ES2351602T3 - PIRROLIDINIAN DERIVATIVES AS LINKS TO THE M3 MUSCARINIC RECEIVER. - Google Patents

Abstract

A compound of the formula I ** (See formula) ** in the form of salt or bipolar ion in which R1 and R3 are each independently a C3-C15 carbocyclic group or a 5- to 12-membered heterocyclic group which has less a heteroatom in the ring selected from nitrogen, oxygen and sulfur; R2 is hydrogen, hydroxy, or C1-C4 alkyl optionally substituted by hydroxy; J is C1-C2 alkylene; R4 is C1-C4 alkyl; R5 is C1 alkyl substituted by -SO-R6, -S (= O) 2-R6, -CO-R6, -CO-O-R6, -CO-NH-R6 or -R7, or R5 is C2-C10 alkyl substituted by -O-R6, -S-R6, -SO-R6, -S (= O) 2-R6, -CO-R6, -O-CO-R6, -CO-O-R6, -NH-CO -R6, -CO-NH-R6, -R7 or -R8, or R5 is C2-C10 alkenyl or C2-C10 alkynyl optionally substituted by -R7 or -R8; R6 is a C3-C15 carbocyclic group or a 5-12 membered heterocyclic group having at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur, or R6 is C1-C10 alkyl optionally substituted by C1-C10 alkoxy, -O-R7, a C3-C15 carbocyclic group or a 5-12 membered heterocyclic group having at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur; R7 is a 5 to 12 membered heterocyclic group having at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur; and R8 is a C3-C15 carbocyclic group.

Description

Pyrrolidinium derivatives as ligands for M3 muscarinic receptor.

This invention relates to compounds organic, its preparation and use as pharmaceutical products.

The WO-A-03/087094, EP-A-1302458 and WO-A-98/21183 describe derivatives of pyrrolidinium as muscarinic receptor ligands

In one aspect the invention provides compounds of the formula I

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one

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in the form of salt or bipolar ion in where

R1 and R3 are each independently a carbocyclic group C 3 -C 15 or a heterocyclic group of 5 to 12 members that have at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur;

R2 is hydrogen, hydroxy, or alkyl C_ {C} {C4} optionally substituted by hydroxy;

J is alkylene C 1 -C 2;

R 4 is alkyl C 1 -C 4;

R 5 is C 1 alkyl substituted by -SO-R 6, -S (= O) 2 -R 6, -CO-R 6, -CO-O-R 6, -CO-NH-R 6 or -R 7, or R 5 is C 2 -C 10 alkyl substituted by -O-R 6, -S-R 6, -SO-R 6, -S (= O) 2 -R 6, -CO-R 6, -O-CO-R 6, -CO-O-R 6, -NH-CO-R 6, -CO-NH-R 6, -R 7 or -R 8,

or R 5 is alkenyl C 2 -C 10 or alkynyl C 2 -C 10 optionally substituted by -R 7 or -R 8;

R 6 is a carbocyclic group C 3 -C 15 or a heterocyclic group of 5 to 12 members that have at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur,

or R 6 is alkyl C 1 -C 10 optionally substituted by alkoxy C 1 -C 10, -O-R 7, a C 3 -C 15 carbocyclic group or a group 5 to 12 member heterocyclic that has at least one heteroatom in the selected ring of nitrogen, oxygen and sulfur;

R 7 is a heterocyclic group of 5 to 12 members that have at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur; Y

R 8 is a carbocyclic group C_ {3} -C_ {15}.

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The terms used in the specification They have the following meanings:

"Optionally substituted" means that the called group can be substituted in one or more positions by a any or any combination of the radicals described.

"Halo" or "Halogen" as used here denotes an element that belongs to a group 17 (previously group VII) of the Periodic Table of the Elements, which may be, for example, fluorine, chlorine, bromine or iodine. Preferably the halo or halogen is fluorine, chlorine or bromine.

The "alkyl C_ {1} -C_ {10} "as used here denotes straight or branched chain alkyl having 1 to 10 atoms of carbon. Preferably, the alkyl C 1 -C 10 is alkyl C 1 -C 5, for example alkyl C_ {1} -C_ {4}.

"Alkylene C_ {1} -C_ {10} "as used here denotes straight or branched chain alkylene having 1 to 10 atoms of carbon. Preferably, the alkylene C 1 -C 10 is alkylene C_ {1} -C_ {4}.

The "alkenyl C_ {2} -C_ {10} "as used here denotes straight or branched chain alkenyl having 2 to 10 atoms of carbon. Preferably, the alkenyl C 2 -C 10 is alkenyl C_ {2} -C_ {4}.

"Alkynyl C_ {2} -C_ {10} "as used here denotes straight or branched chain alkynyl having 2 to 10 atoms of carbon. Preferably, the alkynyl C 2 -C 10 is alkynyl C 2 -C 8, for example alkynyl C_ {2} -C_ {4}.

The "alkoxy C_ {1} -C_ {10} "as used here denotes straight or branched chain alkoxy having 1 to 10 atoms of carbon. Preferably, the C 1 -C 10 alkoxy it is C 1 -C 4 alkoxy.

