2.2.2]octanyl, (2-oxo-2-(pyridin-2-yl)ethyl)-l- azoniabicyclo[2.2.2]-octanyl, (2-(isoxazol-3-ylamino)-2-oxoethyl)-l- azoniabicyclo[2.2.2]-octanyl, (2-oxo-2-(thiophen-2-yl)ethyl)-l-azoniabicyclo- [2.2.2] octanyl, (2-oxo-2-phenylethyl)-l-azoniabicyclo[2.2.2]octanyl, (2- phenoxyethyl)- l-azoniabicyclo[2.2.2]octanyl, (2,3-dihydrobenzofuran-5- yl)ethyl)-l-azoniabicyclo[2.2.2]octanyl, (4-fluorophenethyl)- l-azoniabicyclo- [2.2.2]-octanyl and benzyl-methylpyrrolidinyl.
4. A compound of general formula (IB) according to claim 1
Figure imgf000110_0001
(IB)
wherein Rx is aryl or a group of formula (a) or (b) wherein R3 and R4 are the same or different and are H or selected from the group consisting of aryl, aryl(C1-C6)alkyl and heteroaryl, which may be optionally substituted by one or more substituents selected from the group consisting of halogen atoms, (C1-C6)alkoxy and (C1-C6)haloalkyl or when R3 and R4 are both independently aryl or heteroaryl they may be linked to each other through a (CH2)r with r =0-2, to form a tricyclic ring system wherein any of the methylene (CH2)r groups may be substituted by a heteroatom or heteroaromatic group selected from O, S, N and NH and with the proviso that R3 and R4 are not simultaneously H, R2 is a group of formula (c) or (d)
Figure imgf000110_0002
(c) (d)
wherein n= l or 2, m= l and R5 is a group of formula (e), wherein p=l or 3, P is absent or is selected from the group consisting of O, CO and CO(O), q= l and W is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, aryl, heteroaryl optionally substituted by one or more substituents selected from the group consisting of halogen atoms, OH, CN, (C1-C6)alkyl, (C1-C6)alkoxycarbonyl and (C1-C6)alkoxy.
5. A compound of general formula (I) or (IB) according to claims 1 or 4, wherein Rx is selected from bis(3-fluorophenyl)methyl, 1,2-diphenylethyl, bis(4-chlorophenyl)methyl, bis(4-fluorophenyl)methyl, (4-methoxyphenyl)- (phenyl)methyl, 3-fluorobenzyl, 1,2-diphenylvinyl, 3-fluorobenzyl, benzyl, (3,4-difluorophenyl)(phenyl)methyl, fluorenyl and diphenylvinyl and R2 is selected from 2-oxo-2-phenylethyl- l-azoniabicyclo[2.2.2]octanyl, 2-oxo-2- (thiophen-2-yl)ethyl- l-azoniabicyclo[2.2.2]octanyl, 2-oxo-2-(thiophen-3- yl)ethyl- l-azoniabicyclo[2.2.2]octanyl, 2-(4-methoxyphenyl)-2-oxoethyl)- l- azoniabicyclo[2.2.2]octanyl, 2-(4-fluorophenyl)-2-oxoethyl)- l-azoniabicyclo- [2.2.2] octanyl, 2-oxo-2-p-tolylethyl)- l-azoniabicyclo[2.2.2]octanyl, 2-(5- chlorothiophen-2-yl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octanyl, 2-(4- chlorophenyl)-2-oxoethyl- l-azoniabicyclo[2.2.2]octanyl, l-(2-oxopropyl)- l- azoniabicyclo[2.2.2]octanyl, l-(2-tert-butoxy-2-oxoethyl)- l-azoniabicyclo- [2.2.2] octanyl, l-(2-oxo-2-(pyridin-2-yl)ethyl)- l-azoniabicyclo[2.2.]octanyl, l-(2-(3-(ethoxycarbonyl)isoxazol-5-yl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]- octanyl, l-(2-(4-hydroxyphenyl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octanyl, l-(2-(benzothiophen-5-yl)-2-oxoethyl)- l-azoniabicyclo[2.2.2]octanyl, 1- benzyl- l-azoniabicyclo[2.2.2]octanyl, l-(2-oxo-2-(thiophen-2-yl)ethyl)- l- lazoniabicyclo[2.2.2]octanyl and 1 -methyl- 1 -(2-oxo-2-(thiophen-2- yl)ethyl)piperidinyl.
6. A compound of general formula (IV)
Figure imgf000111_0001
(IV)
wherein Q represents a group of formula (f) or (g)
Figure imgf000111_0002
(f) (g)
R7 is selected from the group consisting of (C1-C6)alkyl and aryl(C1-C6)alkyl, and Ri, X, X', n, m and Y are as defined in claim 1.
7. A compound of general formula (IVA)
Figure imgf000112_0001
(IVA)
according to claim 6, wherein Rx is a group of formula (a)
— CH (a)
R3 and R4 are the same or different and are H or selected from the group consisting of aryl and heteroaryl, which may be optionally substituted by one or more substituents selected from the group consisting of halogen atoms, (C1-C6)alkoxy and
Figure imgf000112_0002
Q is a group of formula (f) or (g)
Figure imgf000112_0003
(f) (g)
wherein R7 is aryl(C1-C6)alkyl.
8. A compound of general formula (IVB)
Figure imgf000112_0004
(IVB)
according to claim 6, wherein Rx is aryl or a group of formula (a) wherein R3 and R4 are the same or different and are H or selected from the group consisting of aryl, aryl(C1-C6)alkyl and heteroaryl, which may be optionally substituted by one or more substituents selected from the group consisting of halogen atoms, (C1-C6)alkoxy and
Figure imgf000113_0001
or when R3 and R4 are both independently aryl or heteroaryl they may be linked to each other through a (CH2)r with r =0-2, to form a tricyclic ring system wherein any of the methylene (CH2)r groups may be a heteroatom or heteroaromatic group selected from O, S, N and NH, and with the proviso that R3 and R4 are not simultaneously H; Q is a group of formula (f) or (g)
Figure imgf000113_0002
(f) (g)
wherein n is 1, m is 2 and R5 is a group of formula (f) wherein p=0, P absent, q is 0 or 1 and W is (C1-C6)alkyl.
9. A pharmaceutical composition comprising a compound of formula (I) or (IV) as defined in any one of the claims 1-8 with one or more pharmaceutically acceptable carriers and/or excipients.
10. A compound of formula (I) or (IV) according to any one of claims 1-8 for use as a medicament.
11. A compound of formula (I) or (IV) according to any one of claims 1-8 for use in the treatment of broncho-obstructive or inflammatory diseases, preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD).
12. Use of a compound of formula (I) or (IV) according to any one of claims 1-8 for the manufacture of a medicament for the prevention and/or treatment of broncho-obstructive or inflammatory diseases, preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD).
13. A combination of a compound of formula (I) or (IV) as defined in any one of the claims 1-8 with one or more active ingredients selected from the classes consisting of beta2-agonists, corticosteroids, P38 MAP kinase inhibitors, IKK2 inhibitors, HNE inhibitors, PDE4 inhibitors, leukotriene modulators, NSAIDs and mucus regulators.
14. A pharmaceutical composition according to claim 9 to be administered by inhalation, such as inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.
15. A device comprising the pharmaceutical composition according to claim 14, which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler and a soft mist nebulizer.
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