AMINOESTERIZED DERIVATIVES

Abstract

The invention relates to novel compounds that are both inhibitors of the phosphodiesterase 4 (PDE4) enzyme and antagonists of the muscarinic receptor m3, methods for preparing such compounds, compositions containing them, and their therapeutic use. Binging m3 assay: Cho-Ki clone cells expressing the human m3 receptor (SwissProt p20309) were harvested in a phosphate-buffered saline solution free of calcium / magnesium chloride and collected by centrifugation at 1500 rpm for 3 min. The pellets were resuspended in ice-cold a buffer (Tris-HCl 15 mL pH 7.4, MgCl2 2 mL, EDTA 0.3 mL, EGTA 1 mL) and homogenized using a Politron PBI (setting 5 for 15 s). The crude membrane fraction was collected by two consecutive centrifugation steps at 40000 g for 20 min at 4 °C, separated by a washing step in buffer a.The resulting pellets were resuspended in buffer b (Tris-HCl 75 MW, pH 7.4, 12.5 MW, MgCl2, EDTA 0.3 MW, EGTA 1 MW, sucrose 250 MW) and aliquots were stored at -80°C. On the day of the experiment, the frozen membranes were resuspended in buffer c (Tris-HCl 50 MW, pH 7.4, MgCB 2.5 MW, EDTA 1 MW). The non-selective muscarinic radioligand [3H]-n-methylscopolamine (Mol. Pharmacol. 45: 899-907) was used to label the m3 binding sites. Binding experiments were performed in duplicate (ten-point concentration curves) in 96-well plates at a radioligand concentration of 0.1-0.3 nM. Non-specific binding was determined in the presence of 10 µm of cold n-methylscopolamine. Samples (final volume 0.75 ml) were incubated at room temperature for 90 minutes.The reaction was stopped by rapid filtration through Unifilter GF / B plates and two washes (0.75 mL) with cold buffer C using a FilterMate Harvester. Radioactivity on the filters was measured using a Tricarb 2500 microplate scintillation counter (PerkinElmer). Representative compounds of the invention, when tested in one of the protocols mentioned above, exhibited an IC50 below 100 nm. Representative compounds of the invention exhibited an IC50 below 100 nm in both the cell-free PDE4 assays and the M3 binding assays.

Description

Buffer c (Tris-HCl 50 mM, pH 7.4, MgCb 2.5 mM, EDTA 1 mM). The non-selective muscarinic radio-electric ligand [3H]-N-methylscopolamine (Mol. Pharmaco. 45: 899-907) was used to label the M3 binding sites. Binding experiments were performed in duplicate (ten-point concentration curves) in 96-well plates at a radioligand concentration of 0.1–0.3 nM. Non-specific binding was determined in the presence of 10 µM cold N-methylscopolamine. Samples (final volume 0.75 mL) were incubated at room temperature for 90 minutes. The reaction was stopped by rapid filtration through GF / B tJnifilter plates and two washes (0.75 mL) with cold buffer c using a Harvester Filtermate. The radioactivity on the filters was measured by a TriCarb 2500 microplate scintillation counter (PerkinElmer).Representative compounds of the invention, when tested in one of the protocols mentioned above, exhibited an IC50 of less than 100 nM. Representative compounds of the invention exhibited an IC50 of less than 100 nM in both PDE4 cell-free assays and in M3 binding rates.

