Indian Patents. 245402:"A COMPOUND WHICH IS A CARBAMATE QUATERNARY AMMONIUM SALT"

Title of Invention	"A COMPOUND WHICH IS A CARBAMATE QUATERNARY AMMONIUM SALT"
Abstract	Carbamates of formula (I) or pharmaceutically acceptable salts thereof, including quaternary ammonium salts of formula (II) are disclosed; as well as processes for their preparation, pharmaceutical compositions comprising them and their use in therapy as antagonists of M3 muscarinic receptors.

Full Text	The present invention relates to a compound which is a carbamate quaternary ammonium salt. This invention relates to new therapeutically useful quinuclidine carbamate derivatives, to some processes for their preparation and to pharmaceutical compositions containing them. The structures according to the invention are antimuscarinic agents with a potent and long lasting effect. In particular, these compounds show high affinity and selectivity for muscarinic M3 receptors over M2 receptors. The M3 subtype of muscarinic receptor is present in'glands and smooth muscle and mediates the excitatory effects of the parasympathetic system on glandular secretion and on the contraction of visceral smooth muscle (Chapter 6, Cholinergic Transmission, in H.P. Rang etal., Pharmacology, 'Churchill Livingstone, New York, 1995), M3 antagonists are therefore known to be useful for treating diseases characterised by an increased parasympathetic tone, by excessive glandular secretion or oy smooth muscle contraction (R,M. Eglen and S,S. Hegde, (1997), Drug News Perspect, 10(8):462-469). Examples of this kind of diseases ars respiratory disorders such as chronic obstructive pulmonary disease (COPD), bronchitis, bronchial hyperreactivity, asthma, cough and rhinitis; urofogical disorders such as urinary incontinence, polfakiuria, neurogenic or unstable bladder, cystospasm and chronic cystitis; gastrointestinal disorders such as irritable bowel syndrome, spastic colitis, diverticulitis and peptic ulceration; and cardiovascular disorders such as vagally induced sinus bradycardia (Chapter 7, Muscarinic Receptor Agonists and Antagonists, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10the edition, McGraw Hill, Ney York, 2001). The compounds of the invention can be used alone or in association with other drugs commonly regarded as effective in the treatment of these diseases. For example, they can be administered in combination with ß2--agonists, steroids, antiallergic drugs, phosphodiesterase IV inhibitors and/or leukotriene D4 (LTD4) antagonists for simultaneous, separate or sequential use in the treatment of a respiratory disease. The present invention provides new quinuclidine carbamate derivatives with potent antagonist activity at muscarinic M3 receptors, which fall under the chemical structure described in formula (II). Formula (If) represents a carbamate quaternary ammonium salt of the following generalstructure: (Structure Removed) wherein R1 represents a group selected from phenyl, 2-furyl, 3-furyf, 2-thienyi, 3-thienyt, benzyl, furan-2-yirnethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, and thiophen-3-ylmethyf; R2 represents a group selected from C1-C8 alkyl, C2 to Cs alkenyl, C2-C8 alkynyl, saturated or unsaturated C3 to C7 cydoalkyi, saturated or unsaturated C3 to C7 cydoalkyjmsthyl, phenyl, benzyl, phenethyl, furan-2-ylmethyI, furan-3-yImethyl, thiophen-2-ylmethyI, thiophsn-3-ylmethyl, pyridyl, and pyridylmethyl; wherein the carbocyclb moieties in the C3 to C7 cydoalkyi, C3 to C7 cydoalkylmethyl, phenyl, benzyl or phenethyl groups can be optionally bridged or fused to another saturated, unsaturated or aromatic earbocydic moiety or to a cyclic moiety comprising carbon atoms and 1 or 2 oxygen atoms wherein the C1-C8 alkyl, C2-C8 alkenyl and C2-C8 alkynyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy groups or C1-C8 alkoxy gropus; the cyclic groups present in R1 and R2 being optionally substituted by one, two or three substituents selected from halogen, straight or branched C1-C8 alkyl, hydroxy, straight or branched C1-C8 alkoxy, ,-SH, straight or branched C1-C8 alkyfthio, nitro, cyano, -NR'R", -COsR', -C(O)-NR'R", -N(R'")C(0)-R,1 -N(R">C(0)NR'R", wherein R R" and R'" each independency represent a hydrogen atom or a straight or branched, C1-C8 alkyl group or R' and R" together with the atom to which they are attached form a cyclic group wherein the C1-C8 alkyl groups are unsubstituted or substituted with ona or more halogen atoms, hydroxy groups or C1-C8 alkoxy groups and the C1-C8 alkoxy and C1-C8 alkylthio groups are unsubstituted or substituted with one or more halogen atoms or hydroxy groups; p is 1 or 2 and the carbamate group is attached at positions 2,3 or 4 of the azoniabicyclic ring, wherein the sequence B-(CH2)n-A-(CH2)m- represents a group selected from 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl, 3-(4-fluorophenoxyJpropyl, 3-thiophen-2-y(propyl, allyl, heptyl and 3-cyanopropyl; X" represents a pharmaceutical acceptable anion of a mono or polyvalent acid; including all individual stereoisomers of formula (II) and mixtures thereof; with the proviso that when the cyclic group present in R1 is unsubsituted or has only one subslituent R2 has at least one substituent; and with the further proviso that the compound is not one of 1-Allyl-3-(R)[ben7.yl-(4-fluorophenyl)carbamoyloxy]-1-a2oniabicyclo[2.2.2]octane trifluoroacetate; 3-(R)[Benzyf-(4-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1- azontablcyclo{2.2.2]octane trifluoroacetate; '1-Allyl-3-(R)(benzyl-p-tolylcarbamoyloxy}-1-azoniabicyclo[2.2.2]octane tnfluoroacetate; 3-(R)(Benzyl-p-tolylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2 2 2]octane trifluoroacetate Further objectives of the present invention are to provide processes for preparing said compounds; pharmaceutical compositions comprising an effective amount of said compounds; the use of the compounds in the manufacture of a medicament for the treatment of diseases susceptible of being improved by antagonism of M3 muscarinic receptors; and methods of treatment of diseases susceptible to amelioration by antagonism of M3- muscarinic receptors, which methods comprise the administration of the compounds of the invention to a subject in need of treatment J. L. G. Nilsson et al. describe in Acta Pharm. Suecica, 5:71-76 (1968) a group of quinudidine carbamate derivatives having antimalarial activity, among which diphenylcarbamic acid 1-azabicyc!o[2.2.2]oct-3-yl ester and ethylphenylcarbamic acid 1-azabicyclo[2.2.2]oct~3-yl ester are mentioned. WO 02/00652 discloses a group of compounds which fall under the general structure of formula (II). The specific compounds disclosed in that application are excluded from the present invention. As used herein, an alkyl, alkenyl or alkynyl group or moiety can be straight or branched, and is a lower alkyl, alkenyl or alkynyl group. A lower alkyl group contains 1 to 8, preferably 1 to 6, carbon atoms. Examples include methyl, ethyl, propyl, including i-propyl, butyl, including n-butyl, sec-butyl and tert-butyl, 1-methylbutyl, 1-ethylpropy), 1,2-dimethyfpropyl, n-hexyl or 1-ethylbutyl groups. More preferably a lower alkyl group contains from 1 to 4 carbon atoms. A lower alkenyl or alkynyl group contains 2 to 8, preferably 2 to 6, carbon atoms. Examples include vinyl, ally!, 1-propenyl, 4-pentenyl, 1-propynyl, 2-propynyl, 1-butyny), 2-bufynyl or 3-butynyl groups. More preferably, a lower alkenyl or alkynyl group contains 2 to 4 carbon atoms. Optionally substituted lower alkyl, aikenyl or alkynyl groups mentioned herein include straight or branched lower alkyl, alkenyl or alkynyl groups as defined above, which may be unsubstituted or substituted in any position by one or more substituents, for example by 1, 2 or 3 substituents. When two or more substituents are present, each substituent may be the same or different. The substituent(s) are typically halogen atoms, preferably fluoride atoms, and hydroxy or alkoxy groups. Alkoxy and alkylthio groups mentioned herein are typically lower aikoxy and alkylthio gioups, that is groups containing from 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, the hydrocarbon chain being branched or straight and optionally substituted in any position by one or more substituents, for example by 1, 2 or 3 substituents. When two or more substituents are present, each subsfrtuent may be the same or different. The substituent(s) are typically halogen atoms, most preferably fluoride atoms, and hydroxy groups. Preferred optionally substituted alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, t-butoxy, tnfluoromethoxy, difluoromethoxy, hydroxymethoxy, 2-hydroxyethoxy or 2-hydroxypropoxy Preferred optionally substituted alkylthio groups include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, sec-butytthio, t-butylthio, trtfluoromethylthio, difluoromethylthio, hydroxymethylthio, 2-hydroxyethylthio or 2-hydroxypropylthio. Cyclic groups mentioned herein include, unless otherwise specified, carbocyclic and heterocyclic groups. The cyclic groups can contain one or more rings. Carbocyclic groups may be aromatic or alicyclic, for example cycloalkyl groups. Heterocyclic groups also include heteroaryl groups.- Cycloalkyl groups and alicyclic groups mentioned herein, unless otherwise specified, typically contain from 3 to 7 carbon atoms. Cycloalkyl groups and alicyclic rings of 3 to 7 carbon atoms include cyclopropy!, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. As used herein an aromatic group typically contains from 5 to 14, preferably 5 to 10 carbon atoms. Examples of aromatic groups include phenyl and naphthalenyl. A heterocyclic or heteroaromatic group mentioned herein is typically a 5 to 10 membered group, such as a 5, 6 or 7 membered group, containing one or more heteroatoms selected from N, S and 0. Typically, 1, 2, 3 or 4 heteroatoms are present, preferably 1 or 2 heteroatoms A heterocyclic or heteroaromatic group may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom. Examples of heterocyclic groups include piperidyl, pyrrolidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, irnidazolyl, imidazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolmyl, cinnolinyl, pteridinyl, quinuclidinyl, triazolyl, pyrazolyl, tetrazolyl and thienyi. Examples of heteroaromatic groups include pyridyl, thienyl, furyl, pyrrolyl, irnidazolyl, benzothiazolyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazoiinyl, cinnolinyl, triazolyl and pyrazolyl. As used heiein a halogen atom includes a fluorine, chlorine, bromine or iodine atom, typically a fluorine, chlorine or bromine atom. As used herein, the term pharmaceutically acceptable salt embraces salts with a pharmaceutical^ acceptable acid or base. Pharmaceutical^ acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, dtphosphoric, hydrobromic, hydroiodic and nitric acid and organic acids, for example citric, furnaric, rnaieic, malic, formic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. In the quaternary ammonium compounds of the present invention, an equivalent of an anion (X") is associated with the positive charge of the N atom. X" may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, formate, methanesulfonate and p-toluenesulfonate. X" is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, trifluoroacetate, formate, methanesulfonate, maleate, oxalate or succinate. More preferably X" is chloride, bromide, formate, trifluoroacetate or methanesulfonate. Preferred compounds of formula (II) according to the invention as defined above are those wherein R1 represents a group selected from phenyl, 2-thienyl, 3-thienyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, furan-2-ylmethyI orfuran-3-ylmethyl, the cyclic groups present in R1 being optionally substituted with one to three substitutents selected from fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, ethyl, tert-butyl, hydroxy and cyano. In particularly preferred embodiments R1 represents a group selected from phenyl, 2-fluorophenyl, 3-flurorophenyl, 4-fluarophenyl, 3-methylphenyl, 4-methylphenyl, 2,5-difluorophenyl, 2,6-difIuorophenyl, 2,4,5-trifIuorophenyl, 5-methylfuran-2-y]methyl, 4-fluoro-2-methylphenyl, 3~fluoro-4-methoxyphenyl, 3-methyI-thiophen-2-ylmethyl, 4,5-dimethyl-thiophen-2-ylmethyl, thiophen-3-ylmethyl, 5-methyl-furan-2-ylmethyl, 5-methyl-2-tnfluoromethyl-furan-3-ylmethyl, and 2,5-dimethyI-furan-3-ylmeihyl, Also preferred are compounds of formula (II) as defined above wherein R2 represents a pent-4-enyl, pentyl, butyl, allyl, benzyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, furan-2-ylmethyl, furan-3-ylmethyi, phenethyl, cyclopentyl, cyciohexyl or cyclohexylmethyl group, the cyclic groups present in R2 being optionally substituted with one to three substitutents selected from fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, ethyls tert-butyl, hydroxy and cyano. In particularly preferred embodiments R2 represents a group selected from 3-fluorobenzyl, 2,4,5-trifhiorobenzyl, 3,4,5-trifluorobenzyl, 5-Bromothiophen-2-ylmethyl, 3,4-dimethoxyphenylethyl, 3-methylthiophen-2-ylmethyl, thiophen-3-ylmethyI, 4-bromo-5-methylthiophen-2-y(methyl, 4,5~dimethylfuran-2-ylmethyl, furan-3-ylmethyl, 2-fluoro-4-methoxybenzyl. 2-(4-fluorophenyl)ethyl, butyl, pent-4-enyl and cyclopentyl. X' represents in the preferred embodiments of formula (II) a chloride, bromide, trifluoroacetate or methanesulphonate anion. Also preferred are compounds of formula (I) or (II) wherein p is 2 and/or wherein the azoniabicyclic ring is substituted in the 3-position. The compounds of the present invention represented by formula (II), may have one or more asymmetric carbons. All possible stereoisomers are included, such as compounds of formula (II) wherein the carbon at the 3-position of the azoniabicyclic ring has either R or S configuration. All single isomers and mixtures of the isomers fall within the scope of the present invention. Particularly preferred individual compounds of formula (II) include: (3R)-3-[(3-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1 -(2-phenoxyethyl)-1 -azomabicyclo[2.2.2]octane bromide (3R)-3-[(3-nuorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2 2.2]octane bromide (3R)-1-(2-Phenoxyethyl)-3-[m"tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane bromide (3R)-1-(3-Phenylpropyl)-3-[m-to!yl-(2,4,5-trifluorobenziyl)carbamoyloxy]-1-azoniabicyclo[2 2 2]octane bromide (3R) 3-[(3-Fluorophenyl)-(3 4,5-trifluorobenzyl)carbamoyloxyI-1-(2-phenoxyethyl)-1-a20niabicyclo[2.2.2]octane bromide (3R)-1-Allyl-3-[[2-(3,4'dimethoxyphenyl)ethyl)-(5-methyIfuran-2-ylmethyl)carbamoyloxy]~1-azoniabicyclo[2.2.2]ocfane bromide (3R)'3-[(5-Bromothiophen-2-y!methyl)-(2,4,5-trifluorophenyl)carbamoyloxyl-1-(3-phenoxypropyl)-1-azoniabicycfo[2.2.2]octane trifluoroacetate (3R)-3-[(4-Fluoro-2-methylpheny!)