"Carbocyclic group C_ {3} -C_ {15} "as used here denotes a carbocyclic group having 3 to 15 carbon atoms in the ring, for example a monocyclic group, either cycloaliphatic, such as a C 3 -C 8 cycloalkyl, for example cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or aromatic, such as phenyl, which can be substituted by one or more, usually one or two, C 1 -C 4 alkyl groups, or a bicyclic group, such as a C 8 bicyclic group, bicyclic C 9 or bicyclic C 10, which may be cycloaliphatic or may be aromatic, such as indanyl, indenyl or naphthyl, successively any of which can be replaced by one or more, usually one or two alkyl groups C_ {1} -C_ {4}. Preferably the group carbocyclic C_ {3} -C_ {15} is a group C 3 -C 10 carbocyclic, for example cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, indanyl or naphthyl. Especially preferred is phenyl. The group C 3 -C 15 carbocyclic can be substituted or not substituted. Preferred substituents include halo by example fluoro, cyano, hydroxy, amino, nitro, carboxy, alkyl C 1 -C 10, haloalkyl C 1 -C 10, alkoxy C 1 -C 10, alkylcarbonyl C 1 -C 10, alkylsulfonyl C 1 -C 10, -SO 2 NH 2, -COO-C 6 -C 10 aryl, -COO-C 7 -C 15 aralkyl, a C 3 -C 15 carbocyclic group and a group 5 to 12 member heterocyclic that has at least one heteroatom in the selected ring of nitrogen, oxygen and sulfur. The "carbocyclic group C 3 -C 15 "is more especially phenyl no replaced.

The "cycloalkyl C_ {3} -C_ {8} "as used here denotes cycloalkyl having 3 to 8 carbon atoms. Preferably the "C 3 -C 8 cycloalkyl" is "C 3 -C 6 cycloalkyl".

"Haloalkyl C_ {1} -C_ {10} "as used here denotes C 1 -C 10 alkyl as defined formerly substituted by one or more halogen atoms, preferably one, two or three halogen atoms. Preferably "C 1 -C 10 haloalkyl" is "C 1 -C 4 haloalkyl".

"Alkylcarbonyl C_ {1} -C_ {10} "as used here denotes C 1 -C 10 alkyl as defined previously linked to a carbonyl group. Preferably "C 1 -C 10 alkylcarbonyl" is "C 1 -C 4 alkylcarbonyl".

"Alkylsulfonyl C_ {1} -C_ {10} "as used here denotes C 1 -C 10 alkyl as defined previously linked to -SO2 -. Preferably "C 1 -C 10 alkylsulfonyl" is "C 1 -C 4 alkylsulfonyl".

The "5-12 membered heterocyclic group that it contains at least one heteroatom in the selected ring of nitrogen, oxygen and sulfur "as used here denotes a group monoheterocyclic, biheterocyclic or triheterocyclic, which can be saturated or unsaturated that has 5 to 12 atoms in the ring. The monoheterocyclic groups include furyl, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, thiadiazolyl, isothiazolyl, oxadiazolyl, pyridinyl, oxazolyl, isoxazolyl, piperidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperazinyl, morpholinyl, triazinyl, oxazinyl or thiazolyl. Biheterocyclic groups include benzazolyl, benzimidazolyl, indazolyl and benzothiazolyl. Preferably the 5 to 12 member heterocyclic group is a heterocyclic group of 5 to 9 members. Heterocyclic groups of 5 to 9 members Preferred include furyl, pyrrolyl, triazolyl, thienyl, thiadiazolyl, oxazolyl, isoxazolyl, piperidinyl, pyridinyl, pyrazinyl, benzazolyl, benzimidazolyl, indazolyl and benzothiazolyl, but especially thienyl. Heterocyclic group 5 to 12 members can be substituted or unsubstituted, for example by one, two, three or four substituents. Substituents Preferred include halo, cyano, oxo, hydroxy, carboxy, nitro, C 1 -C 10 alkyl, alkylcarbonyl C 1 -C 10 and alkoxy C 1 -C 10 optionally substituted by aminocarbonyl

The "aminocarbonyl" as used here denotes amino attached to the nitrogen atom to a group carbonyl

The "C 6 -C 10 aryl" as used here denotes a carbocyclic aromatic group monovalent that contains 6 to 10 carbon atoms and that can be, for example, a monocyclic group such as phenyl or a group bicyclic such as naphthyl. Preferably aryl C 6 -C 10 is aryl C 6 -C 8, especially phenyl.

The "aralkyl C_ {7} -C_ {15} "as used here denotes alkyl, for example C 1 -C 5 alkyl as defined here above, substituted by aryl C_ {6} -C_ {10} as defined here above. Preferably C 7 -C 15 aralkyl is C 7 -C 10 aralkyl such as phenylC 1 -C 4 alkyl.

Through this specification and in the claims that follow, unless the context requires it to otherwise, the word "understand", or variations such as "understand" or "understand", it will be understood to imply the inclusion of a fixed integer or stage or group of integers or stages but not the exclusion of any other integer or stage or group of integers or stages.

Preferred compounds include those of formula I in the form of salt or bipolar ion where

R1 and R3 are each independently a carbocyclic group C 3 -C 15 or a heterocyclic group of 5 to 12 members that have at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur;

R2 is hydroxy;

J is alkylene C 1 -C 2;

R 4 is alkyl C 1 -C 4;

R 5 is C 1 alkyl substituted by -CO-R 6 or -CO-NH-R 6,

or R 5 is alkyl C 2 -C 10 substituted by -O-R 6, -S-R 6, -O-CO-R 6 or -R 8,

or R 5 is alkenyl C 2 -C 10 or alkynyl C 2 -C 10 optionally substituted by -R 8;

R 6 is a carbocyclic group C 3 -C 15,

or R 6 is alkyl C 1 -C 10 optionally substituted by alkoxy C 1 -C 10, O-R 8 or a C 3 -C 15 carbocyclic group; Y

R 8 is a carbocyclic group C_ {3} -C_ {15}.