Claims

3221EUR / IS 15,731,261.2 DEMANDS 1. Compound conforming to the general formula 'OW in which Each radical Ri represents a hydrogen atom or is independently selected from the group consisting of: a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a hydroxyl group, a -SCNRIRII group, a -CN group, a -NRISCRI group, a -NRIRII group, a -(CO)NRIRII group, and a -NR|(CO)R||| group, and wherein said C1-C4 alkyl group is optionally substituted by one or more groups selected from: a C3-C7 cycloalkyl group, a hydroxyl group, and a -NRIRII group; and wherein said C1-C4 alkoxy group is optionally substituted by one or more groups selected from one or more halogen atoms or C3-C7 cycloalkyl groups, in which: RI represents a hydrogen atom or an alkyl group in Cl- RII represents a hydrogen atom or an alkyl group in CiC; RIII represents a hydrogen atom or an alkyl group in CiC; n represents an integer that lies in the range from 1 to 3; each radical R2 represents a hydrogen atom or is independently selected from the group consisting of: a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a hydroxyl group, a -SCNRIR group, a -CN group, a -NRISCRI group, a -NRIRII group, a -(CO)NRIRII group, and a -NR|(CO)R| group, and wherein said C1-C4 alkyl group is optionally substituted by one or more groups selected from: a C3-C7 cycloalkyl group, a hydroxyl group, and a -NRIRII group; and wherein said C1-C4 alkoxy group is optionally substituted by one or more groups selected from one or more halogen atoms or C3-C7 cycloalkyl groups, in which: RI represents a hydrogen atom or an alkyl group in Cl-Ce; RII represents a hydrogen atom or a C1-C6 alkyl group; RI" represents a hydrogen atom or a C1-C6 alkyl group; m represents an integer that lies in the range from 1 to 3; R3 and R4 are identical or different and are chosen independently from the group consisting of: a hydrogen atom, a cycloalkyl(C3-C7)carbonyl group, a C1-C6 alkyl group optionally substituted by one or more substituents chosen from a C3-C7 cycloalkyl group and a C5-C7 cycloalkenyl group, a C1-C6 haloalkyl group, a C3-C7 cycloalkyl group, a C5-C7 cycloalkenyl group, a C2-C6 alkenyl group, and a C2-C6 alkynyl group; or R3 and R 4 , together with the interconnecting atoms, form a 2,2-difluoro-1,3-dioxolane nucleus corresponding to the formula (r) condensed to the phenyl fraction which bears -OR3 and -OR4 groups, formula in which the asterisks indicate the carbon atoms shared with such a phenyl nucleus: each radical Rs is chosen from the group consisting of: a CN group, an NO2 group, a CF3 group and halogen atoms; k is equal to zero or represents an integer that lies in the range of 1 to 3; X' is equal to 0 or 1; It is chosen from a bond and a group -(CHp- in which P represents an integer that lies in the range from 1 to 4; Wi is chosen from a divalent arylene group, a heteroarylene group and a saturated monocyclic heterocycloalkylene group; L represents a group cnoisi among: a bond, a -(CHq-) group in which q is equal to 1 or 2, a [1]-(C0)-[X]-(CH2)t-[2] group, and a [1]-(SO2)-[X]-(CH2)t-[2] group, in which [1] and [2] respectively represent the point of attachment of the 2a group to the Wi nucleus and to the nitrogen atom in the chain; and in which [X] represents a bond or a substituted or unsubstituted arylene group; t represents an integer that lies in the range of 1 to 4; ٧٧2 is chosen from an aryl group and a heteroaryl group; L represents a bond or group -(CH- ; 96 is chosen from the group consisting of: a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, and a -CN group, wherein said C1-C4 alkyl group is optionally substituted by one or more groups chosen from: a C3-C7 cycloalkyl group, a C1-C4 alkoxy group, and a hydroxyl group; or alternatively, where 96 represents a C1-C4 alkyl group, W2 represents a phenyl ring, one of the radicals Ri represents an alkyl group in the ortho position relative to L, the two radicals Ri and Re may be linked to form with 72 a condensed cyclic radical chosen from a 1H-cyclopropabenzene-1,1-diyl radical, an indane-1,1-diyl radical (also called: 2,3-dihydro-1H- indene-1,1-diyl), an indane-2,2-diy!e radical (also called: 2,3-dihydro-1 H-indene-2,2-diyl), a 1,2,3,4-tetrahydronaphthaene-1,1 -diyl radical. and a 1,2,3,4-tetrahydronaphthalene-2,2-diyl radical; R? is chosen from a hydrogen atom and a C1-C4 alkyl group optionally substituted by a hydroxyl group or a -NR11R12 group and in which Ru and R12 are chosen independently from: a hydrogen atom, a C1-C4 alkyl group, or, jointly with the nitrogen atom to which they are bonded, may form a saturated heterocycloalkyl group possessing an additional heteroatom which is chosen from an oxygen atom, a sulfur atom, and an NH group; A represents a nitrogen group which is chosen from: - a group (a), namely a group -(CHs-NRsRg) in which s represents an integer in the range of 1 to 4, and Rs and R9 independently represent a hydrogen atom or alkyl group in C1-C4; and - a group (b) chosen from a group meeting the formula (i), (ii), (iii) or (iv): in which: f = 1, 2 or 3; g = 1, 2 or 3; The asterisk (*) represents the point of attachment to the oxygen atom of the formula. in which said group (b) is optionally substituted by one or two Rio groups which are, at each occurrence, independently chosen from a C1-C4 alkyl group and a benzyl group; its deuterated derivative, as well as one of its pharmaceutically acceptable salts or solvates.