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(2--phenoxyethyl)-1-azoniabicyclo{2.2.2]octane trifluoroacetate (3R)-3-[(3-F!uoro-4-methoxyphenyI)thiophen-3-ylmethylcarbamoyloxy]-1-(3- phenylallyl)-1-azoniabicyclo[2.2 2]octane trifluoroacetate (3R)-1-Phenethyl-3-[thiophen-3-ylmethyl-(2,4,5-trifluorobenzy!)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane trifluoroacetate (3R)-3-[(4-Bromo-5-methyithiophen-2-ylmethyl)-(3-methylthiophen-2- ylmethyl)carbarnoyloxy]-1-(3-phenylpropyl}-1-azoniabicyclo[2.2.23octane trifluoroacetate (3R)-3^(4,5-Dimethylfuran-2-ylmethyl)-(5-methy!furan-2-y!methyl)carbamoyloxy]-1-[3-(3-hydroxyphenoxy)propy]]-1-azoniabicycIo[2.2.2]octane trifluoroacetate (3R)-1-[3-(4-F!uorophenoxy)propyl]-3-[furan-3-ylmethy\|-(5-methyl-2- trifluoromethylfuran-3-yimethyl)carbarnoyIoxy]-1-azoniabiGyclo[2.2.2]octane trifluoroacetate (3R)-3-[(2,5-Dimethylfuran-3'ylmethyl)-(2'fluoro-4-methoxybenzyl)carbamoyloxy]-1-(3-thiophen-2-ylpropyl)-1-azoniabicyc!o[2.2.2]octane trifluoroacetate (3R)-1-AI\|yl-3'[2-(4-fluorophenyl)ethyl]-(3-methyfthiophen-2-ylmethyl)carbamoyloxyl-1-a£oniabicycio[2.2.2]octane trifluoroacetate {3R)-3-[Butyl-(2)5-dffluoropheny])carbamoyloxy]-1-heptyl-1-azoniabicydo[2 2.2]octane trifluoroacetate (3R)-1-(3-cyanopropyl)-3-[(2,6-difluorophenyl)pent-4-enylcarbamoyloxyl-1-azoniabicyclo[2.2.2]ociane trifluoroacetate (3R)-3'[(3-FluorophenylV(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(3-prienylpropyi)-1-a7oniabicyclo[2 2.2]octane bromide (3R)-34(5-Ethyllhiophen-2-ylmethyl)K3-methylthiophen-2-ylmethyl)cafbarnoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide (3R)-3-[(4-Ffuoro-2-methyIphenyl)-(3-methylthiophen-2-ylmethyl)carbamoy]oxy]-1-(2-pnenoxyethyl)-1-azoniabicyclo[2.2.2joctane bromide (3R)-3-[(3-Ruoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyloxy]-1-(3-phcnylallyl)-1-azoniabicyclo[2.2 2]odane bromide (3R)-1-Ally!-3-[2-(4-fluorophenyl)ethyl]-(3-methylthiophen-2-ylrriethy])carbannoy!oxy]-1-azoniabicyclo[2.2.2]octane bromide The quaternary ammonium derivatives of general formula (II), may be prepared by reaction of an alkylating agent of general formula (VI) with compounds of general formula (I), as described in the following scheme. In formulas (I), (II) and (VI), R1, R2, A, B, X, n, m and p are as defined above. (Formula Removed) In formula (VI), W represents any suitable leaving group, such as a group X as defined above. Preferably, W represents a group X. This alkylation reaction may be carried out by two different experimental procedures, (c) and (d) which are described in the experimental section below, in particular method (d) provides a new experimental process, using solid phase extraction methodologies that allow the parallel preparation of several compounds. If W represents a group other than X, the quaternary ammonium salt of formula (II) is produced from the product of method (c) or (d) by carrying out an exchange reacfion according to standard methods to replace the anion W" with the desired anion X". Methods (c) and (d) are described in the experimental section. Compounds of general formula (VI) which are not commercially available have been prepared by synthesis according to standard methods. For example, compounds wherein n = 0 and A~ -0-, -S- or --NR4, wherein R4 is as defined above, were obtained by reaction of the corresponding alcohol, thiol or amine derivative or its sodium or potassium salt with an alkylating agent of general formula Y-(CH2)m-W, wherein W may be a halogen and Y may be a halogen or a sulphonate ester. In other examples, compounds of general formula (VI), where n>=1 were synthesised from the corresponding alcohol derivative of general formula (VII) by known methods. (Structure Removed) (VI!) The structures of the prepared compounds were confirmed by 1H-NMR and MS. The NMR were recorded using a Varian 300 MHz instrument and chemical shifts are expressed as parts per million (8) from the internal reference tetramethyl silane. Their purity was determined by HPLC, using reverse phase chromatography on a Waters instrument. Molecular ions were obtained by electrospray ionization mass spectrometry on a Hewlett Packard instrument. HPLC-MS experiments were performed on a Gilson instrument equipped with a binary pump (Gilson piston pump 321); a vacuum degasser (Gilson 864); an injector-fraction collector (Gilson liquid handler 215); two injection modules, anneal and preparative (Gilson 819); a valve (Gilson v'aivemafe rowj; a 1/1000 splitter (Acurafe fay LC Packings); a make-up pump (Giteon 307); a diode array detector (Gilson 170) and a MS detector (a Thermoquest Finnigan aQa, a quadrupole mass Spectrometer with ES an APCI ionisation modes). The HPLC-MS instrument was controlled by an IBM PC. Method (c) Example 1 Preparation of (3R)-1-(2-phenoxyethyI).3-[m-tolyl-(2,4,5- trif!uorobenzyl)carbamovioxy]-1-azoniabicyclol:2.2.2]octane bromide 0.300 g (0.742 mmol) of m toiyl-(2,4,5-trifluorobenzyl)carbamic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester, 7.0 rnl of tetrahydrofuran and 0.253 g (1.258 mmol) of (2-bramoethoxy)benzene were mixed. The solution was refluxed for 55 hours and allowed to continue stirring at room temperature during 16 more hours. After this time the solvent was evaporated in vacuo. Ether was added and the mixture stirred to obtain a solid. This solid was treated with ether several times in order to eliminate the residual alkylating agent. Finally the suspension was filtered and the solid obtained washed with ether and dried. The yield was 0.34 g (75.5%). m.p.: 137.3-139.1°C MS [M-8rj+. 525 1H-NMR(DMSO-d6): δ 1.40,1.70 (m, 1H), 1.70-2.05 (m, 3H), 2.20 (m, 1H), 2.25 (s, 3H), 3.25-3.40 (m, 1H), 3.40-3.8o (m, 6H), 3.95-4.10 (m, 1H), 4.44 (m, 2H), 4.90 (m, 2H), 5,01 (m. 1H), 6 95-7.30 (rn, 7H), 7.30-7.60 (m, 4H). Example 2 Preparation of (3R)-1-AIlyl_3-[[2-(3,4-dimethoxypheny[}ethyl]-(5-methylfuran-2- ylmethyl)carbamoy!oxyl-1azonlabicyclot2.2.2]octane bromide 0.300 g (0.7 mmol) of [2-(3,4-Dirnethoxyphenyl)ethylj-(5-metfiylfuran-2-ylmethyl)carbamic acid (3R)-1-azabicyclo[2.2.2]oct-3-yI ester were dissolved in 5 ml of CHCI3 and 3.6" ml of acetoniirile. To this solution 0.30 ml (0.423 g, 3.5 mmol) of aflyl bromide were added and the mixture was stirred during 21 hours at room temperature under N2 atmosphere. Solvents were evaporated. The residue was treated with ether several times to obtain an oil, which was redissolved in CHCIj and evaporated to dryness to give 0.365 g (94.8%) ofthe title product. MS [M-Br]+: 469 Also included within the scope of the present invention are pharmaceutical compositions which comprise, as the active ingredient, at least one qurnuclidine derivative of general formula (II) in association with a pharmaceutically acceptable carrier or diluent. Preferably the composition is made up in a form suitable for oral administration. The pharmaceutically acceptable carrier or diluents which are mixed with the active compound or compounds, to form the composition of this invention are well-known perse and the actual excipients used depend inter alia on the intended method of administration of the composition. Compositions of this invention are preferably adapted for oral administration. In this case, the composition for oral administration may take the form of tablets, film-coated tablets, liquid inhalant, powder inhalant and inhalation aerosol; all containing one or more compounds of the invention; such preparations may be made by methods . well-known in the art The diluents which may be used in the preparations of the compositions include {hose liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents, if desired. Tablets or film-coated tablets may conveniently contain between 0.1 mg and 500 mg, preferably from 0.5 to 200 mg of active ingredient. The inhalant compositions may contain between 1µg and 1,000 µg, preferably from 10 to 800 µg of active ingredient. In human therapy, the dose of the compound of general formula (II) will depend on the desired effect and duration of treatment; adult doses are generally between 0.5 mg and 300 mg per day as tablets and 10 µg and 800 µg per day as inhalant composition. The compounds of the present invention, or pharmaceutical compositions containing them, may be used together with a ß2 agonist, steroid, antiallergic drug and/or phosphodiesterase IV inhibitor, for simultaneous, separate or sequential use in the treatment of a respiratory disease. Pharmacological Action The following examples demonstrate the excellent pharmacological activities of the compounds of the present invention. The results on human muscarinic receptor binding and in the test on bronchospasm in guinea pig, were obtained as described below. Human muscarinic receptor studies. The binding of [3 H]-NMS to human muscarinic receptors was performed according to Waelbroeck et al (1990), Mol. Pharmacol., 38: 267-273, Assays were carried out at 25°C Membrane preparations from stably transfected Chinese hamster ovary-K1 cells (CHO) expressing the genes for the human muscarinic M3 receptors were used For determination of IC5t), membrane preparations were suspended in DPBS to a final concentration of 89 µg/ml for the M3 subtype. The membrane suspension was incubated with the tritiated compound for 60 min. After incubation the membrane fraction was separated by filtration and the bound radioactivity determined. Non specific binding was determined by addition of 10-4 M atropine. At least six concentrations were assayed in duplicate to generate individual displacement curves. Our results show that the compounds of the present invention have high affinities for muscarinic M3 receptors. Preferred compounds of the invention have an IC5o[nM} value for M3 receptors of less than 35 nM, most preferably less than 10 nM. The preferred compounds of the invention also show high selectivity for M3 receptors with respect to M2 receptors Thus, the ratio IC50 M2 / IC50 M3 is higher than 5, preferably higher than 10, most preferable higher than 15. Test on bronchospasm in guinea pig The studies were performed according to H. Konzett and F. RSssler (1940), Arch Exp. Path. Pharmacol. 195, 71-74. Aqueous solutions of the agents to be tested were nebulized and inhaled by anaesthetized ventilated male guinea pigs (Dunkin-Hartley). 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 compounds of the present invention showed bronchodilator activity with high potency and a long duration of action. From the above described results one of ordinary skill in the art can readily understand that the compounds of the present invention have excellent antlmuscarinic activity (M3) and thus are useful for the treatment of diseases in which the muscarinic M3 receptor is implicated, including respiratory diseases such as chronic obstructive pulmonary disease, bronchitis, asthma, bronchial hyper reactivity and rhinitis; urinary diseases such as urinary incontinence, pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm and chronic cystitis; gastrointestinal diseases such as irritable bowel syndrome, spastic colitis, diverticulitis and peptic ulceration; and cardiovascular disorders such as vagally induced sinus bradicardia. For example, the compounds of the present invention are useful for the treatment of respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, and rhinitis; urinary diseases such as urinary incontinence and pollakinuria in neuripenia pollakinuna, neurogenic bladder, nocturnal enuresis, unstable bladder, cytospasm and chronic cystitis; and gastrointestinal diseases such as irritable bowel syndrome, spastic colitis and diverticulitis. The present invention further provides a compound of formula (II) or a pharmaceutically acceptable composition comprising a compound of formula (II) for use in a method of treatment of the human or animal body by therapy, in particular for the treatment of respiratory, urinary or gastrointestinal disease. The present invention further provides the use of a compound of formula (II) or a pharmaceutically acceptable composition comprising a compound of or (II) for the manufacture of a medicament for the treatment of respiratory, urinary or gastrointestinal disease. Further, the compounds of formula (II) and pharmaceutical compositions comprising a compound of formula (It) can be used in a method of treating respiratory, urinary or gastrointestinal disease, which method comprises administering to a human or animal patient in need of such treatment an effective amount of a compound of • formula (il) or a pharmaceutical composition comprising a compound of formula (II). Further, the compounds of formula (II) and pharmaceutical compositions comprising a compound of formula (II) can be used in combination with other drugs effective in the treatment of these diseases. For example with ß2 agonists, steroids, antiallergic drugs, phosphodiesterase IV inhibitors and/or leukotriene DA (LTD4) inhibitors, for simultaneous, separate or sequential use in the treatment of a respiratory disease. The present invention therefore provides a combination product comprising - -. (i) -a compound according to the invention; and (ii) another compound effective in the treatment of a respiratory, urological or gastrointestinal disease or disorder for simultaneous, separate or sequential use. The compound (ii) which is effective in the treatment of a respiratory, urological or gastrointestinal disease or disorder may be a ß2 agonist, steroid, antiallergic drug, phosphodiesterase IV inhibitor and/or leukotriene D4 (LTD4) antagonist. Preferably, the product is for simultaneous, separate or sequential use in the treatment of a respiratory disease. The present invention will be further illustrated by the following examples. The examples are given by way of illustration only and are not to be construed as limiting. Example 3 (3R)-3-[(3-F!uorobenzyll)-(3-fluorophenyl)carbannoyloxy]-1-(2-phenoxyethyl)-1-azoniablcycfo[2.2,2]octane bromide The title compound was synthesised according to method c. The yield of the final step was 0.32 g, 69.2%. m.p : 142.8-143.6°C MS [M-BFJ +' 493. : - - 1H-NMR(DMSO-d3): δ1.50-1.70 (m, 1H), 1.70-1.85 (m, 1H), 1.85-2.05 (m, 2H), 2.23 (m, 1H), 3.25-3.40 (m, 1H), 3.40-3.75 (m, 6H), 3.95-4.10 (m, 1H), 4,44 (m, 2H), 4.90-5.10 (m, 3H), 6.90-7.25 (m, 8H), 7.25-7.45 (m, 5H). Example 4 (3R)-3-[(3-FIuorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.Z2]octane bromide The title compound was synthesised according to method c. The yiefd of the final step was 0.24 g, 52,1%. m.p.: 64.5-66.0°C MS [M-Br]+: 491 1H-NMR(DMSO-d6): .δ 1.50-1.65 (m, 1H), 1.65-180 (m, 1H). 