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Especially preferred compounds include those of the formula I in the form of salt or bipolar ion where

R1 and R3 are each independently a carbocyclic group C 3 -C 10, preferably phenyl, or a 5 to 9 member heterocyclic group that has at least one heteroatom in the selected ring of nitrogen, oxygen and sulfur, preferably thienyl;

R2 is hydroxy;

J is alkylene C 1 -C 2;

R 4 is alkyl C 1 -C 4;

R 5 is C 1 alkyl substituted by -CO-R 6 or -CO-NH-R 6,

or R 5 is alkyl C 2 -C 5 substituted by -O-R 6, -S-R 6, -O-CO-R 6 or -R 8,

or R 5 is alkenyl C 2 -C 4 or alkynyl C 2 -C 8 optionally substituted by -R 8; R 6 is a carbocyclic group C 3 -C 10, preferably phenyl, or R 6 it is C 1 -C 15 -alkyl optionally substituted by alkoxy C 1 -C 4, O-R 8 or a group C 3 -C 10 carbocyclic; and R 8 is a C 3 -C 10 carbocyclic group, preferably phenyl.

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The compounds of the formula I are salts of quaternary ammonium Suitable counterions are counterions pharmaceutically suitable including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, format, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate and benzenesulfonate.

Compounds of formula I containing a Basic center are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. The pharmaceutically acceptable acid addition salts of compound of formula I include those of acids inorganic, for example, halogenated hydro acids such as acid hydrofluoric, hydrochloric acid, hydrobromic acid or acid iodide, nitric acid, sulfuric acid, phosphoric acid; Y organic acids, for example monocarboxylic aliphatic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, carboxylic aromatic acids such as benzoic acid, acid p-chlorobenzoic acid, diphenylacetic acid or acid triphenylacetic, aromatic hydroxy acids such as acid o-hydroxybenzoic acid p-hydroxybenzoic acid 1-hydroxynaphthalene-2-carboxylic or acid 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as methanesulfonic acid or acid benzenesulfonic. These salts can be prepared from the compounds of formula I by salt forming procedures known.

Compounds of the formula I containing acidic groups, for example carboxyl groups, are also capable of forming salts with bases, in particular pharmaceutically acceptable bases such as those well known in the art; such suitable salts include metal salts, particularly alkali metal salts or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with pharmaceutically acceptable ammonia or organic amines or heterocyclic bases such as ethanolamines, benzylamines or pyridine. These salts can be prepared from the compounds of the formula I by methods that form salts
known.

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In those compounds where there is one or more chiral centers of the compounds exist in isomeric forms optically active individual or as mixtures thereof, by example as racemic or diastereomeric mixtures. For example in those compounds where the functional group represented by J creates a chiral center attached to the carbon atom in the ring, the quaternary nitrogen atom is also a chiral center and so There are four possible diastereoisomers. The present invention encompasses both optically active R and S isomers individual as well as mixtures, for example racemic mixtures or diastereomeric thereof. Particularly the compounds Preferred of the invention are simple isomers, either simple enantiomers or simple diastereoisomers. So amazing these simple isomers allow you to select the most powerful component of a mixture and surprisingly can offer improved residence times on the M3 receiver therefore providing agents with long duration of action that They are particularly suitable for dosing once a day.

Especially the preferred compounds specific to the invention are those described below in the Examples

The invention also provides a process for the preparation of compounds of the formula I comprising:

(i) (A) react a compound of the formula II

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2

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or a protected form thereof where R 1, R 2, R 3, R 4 and J are as defined here above, with a compound of the formula III

IIIX-R 5

where R 5 is as defined here above and X is chlorine, bromine or iodine;

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(B) react a compound of the formula IV

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3

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or a protected form thereof where R 1, R 2, R 3, R 5 and J are as defined here above, with a compound of the formula V

VX-R 4

where R 4 is as defined here above and X is chlorine, bromine or iodine;

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(C) for the preparation of compounds of the formula I where R 5 is -Q-NH-CO-R 6, reacting a compound of the formula VI

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4

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or a protected form thereof where R 1, R 2, R 3, R 4 and J are as defined here above and Q is alkylene C 1 -C 10, with a compound of the formula VII

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5

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or a derivative that forms amide of same where R 6 is as defined hereinbefore; or

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(D) for the preparation of compounds of the formula I where R 5 is C 1 -C 10 alkyl replaced by a carbocyclic group C_ {3} -C_ {15} which is replaced by carboxy, which converts a compound of the formula I where R 1, R 2, R 3, R 4 and J are as defined hereinbefore and R 5 is C 1 -C 10 alkyl substituted by a C 3 -C 15 carbocyclic group that is replaced by -COO-aryl C 6 -C 10 or -COO-aralkyl C 7 -C 15; Y

(ii) recover the product in the form of salt or bipolar ion.

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The process variant can be made (A) using known procedures to react amines heterocyclics saturated with halogenoids or analogously as described in the Examples. The reaction is carried out in a manner suitable in an organic solvent, for example dimethylsulfoxide, dimethylformamide, ether, acetonitrile or acetone. The reaction is carried out at a temperature between 20 ° C to 120 ° C, so convenient between room temperature and 80ºC.

The process variant can be made (B) using known procedures to react amines heterocyclics saturated with halogenoids or analogously as described in the Examples. The reaction is carried out in a manner suitable in an organic solvent, for example dimethylsulfoxide, dimethylformamide, ether, acetonitrile or acetone. The reaction is carried out at a temperature between 20 ° C to 120 ° C, so convenient between room temperature and 80ºC.

The process variant can be carried out (C) using known procedures to react carboxylic acids (or amide derivatives thereof) such as derivatives of acid halides) with amines, or of form analogous for example as described below in the Examples. The reaction is carried out conveniently by reacting the carboxylic acid with the amine using a solvent organic, for example dimethylformamide, in the presence of one or more coupling agents, for example hexafluoro phosphate O- (7-azabenzotriazol-1-yl) -1,1,3-, 3-tetramethyluronium (HATU), and a base, for example diisopropylethylamine (DIPEA). The Suitable reaction temperatures are from 10 ° C to 40 ° C, for example room temperature.

The process variant can be made (D) using known procedures to convert esters to form the corresponding carboxylic acids, or analogously as described in the Examples. The reaction can lead to conveniently carried out by catalytic hydrogenation, by example with 10% Palladium on Carbon, for example in a solvent organic, such as dimethylformamide. The reaction is carried out of Convenient form at room temperature.