2. Compound according to claim 1, wherein A is represented by a group corresponding to formula (i), (ii), (iii) or (iv) as defined in claim 1.

3. Compound according to claim 1 or 2, in which X' is equal to 1, represented by formula (IA) in which Ri, R2, R3, R4, Rs, Re, R7, l, 11, Wi, 2أ, W2, A, m, n, and k are as defined in claim 1 or 2, its deuterated derivative, and one of its pharmaceutically acceptable salts or solvates.

4. Compound according to claim 1, wherein W2 represents a phenyl ring, I represents a bond and one of the radicals Ri, in ortho position with respect to L, and Rs can be linked to form a cyclic radical, represented by the general formula (IB) (IB) in which Ri, R2, R3, R4, Rs, R7, A, 11, Wi, !2, m, k and X' are as defined in claim 1 for compounds corresponding to formula (I), its deuterated derivative, and one of its pharmaceutically acceptable salts or solvates.

5. Compound according to claim 4, in which 11 represents a bond, Wi represents a divalent group selected from: a thiophene-2,5-diy!e group, a thiophene-2,4-diy!e group, a phenylene-1,4-diyl group, a phenylene-1,3-diyl group and a phenylene-1,2-diyl group; 2a represents a -(CH2)- group, R7 represents a hydrogen atom and Ri, R2, R3, R4, Rs, A, m and k are as defined in claim 1 for compounds corresponding to formula (I), its deuterated derivative, and one of its pharmaceutically acceptable salts or solvates.

6. Compound according to claim 1, in which W2 represents a phenyl ring and L represents a bond, represented by the general form (IC): in which Re is selected from a methyl group, an ethyl group, a hydroxymethyl group, an l-hydroxyethyl group, a 2-hydroxyethyl group, a methoxymethyl group, a trifluoromethyl group and a difluoromethyl group, and Ri, R2, R3, R4, Rs, R7, A, li, Wi, 2a, m, n, k and X' are as defined in claim 1 for compounds conforming to formula (I), one of its pharmaceutically acceptable salts or solvates.

7. Compound according to claim 6, wherein 11 represents a bond, Wi represents a divalent group selected from a thiophene-2,5-diy!e group, a thiophene-2,4-diy!e group, a phenylene-1,4-diyl group, a phenylene-1,3-diyl group and a phenylene-1,2-diyl group; 1.2 represents a -(CH-) group; R7 represents a hydrogen atom or a methyl group; Rs is selected from a methyl group, an ethyl group, a hydroxymethyl group, an l-hydroxyethyl group, a 2-hydroxyethyl group, a methoxymethyl group, a trifluoromethyl group and a difluoromethyl group; and Ri, R2, R3, R4, Rs, A, m, n, k and X' are as defined in claim 1 for compounds conforming to formula (I), one of its pharmaceutically acceptable salts or solvates.

