Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors

1. An N-oxide compound of formula (IA):

wherein:

R 1 and R 2 are different or the same and are each independently:

H;

(C 1 -C 6 ) haloalkyl

(C 1 -C 6 ) alkyl, optionally substituted by one or more substituents selected from (C 3 -C 7 ) cycloalkyl or (C 5 -C 7 ) cycloalkenyl;

(C 3 -C 7 ) cycloalkyl;

(C 5 -C 7 ) cycloalkenyl;

(C 2 -C 6 ) alkenyl; or

(C 2 -C 6 ) alkynyl;

n is 0, 1 or 2;

R 3 is an optional substituent which, at each occurrence, is independently:

(C 1 -C 6 ) alkyl optionally substituted by one or more (C 3 -C 7 ) cycloalkyl;

(C 1 -C 6 ) haloalkyl;

OR 4 wherein R 4 is selected from the group consisting of H, (C 1 -C 10 ) alkyl optionally substituted by (C 3 -C 7 ) cycloalkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 7 ) cycloalkyl;

a halogen atom;

a group —NR 5 SO 2 R 6 wherein

R 5 is selected in the group consisting of hydrogen; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkyl which is substituted by a group —NR 7 R 8 wherein R 7 and R 8 are independently H, (C 1 -C 6 ) alkyl, or together with the nitrogen atom to which they are attached form a (C 5 -C 7 ) heterocycloalkyl group; (C 1 -C 6 ) alkyl which is substituted by an heteroaryl group; and

R 6 is (C 1 -C 4 ) alkyl optionally substituted by (C 3 -C 7 ) cycloalkyl; or a phenyl ring optionally substituted with one or two halogen atoms, hydroxy, (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy groups or with a group —C(O)NR 9 R 10 wherein R 9 and R 10 are independently hydrogen, (C 1 -C 4 ) alkyl groups, or together with the nitrogen atom to which they are attached form a (C 5 -C 7 ) heterocycloalkyl group;

a group —SO 2 R 11 wherein

R 11 is selected from (C 1 -C 6 ) alkyl; a phenyl ring which is optionally substituted with one or two groups selected in the list consisting of: halogen atom, hydroxyl, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, a —C(O)NR 12 R 13 group, wherein R 12 and R 13 are independently hydrogen, (C 1 -C 4 ) alkyl groups, or together with the nitrogen atom to which they are attached form a (C 5 -C 7 ) heterocycloalkyl group, and a group —NR 14 R 15 , wherein R 14 and R 15 are independently hydrogen, (C 1 -C 4 ) alkyl groups, or together with the nitrogen atom to which they are attached form a (C 5 -C 7 ) heterocycloalkyl group;

a group —C(O)R 16 wherein

R 16 is a phenyl ring which is optionally substituted with one or two groups selected in the list consisting of: halogen atom, hydroxyl, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, a —C(O)NR 23 R 24 group wherein R 23 and R 24 are independently hydrogen, (C 1 -C 4 ) alkyl groups, or together with the nitrogen atom to which they are attached form a (C 5 -C 7 )heterocycloalkyl group, and a group —NR 25 R 26 , wherein R 25 and R 26 are independently hydrogen, (C 1 -C 4 ) alkyl groups, or together with the nitrogen atom to which they are attached form a (C 5 -C 7 ) heterocycloalkyl group; or

a group —SO 2 NR 17 R 18 wherein

R 17 is H or (C 1 -C 6 ) alkyl; and

R 18 is selected from hydrogen; (C 1 -C 6 )alkyl; (C 1 -C 6 ) alkyl which is substituted by a group —NR 19 R 20 wherein R 19 and R 20 are independently H or (C 1 -C 6 ) alkyl, or together with the nitrogen atom to which they are attached form a (C 5 -C 7 )heterocycloalkyl group; a phenyl ring optionally substituted with one or two halogen atoms, hydroxy, (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy groups or with a group —C(O)NR 21 R 22 wherein R 21 and R 22 are independently hydrogen, (C 1 -C 4 ) alkyl groups, or together with the nitrogen atom to which they are attached form a (C 5 -C 7 ) heterocycloalkyl group;

or a pharmaceutically acceptable salt thereof.

2. An N-oxide compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is (C 1 -C 6 ) haloalkyl and R 2 is (C 1 -C 6 ) alkyl which is substituted by (C 3 -C 7 ) cycloalkyl.

3. An N-oxide compound or pharmaceutically acceptable salt according to claim 1 , which has the absolute configuration of carbon (1) shown in formula (IA)′:

4. An N-oxide compound, which is selected from the group consisting of:

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(thiophene-3-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(5-methylthiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(3-methoxythiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(5-chlorothiophene-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-chloro-4-(methylsulfonyl)thiophene-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(5-methoxythiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(4,5-dimethylthiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-chlorothiophene-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(3-(N-methylsulfamoyl)thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(3-(N-methyl-N-(2-morpholinoethyl)sulfamoyl)thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(3-(N-(2-morpholinoethyl)methylsulfonamido)thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(3-(methylsulfonamido)thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(5-(N-(2-morpholinoethyl)methylsulfonamido)thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(4-(methylsulfonamido)thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(4-(4-chlorophenylsulfonyl)thiophene-3-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-pyridine 1-oxide;

(S)-4-(2-(3-benzoylthiophene-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(3-(3-(dimethylcarbamoyl)phenylsulfonamido)thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(5-(N-(3-(dimethylcarbamoyl)phenyl)sulfamoyl)thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(5-(N-(4-(dimethylcarbamoyl)phenyl)sulfamoyl)thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(5-(N-(pyridin-3-ylmethyl)methylsulfonamido)thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(5-(N-(2-(pyrrolidin-1-yl)ethyl)methylsulfonamido)thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(4-methoxy-5-(N-(2-morpholinoethyl)methylsulfonamido)-thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(5-(1-cyclopropyl-N-(2-morpholinoethyl)-methylsulfonamido)thiophene-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(5-(1-cyclopropyl-N-(2-(pyrrolidin-1-yl)ethyl)-methylsulfonamido)thiophene-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide;

(S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-(thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide; and

(S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide;

or a pharmaceutically acceptable salt of said N-oxide compound.

5. A combination, comprising an N-oxide compound or pharmaceutically acceptable salt according to claim 1 and a second pharmaceutical active component selected from the group consisting of beta2-agonist, a corticosteroid, and an antimuscarinic agent.

6. A pharmaceutical composition, comprising an N-oxide compound or pharmaceutically acceptable salt according to claim 1 and one or more pharmaceutically acceptable carriers and/or excipients.

7. A pharmaceutical composition, comprising a combination according to claim 5 and one or more pharmaceutically acceptable carriers and/or excipients.

8. A kit, comprising a pharmaceutical composition according to claim 6 and a device which is selected from a single- or multi-dose dry powder inhaler, a metered dose inhaler or a nebulizer.

9. A pharmaceutical composition, comprising an N-oxide compound or pharmaceutically acceptable salt according to claim 2 and one or more pharmaceutically acceptable carriers and/or excipients.

10. A pharmaceutical composition, comprising an N-oxide compound or pharmaceutically acceptable salt according to claim 3 and one or more pharmaceutically acceptable carriers and/or excipients.

11. A pharmaceutical composition, comprising an N-oxide compound or pharmaceutically acceptable salt according to claim 4 and one or more pharmaceutically acceptable carriers and/or excipients.