1.80-2.10 (m, 4H), 2.20 (m,.1H), 2.60 (t, 2H), 3.05-3.55 (m, 7H), 3.80-3.90 (m, 1H), 4.90-5.10 (m, 3H), 7.05- 7.45 (m, 13H). Example 5 (3R)-1-(3-Phenylpropyl)-3-[m-tolyl-{2,4,5-trifluoroben2yl)carbamoyloxy]-1-azoniabicycloj;2.2.2]octane bromide The title compound was synthesised according io method c. The yield of the final step was 0.32 g , 72.5%. m.p.: 113.1-114.8°C MS [M-Br] \ 523 1H-NMR(DMSO-d6):.δ 1.40-1.60 (m, 1H), 1.60-1.80 (m, 1H), 1.80-2.10 (m, 4H), 2.18 (m, 1H), 2.26 (s. 3H), 2.60 4 98 (m, 1H), 7.0-7.15 (m, 2H), 7.15-7.40 (m, 7H)r 7.40-7.60 (m, 2H). Example 6 (3R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy].1-.(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane bromide The title compound was synthesised according to method c The yield of the final step was 0.15 g, 75%. m.p.: 173 9-175.5*0 MS [M-Br]+: 529 1H-NMR(DMSO-da): .δ 1.50-2.05 (m. 4H), 2.24 (m, 1H), 3 25-3.85 (m, 7H), 4 03 (m, 1H), 4.45 (m, 2H), 4.95 (m, 2H), 5.04 (m, 1H), 6.95-7.15 (m, 4H), 7 20-7.45 (m, 7H). Exampla 7 (3R}-3-[(4-F?uoro-2-methyfphenyi)-(3-methyfthiopberi-2-ylmethyl)carbamoyJoxy]-1-(2-phenoxyethyl)-1-azoniabicycIo[2.2.2]octane bromide The title compound was synthesised according to methods a and c . The yield of the final step was 0 5 g, 84.7%. MS [M-Br] +; 509 1H-NMR(DMSQ-d8): δ 1.15-1.45 (m, 1H), 1.60-2.20 (m, 10H), 2.90-3.10 (m, 1H), 3.30-3.85 (m, 6H), 3.90-4.20 (m, 1H), 4.30-4.55 (m, 2H), 4.75-5.15 (m, 3H), 6.78 (m, 1H), 6.90-7.20 (m, 6H), 7.35 (m, 3H). Example 8 (3R)-3-[(3-FIuoro-4-methoxyphenyI)thiophen-3-ylmethylcarbamoyloxy]-1-(3-phenylallyI)-1-azoniabicydo[2.2.2]octane bromide The title compound was synthesised according to method c. The yield of the final step was 1,9 g, 97,1%. MS [M-Br]+: 507 1H-NMR(DMSO-d6): δ 1.40-1.65 (m, 1H), 1.65-2.05 3.30 (m, 1H), 3.30-3.60 (m, 4H), 3.78 (s, 3H), 3.80-3.95 (m, 1H), 3.95-4.10 (m. 2H), 4.80 (m, 2H), 5.0 (m, 1H), 6.42 (m, 1H), 6,85 (m, 1H), 6.90-7.15 (m, 3H), 7.20-7.50 (m,7H), 7.58 (m, 1H). Example 9 (3R)-1-Allyl-3-[2-{4-fluorophenyl)ethyl]-(3-methyIthiophen-2-ylmethyj)carbamoyloxy]-1 -azoniabicyclo[2.2.2]octane bromide The title compound was synthesised according to method c. The yield of the final step was 0.4g, 51.3% MS [M-Brf: 443 1H-NMR(DMSO-d6): δ 1.80-2.10 (m, 4H), 2.20 (s, 3H), 2.25-2.30 (m, 1H), 2.77 (m, 2H), 3.15-3.70 (m, 7H), 3.82 (m, 1H), 3.90 1H), 5.56-5.66 (m, 2H), 5.90-6.10 (m, 1H), 6.87 (m, 1H), 7.10-7.30 (m, 4H), 7.36 (m, 1H). The following examples illustrate pharmaceutical compositions according to the present invention and procedures for their preparation. Example 10 Preparation of a pharmaceutical composition: tablets Formulation' Compound of the present invention 5.0 mg Lactose 113.6 mg Microcrystalline cellulose 28.4 mg Light silicic anhydride 1.5 mg Magnesium stearate 1.5 mg Using a mixer machine, 15 g of the compound of the present invention was mixed with 340.8 g of lactose and 85.2 g of rnicrocrystalline cellulose. The mixture was subjected to compression moulding using a roller compactor to give a flake-like compressed material. The flake-like compressed material was pulverized using a hammer mill, and the pulverized material was screened through a 20 mesh screen. A 4.5 g portion of light silicic anhydride and 4.5 g of magnesium stearate were added to the screened material and mixed. The mixer product was subjected to a tablets making machine equipped with a die/punch system of 7.5 mm in diameter, thereby obtaining 3,000 tablets each having 150 mg in weight. Example 11 Preparation of a pharmaceutical composition: tablets coated Formulation: , Compound of the present invention 5.0 mg Lactose 95.2 mg Corn starch 40.8 mg Polyvinylpyrrolidone ..,. 7.5 mg Magnesium stearate 1.5 mg Hydroxypropylcellulose 2.3 mg Polyethylene glycol 0.4 mg Titanium dioxide 1.1 mg Purified talc 0.7 mg Using a fluidized bed granulating machine, 15 g of the compound of the present invention was mixed with 285.6 g of lactose and 122.4 g of corn starch. Separately, 22.5 g of polyvinylpyrrolidone was dissolved in 127.5 g of water to prepare a binding solution. Using a fluidized bed granulating machine, the binding solution was sprayed on the above mixture to give granulates, A 4.5 g portion of magnesium stearate was added to the obtained granulates and mixed. The obtained mixture was subjected to a tablet making machine equipped with a die/punch biconcave system of 6.5 mm in diameter, thereby obtaining 3,000 tablets, each having 150 mg in weight. Separately, a coating solution was prepared by suspending 5.9 g of hydroxypropylmethylce!lulo5e 2910,1.2 g of polyethylene glycol 6000, 3.3 g of titanium dioxide and 2.1 g of purified talc in 72.6 g of water, Using a High Coated, the 3,000 tablets prepared above were coated with the coating solution to give film-coated tablets, each having 154.5 mg in weight. Example 12 Preparation of a pharmaceutical composition: liquid inhalant Formulation: Compound of the present invention 400 µg Physiological saline 1 ml A 40 mg portion of the compound of the present invention was dissolved in 90 ml of physiological saline, and the solution was adjusted to a total volume of 100 ml with the same saline solution, dispensed in 1 ml portions into 1 ml capacity ampoule and then sterilized at 115° for 30 minutes to give liquid inhalant. Example 13 Preparation of a pharmaceutical composition: powder, inhalant Formulation- Compound of the present invention 200 µg Lactose 4,000 µg A 20 g portion of the compound of the present invention was uniformly mixed with 400 g of lactose, and a 200 mg portion of the mixture was packed in a powder inhaler for exclusive use to produce a powder inhalant. Example 14 Preparation of a pharmaceutical composition: inhalation aerosol. Formulation: Compound of the present invention 200 µg Dehydrated (Absolute) ethyl alcohol USP 8,400 µg i,1,1,2-Tetrafluoroethane{HFC-134A) 46,810 µg The active ingredient concentrate is prepared by dissolving 0.0480 g of the compound of the present invention in 2.0160 g of ethyl alcohol. The concentrate is added to an appropriate filling apparatus. The active ingredient concentrate is dispensed into aerosol container, the headspace of the container is purged with Nitrogen or HFC-134A vapour (purging ingredients should not contain more than 1 ppm oxygen) and is sealed with valve. 11.2344 g of HFC-134A propellant is then pressure filled into the sealed container. We Claim: 1. A compound which is a carbamate quaternary ammonium salt of formula (II): (Formula Removed) wherein Rl represents a group selected from phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen- 3 -ylmethyl; R2 represents a group selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, saturated or unsaturated C3-C7 cycloalkyl, saturated or unsaturated C3-C7 cycloalkylmethyl, phenyl, benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl, and pyridylmethyl; wherein the carbocyclic moieties in the C3-C7 cycloalkyl, C3-C7 cycloalkylmethyl, phenyl, benzyl or phenethyl groups can be optionally bridged or fused to another saturated, unsaturated or aromatic carbocyclic moiety or to a cyclic moiety comprising carbon atoms and 1 or 2 oxygen atoms; wherein the C1-C8 alkyl, C2-C8 alkenyl and C2-C8 alkynyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy groups or C1-C8 alkoxy groups; the cyclic groups present in R1 and R2 being optionally substituted by one, two or three substituents selected from halogen, straight or branched, C1-C8 alkyl, hydroxy, straight or branched, C1-C8 alkoxy, -SH, straight or branched C1-C8 alkylthio, nitro, cyano, NR'R", -CO2R', -C(0)-NR'R", -N(R")C(0)-R', -N(R")-C(0)NR'R", wherein R', R" and R'" each independently represents a hydrogen atom or a straight or branched, C1-C8 alkyl group or R' and R" together with the atom to which they are attached form a cyclic group; wherein the C1-C8 alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy groups or C1-C8 alkyoxy groups and the C1-C8 alkoxy and C1-C8 alkylthio groups are unsubstituted or substituted with one or more halogen atoms or hydroxy groups; p is 1 or 2 and the carbamate group is attached at positions 2, 3 or 4 of the azoniabicyclic ring, wherein the sequence B-(CH2)n-A-(CH2)m- represents a group selected from 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl, 3-thiophen-2-ylpropyl, allyl, heptyl and 3-cyanopropyl; X represents a pharmaceutically acceptable anion of a mono or polyvalent acid; including all individual stereoisomers of formula (II) and mixtures thereof; with the proviso that when the cyclic group present in Rl is unsubstituted or has only one substitutent R2 has at least one substituent; and with the further, proviso that the compound is not one of: l-Allyl-3-(R)[benzyl-(4-fluorophenyl)carbamoyloxy]-l-azoniabicyclo[2.2. 2]octane; trifluoroacetate 3-(R)[Ben2yl-(4-fluorophenyl)carbamoyloxy]-1 -(3-phenylpropyl)-1 -azoniabicyclo[2.2.2]octane; trifluoroacetate 1 -Allyl-3-(R) (benzyl-p-tolyl-carbamoyloxy)-1 -azoniabicyclo[2.2.2] octane; trifluoroacetate 3-(R) [Benzyl-p-tolylcarbamoyloxy) -1 - (3-phenylpropyl) -1 -azoniabicyclo[2.2.2]octane; trifluoroacetate. 2. A compound as claimed in claim 1 wherein Rl represents a group selected from phenyl, 2-thienyl, 3-thienyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, furan-2-ylmethyl or furan-3-ylmethyl, the cyclic groups present in Rl being optionally substituted with one to three substitutents selected from fluorine, chlorine, bromine, methyl, methoxy, trifhioromethyl, ethyl, tert-butyl, hydroxy and cyano. 3. A compound as claimed in claim 2 wherein Rl represents a group selected from phenyl, 2-fluorophenyl, 3-flurorophenyl, 4-fluorophenyl, 3-methylphenyl, 4-methylphenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,4,5-trifluorophenyl, 5-methylfuran-2-ylmethyl, 4-fluoro-2-methylphenyl, 3-fluoro-4-methoxyphenyl, 3-methyl-thiophen-2-ylmethyl, 4,5-dimethyl-thiophen-2-ylmethyl, thiophen-3-ylmethyl, 5-methyl-furan-2-ylmethyl, 5-methyl-2-trifluoromethyl-furan-3-ylmethyl, and 2,5-dimethyl-furan-3- ylmethyl. 4. A compound as claimed in any one of claims 1 to 3 wherein R2 represents a pent-4-enyl, pentyl, butyl, allyl, benzyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, furan-2-ylmethyl, furan-3-ylmethyl, phenethyl, cyclopentyl, cyclohexyl or cyclohexylmethyl group, the cyclic groups present in R2 being optionally substituted with one to three substitutents selected from fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, ethyl, tert-butyl, hydroxy and cyano. 5. A compound as claimed in claim 4 wherein R2 represents a group selected from 3-fluorobenzyl, 2,4,5-trifluorobenzyl, 3,4,5-trifluorobenzyl, 5-Bromothiophen-2-ylmethyl, 3,4-dimethoxyphenylethyl, 3-methylthiophen-2-ylmethyl, thiophen-3-ylmethyl, 4-bromo-5-methylthiophen-2-ylmethyl, 4,5-dimethylfuran-2-ylmethyl, furan-3-ylmethyl, 2-fluoro-4-methoxybenzyl, 2-(4-fluorophenyl)ethyl, butyl, pent-4-enyl and cyclopentyl. 6. A compound as claimed in any one of the preceding claims wherein X" represents a chloride, bromide, trifluoroacetate or methanesulphonate anion. 7. A compound as claimed in any one of the preceding claims, wherein p is 2. 8. A compound as claimed in any one of the preceding claims, wherein the azoniabicyclic ring is substituted in the 3-position. 9. A compound as claimed in claim 8 wherein the carbon at the 3-position of the azoniabicyclic ring has R configuration. 10. A compound as claimed in claim 8 wherein the carbon at the 3-position of the azoniabicyclic ring has S configuration. 11. A compound as claimed in any one of the preceding claims, which is a single isomer. 12. A compound as claimed in claim 1 which is one of. (3R)-3-[(3-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]- l-(2-phenoxyethyl)-1 azoniabicyclo[2.2.2]octane bromide (3R)-3-[(3-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide (3R)-l-(2-Phenoxyethyl)-3-[m-tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-l-azoniabicyclo[2.2.2]octane bromide (3R)-l-(3-Phenylpropyl)-3-[m-tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-l-azoniabicyclo[2.2.2]octane bromide (3R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-l-(2-phenoxyethyl)-1 -azoniabicyclo[2.2.2)octane bromide (3R)-l-Allyl-3-[[2-(3,4-dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamoyloxy]-l-azoniabicyclo[2.2.2]octane bromide (3R) -3-[(5-Bromothiophen-2-ylmethyl) - (2,4,5-trifluorophenyl) carbamoyloxy] -1 -(3-phenoxypropyl)-l-azoniabicyclo[2.2.2]octane trifluoroacetate (3R)-3-[(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2- ylmethyl) carbamoyloxy] -1 - (2 -phenoxyethyl) -1 -azoniabicyclo [2.2.2] octane trifluoroacetate (3R)-3-[(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyloxy]-l-(3-phenylallyl) -1 -azoniabicyclo [2.2. 2j octane trifluoroacetate (3R)-l-Phenethyl-3-[thiophen-3-ylmethy-(2,4,5-trifluorobenzyl)carbamoyloxy]-1- azoniabicyclo[2.2.2]octane trifluoroacetate (3R)-3-[(4-Bromo-5-methyfthiophen-2-ylmethyl)-(3-methylthiophen-2-ylmethyl) carbamoyloxy] -1 - (3 -phenylpropyl) -1 -azoniabicyclo[2.2.2] octane trifluoroacetate (3R)-3[(4,5-Dimethylfuran-2-ylmethyl)-(5-methylfurari-2- ylmethyl) carbamoyloxy] -1 - [3 - (3 -hydroxyphenoxy) propyl] -1 -azoniabicyclo [2.2 .2]octane trifluoroacetate (3R)-l-[3-(4-Fluorophenoxy)propyl]-3-[furan-3-ylmethyl-(5-methyl-2-trifluoromethylfuran-3-ylmethyl)carbamoyloxy] -1 -azoniabicyclo[2.2.2] octane trifluoroacetate (3R)-3-[(2,5-Dimethylfuran-3-ylmethyl)-(2-fluoro-4-methoxybenzyl) carbamoyloxy]- l-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate (3R)-l-Allyl-3-[2-(4-fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1 -azoniabicyclo[2.2.2]octane trifluoroacetate (3R)-3-[Butyl-(2,5-difluorophenyl) carbamoyloxy]-1 -heptyl-1 -azoniabicyclo[2.2.2]octane trifluoroacetate (3R)-l-(3-cyanopropyl)-3-[(2,6-difluorophenyl)pent-4-enylcarbamoyloxy]-l-azoniabicyclo[2.2.2]octane trifluoroacetate (3R)-3-[(3-Fluorophenyl)-(3,4,5-trifluoroben2yl)carbamoyloxy]-l-(3-phenylpropyl)-l-azoniabicyclo[2.2.2]octane bromide (3R)-3-[(5-Ethylthiophen-2-ylmethyl)-(3-methylthiophen-2- ylmethyl) carbamoyloxy] -1 - (3 -phenylpropyl) -1 - azoniabicyclo [2.2.2] octane bromide (3R)-3-[(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2- ylmethyl) carbamoyloxy] -1-(2 -phenoxyethyl) -1 -azoniabicyclo [2.2.2] octane bromide (3R)-3-[(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyloxy]-l-(3-phenylallyl)-1 -azoniabicyclo[2.2.2]octane bromide (3R)-l-Allyl-3-[2-(4-fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl) carbamoyloxy] -1 - azoniabicyclo [2.2.2] octane bromide 13. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 12 in admixture with a pharmaceutically acceptable carrier or diluent of a kind such as herein defined wherein the ratio of said compound to diluent or carrier is as herein defined.

