Phenethanolamine derivatives for treatment of respiratory diseases

1. A compound of formula (I)

or a salt, solvate, or physiologically functional derivative thereof, wherein:

m is an integer of from 2 to 8;

n is an integer of from 2 to 5;

with the proviso that m+n is 4 to 10;

R 1 is selected from hydrogen, C 1-6 alkyl, hydroxy, halo, C 1-6 haloalkyl, —XC(O)NR 9 R 10 , —XNR 8 C(O)R 9 , —XNR 8 C(O)NR 9 R 10 , —XNR 8 SO 2 R 9 , —XSO 2 NR 11 R 12 , XNR 8 SO 2 R 9 R 10 , —XNR 9 R 10 , XN + R 8 R 9 R 10 , —XNR 8 C(O)OR 9 , —XCO 2 R 9 , —XNR 8 C(O)NR 8 C(O)NR 9 R 10 , —XSR 9 , XSOR 9 , and —XSO 2 R 9 ;

or R 1 is selected from —X-aryl, —X-hetaryl, and —X-(aryloxy), each optionally substituted by 1 or 2 groups independently selected from hydroxy, C 1-6 alkoxy, halo, C 1-6 alkyl, C 1-6 haloalkyl, —NHC(O)(C 1-6 alkyl), —SO 2 (C 1-6 alkyl), —SO 2 (aryl), —SO 2 NH 2 , —SO 2 NH(C 1-6 alkyl), —SO 2 NH(C 3-7 cycloalkyl), —CO 2 H, —CO 2 (C 1-6 alkyl), —SO 2 NH(C 3-7 cycloalkylC 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, C 1-6 alkoxy, halo, C 1-6 alkyl, or C 1-6 haloalkyl;

X is —(CH 2 ) p — or C 2-6 alkenylene;

p is an integer from 0 to 6,

R 8 and R 9 are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl, hetaryl, hetaryl(C 1-6 alkyl)- and aryl(C 1-6 alkyl)- and R 8 and R 9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, —NHC(O)(C 1-6 alkyl), —SO 2 (C 1-6 alkyl), —SO 2 (aryl), —CO 2 H, —CO 2 (C 1-4 alkyl), —NH 2 , —NH(C 1-6 alkyl), aryl(C 1-6 alkyl)-, aryl(C 2-6 alkenyl)-, aryl(C 2-6 alkynyl)-, hetaryl(C 1-6 alkyl)-, —NHSO 2 aryl, —NH(hetarylC 1-6 alkyl), —NHSO 2 hetaryl, —NHSO 2 (C 1-6 alkyl), —NHC(O)aryl, or —NHC(O)hetaryl:

R 10 is selected from hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl;

R 11 and R 12 are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl, hetaryl, hetaryl(C 1-6 alkyl)- and aryl(C 1-6 alkyl)-, or R 11 and R 12 ,together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring;

and R 11 and R 12 are each optionally substituted by one or two groups independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl;

where R 1 is —XNR 8 C(O)NR 9 R 10 , R 8 and R 9 may, together with the —NC(O)N— portion of the group R 1 to which they are bonded, form a 5-, 6- or 7-membered saturated or unsaturated ring;

where R 1 is —XNR 8 C(O)OR 9 , R 8 and R 9 may, together with the —NC(O)O— portion of the group R 1 to which they are bonded, form a 5-, 6- or 7-membered saturated or unsaturated ring;

where R 1 is —XC(O)NR 9 R 10 or —XNR 8 C(O)NR 9 R 10 , R 9 and R 10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring;

R 2 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo, aryl, aryl(C 1-6 alkyl)-, C 1-6 haloalkoxy, and C 1-6 haloalkyl;

R 3 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo, aryl, aryl(C 1-6 alkyl)-, C 1-6 haloalkoxy, and C 1-6 haloalkyl;

R 4 and R 5 are independently selected from hydrogen and C 1-4 alkyl with the proviso that the total number of carbon atoms in R 4 and R 5 is not more than 4; and,

R 6 and R 7 are independently selected from hydrogen and C 1-4 alkyl with the proviso that the total number of carbon atoms in R 4 and R 5 is R 6 and R 7 is not more than 4.