8. Compound according to claim 1, in which 11 represents a bond, Wi is selected from a divalent saturated monocyclic heterocycloalkylene group, represented by the general formula (ID) and in which Y represents a sulfur atom or a CH group; L represents a group chosen from: a -(CHq-) group in which q is equal to 1 or 2, a [1]-(C0)-[X]-(CH2)t-[2] group, and a [1]-(SO2)-[X]-(CH2)t-[2] group, in which [1] and [2] represent respectively the point of attachment of the 2- group to the saturated monocyclic heterocycloalkylene nucleus (Wi) and to the nitrogen atom in the chain; and in which [X] represents a bond or a substituted or unsubstituted arylene group chosen from phenylene-1,4-, -1,3- and -1,2-diyl groups; t represents an integer that lies in the range of 1 to 4; and wherein Ri, R2, Rs, R4, Rs, Re, R?, A, W2, L, m, n, k and X' are as defined in claim 1 for compounds corresponding to formula (I), as well as one of its pharmaceutically acceptable salts or solvates.

9. A compound according to any one of claims 1 to 8, represented by formula (I)', wherein the absolute configuration of the carbon atom (1) is as shown below: in which Ri, R2, R3, R4, Rs, Re, R7, 11, Wi, !2, W2, I, A, n, m, k and X' are as defined in claim 1 for compounds corresponding to formula (I), as well as one of its pharmaceutically acceptable salts or solvates.