When a compound of formula II is a single enantiomer or is it achiral, the alkylation of the amine tertiary gives a compound of the formula I resulting in a mixture of two diastereoisomers. These isomers can be separated by conventional techniques, for example by crystallization Fractional or column chromatography.

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The compounds of formula II may exist in individual optically active isomeric forms or as mixtures thereof, for example as racemic mixtures or diastereomeric. Preferred compounds of formula II are the compounds of the formula IIa or IIb

6

or a protected form thereof where R 1, R 2, R 3, R 4 and J are as defined here previously.

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The compounds of formula II are known or they can prepare by reacting a compound of the formula VIII

7

or a protected form thereof where R 1, R 2 and R 3 are as defined herein above and R a is C 1 -C 4 alkyl, with a compound of the formula IX

8

where R 4 and J are as defined here above. The reaction can be carried out. using known procedures to react carboxylic esters with alcohols or in analogous form as described in the Examples. The reaction is carried out in a manner suitable in an organic solvent, for example cyclohexane or toluene, preferably in the presence of an alkali metal by example sodium and under an inert atmosphere such as argon. The reaction can be carried out at a temperature between 40 ° C at 120 ° C, but preferably under conditions of Reflux.

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The compounds of the formula II where R2 is hydroxyl can be prepared by reacting a compound of the formula X

9

or a protected form thereof where R 1, R 4 and J are as defined hereinbefore, with a compound of the formula XI

XIXMg-R3

where R3 is as defined here above and X is chlorine, bromine or iodine.

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The compounds of the formula III are known or they can prepare by known procedures, or in form analogous as described in the Examples.

The compounds of formula IV may exist in individual optically active isomeric forms or as mixtures thereof, for example as racemic mixtures or diastereomeric. Preferred compounds of formula IV are compounds of the formula IVa or IVb

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10

or

eleven

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or a protected form thereof where R 1, R 2, R 3, R 5 and J are as defined here previously.

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The compounds of the formula can be prepared IV by reacting a compound of formula VIII or a form protected therefrom where R 1, R 2 and R 3 are as defined here above and R a is alkyl C 1 -C 4, with a compound of the formula XII

12

where R 5 and J are as defined here above. The reaction can be carried out. using known procedures to react esters carboxylic acids with alcohols or analogously as described in the examples. The reaction is conveniently carried out in a organic solvent, for example cyclohexane or toluene, preferably in the presence of an alkali metal for example sodium and under an inert atmosphere such as argon. The reaction is can be carried out at a temperature between 40ºC to 120ºC, but preferably under conditions of Reflux.

The compounds of the formula V are known or they can prepare by known procedures, or in form analogous as described in the Examples.

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The compounds of formula VI are novel and they can be prepared by reacting a compound of the formula II where R 1, R 2, R 3, R 4 and J are as defined here above, with a compound of the formula XIII

13

where X is chlorine, bromine or iodine, Q is C 1 -C 10 alkylene and W is a group protective. This reaction can be carried out using known procedures for reacting heterocyclic amines with haloalkylamines, or analogously as described in the Examples The reaction is conveniently carried out in a organic solvent, for example dimethylformamide. The reaction is It can be carried out at a temperature between 40ºC to 80ºC, preferably between 50 ° C to 70 ° C, but especially approximately 60 ° C. The protecting group is preferably a group tert-butoxycarbonyl.

Compounds of the formula VII or VIII or can be prepared by known procedures, or in analogously as described in the Examples.

The compounds of formula IX and XII are known or can be prepared by renting the secondary amine correspondent. For example the compounds of formula IX where R 4 is methyl can be prepared by reacting a compound of the formula XIV

14

where J is as defined here formerly with formaldehyde in the presence of formic acid. The reaction is conveniently carried out in a solvent, by water example, at a temperature of 40ºC to 120ºC, but preferably about 80 ° C. Alternatively, they can be Prepare the compounds of formula X by reacting a compound of formula XII where J is as defined here above with a compound of the formula III where R 5 is as defined here above and X is chlorine, bromine or iodine. The reaction is conveniently carried out in a solvent organic, for example acetonitrile, at a temperature of 40 ° C at 120 ° C, but preferably under reflux in the presence of a base, for example carbonate of potassium.

The compounds of formula X can be prepared by reacting a compound of formula IX where R 4 and J are as defined here above, with a compound of the formula XV

fifteen

where R1 is as defined here above and X is chlorine, bromine or iodine.

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The compounds of the formula XI are known, XIII, XIV or XV or can be prepared by procedures known, or analogously as described in the Examples.

When referring to groups here Protected functional or protective groups, groups protectors can be chosen according to the nature of the functional group, for example as described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, John Wiley & Sons Inc, Third Edition, 1999, whose reference also describes appropriate procedures for group replacement hydrogen protectors.

The compounds of the formula I are salts of quaternary ammonium and can be converted into different forms of salt using ion exchange chromatography. Can be get the compounds in the form of hydrates or solvates that They contain a solvent used for crystallization. Can be recover the compounds of the formula I from the reaction mixtures and purify using known methods. The compounds are isolated initially as diastereomeric mixtures however in most of the cases are preferably used in compositions pharmaceuticals of the invention as well as enantiomers or simple diastereoisomers.