2. A compound of formula (I)

or a salt, solvate, or physiologically functional derivative thereof, wherein:

m is an integer of from 2 to 8;

n is an integer of from 2 to 5;

with the proviso that m+n is 4 to 10;

R 1 is selected from hydrogen, C 1-6 alkyl, hydroxy, halo, C 1-6 haloalkyl, —XC(O)NR 9 R 10 , —XNR 8 C(O)R 9 , —XNR 8 C(O)NR 9 R 10 , —XNR 8 SO 2 R 9 , —XSO 2 NR 11 R 12 ;, —XNR 9 R 10 , —XNR 8 C(O)OR 9 ,

or R 1 is selected from —X-aryl, —X-hetaryl, or —X-(aryloxy), each optionally substituted by 1 or 2 groups independently selected from hydroxy, C 1-6 alkoxy, halo, C 1-6 alkyl, C 1-6 haloalkyl, —NHC(O)(C 1-6 alkyl), —SO 2 (C 1-6 alkyl), —SO 2 (aryl), —SO 2 NH 2 , —SO 2 NH(C 1-6 alkyl), —SO 2 NH(C 3-7 cycloalkyl), —CO 2 H, —CO 2 (C 1-6 alkyl), —SO 2 NH(C 3-7 cycloalkylC 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, C 1-6 alkoxy, halo, C 1-6 alkyl, or C 1-6 haloalkyl;

X is —(CH 2 ) p — or C 2-6 alkenylene;

p is an integer from 0 to 6,;

R 8 and R 9 are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl, hetaryl, hetaryl(C 1-6 alkyl)- and aryl(C 1-6 alkyl)- and R 8 and R 9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, —NHC(O)(C 1-6 alkyl), —SO 2 (C 1-6 alkyl), —SO 2 (aryl), —CO 2 H, and —CO 2 (C 1-4 alkyl), —NH 2 , —NH(C 1-6 alkyl), aryl(C 1-6 alkyl)-, aryl(C 2-6 alkenyl)-, aryl(C 2-6 alkynyl)-, hetaryl(C 1-6 alkyl)-, —NHSO 2 aryl, —NH(hetarylC 1-6 alkyl), —NHSO 2 hetaryl, —NHSO 2 (C 1-6 alkyl), —NHC(O)aryl, or —NHC(O)hetaryl:

R 10 is selected from hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl;

R 11 and R 12 are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl, hetaryl, hetaryl(C 1-6 alkyl)- and aryl(C 1-6 alkyl)-, or R 11 and R 12 , together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring;

and R 11 and R 12 are each optionally substituted by one or two groups independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl;

where R 1 is —XNR 8 C(O)NR 9 R 10 , R 8 and R 9 may, together with the portion —NC(O)N— of the group R 1 to which they are bonded, form a 5-, 6-, or 7-membered saturated or unsaturated ring;

where R 1 is —XNR 8 C(O)OR 9 , R 8 and R 9 may, together with the portion —NC(O)O— of the group R 1 to which they are bonded, form a 5-, 6-, or 7-membered saturated or unsaturated ring;

where R 1 is —XC(O)NR 9 R 10 or —XNR 8 C(O)NR 9 R 10 , R 9 and R 10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring;

R 2 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo, aryl, aryl(C 1-6 alkyl)-, C 1-6 haloalkoxy, and C 1-6 haloalkyl;

R 3 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo, aryl, aryl(C 1-6 alkyl)-, C 1-6 haloalkoxy, and C 1-6 haloalkyl;

R 4 and R 5 are independently selected from hydrogen and C 1-4 alkyl with the proviso that the total number of carbon atoms in R 4 and R 5 is not more than 4; and,

R 6 and R 7 are independently selected from hydrogen and C 1-4 alkyl with the proviso that the total number of carbon atoms in R 4 and R 5 is not more than 4.