10. Compose according to claim 1, which is chosen from the list consisting of: the 5-[[[1 -methyl-2-oxo-1 -phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]methyl]-thiophen-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1-(3,4-dimethoxypheny!)ethyl], formate carboxylate salt; the 4-[[[1 -methyl-2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]methyl]-benzoate of [(1 S)-2-(3,5-dichloro-1-oxydo-pyridin-1 -ium-4-yl)-1 -(3,4-dimethoxyphenyethyl]; 1 -[[4-[(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1 -(3,4-dimethoxy-phenyl)ethoxy]carbonylphenyl]methylamino]indane-1 -carboxylate of [(3R)-quinuclidin-3-yl]; the 5-[[[1 [(3R)-quinuclidin-3-yl]oxycarbonylindan-1 -yl]amin0]methyl]thi0phene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1 -(3,4-dimethoxyphenyl)ethyl]; the 5-[[[1 -methyl-2-[(1 -methyl-4-piperidyl)oxy]-2-oxo-1 -phenylethyl]amino]-methyl]thiophen-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]; the 5-[[[1 -phenyl-1 -[(3R)-quinuclidin-3-yl]oxycarbonyl-propyl]amino]methyl]-thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1-(3,4-dimeth0xyphenyl)ethyl]; the unique diasteomer of 5-[[[1 -methyl-2-oxo-1 -phenyl-2-[(3R)-quinuclidin-3-yl]oxyethyl]amino]methyl]thiophen-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the unique diasteomer of 5-[[[1-methyl-2-0X0-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxyethyl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -oxydo-pyridin-l-ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the unique diasteomer of 4-[[[1-methyl-2-oxo-1-phenyl-2-[(3R)-quinuclidin- 3-yl]Oxy-ethyl]amine]methyl]benzoate of [(1S)-2-(3,5-dichloro-1-oxido-pyridin- 1 -ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] ; the unique diasteomer of 1-[[4-[(1S)-2-(3,5-dichloro-1-oxydopyridin-1-ium- [(3R)-quinucüdin-3-yl] 4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonylphenyl]methylamino]indane-1-carboxylate; the unique diasteoisomer of [(3R)-quinucüdin-3-yl] 1-[[4-[(1S)-2-(3,5-dichloro-1-oxydopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonylphenyl]methylamino]indane-1-carboxylate; the unique diasteomer of the 5-[[[1-[(3R)-quinuclidin-3-yl]oxycarbonylindan-1-yl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -oxydo-pyridin-l-ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the unique diasteomer of the 5-[[[1-[(3R)-quinuclidin-3-yl]oxycarbonylindan-1-yl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -oxydo-pyridin-l-ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the unique diasteomer of the 5-[[[1 -methyl-2-[(1 -methyl-4-piperidyl)oxy]-2-oxo-1 -phenylethyl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the unique diastereomer of the 5-[[[1-methyl-2-[(1-methyl-4-piperidyl)oxy]-2-oxo-1 -phenylethyl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the 5-[[[1 -methyl-2-[(3R)-1 -oxydoquinuclidin-l -ium-3-yl]oxy-2-oxo-1 -phenyl-ethyl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -oxide-pyridin-l -ium-4-yl)-1 -(3,4-dimethoxyphenyl)ethyl]; [(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1 -(3,4-dimethoxyphenyl)ethyl] 5-[[[1 -(2-dimethylaminoethyloxycarbonyl)indan-1 -yl]amino]methyl]thiophene-2-carboxylate; the 5-[[[1 -[(1 -methyl-4-piperidyl)oxycarbonyl]indan-1 -yl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1 -(3,4-dimethoxyphenyethyl]; the 5-[[[1 -(hydroxymethyl)-2-[(1 -methyl-4-piperidyl)oxy]-2-oxo-1 -phenyl-ethyl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -oxydo-pyridin-l-ium-4-yl)-1 -(3,4-dimethoxyphenyl)ethyl]; the 5-[[[1-(hydroxymethyl)-2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]-methylamino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -oxydo-pyridin-l -ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the 5-[[[1-(hydroxymethyl)-2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -oxydo-pyridin-l -ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the 5-[[[1 -(methoxymethyl)-2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -oxydo-pyridin-l -ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the unique diasteomer of the 5-[[[1 -(2-dimethylaminoethyloxycarbonyl)indan-1 -yl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -oxydo-pyridin-l -ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the unique diasteomer of the 5-[[[1 -(2-dimethylaminoethyloxycarbonyl)indan-1 -yl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -oxydo-pyridin-l -ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the unique diasteomer of the 5-[[[1-[(1-methyl-4-piperidyl)oxycarbonyl]indan-1-yl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -oxydo-pyridin-l -ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the unique diasteomer of 5-[[[1-phenyl-1-[(3R)-quinuclidin-3-yl]oxycarbonyl-propyl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-l -0xyd0-pyridin-1 -ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the unique diasteomer of 5-[[[1-phenyl-1-[(3R)-quinuclidin-3-yl]oxycarbonyl-propyl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-l -0xyd0-pyridin-1 -ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the unique diasteomer of 5-[[[1-(hydroxymethyl)-2-[(1-methyl-4-piperidyl)oxy]-2-oxo-1-phenyl-ethyl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1 -(3,4-dimethoxyphenyl)_ ethyl]; the unique diasteomer of 5-[[[1-(hydroxymethyl)-2-[(1-methyl-4-piperidyl)oxy]-2-oxo-1-phenyl-ethyl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1 -(3,4-dimethoxyphenyl)_ ethyl] ; the unique diasteomer of 5-[[[1-(hydroxymethyl)-2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-l -0xyd0-pyridin-1 -ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl] the unique diasteomer of 5-[[[1-(hydroxymethyl)-2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-l -0xyd0-pyridin-1 -ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; the unique diasteomer of 5-[[[1-(hydroxymethyl)-2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]-methyl-amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1 -(3,4-dimethoxyphenyl)_ ethyl]; the unique diasteomer of 5-[[[1-(hydroxymethyl)-2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]-methyl-amino]methyl]thiophene-2-carboxylate of [(1 S)-2-(3,5-dichloro-1 -0xyd0-pyridin-1 -ium-4-yl)-1 -(3,4-dimethoxyphenyl)-ethyl] ; the unique diastereomer of 5-[[[1-(methoxymethyl)-2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]methyl]thiophen-2-carboxylate of [(13)-2-(3,5-dichloro-l-oxyd0-pyridin-1-ium-4-yl)-1 _(3,4-dimethoxyphenyl)ethyl]; and one of their pharmaceutically acceptable salts or solvates.

11. Pharmaceutical composition comprising a compound as defined in any one of claims 1 to 10, in mixture with one or more pharmaceutically acceptable carriers.

12. Pharmaceutical composition according to claim 11, further comprising another active ingredient.

13. Compounded according to any one of claims 1 to 10, for use as a medicinal product.

14. Compound according to any one of claims 1 to 10, for use in the prevention and / or treatment of a disease of the respiratory system, characterized by an obstruction of the airways.

15. Compound for its use as defined in claim 14, wherein the respiratory system disease is selected from asthma and COPD.