The compounds of the formula I in salt form pharmaceutically acceptable or bipolar ion, hereinafter referred to as alternatively as agents of the invention, they are useful as pharmaceutical products. In accordance with the foregoing the invention also provides a compound of the formula I in salt form pharmaceutically acceptable or bipolar ion for use as pharmaceutical products. The agents of the invention act as muscarinic antagonists, particularly antagonists of M3 muscarinic receptor thus acting as inhibitors of bronchoconstriction

The affinity (Ki) of the agents of the invention in the human muscarinic acetylcholine M3 receptor you can determine in a competitive filtration binding assay with the antagonist n-methyl scopolamine chloride [<3> H] radiolabeled (NMS):

Prepared membranes are transfected of CHO cells stably with the human M3 receptor at 10 mg of protein / well are then incubated with serial dilutions of the Agents of the invention, [3 H] NMS at Kd concentration (0.25 nM) and assay buffer (20 mmol of HEPES, 1 mmol of MgCl2 at pH 7.4) for 17 hours at room temperature. The essay takes carried out in a final volume of 250 mL, in the presence of a final dimethyl sulfoxide concentration of 1%. Total union of [3 H] NMS is determined in the absence of the agents of the invention with a corresponding substituted volume of shock absorber of testing. The non-specific binding of [3 H] NMS is determined in the presence of 300 nM of ipratropium bromide. After the period incubation, the membranes are harvested on a filter plate Unifilter? GF / B containing 0.05% polyethyleneimine, using a Brandel? 9600 filtration harvester. They are dried the filter plates for two hours at 35 ° C before the addition of Microscint? "O" cocktail, and read in a scintillator Packard Topcount ™ using a Twinkle Protocol 3 H. All IC50s are calculated with the help of graphic packaging XL-Fit and K, the values are derived using the Cheng-Prusoff correction (Cheng Y., Prusoff W. H. (1973) Biochem. Pharmacol 22 3099-3109).

The compounds of the Examples below they generally have IC 50 values below 1 mM in the previous essay. For example, the compounds of Examples 1, 12 and 24 have M3 K, the values of 2.14, 0.39 and 0.68 nM respectively.

Taking into account the inhibition of the binding of acetyl choline to M3 muscarinic receptors, the agents of the invention are useful in the treatment of conditions mediated by the muscarinic M3 receptor, particularly those associated with the increased parasympathetic tone that leads to, for example, excessive glandular secretion or smooth muscle contraction. He treatment according to the invention can be symptomatic or prophylactic.

Taking into account their muscarinic activity, the agents of the invention are useful in the relaxation of bronchial smooth muscle and the relief of bronchoconstriction. Broncoconstriction relief can be measured in models such as in vivo plethysmography models by Chong et al , J. Pharmacol. Toxicol Methods 1998, 39, 163, Hammelmann et al , Am. J. Respir. Crit. Care Med., 1997, 156, 766 and similar models. The agents of the invention are therefore useful in the treatment of obstructive or inflammatory airway diseases. In view of its long-lasting action, it is possible to administer the agents of the invention once a day in the treatment of such diseases. In another aspect, the agents of the invention commonly exhibit characteristics that indicate a low incidence of side effects commonly found with β2 agonists such as tachycardia, tremor and restlessness, such agents according to the above are suitable for use in a treatment on demand (rescue) as well as prophylactic treatment of obstructive airway diseases or
inflammatory

Respiratory diseases obstructive or inflammatory to which the present invention is you can apply include asthma of any type or origin that includes intrinsic asthma (nonallergic) and extrinsic asthma (allergic). Too It should be understood that asthma treatment encompasses the treatment of subjects, for example under 4 or 5 years of age, who exhibit wheezing symptoms and is diagnosed or diagnosable as "wheezing infants", an established patient category of important medical concern and now often identified as early or early stage asthmatic. (For convenience this asthmatic condition is referred to as "difficulty syndrome respiratory system ").

Prophylactic efficacy in the treatment of asthma will be evidenced by the reduced frequency or severity of symptomatic attack, for example bronchial or asthmatic attack acute, improved lung function or hyperreactivity of the pathways improved respiratory It can be further evidenced by reduced requirement for other symptomatic therapy, that is therapy for or intended to restrict or abort the attack symptomatic when this occurs, for example anti-inflammatory (for example corticosteroid) or bronchodilator The prophylactic benefit in asthma can in particular be evident in subjects prone to "depression morning "." Morning depression "is an asthmatic syndrome recognized, common in a substantial percentage of asthmatics and characterized by asthma attack, for example between the hours of approximately 4 to 6 am, that is at a substantial time and normally distant from any therapy for symptomatic asthma previously administered

Other diseases and conditions of the pathways obstructive or inflammatory respiratory conditions to which apply the present invention include difficulty syndrome respiratory / adult (ARDS), disease of the airways respiratory or chronic obstructive pulmonary (COPD or COAD), which include chronic bronchitis, or dyspnea associated with it, emphysema, as well as exacerbation of hyperreactivity of the pathways consequent respiratory as a result of another therapy of drug, in particular another inactivated drug therapy. The invention can also be applied to the treatment of bronchitis of any type or origin that includes, for example, acute bronchitis, arachidic, catarrhal, pseudomembranous, chronic or ftinoid. Additional diseases of the obstructive airways or inflammatory to which the present invention can be applied include pneumoconiosis (an inflammatory disease, commonly occupational, lungs, often accompanied by airway obstruction, either chronic or acute and caused by repeated inhalation of powders) of any kind or origin, which includes, for example, aluminosis, anthracosis, asbestosis, calicosis, cystic fibrosis, ptilosis, siderosis, silicosis, tabacosis and bisinosis.

Taking into account their muscarinic activity, the Agents of the invention are also useful in the treatment of a condition that requires relaxation of the smooth muscle of the uterus, bladder, or vascular system. They are useful for prevention or relief of premature labor pains in pregnancy. They are also useful in the treatment of chronic and acute urticaria, psoriasis, allergic conjunctivitis, actinitis, rhinitis that includes rhinitis allergic, mastocytosis, urinary disorders such as urinary incontinence (particularly that caused by a overactive bladder), pollakiuna, unstable or neurogenic bladder, cytospasm and chronic cystitis; gastrointestinal disorders such like irritable bowel syndrome, spastic colitis, diverticulitis and peptic ulceration; and cardiovascular disorders such as vagally induced sinus bradycardia, as well as also in ophthalmic interventions.