Full Text

The present invention relates to a compound which is a carbamate quaternary ammonium salt.
This invention relates to new therapeutically useful quinuclidine carbamate derivatives, to some processes for their preparation and to pharmaceutical compositions containing them.
The structures according to the invention are antimuscarinic agents with a potent and long lasting effect. In particular, these compounds show high affinity and selectivity for muscarinic M3 receptors over M2 receptors. The M3 subtype of muscarinic receptor is present in'glands and smooth muscle and mediates the excitatory effects of the parasympathetic system on glandular secretion and on the contraction of visceral smooth muscle (Chapter 6, Cholinergic Transmission, in H.P. Rang etal., Pharmacology, 'Churchill Livingstone, New York, 1995),
M3 antagonists are therefore known to be useful for treating diseases characterised by an increased parasympathetic tone, by excessive glandular secretion or oy smooth muscle contraction (R,M. Eglen and S,S. Hegde, (1997), Drug News Perspect, 10(8):462-469).
Examples of this kind of diseases ars respiratory disorders such as chronic obstructive pulmonary disease (COPD), bronchitis, bronchial hyperreactivity, asthma, cough and rhinitis; urofogical disorders such as urinary incontinence, polfakiuria, neurogenic or unstable bladder, cystospasm and chronic cystitis; gastrointestinal disorders such as irritable bowel syndrome, spastic colitis, diverticulitis and peptic ulceration; and cardiovascular disorders such as vagally induced sinus bradycardia (Chapter 7, Muscarinic Receptor Agonists and Antagonists, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10the edition, McGraw Hill, Ney York, 2001).
The compounds of the invention can be used alone or in association with other drugs commonly regarded as effective in the treatment of these diseases. For example, they can be administered in combination with ß2--agonists, steroids, antiallergic drugs, phosphodiesterase IV inhibitors and/or leukotriene D4 (LTD4) antagonists for simultaneous, separate or sequential use in the treatment of a respiratory disease.
The present invention provides new quinuclidine carbamate derivatives with potent antagonist activity at muscarinic M3 receptors, which fall under the chemical structure described in formula (II).
Formula (If) represents a carbamate quaternary ammonium salt of the following generalstructure:
(Structure Removed)
wherein
R1 represents a group selected from phenyl, 2-furyl, 3-furyf, 2-thienyi, 3-thienyt, benzyl, furan-2-yirnethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, and thiophen-3-ylmethyf;
R2 represents a group selected from C1-C8 alkyl, C2 to Cs alkenyl, C2-C8 alkynyl, saturated or unsaturated C3 to C7 cydoalkyi, saturated or unsaturated C3 to C7 cydoalkyjmsthyl, phenyl, benzyl, phenethyl, furan-2-ylmethyI, furan-3-yImethyl, thiophen-2-ylmethyI, thiophsn-3-ylmethyl, pyridyl, and pyridylmethyl; wherein the carbocyclb moieties in the C3 to C7 cydoalkyi, C3 to C7 cydoalkylmethyl, phenyl, benzyl or phenethyl groups can be optionally bridged or fused to another saturated, unsaturated or aromatic earbocydic moiety or to a cyclic moiety comprising carbon atoms and 1 or 2 oxygen atoms wherein the C1-C8 alkyl, C2-C8 alkenyl and C2-C8 alkynyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy groups or C1-C8 alkoxy gropus;
the cyclic groups present in R1 and R2 being optionally substituted by one, two or three substituents selected from halogen, straight or branched C1-C8 alkyl, hydroxy, straight or branched C1-C8 alkoxy, ,-SH, straight or branched C1-C8 alkyfthio, nitro, cyano, -NR'R", -COsR', -C(O)-NR'R", -N(R'")C(0)-R,1 -N(R">C(0)NR'R", wherein R R" and R'" each independency represent a hydrogen atom or a straight or branched, C1-C8 alkyl group or R' and R" together with the atom to which they are attached form a cyclic group wherein the C1-C8 alkyl groups are unsubstituted or substituted with ona or more halogen atoms, hydroxy groups or C1-C8 alkoxy groups and the C1-C8 alkoxy and C1-C8
alkylthio groups are unsubstituted or substituted with one or more halogen atoms or hydroxy groups;
p is 1 or 2 and the carbamate group is attached at positions 2,3 or 4 of the azoniabicyclic ring,
wherein the sequence B-(CH2)n-A-(CH2)m- represents a group selected from 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl, 3-(4-fluorophenoxyJpropyl, 3-thiophen-2-y(propyl, allyl, heptyl and 3-cyanopropyl;
X" represents a pharmaceutical acceptable anion of a mono or polyvalent acid;
including all individual stereoisomers of formula (II) and mixtures thereof;
with the proviso that when the cyclic group present in R1 is unsubsituted or has only one subslituent R2 has at least one substituent;
and with the further proviso that the compound is not one of
1-Allyl-3-(R)[ben7.yl-(4-fluorophenyl)carbamoyloxy]-1-a2oniabicyclo[2.2.2]octane
trifluoroacetate;
3-(R)[Benzyf-(4-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-
azontablcyclo{2.2.2]octane trifluoroacetate;
'1-Allyl-3-(R)(benzyl-p-tolylcarbamoyloxy}-1-azoniabicyclo[2.2.2]octane tnfluoroacetate;
3-(R)(Benzyl-p-tolylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2 2 2]octane
trifluoroacetate
Further objectives of the present invention are to provide processes for preparing said compounds; pharmaceutical compositions comprising an effective amount of said compounds; the use of the compounds in the manufacture of a medicament for the treatment of diseases susceptible of being improved by antagonism of M3 muscarinic receptors; and methods of treatment of diseases susceptible to amelioration by antagonism of M3- muscarinic receptors, which methods comprise the administration of the compounds of the invention to a subject in need of treatment
J. L. G. Nilsson et al. describe in Acta Pharm. Suecica, 5:71-76 (1968) a group of quinudidine carbamate derivatives having antimalarial activity, among which diphenylcarbamic acid 1-azabicyc!o[2.2.2]oct-3-yl ester and ethylphenylcarbamic acid 1-azabicyclo[2.2.2]oct~3-yl ester are mentioned.
WO 02/00652 discloses a group of compounds which fall under the general structure of formula (II). The specific compounds disclosed in that application are excluded from the present invention.
As used herein, an alkyl, alkenyl or alkynyl group or moiety can be straight or branched, and is a lower alkyl, alkenyl or alkynyl group. A lower alkyl group contains 1 to 8, preferably 1 to 6, carbon atoms. Examples include methyl, ethyl, propyl, including i-propyl, butyl, including n-butyl, sec-butyl and tert-butyl, 1-methylbutyl, 1-ethylpropy), 1,2-dimethyfpropyl, n-hexyl or 1-ethylbutyl groups. More preferably a lower alkyl group contains from 1 to 4 carbon atoms. A lower alkenyl or alkynyl group contains 2 to 8, preferably 2 to 6, carbon atoms. Examples include vinyl, ally!, 1-propenyl, 4-pentenyl, 1-propynyl, 2-propynyl, 1-butyny), 2-bufynyl or 3-butynyl groups. More preferably, a lower alkenyl or alkynyl group contains 2 to 4 carbon atoms.
Optionally substituted lower alkyl, aikenyl or alkynyl groups mentioned herein include straight or branched lower alkyl, alkenyl or alkynyl groups as defined above, which may be unsubstituted or substituted in any position by one or more substituents, for example by 1, 2 or 3 substituents. When two or more substituents are present, each substituent may be the same or different. The substituent(s) are typically halogen atoms, preferably fluoride atoms, and hydroxy or alkoxy groups.
Alkoxy and alkylthio groups mentioned herein are typically lower aikoxy and alkylthio gioups, that is groups containing from 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, the hydrocarbon chain being branched or straight and optionally substituted in any position by one or more substituents, for example by 1, 2 or 3 substituents. When two or more substituents are present, each subsfrtuent may be the same or different. The substituent(s) are typically halogen atoms, most preferably fluoride atoms, and hydroxy groups. Preferred optionally substituted alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, t-butoxy, tnfluoromethoxy, difluoromethoxy, hydroxymethoxy, 2-hydroxyethoxy or 2-hydroxypropoxy Preferred optionally substituted alkylthio groups include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, sec-butytthio, t-butylthio,
trtfluoromethylthio, difluoromethylthio, hydroxymethylthio, 2-hydroxyethylthio or 2-hydroxypropylthio.
Cyclic groups mentioned herein include, unless otherwise specified, carbocyclic and heterocyclic groups. The cyclic groups can contain one or more rings. Carbocyclic groups may be aromatic or alicyclic, for example cycloalkyl groups. Heterocyclic groups also include heteroaryl groups.-
Cycloalkyl groups and alicyclic groups mentioned herein, unless otherwise specified, typically contain from 3 to 7 carbon atoms. Cycloalkyl groups and alicyclic rings of 3 to 7 carbon atoms include cyclopropy!, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
As used herein an aromatic group typically contains from 5 to 14, preferably 5 to 10 carbon atoms. Examples of aromatic groups include phenyl and naphthalenyl.
A heterocyclic or heteroaromatic group mentioned herein is typically a 5 to 10 membered group, such as a 5, 6 or 7 membered group, containing one or more heteroatoms selected from N, S and 0. Typically, 1, 2, 3 or 4 heteroatoms are present, preferably 1 or 2 heteroatoms A heterocyclic or heteroaromatic group may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom. Examples of heterocyclic groups include piperidyl, pyrrolidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, irnidazolyl, imidazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolmyl, cinnolinyl, pteridinyl, quinuclidinyl, triazolyl, pyrazolyl, tetrazolyl and thienyi. Examples of heteroaromatic groups include pyridyl, thienyl, furyl, pyrrolyl, irnidazolyl, benzothiazolyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazoiinyl, cinnolinyl, triazolyl and pyrazolyl.
As used heiein a halogen atom includes a fluorine, chlorine, bromine or iodine atom, typically a fluorine, chlorine or bromine atom.
As used herein, the term pharmaceutically acceptable salt embraces salts with a pharmaceutical^ acceptable acid or base. Pharmaceutical^ acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, dtphosphoric,
hydrobromic, hydroiodic and nitric acid and organic acids, for example citric, furnaric, rnaieic, malic, formic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
In the quaternary ammonium compounds of the present invention, an equivalent of an anion (X") is associated with the positive charge of the N atom. X" may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, formate, methanesulfonate and p-toluenesulfonate. X" is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, trifluoroacetate, formate, methanesulfonate, maleate, oxalate or succinate. More preferably X" is chloride, bromide, formate, trifluoroacetate or methanesulfonate.
Preferred compounds of formula (II) according to the invention as defined above are those wherein R1 represents a group selected from phenyl, 2-thienyl, 3-thienyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, furan-2-ylmethyI orfuran-3-ylmethyl, the cyclic groups present in R1 being optionally substituted with one to three substitutents selected from fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, ethyl, tert-butyl, hydroxy and cyano.
In particularly preferred embodiments R1 represents a group selected from phenyl, 2-fluorophenyl, 3-flurorophenyl, 4-fluarophenyl, 3-methylphenyl, 4-methylphenyl, 2,5-difluorophenyl, 2,6-difIuorophenyl, 2,4,5-trifIuorophenyl, 5-methylfuran-2-y]methyl, 4-fluoro-2-methylphenyl, 3~fluoro-4-methoxyphenyl, 3-methyI-thiophen-2-ylmethyl, 4,5-dimethyl-thiophen-2-ylmethyl, thiophen-3-ylmethyl, 5-methyl-furan-2-ylmethyl, 5-methyl-2-tnfluoromethyl-furan-3-ylmethyl, and 2,5-dimethyI-furan-3-ylmeihyl,
Also preferred are compounds of formula (II) as defined above wherein R2 represents a pent-4-enyl, pentyl, butyl, allyl, benzyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, furan-2-ylmethyl, furan-3-ylmethyi, phenethyl, cyclopentyl, cyciohexyl or cyclohexylmethyl group, the cyclic groups present in R2 being optionally substituted with one to three substitutents selected from fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, ethyls tert-butyl, hydroxy and cyano.