The agents of the invention are also useful. as co-therapeutic agents for use in combination with others drug substances such as drug substances anti-inflammatory, bronchodilators, antihistamines, decongestants or cough suppressants, particularly in the treatment of diseases of the pathways obstructive or inflammatory respiratory such as those mentioned above, for example as enhancers of the therapeutic activity of such drugs or as a means to reduce the required dosage or the potential side effects of such drugs An agent of the invention can be mixed with one or more than other drug substances in a pharmaceutical composition fixed or can be administered separately, before, simultaneously with or after the other drug substances. From In accordance with the foregoing the invention includes a combination of a agent of the invention as described above with a anti-inflammatory drug substance, bronchodilator, antihistamine, decongestant, or cough suppressant, said the invention and said drug substance is in the same or Different pharmaceutical composition.

Such drugs Anti-inflammatories include steroids, for example glucocorticosteroids such as budesonide, beclamethasone, fluticasone, ciclesonide or mometasone, or the steroids described in WO 02/88167, WO 02/12266, WO 02/100879 or WO 02/00679, especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101, and no steroid agonists Steroids such as those described in WO 00/00531, WO 10/02143, WO 03/082280, WO 03/082787, WO 03/104195, WO 04/005229; LTB4 antagonists such as those described in the US 5451700, also LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; inhibitors of PDE4 such as cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plow), Arofylline (Almirall Prodesfarma), PD189659 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID (TM) CC-10004 (Celgene), KW-4490 (Kyowa Hakko Kogyo), WO 03/104204, WO 03/104205, WO 04/000814, WO 04/000839  and WO 04005258 (Merck), as well as those described in WO 98/18796 and WO 03/39544; A2a agonists such as those described in EP 1052264, EP 1241176, EP 409595A2, WO 94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO99 / 41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462, and WO 03/086408; and A2b antagonists such as those described in WO 02/42298.

The agents of the invention are useful in combination therapy with chemokine receptor antagonists,  calcium channel blockers, antagonists alpha-adrenoceptors, dopamine agonists, endothelin antagonists, substance P antagonists, 5-LO inhibitors, antagonists of VLA-4 and theophylline.

The agents of the invention are also particularly useful as co-therapeutic agents for use in combination with beta-2 agonists adrenoceptor or corticosteroids. The agonists of Suitable beta-2 adrenoceptor include salbutamol, terbutaline, salmeterol and, especially, formoterol and salts pharmaceutically acceptable thereof, and compounds (in the form salt or solvate free) of formula I of WO 0075114, whose document is incorporated herein by reference, preferably those compounds of the Examples thereof, especially a compound of the formula

16

and pharmaceutically salts acceptable thereof, as well as compounds (in form salt or solvate free) of formula I of WO 04/16601, preferably the compounds of Examples 1, 3, 4, 5 and 79.

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Antihistamine drug substances Co-therapeutics include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenidramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, Mizolastine and Tefenadine.

You can use the combinations of agents of the invention and one or more agonists of beta-2 adrenoceptor, steroids, inhibitors PDE4, A2a agonists, A2b antagonists and LTD4 antagonists, by example, in the treatment of diseases of the pathways respiratory, which include asthma and particularly COPD. The Preferred triple combinations comprise an agent of the invention, a beta-2 adrenoceptor agonist and a steroid.

In accordance with the foregoing, this invention also provides a method for treating a obstructive or inflammatory airway disease that comprises administering to a subject, particularly a subject human, in need thereof a compound of the formula I, or a pharmaceutically acceptable salt or solvate thereof, as described above. In another aspect, the invention provides a compound of the formula I, or a pharmaceutically acceptable salt or solvate thereof, as described above for use in the preparation of a medicine for the treatment of a disease of the obstructive or inflammatory airways.

The agents of the invention by any appropriate route, for example orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; topically on the skin, for example in the treatment of psoriasis; intranasally, for example in the hay fever treatment; or, preferably, by inhalation, particularly in the treatment of diseases of the  obstructive or inflammatory airways. In particular, the Agents of the invention can be supplied as a formulation Inhalable for the treatment of COPD and asthma.

In a further aspect, the invention also provides a pharmaceutical composition comprising a compound of formula I in free form or in the form of a salt pharmaceutically acceptable or solvate thereof, optionally together with a pharmaceutically acceptable diluent or carrier of the same. Such compositions can be prepared using diluents. or conventional excipients and techniques known in science medical Thus oral dosage forms may include tablets and capsules Formulations for topical administration they can take the form of creams, ointments, gels or systems of transdermal delivery, for example patches. The compositions for inhalation may comprise aerosol or other formulations Atomizable or dry powder formulations.

When the composition comprises a formulation in aerosol, this preferably contains, for example, a hydro-fluoroalkane (HFA) propellant such as HFA134a or HFA227 or a mixture of these, and may contain one or more co-solvents known in the art such as ethanol (up to 20% by weight), and / or one or more surfactants such as oleic acid or sorbitan trioleate, and / or one or more agents dough formers such as lactose. When the composition comprises a dry powder formulation, preferably contains, for example, the compound of the formula I having a diameter of particle up to 10 microns, optionally together with a diluent or carrier, such as lactose, of the size distribution of desired particle and a compound that helps protect against deterioration of product performance due to humidity for example magnesium stearate. When the composition comprises a nebulized formulation, preferably contains, for example, the compound of the formula I either dissolved or suspended, in a vehicle containing water, a co-solvent such as ethanol or Propylene glycol and a stabilizer, which can be a surfactant.

The invention also includes (A) a compound of formula I as described above in free form, or a pharmaceutically acceptable salt or solvate thereof, in the form inhalable; (B) an inhalable medicament comprising such a compound in inhalable form together with a pharmaceutically carrier acceptable in the inhalable form; (C) a pharmaceutical product that comprises such a compound in inhalable form in association with a inhalation device; and (D) an inhalation device that It contains such a compound in inhalable form.

The dosages of the agents of the invention employed in the practice of the present invention will vary  of course depending, for example, on the particular condition to be treated, the desired effect and the mode of administration. In general, adequate daily dosages for administration by inhalation they are of the order of 0.0001 to 30 mg / kg, typically 0.01 to 10 mg per patient, while for oral administration the appropriate daily doses are of the order of 0.01 to 100 mg / kg.

The invention is illustrated by the following Examples

Examples

All the compounds of these examples are isolated initially as mixtures of diastereoisomers in the atom of quaternary nitrogen. When a diastereoisomer is indicated individual in these examples this is isolated by crystallization fractional of such a mixture. The stereochemistry of these isomers Simple is determined by nmr and / or ray crystallography x.

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Especially the preferred compounds of the formula I include compounds of formula XVI

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17

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where T is as shown in the Tables 1 below, the preparation methods are described below. All compounds are quaternary ammonium salts. The board It also shows mass spectrometry data. The counterion relevant is identified in the relevant method of preparation.

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TABLE 1

18

19

twenty

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Especially the preferred compounds Additional of the formula I include the compounds of the formula XVII

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twenty-one

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where T is as shown in the Table 2 below, the preparation methods are described below. All compounds are quaternary ammonium salts. The board It also shows mass spectrometry data. The counterion relevant is identified in the relevant method of preparation.

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TABLE 2

22

2. 3

Preparation of intermediate compounds

The abbreviations used are as follows: DCM is dichloromethane, DMF is dimethylformamide, and DMSO is dimethylsulfoxide and THF is tetrahydrofuran.

Ester of (S) -1-methyl-pyrrolidin-2-ylmethyl of acid hydroxy diphenyl acetic acid

They are suspended ((S) -1-Methyl-pyrrolidin-2-yl) -methanol (2.38 ml, 20 mmol) and acid methyl ester hydroxy diphenyl acetic (7.27 g, 30 mmol) in toluene (20 ml). 4A molecular sieve (3 g) is added and the suspension is heated under stirring at 80 ° C. Sodium is added (0.46 g, 20 mmol) and the reaction mixture is stirred at 80 ° C for 3 hours. The reaction mixture is cooled to room temperature, Filter the solid, and wash with toluene. The filtrate is washed a once with saturated aqueous NaHCO3 solution (50 ml) and twice with 1M aqueous HCl (30 ml each). The acidic aqueous layers combined are adjusted to pH 8 with aqueous NaHCO3 solution saturated The emulsion is extracted with ethyl acetate (50 ml). The combined ethyl acetate layers are dried over sulfate sodium, filtered and evaporated until dried to give the product like a yellow oil that crystallizes at rest. (M + H) +: 326.2

Ester is prepared from (R) -1-methyl-pyrrolidin-2-yl-methyl of hydroxy diphenyl acetic acid of analogous form

Ester of (S) -1-methyl-pyrrolidin-2-ylmethyl of acid hydroxy-di-thiophene-2-yl-acetic

To a mixture of 4A molecular sieve, ((S) -1-Methyl-pyrrolidin-2-yl) -methanol (3.71 g, 31.2 mmol) and acid methyl ester hydroxidi-thiophene-2-yl-acetic (3.96 g, 15.6 mmol) in toluene (40 ml) sodium (65 mg) is added and the suspension is heated under stirring at 80 ° C for 3.5 hours. Then additional sodium (65 mg) is added and the reaction mixture is stir at 80 ° C for 16 hours. The reaction mixture is cooled to room temperature, diluted with diethyl ether (100 ml) and extract with 1M HCl (2 x 100 ml). The acidic aqueous layers combined they are washed with diethyl ether (50 ml) and basified with 4M sodium hydroxide while cooling on ice. The solution It is then extracted with ethyl acetate and diethyl ether. Layers combined organics are dried over magnesium sulfate, filtered and evaporate until dried to give the title product.

Preparation of Specific Examples

The abbreviations used are as follows: DCM is dichloromethane, DMF is dimethylformamide, and DMSO is dimethylsulfoxide, HPLC is high liquid chromatography performance.

Example 1 Trifluoroacetate (S) -2- (2-Hydroxy-2,2-diphenyl-acetoxymethyl) -1-methyl-1-oct-2-inyl-pyrrolidinium

200 ml of a 1.1 M solution of 1-bromooct-2-ina in 200 ml DMSO of a 0.368 M ester solution of (S) -1-methyl-pyrrolidin-2-ylmethyl of hydroxy diphenyl acetic acid in DMSO with a robotic liquid controller in a 96-well plate. Plate Wells are sealed and placed in an oven at 40 ° C for 48 hours. The well plate is cooled to room temperature and the mixture of reaction is purified by mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid for Produce the title compound as an oil. The product is it isolates as a mixture of diastereoisomers that varies in stereochemistry in the quaternary nitrogen atom. The counterion present after preparative HPLC is a mixture that varies from bromide and trifluoroacetate.

The compounds of Examples 2 to 37 are they prepare analogously using the starting compounds appropriate.