In particularly preferred embodiments R2 represents a group selected from 3-fluorobenzyl, 2,4,5-trifhiorobenzyl, 3,4,5-trifluorobenzyl, 5-Bromothiophen-2-ylmethyl,
3,4-dimethoxyphenylethyl, 3-methylthiophen-2-ylmethyl, thiophen-3-ylmethyI, 4-bromo-5-methylthiophen-2-y(methyl, 4,5~dimethylfuran-2-ylmethyl, furan-3-ylmethyl, 2-fluoro-4-methoxybenzyl. 2-(4-fluorophenyl)ethyl, butyl, pent-4-enyl and cyclopentyl.
X' represents in the preferred embodiments of formula (II) a chloride, bromide, trifluoroacetate or methanesulphonate anion.
Also preferred are compounds of formula (I) or (II) wherein p is 2 and/or wherein the azoniabicyclic ring is substituted in the 3-position.
The compounds of the present invention represented by formula (II), may have one or more asymmetric carbons. All possible stereoisomers are included, such as compounds of formula (II) wherein the carbon at the 3-position of the azoniabicyclic ring has either R or S configuration. All single isomers and mixtures of the isomers fall within the scope of the present invention.
Particularly preferred individual compounds of formula (II) include:
(3R)-3-[(3-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1 -(2-phenoxyethyl)-1 -azomabicyclo[2.2.2]octane bromide
(3R)-3-[(3-nuorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2 2.2]octane bromide
(3R)-1-(2-Phenoxyethyl)-3-[m"tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane bromide
(3R)-1-(3-Phenylpropyl)-3-[m-to!yl-(2,4,5-trifluorobenziyl)carbamoyloxy]-1-azoniabicyclo[2 2 2]octane bromide
(3R) 3-[(3-Fluorophenyl)-(3 4,5-trifluorobenzyl)carbamoyloxyI-1-(2-phenoxyethyl)-1-a20niabicyclo[2.2.2]octane bromide
(3R)-1-Allyl-3-[[2-(3,4'dimethoxyphenyl)ethyl)-(5-methyIfuran-2-ylmethyl)carbamoyloxy]~1-azoniabicyclo[2.2.2]ocfane bromide (3R)'3-[(5-Bromothiophen-2-y!methyl)-(2,4,5-trifluorophenyl)carbamoyloxyl-1-(3-phenoxypropyl)-1-azoniabicycfo[2.2.2]octane trifluoroacetate (3R)-3-[(4-Fluoro-2-methylpheny!)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(2--phenoxyethyl)-1-azoniabicyclo{2.2.2]octane trifluoroacetate (3R)-3-[(3-F!uoro-4-methoxyphenyI)thiophen-3-ylmethylcarbamoyloxy]-1-(3-
phenylallyl)-1-azoniabicyclo[2.2 2]octane trifluoroacetate
(3R)-1-Phenethyl-3-[thiophen-3-ylmethyl-(2,4,5-trifluorobenzy!)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane trifluoroacetate
(3R)-3-[(4-Bromo-5-methyithiophen-2-ylmethyl)-(3-methylthiophen-2-
ylmethyl)carbarnoyloxy]-1-(3-phenylpropyl}-1-azoniabicyclo[2.2.23octane
trifluoroacetate
(3R)-3^(4,5-Dimethylfuran-2-ylmethyl)-(5-methy!furan-2-y!methyl)carbamoyloxy]-1-[3-(3-hydroxyphenoxy)propy]]-1-azoniabicycIo[2.2.2]octane trifluoroacetate
(3R)-1-[3-(4-F!uorophenoxy)propyl]-3-[furan-3-ylmethy|-(5-methyl-2-
trifluoromethylfuran-3-yimethyl)carbarnoyIoxy]-1-azoniabiGyclo[2.2.2]octane
trifluoroacetate
(3R)-3-[(2,5-Dimethylfuran-3'ylmethyl)-(2'fluoro-4-methoxybenzyl)carbamoyloxy]-1-(3-thiophen-2-ylpropyl)-1-azoniabicyc!o[2.2.2]octane trifluoroacetate
(3R)-1-AI|yl-3'[2-(4-fluorophenyl)ethyl]-(3-methyfthiophen-2-ylmethyl)carbamoyloxyl-1-a£oniabicycio[2.2.2]octane trifluoroacetate
{3R)-3-[Butyl-(2)5-dffluoropheny])carbamoyloxy]-1-heptyl-1-azoniabicydo[2 2.2]octane trifluoroacetate
(3R)-1-(3-cyanopropyl)-3-[(2,6-difluorophenyl)pent-4-enylcarbamoyloxyl-1-azoniabicyclo[2.2.2]ociane trifluoroacetate
(3R)-3'[(3-FluorophenylV(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(3-prienylpropyi)-1-a7oniabicyclo[2 2.2]octane bromide
(3R)-34(5-Ethyllhiophen-2-ylmethyl)K3-methylthiophen-2-ylmethyl)cafbarnoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide
(3R)-3-[(4-Ffuoro-2-methyIphenyl)-(3-methylthiophen-2-ylmethyl)carbamoy]oxy]-1-(2-pnenoxyethyl)-1-azoniabicyclo[2.2.2joctane bromide (3R)-3-[(3-Ruoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyloxy]-1-(3-phcnylallyl)-1-azoniabicyclo[2.2 2]odane bromide
(3R)-1-Ally!-3-[2-(4-fluorophenyl)ethyl]-(3-methylthiophen-2-ylrriethy])carbannoy!oxy]-1-azoniabicyclo[2.2.2]octane bromide
The quaternary ammonium derivatives of general formula (II), may be prepared by reaction of an alkylating agent of general formula (VI) with compounds of general formula (I), as described in the following scheme. In formulas (I), (II) and (VI), R1, R2, A, B, X, n, m and p are as defined above.
(Formula Removed)
In formula (VI), W represents any suitable leaving group, such as a group X as defined above. Preferably, W represents a group X.
This alkylation reaction may be carried out by two different experimental procedures, (c) and (d) which are described in the experimental section below, in particular method (d) provides a new experimental process, using solid phase extraction methodologies that allow the parallel preparation of several compounds. If W represents a group other than X, the quaternary ammonium salt of formula (II) is produced from the product of method (c) or (d) by carrying out an exchange reacfion according to standard methods to replace the anion W" with the desired anion X".
Methods (c) and (d) are described in the experimental section. Compounds of general formula (VI) which are not commercially available have been prepared by synthesis according to standard methods. For example, compounds wherein n = 0 and A~ -0-, -S- or --NR4, wherein R4 is as defined above, were obtained by reaction of the corresponding alcohol, thiol or amine derivative or its sodium or potassium salt with an alkylating agent of general formula Y-(CH2)m-W, wherein W may be a halogen and Y may be a halogen or a sulphonate ester. In other examples, compounds of general formula (VI), where n>=1 were synthesised from the corresponding alcohol derivative of general formula (VII) by known methods.
(Structure Removed)
(VI!)
The structures of the prepared compounds were confirmed by 1H-NMR and MS. The NMR were recorded using a Varian 300 MHz instrument and chemical shifts are expressed as parts per million (8) from the internal reference tetramethyl silane. Their purity was determined by HPLC, using reverse phase chromatography on a Waters instrument. Molecular ions were obtained by electrospray ionization mass spectrometry on a Hewlett Packard instrument. HPLC-MS experiments were performed on a Gilson instrument equipped with a binary pump (Gilson piston pump 321); a vacuum degasser (Gilson 864); an injector-fraction collector (Gilson liquid handler 215); two injection modules, anneal and preparative (Gilson 819); a valve (Gilson v'aivemafe rowj; a 1/1000 splitter (Acurafe fay LC Packings); a make-up pump (Giteon 307); a diode array detector (Gilson 170) and a MS detector (a Thermoquest Finnigan aQa, a quadrupole mass Spectrometer with ES an APCI ionisation modes). The HPLC-MS instrument was controlled by an IBM PC.
Method (c)
Example 1
Preparation of (3R)-1-(2-phenoxyethyI).3-[m-tolyl-(2,4,5-
trif!uorobenzyl)carbamovioxy]-1-azoniabicyclol:2.2.2]octane bromide
0.300 g (0.742 mmol) of m toiyl-(2,4,5-trifluorobenzyl)carbamic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester, 7.0 rnl of tetrahydrofuran and 0.253 g (1.258 mmol) of (2-bramoethoxy)benzene were mixed. The solution was refluxed for 55 hours and allowed to continue stirring at room temperature during 16 more hours. After this time the solvent was evaporated in vacuo. Ether was added and the mixture stirred to obtain a solid. This solid was treated with ether several times in order to eliminate the residual alkylating agent. Finally the suspension was filtered and the solid obtained washed with ether and dried. The yield was 0.34 g (75.5%). m.p.: 137.3-139.1°C MS [M-8rj+. 525
1H-NMR(DMSO-d6): δ 1.40,1.70 (m, 1H), 1.70-2.05 (m, 3H), 2.20 (m, 1H), 2.25 (s, 3H), 3.25-3.40 (m, 1H), 3.40-3.8o (m, 6H), 3.95-4.10 (m, 1H), 4.44 (m, 2H), 4.90 (m, 2H), 5,01 (m. 1H), 6 95-7.30 (rn, 7H), 7.30-7.60 (m, 4H).
Example 2
Preparation of (3R)-1-AIlyl_3-[[2-(3,4-dimethoxypheny[}ethyl]-(5-methylfuran-2-
ylmethyl)carbamoy!oxyl-1azonlabicyclot2.2.2]octane bromide
0.300 g (0.7 mmol) of [2-(3,4-Dirnethoxyphenyl)ethylj-(5-metfiylfuran-2-ylmethyl)carbamic acid (3R)-1-azabicyclo[2.2.2]oct-3-yI ester were dissolved in 5 ml of CHCI3 and 3.6" ml of acetoniirile. To this solution 0.30 ml (0.423 g, 3.5 mmol) of aflyl bromide were added and the mixture was stirred during 21 hours at room temperature under N2 atmosphere. Solvents were evaporated. The residue was treated with ether several times to obtain an oil, which was redissolved in CHCIj and evaporated to dryness to give 0.365 g (94.8%) ofthe title product. MS [M-Br]+: 469
Also included within the scope of the present invention are pharmaceutical compositions which comprise, as the active ingredient, at least one qurnuclidine derivative of general formula (II) in association with a pharmaceutically acceptable carrier or diluent. Preferably the composition is made up in a form suitable for oral administration.
The pharmaceutically acceptable carrier or diluents which are mixed with the active compound or compounds, to form the composition of this invention are well-known perse and the actual excipients used depend inter alia on the intended method of administration of the composition.
Compositions of this invention are preferably adapted for oral administration. In this case, the composition for oral administration may take the form of tablets, film-coated tablets, liquid inhalant, powder inhalant and inhalation aerosol; all containing one or more compounds of the invention; such preparations may be made by methods . well-known in the art
The diluents which may be used in the preparations of the compositions include {hose liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents, if desired. Tablets or film-coated tablets may conveniently contain between 0.1 mg and 500 mg, preferably from 0.5 to 200 mg of active ingredient. The inhalant compositions may contain between 1µg and 1,000 µg, preferably from 10 to 800 µg of active ingredient. In human therapy, the dose of the compound of general formula (II) will depend on the desired effect and duration of treatment; adult doses are generally between 0.5 mg and 300 mg per day as tablets and 10 µg and 800 µg per day as inhalant composition.
The compounds of the present invention, or pharmaceutical compositions containing them, may be used together with a ß2 agonist, steroid, antiallergic drug and/or phosphodiesterase IV inhibitor, for simultaneous, separate or sequential use in the treatment of a respiratory disease.
Pharmacological Action
The following examples demonstrate the excellent pharmacological activities of
the compounds of the present invention. The results on human muscarinic receptor
binding and in the test on bronchospasm in guinea pig, were obtained as described
below.
Human muscarinic receptor studies.
The binding of [3 H]-NMS to human muscarinic receptors was performed according to Waelbroeck et al (1990), Mol. Pharmacol., 38: 267-273, Assays were carried out at 25°C Membrane preparations from stably transfected Chinese hamster ovary-K1 cells (CHO) expressing the genes for the human muscarinic M3 receptors were used
For determination of IC5t), membrane preparations were suspended in DPBS to a final concentration of 89 µg/ml for the M3 subtype. The membrane suspension was incubated with the tritiated compound for 60 min. After incubation the membrane fraction was separated by filtration and the bound radioactivity determined. Non specific binding was determined by addition of 10-4 M atropine. At least six concentrations were assayed in duplicate to generate individual displacement curves. Our results show that the compounds of the present invention have high affinities for muscarinic M3 receptors. Preferred compounds of the invention have an IC5o[nM} value for M3 receptors of less than 35 nM, most preferably less than 10 nM.
The preferred compounds of the invention also show high selectivity for M3 receptors with respect to M2 receptors Thus, the ratio IC50 M2 / IC50 M3 is higher than 5, preferably higher than 10, most preferable higher than 15.
Test on bronchospasm in guinea pig
The studies were performed according to H. Konzett and F. RSssler (1940), Arch Exp. Path. Pharmacol. 195, 71-74. Aqueous solutions of the agents to be tested

were nebulized and inhaled by anaesthetized ventilated male guinea pigs (Dunkin-Hartley). 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 compounds of the present invention showed bronchodilator activity with high potency and a long duration of action.
From the above described results one of ordinary skill in the art can readily understand that the compounds of the present invention have excellent antlmuscarinic activity (M3) and thus are useful for the treatment of diseases in which the muscarinic M3 receptor is implicated, including respiratory diseases such as chronic obstructive pulmonary disease, bronchitis, asthma, bronchial hyper reactivity and rhinitis; urinary diseases such as urinary incontinence, pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm and chronic cystitis; gastrointestinal diseases such as irritable bowel syndrome, spastic colitis, diverticulitis and peptic ulceration; and cardiovascular disorders such as vagally induced sinus bradicardia. For example, the compounds of the present invention are useful for the treatment of respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, and rhinitis; urinary diseases such as urinary incontinence and pollakinuria in neuripenia pollakinuna, neurogenic bladder, nocturnal enuresis, unstable bladder, cytospasm and chronic cystitis; and gastrointestinal diseases such as irritable bowel syndrome, spastic colitis and diverticulitis.
The present invention further provides a compound of formula (II) or a pharmaceutically acceptable composition comprising a compound of formula (II) for use in a method of treatment of the human or animal body by therapy, in particular for the treatment of respiratory, urinary or gastrointestinal disease.
The present invention further provides the use of a compound of formula (II) or a pharmaceutically acceptable composition comprising a compound of or (II) for the manufacture of a medicament for the treatment of respiratory, urinary or gastrointestinal disease.
Further, the compounds of formula (II) and pharmaceutical compositions comprising a compound of formula (It) can be used in a method of treating respiratory, urinary or gastrointestinal disease, which method comprises administering to a human