Claims (13)

1. A compound of the formula I 24 in the form of salt or bipolar ion in where R1 and R3 are each independently a carbocyclic group C 3 -C 15 or a heterocyclic group of 5 to 12 members that have at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur; R2 is hydrogen, hydroxy, or alkyl C_ {C} {C4} optionally substituted by hydroxy; J is alkylene C 1 -C 2; R 4 is alkyl C 1 -C 4; R 5 is C 1 alkyl substituted by -SO-R 6, -S (= O) 2 -R 6, -CO-R 6, -CO-O-R 6, -CO-NH-R 6 or -R 7, or R 5 is C 2 -C 10 alkyl substituted by -O-R 6, -S-R 6, -SO-R 6, -S (= O) 2 -R 6, -CO-R 6, -O-CO-R 6, -CO-O-R 6, -NH-CO-R 6, -CO-NH-R 6, -R 7 or -R 8, or R 5 is alkenyl C 2 -C 10 or alkynyl C 2 -C 10 optionally substituted by -R 7 or -R 8; R 6 is a carbocyclic group C 3 -C 15 or a heterocyclic group of 5 to 12 members that have at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur, or R 6 is alkyl C 1 -C 10 optionally substituted by alkoxy C 1 -C 10, -O-R 7, a C 3 -C 15 carbocyclic group or a group 5 to 12 member heterocyclic that has at least one heteroatom in the selected ring of nitrogen, oxygen and sulfur; R 7 is a heterocyclic group of 5 to 12 members that have at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur; Y R 8 is a carbocyclic group C_ {3} -C_ {15}.

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2. A compound according to claim 1, where R1 and R3 are each independently a carbocyclic group C 3 -C 15 or a heterocyclic group of 5 to 12 members that have at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur; R2 is hydroxy; J is alkylene C 1 -C 2; R 4 is alkyl C 1 -C 4; R 5 is C 1 alkyl substituted by -CO-R 6 or -CO-NH-R 6, or R 5 is alkyl C 2 -C 10 substituted by -O-R 6, -S-R 6, -O-CO-R 6 or -R 8, or R 5 is alkenyl C 2 -C 10 or alkynyl C 2 -C 10 optionally substituted by -R 8; R 6 is a carbocyclic group C 3 -C 15, or R 6 is alkyl C 1 -C 10 optionally substituted by alkoxy C 1 -C 10, O-R 8 or a C 3 -C 15 carbocyclic group; Y R 8 is a carbocyclic group C_ {3} -C_ {15}.

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3. A compound according to claim 2, where R1 and R3 are each independently to carbocyclic group C 3 -C 10, preferably phenyl, or a 5 to 9 member heterocyclic group that has at least one heteroatom in the selected ring of nitrogen, oxygen and sulfur, preferably thienyl; R2 is hydroxy; J is alkylene C 1 -C 2; R 4 is alkyl C 1 -C 4; R 5 is C 1 alkyl substituted by -CO-R 6 or -CO-NH-R 6, or R 5 is alkyl C 2 -C 5 substituted by -O-R 6, -S-R 6, -O-CO-R 6 or -R 8, or R 5 is alkenyl C 2 -C 4 or alkynyl C 2 -C 8 optionally substituted by -R 8; R 6 is a carbocyclic group C 3 -C 10, preferably phenyl, or R 6 is alkyl C 1 -C 15 optionally substituted by alkoxy C 1 -C 4, O-R 8 or a C 3 -C 10 carbocyclic group; Y R 8 is a carbocyclic group C 3 -C 10, preferably phenyl.

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4. A compound according to claim 1, which is also a compound of the formula XVI

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25

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where T is as shown in the next table.

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26 27 28 29

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5. A compound according to claim 1, which is also a compound of the formula XVII where T

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30

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Where T is as shown in the following table:

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31 32 6. A compound according to any one of the preceding claims in combination with at least a drug substance that is a drug substance anti-inflammatory, bronchodilator, antihistamine, decongestant or cough suppressant. 7. A compound according to any one of claims 1 to 5 for use as a product pharmacist. 8. A pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 5. 9. A compound according to any one of claims 1 to 5 for use in the treatment of a muscarinic M3 receptor mediated condition. 10. A compound according to any one of claims 1 to 5 for use in the treatment of a obstructive airway disease or inflammatory 11. The use according to claim 9 or 10, in which the compound is a single enantiomer. 12. A process for the preparation of a compound of the formula I as claimed in claim 1 which includes: (i) (A) react a compound of the formula II 33 or a protected form thereof where R 1, R 2, R 3, R 4 and J are as defined in claim 1, with a compound of the formula III IIIX-R 5 where R 5 is as defined in claim 1 and X is chlorine, bromine or iodine;

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(B) react a compound of the formula IV 3. 4 or a protected form thereof where R 1, R 2, R 3, R 5 and J are as defined in claim 1, with a compound of the formula V VX-R 4 where R 4 is as defined in claim 1 and X is chlorine, bromine or iodine;

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(C) for the preparation of compounds of the formula I where R 5 is -Q-NH-CO-R 6, reacting a compound of the formula VI 35

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or a protected form thereof where R 1, R 2, R 3, R 4 and J are as defined in claim 1 and Q is alkylene C 1 -C 10, with a compound of the formula VII 36 or a derivative that forms amide of same wherein R 6 is as defined in claim 1; or (D) for the preparation of compounds of the formula I where R 5 is C 1 -C 10 alkyl replaced by a carbocyclic group C_ {3} -C_ {15} which is replaced by carboxy, which converts a compound of the formula I where R 1, R 2, R 3, R 4 and J are as defined in claim 1 and R 5 is C 1 -C 10 alkyl substituted by a C 3 -C 15 carbocyclic group that is replaced by either -COO-aryl C 6 -C 10 or -COO-aralkyl C 7 -C 15; Y (ii) recover the product in the form of salt or bipolar ion.

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13. A compound of the formula VI 37 in the form of salt or bipolar ion in where R1 and R3 are each independently a carbocyclic group C 3 -C 15 or a heterocyclic group of 5 to 12 members that have at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur; R2 is hydrogen, hydroxy, or alkyl C_ {C} {C4} optionally substituted by hydroxy; J is alkylene C 1 -C 2; R 4 is alkyl C 1 -C 4; Y Q is alkylene C_ {1} -C_ {10}.