or animal patient in need of such treatment an effective amount of a compound of • formula (il) or a pharmaceutical composition comprising a compound of formula (II).
Further, the compounds of formula (II) and pharmaceutical compositions comprising a compound of formula (II) can be used in combination with other drugs effective in the treatment of these diseases. For example with ß2 agonists, steroids, antiallergic drugs, phosphodiesterase IV inhibitors and/or leukotriene DA (LTD4) inhibitors, for simultaneous, separate or sequential use in the treatment of a respiratory disease.
The present invention therefore provides a combination product comprising - -. (i) -a compound according to the invention; and
(ii) another compound effective in the treatment of a respiratory, urological or gastrointestinal disease or disorder
for simultaneous, separate or sequential use.
The compound (ii) which is effective in the treatment of a respiratory, urological or gastrointestinal disease or disorder may be a ß2 agonist, steroid, antiallergic drug, phosphodiesterase IV inhibitor and/or leukotriene D4 (LTD4) antagonist. Preferably, the product is for simultaneous, separate or sequential use in the treatment of a respiratory disease.
The present invention will be further illustrated by the following examples. The examples are given by way of illustration only and are not to be construed as limiting.
Example 3
(3R)-3-[(3-F!uorobenzyll)-(3-fluorophenyl)carbannoyloxy]-1-(2-phenoxyethyl)-1-azoniablcycfo[2.2,2]octane bromide
The title compound was synthesised according to method c. The yield of the final step was 0.32 g, 69.2%. m.p : 142.8-143.6°C
MS [M-BFJ +' 493. : - -
1H-NMR(DMSO-d3): δ1.50-1.70 (m, 1H), 1.70-1.85 (m, 1H), 1.85-2.05 (m, 2H), 2.23 (m, 1H), 3.25-3.40 (m, 1H), 3.40-3.75 (m, 6H), 3.95-4.10 (m, 1H), 4,44 (m, 2H), 4.90-5.10 (m, 3H), 6.90-7.25 (m, 8H), 7.25-7.45 (m, 5H).
Example 4

(3R)-3-[(3-FIuorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.Z2]octane bromide
The title compound was synthesised according to method c. The yiefd of the final step
was 0.24 g, 52,1%.
m.p.: 64.5-66.0°C
MS [M-Br]+: 491
1H-NMR(DMSO-d6): .δ 1.50-1.65 (m, 1H), 1.65-180 (m, 1H). 1.80-2.10 (m, 4H), 2.20
(m,.1H), 2.60 (t, 2H), 3.05-3.55 (m, 7H), 3.80-3.90 (m, 1H), 4.90-5.10 (m, 3H), 7.05-
7.45 (m, 13H).
Example 5
(3R)-1-(3-Phenylpropyl)-3-[m-tolyl-{2,4,5-trifluoroben2yl)carbamoyloxy]-1-azoniabicycloj;2.2.2]octane bromide
The title compound was synthesised according io method c. The yield of the final step
was 0.32 g , 72.5%.
m.p.: 113.1-114.8°C
MS [M-Br] \ 523
1H-NMR(DMSO-d6):.δ 1.40-1.60 (m, 1H), 1.60-1.80 (m, 1H), 1.80-2.10 (m, 4H), 2.18
(m, 1H), 2.26 (s. 3H), 2.60 4 98 (m, 1H), 7.0-7.15 (m, 2H), 7.15-7.40 (m, 7H)r 7.40-7.60 (m, 2H).
Example 6
(3R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy].1-.(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane bromide
The title compound was synthesised according to method c The yield of the final step
was 0.15 g, 75%.
m.p.: 173 9-175.5*0
MS [M-Br]+: 529
1H-NMR(DMSO-da): .δ 1.50-2.05 (m. 4H), 2.24 (m, 1H), 3 25-3.85 (m, 7H), 4 03 (m,
1H), 4.45 (m, 2H), 4.95 (m, 2H), 5.04 (m, 1H), 6.95-7.15 (m, 4H), 7 20-7.45 (m, 7H).
Exampla 7
(3R}-3-[(4-F?uoro-2-methyfphenyi)-(3-methyfthiopberi-2-ylmethyl)carbamoyJoxy]-1-(2-phenoxyethyl)-1-azoniabicycIo[2.2.2]octane bromide
The title compound was synthesised according to methods a and c . The yield of the final step was 0 5 g, 84.7%. MS [M-Br] +; 509
1H-NMR(DMSQ-d8): δ 1.15-1.45 (m, 1H), 1.60-2.20 (m, 10H), 2.90-3.10 (m, 1H), 3.30-3.85 (m, 6H), 3.90-4.20 (m, 1H), 4.30-4.55 (m, 2H), 4.75-5.15 (m, 3H), 6.78 (m, 1H), 6.90-7.20 (m, 6H), 7.35 (m, 3H).
Example 8
(3R)-3-[(3-FIuoro-4-methoxyphenyI)thiophen-3-ylmethylcarbamoyloxy]-1-(3-phenylallyI)-1-azoniabicydo[2.2.2]octane bromide
The title compound was synthesised according to method c. The yield of the final step
was 1,9 g, 97,1%.
MS [M-Br]+: 507
1H-NMR(DMSO-d6): δ 1.40-1.65 (m, 1H), 1.65-2.05 3.30 (m, 1H), 3.30-3.60 (m, 4H), 3.78 (s, 3H), 3.80-3.95 (m, 1H), 3.95-4.10 (m. 2H),
4.80 (m, 2H), 5.0 (m, 1H), 6.42 (m, 1H), 6,85 (m, 1H), 6.90-7.15 (m, 3H), 7.20-7.50
(m,7H), 7.58 (m, 1H).
Example 9
(3R)-1-Allyl-3-[2-{4-fluorophenyl)ethyl]-(3-methyIthiophen-2-ylmethyj)carbamoyloxy]-1 -azoniabicyclo[2.2.2]octane bromide
The title compound was synthesised according to method c. The yield of the final step
was 0.4g, 51.3%
MS [M-Brf: 443
1H-NMR(DMSO-d6): δ 1.80-2.10 (m, 4H), 2.20 (s, 3H), 2.25-2.30 (m, 1H), 2.77 (m,
2H), 3.15-3.70 (m, 7H), 3.82 (m, 1H), 3.90 1H), 5.56-5.66 (m, 2H), 5.90-6.10 (m, 1H), 6.87 (m, 1H), 7.10-7.30 (m, 4H), 7.36 (m,
1H).
The following examples illustrate pharmaceutical compositions according to the present invention and procedures for their preparation.
Example 10
Preparation of a pharmaceutical composition: tablets
Formulation'
Compound of the present invention 5.0 mg
Lactose 113.6 mg
Microcrystalline cellulose 28.4 mg
Light silicic anhydride 1.5 mg
Magnesium stearate 1.5 mg
Using a mixer machine, 15 g of the compound of the present invention was mixed with 340.8 g of lactose and 85.2 g of rnicrocrystalline cellulose. The mixture was subjected to compression moulding using a roller compactor to give a flake-like compressed material. The flake-like compressed material was pulverized using a hammer mill, and the pulverized material was screened through a 20 mesh screen. A 4.5 g portion of light silicic anhydride and 4.5 g of magnesium stearate were added to the screened material and mixed. The mixer product was subjected to a tablets making machine equipped with a die/punch system of 7.5 mm in diameter, thereby obtaining 3,000 tablets each having 150 mg in weight.
Example 11
Preparation of a pharmaceutical composition: tablets coated
Formulation: ,
Compound of the present invention 5.0 mg
Lactose 95.2 mg
Corn starch 40.8 mg
Polyvinylpyrrolidone ..,. 7.5 mg
Magnesium stearate 1.5 mg
Hydroxypropylcellulose 2.3 mg
Polyethylene glycol 0.4 mg
Titanium dioxide 1.1 mg
Purified talc 0.7 mg
Using a fluidized bed granulating machine, 15 g of the compound of the present invention was mixed with 285.6 g of lactose and 122.4 g of corn starch. Separately, 22.5 g of polyvinylpyrrolidone was dissolved in 127.5 g of water to prepare a binding solution. Using a fluidized bed granulating machine, the binding solution was sprayed on the above mixture to give granulates, A 4.5 g portion of magnesium stearate was added to the obtained granulates and mixed. The obtained mixture was subjected to a tablet making machine equipped with a die/punch biconcave system of 6.5 mm in diameter, thereby obtaining 3,000 tablets, each having 150 mg in weight. Separately, a coating solution was prepared by suspending 5.9 g of hydroxypropylmethylce!lulo5e 2910,1.2 g of polyethylene glycol 6000, 3.3 g of titanium dioxide and 2.1 g of purified talc in 72.6 g of water, Using a High Coated, the 3,000 tablets prepared above were coated with the coating solution to give film-coated tablets, each having 154.5 mg in weight.
Example 12
Preparation of a pharmaceutical composition: liquid inhalant
Formulation:
Compound of the present invention 400 µg
Physiological saline 1 ml
A 40 mg portion of the compound of the present invention was dissolved in 90 ml of physiological saline, and the solution was adjusted to a total volume of 100 ml with the same saline solution, dispensed in 1 ml portions into 1 ml capacity ampoule and then sterilized at 115° for 30 minutes to give liquid inhalant.
Example 13
Preparation of a pharmaceutical composition: powder, inhalant
Formulation-
Compound of the present invention 200 µg
Lactose 4,000 µg
A 20 g portion of the compound of the present invention was uniformly mixed with 400 g of lactose, and a 200 mg portion of the mixture was packed in a powder inhaler for exclusive use to produce a powder inhalant.
Example 14
Preparation of a pharmaceutical composition: inhalation aerosol.
Formulation:
Compound of the present invention 200 µg
Dehydrated (Absolute) ethyl alcohol USP 8,400 µg
i,1,1,2-Tetrafluoroethane{HFC-134A) 46,810 µg
The active ingredient concentrate is prepared by dissolving 0.0480 g of the compound of the present invention in 2.0160 g of ethyl alcohol. The concentrate is added to an appropriate filling apparatus. The active ingredient concentrate is dispensed into aerosol container, the headspace of the container is purged with Nitrogen or HFC-134A vapour (purging ingredients should not contain more than 1 ppm oxygen) and is sealed with valve. 11.2344 g of HFC-134A propellant is then pressure filled into the sealed container.

We Claim:
1. A compound which is a carbamate quaternary ammonium salt of formula (II):
(Formula Removed)
wherein
Rl represents a group selected from phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen- 3 -ylmethyl;
R2 represents a group selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, saturated or unsaturated C3-C7 cycloalkyl, saturated or unsaturated C3-C7 cycloalkylmethyl, phenyl, benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl, and pyridylmethyl; wherein the carbocyclic moieties in the C3-C7 cycloalkyl, C3-C7 cycloalkylmethyl, phenyl, benzyl or phenethyl groups can be optionally bridged or fused to another saturated, unsaturated or aromatic carbocyclic moiety or to a cyclic moiety comprising carbon atoms and 1 or 2 oxygen atoms; wherein the C1-C8 alkyl, C2-C8 alkenyl and C2-C8 alkynyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy groups or C1-C8 alkoxy groups;
the cyclic groups present in R1 and R2 being optionally substituted by one, two or three substituents selected from halogen, straight or branched, C1-C8 alkyl, hydroxy, straight or branched, C1-C8 alkoxy, -SH, straight or branched C1-C8 alkylthio, nitro, cyano, NR'R", -CO2R', -C(0)-NR'R", -N(R")C(0)-R', -N(R")-C(0)NR'R", wherein R', R" and R'" each independently represents a hydrogen atom or a straight or branched, C1-C8 alkyl group or R' and R" together with the atom to which they are attached form a cyclic group; wherein the C1-C8
alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy groups or C1-C8 alkyoxy groups and the C1-C8 alkoxy and C1-C8 alkylthio groups are unsubstituted or substituted with one or more halogen atoms or hydroxy groups;
p is 1 or 2 and the carbamate group is attached at positions 2, 3 or 4 of the azoniabicyclic ring,
wherein the sequence B-(CH2)n-A-(CH2)m- represents a group selected from 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl, 3-thiophen-2-ylpropyl, allyl, heptyl and 3-cyanopropyl;
X represents a pharmaceutically acceptable anion of a mono or polyvalent acid;
including all individual stereoisomers of formula (II) and mixtures thereof;
with the proviso that when the cyclic group present in Rl is unsubstituted or has only one substitutent R2 has at least one substituent; and
with the further, proviso that the compound is not one of:
l-Allyl-3-(R)[benzyl-(4-fluorophenyl)carbamoyloxy]-l-azoniabicyclo[2.2. 2]octane; trifluoroacetate
3-(R)[Ben2yl-(4-fluorophenyl)carbamoyloxy]-1 -(3-phenylpropyl)-1 -azoniabicyclo[2.2.2]octane; trifluoroacetate
1 -Allyl-3-(R) (benzyl-p-tolyl-carbamoyloxy)-1 -azoniabicyclo[2.2.2] octane; trifluoroacetate
3-(R) [Benzyl-p-tolylcarbamoyloxy) -1 - (3-phenylpropyl) -1 -azoniabicyclo[2.2.2]octane; trifluoroacetate.
2. A compound as claimed in claim 1 wherein Rl represents a group selected from phenyl, 2-thienyl, 3-thienyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, furan-2-ylmethyl or furan-3-ylmethyl, the cyclic groups present in Rl being optionally substituted with one to three substitutents selected from
fluorine, chlorine, bromine, methyl, methoxy, trifhioromethyl, ethyl, tert-butyl, hydroxy and cyano.
3. A compound as claimed in claim 2 wherein Rl represents a group selected from phenyl, 2-fluorophenyl, 3-flurorophenyl, 4-fluorophenyl, 3-methylphenyl, 4-methylphenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,4,5-trifluorophenyl, 5-methylfuran-2-ylmethyl, 4-fluoro-2-methylphenyl, 3-fluoro-4-methoxyphenyl, 3-methyl-thiophen-2-ylmethyl, 4,5-dimethyl-thiophen-2-ylmethyl, thiophen-3-ylmethyl, 5-methyl-furan-2-ylmethyl, 5-methyl-2-trifluoromethyl-furan-3-ylmethyl, and 2,5-dimethyl-furan-3- ylmethyl.
4. A compound as claimed in any one of claims 1 to 3 wherein R2 represents a pent-4-enyl, pentyl, butyl, allyl, benzyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, furan-2-ylmethyl, furan-3-ylmethyl, phenethyl, cyclopentyl, cyclohexyl or cyclohexylmethyl group, the cyclic groups present in R2 being optionally substituted with one to three substitutents selected from fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, ethyl, tert-butyl, hydroxy and cyano.
5. A compound as claimed in claim 4 wherein R2 represents a group selected from 3-fluorobenzyl, 2,4,5-trifluorobenzyl, 3,4,5-trifluorobenzyl, 5-Bromothiophen-2-ylmethyl, 3,4-dimethoxyphenylethyl, 3-methylthiophen-2-ylmethyl, thiophen-3-ylmethyl, 4-bromo-5-methylthiophen-2-ylmethyl, 4,5-dimethylfuran-2-ylmethyl, furan-3-ylmethyl, 2-fluoro-4-methoxybenzyl, 2-(4-fluorophenyl)ethyl, butyl, pent-4-enyl and cyclopentyl.
6. A compound as claimed in any one of the preceding claims wherein X" represents a chloride, bromide, trifluoroacetate or methanesulphonate anion.
7. A compound as claimed in any one of the preceding claims, wherein p is 2.
8. A compound as claimed in any one of the preceding claims, wherein the azoniabicyclic ring is substituted in the 3-position.
9. A compound as claimed in claim 8 wherein the carbon at the 3-position of the azoniabicyclic ring has R configuration.
10. A compound as claimed in claim 8 wherein the carbon at the 3-position of the azoniabicyclic ring has S configuration.
11. A compound as claimed in any one of the preceding claims, which is a single isomer.
12. A compound as claimed in claim 1 which is one of.
(3R)-3-[(3-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]- l-(2-phenoxyethyl)-1 azoniabicyclo[2.2.2]octane bromide
(3R)-3-[(3-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide
(3R)-l-(2-Phenoxyethyl)-3-[m-tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-l-azoniabicyclo[2.2.2]octane bromide
(3R)-l-(3-Phenylpropyl)-3-[m-tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-l-azoniabicyclo[2.2.2]octane bromide
(3R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-l-(2-phenoxyethyl)-1 -azoniabicyclo[2.2.2)octane bromide
(3R)-l-Allyl-3-[[2-(3,4-dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamoyloxy]-l-azoniabicyclo[2.2.2]octane bromide
(3R) -3-[(5-Bromothiophen-2-ylmethyl) - (2,4,5-trifluorophenyl) carbamoyloxy] -1 -(3-phenoxypropyl)-l-azoniabicyclo[2.2.2]octane trifluoroacetate
(3R)-3-[(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-
ylmethyl) carbamoyloxy] -1 - (2 -phenoxyethyl) -1 -azoniabicyclo [2.2.2] octane
trifluoroacetate
(3R)-3-[(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyloxy]-l-(3-phenylallyl) -1 -azoniabicyclo [2.2. 2j octane trifluoroacetate
(3R)-l-Phenethyl-3-[thiophen-3-ylmethy-(2,4,5-trifluorobenzyl)carbamoyloxy]-1- azoniabicyclo[2.2.2]octane trifluoroacetate
(3R)-3-[(4-Bromo-5-methyfthiophen-2-ylmethyl)-(3-methylthiophen-2-ylmethyl) carbamoyloxy] -1 - (3 -phenylpropyl) -1 -azoniabicyclo[2.2.2] octane trifluoroacetate
(3R)-3[(4,5-Dimethylfuran-2-ylmethyl)-(5-methylfurari-2-
ylmethyl) carbamoyloxy] -1 - [3 - (3 -hydroxyphenoxy) propyl] -1 -azoniabicyclo [2.2
.2]octane trifluoroacetate
(3R)-l-[3-(4-Fluorophenoxy)propyl]-3-[furan-3-ylmethyl-(5-methyl-2-trifluoromethylfuran-3-ylmethyl)carbamoyloxy] -1 -azoniabicyclo[2.2.2] octane trifluoroacetate
(3R)-3-[(2,5-Dimethylfuran-3-ylmethyl)-(2-fluoro-4-methoxybenzyl) carbamoyloxy]- l-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate
(3R)-l-Allyl-3-[2-(4-fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1 -azoniabicyclo[2.2.2]octane trifluoroacetate
(3R)-3-[Butyl-(2,5-difluorophenyl) carbamoyloxy]-1 -heptyl-1 -azoniabicyclo[2.2.2]octane trifluoroacetate
(3R)-l-(3-cyanopropyl)-3-[(2,6-difluorophenyl)pent-4-enylcarbamoyloxy]-l-azoniabicyclo[2.2.2]octane trifluoroacetate
(3R)-3-[(3-Fluorophenyl)-(3,4,5-trifluoroben2yl)carbamoyloxy]-l-(3-phenylpropyl)-l-azoniabicyclo[2.2.2]octane bromide
(3R)-3-[(5-Ethylthiophen-2-ylmethyl)-(3-methylthiophen-2-
ylmethyl) carbamoyloxy] -1 - (3 -phenylpropyl) -1 - azoniabicyclo [2.2.2] octane
bromide
(3R)-3-[(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-
ylmethyl) carbamoyloxy] -1-(2 -phenoxyethyl) -1 -azoniabicyclo [2.2.2] octane
bromide
(3R)-3-[(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyloxy]-l-(3-phenylallyl)-1 -azoniabicyclo[2.2.2]octane bromide
(3R)-l-Allyl-3-[2-(4-fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl) carbamoyloxy] -1 - azoniabicyclo [2.2.2] octane bromide
13. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 12 in admixture with a pharmaceutically acceptable carrier or diluent of a kind such as herein defined wherein the ratio of said compound to diluent or carrier is as herein defined.

Documents:

4058-delnp-2004-abstract.pdf

4058-delnp-2004-assignment.pdf

4058-delnp-2004-claims.pdf

4058-delnp-2004-complete specification (granted).pdf

4058-delnp-2004-correpsondence-others.pdf

4058-delnp-2004-correpsondence-po.pdf

4058-delnp-2004-description (complete).pdf

4058-delnp-2004-form-1.pdf

4058-delnp-2004-form-13.pdf

4058-delnp-2004-form-18.pdf

4058-delnp-2004-form-2.pdf

4058-delnp-2004-form-3.pdf

4058-delnp-2004-form-5.pdf

4058-delnp-2004-form-6.pdf

4058-delnp-2004-gpa.pdf

4058-delnp-2004-pct-101.pdf

4058-delnp-2004-pct-210.pdf

4058-delnp-2004-pct-220.pdf

4058-delnp-2004-pct-301.pdf

4058-delnp-2004-pct-304.pdf

4058-delnp-2004-pct-306.pdf

4058-delnp-2004-pct-308.pdf

4058-delnp-2004-pct-332.pdf

4058-delnp-2004-pct-401.pdf

4058-delnp-2004-pct-402.pdf

4058-delnp-2004-pct-416.pdf

4058-delnp-2004-petition-137.pdf

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Patent Number

245402

Indian Patent Application Number

4058/DELNP/2004

PG Journal Number

03/2011

Publication Date

21-Jan-2011

Grant Date

18-Jan-2011

Date of Filing

20-Dec-2004

Name of Patentee

LABORATORIES ALMIRALI, S.A.

Applicant Address

LINDENHOF, DORFSTRASSE 38, 6340 BAAR, SWITZERLAND.

Inventors:

#	Inventor's Name	Inventor's Address
1	MARIA PRAT QUINONES	C/O ANDREA DORIA 2, 1 1, 08003 BARCELONA, SPAIN.
2	MARIA ANTONIA BUIL ALBERO	C/O PARIS 50, 1 4, 08029 BARCELONA, SPAIN.
3	MARIA DOLORS FERNANDEZ FORNER	C/O ROGER DE FLOR 221, 5 4, 08025 BARCELONA, SPAIN.

PCT International Classification Number

C07D 453/02

PCT International Application Number

PCT/EP03/06472

PCT International Filing date

2003-06-18

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	P200201439	2002-06-21	Spain