3. A compound according to claim 1 of formula (Ia)

or a salt, solvate, or physiologically functional derivative thereof, wherein R 1 , R 2 , R 3 , R 6 and R 7 are as defined for claim 1 and m is 4 or 5.

4. A compound according to any one of claims 1 to 3 which is selected from the group consisting of:

N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}ethoxy)methyl]phenyl}-N′-phenylurea;

4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;

N-(3-{[({3-[(2-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}ethoxy)methyl]phenyl}amino)carbonyl]amino}phenyl)pyridine-3-carboxamide;

4-{(1R)-1-Hydroxy-2-[(6-{2-[(3-hydroxybenzyl)oxy]ethoxy}hexyl)amino]ethyl}-2-(hydroxymethyl)phenol;

4-{(1R)-2-[(6-{2-[(3,5-Dimethylbenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;

N-{3-[(2-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)pentyl]oxy}ethoxy)methyl]phenyl}-N′-phenylurea;

and salts, solvates, and physiologically functional derivatives thereof.

5. A pharmaceutical formulation comprising a compound according to claim 1 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.

6. A combination comprising a compound according to claim 1 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and one or more other therapeutic ingredients.

7. A combination according to claim 6 wherein the other therapeutic ingredient is selected from the group consisting of a PDE4 inhibitor, a corticosteroid or and an anti-cholinergic agent.

8. A combination according to claim 7 wherein the additional therapeutic ingredient is 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester.

9. A method for the prophylaxis or treatment of a clinical condition in a mammal, for which a selective β 2 -adrenoreceptor agonist is indicated, which comprises administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

10. A process for preparing a compound as defined according to any one of claims 1 to 3 claim 1, wherein said process is one of (A), (B), or (C):

(A) deprotecting a protected intermediate of formula (II):

 or a salt or solvate thereof, wherein R 4 , R 5 , R 6 , R 7 , m, and n are as defined for the compound of formula (I) or (Ia), and R 1α , R 2α , and R 3α R 1a , R 2a , and R 3a are each independently either the same as R 1 , R 2 , and R 3 respectively as defined for the compound of formulae (I) or (Ia) or a precursor for said group R 1 , R 2 , or R 3 , and R 13 , R 14 , and R 15 are each independently either hydrogen or a protecting group provided that at least one of R 13 , R 14 , and R 15 is a protecting group, and R 19 is hydrogen or a protecting group;

(B) alkylating an amine of formula (XIX):

 wherein R 13 , R 14 , R 15 and R 19 are as hereinbefore defined, with a compound of formula (VI):

 wherein L 1 represents a leaving group such as halo, and removing any protecting groups present on the alkylated compound; and

(C) reacting an amine of formula (XIX) as defined hereinabove, with a compound of formula (XX):

 wherein R 4 , R 6 , R 7 , R 1α , R 2α , and R 3α R 1a , R 2a , R 3a , m and n are as hereinbefore defined; under conditions suitable to effect reductive amination,

 wherein any one of (A), (B), or (C) may optionally employ one or more of the following steps in any order:

(i) removing any protecting groups;

(ii) separating an enantiomer or diastereoisomer from a mixture of enantiomers or diastereoisomers;

(iii) converting the product to a corresponding salt, solvate, or physiologically functional derivative thereof.;

(iv) converting a group R 1α , R 2α , and/or R 3α R 1a , R 2a and/or R 3a to a group R 1 , R 2 and/or R 3 respectively.

11. A compound of formula (I) according to claim 1 wherein the group R 1 is attached to the meta-position relative to the —OCR 6 R 7 —link.

12. A compound of formula (I) according to claim 1 , wherein the groups R 2 and R 3 are each independently attached to the ortho position relative to the —OCR 6 R 7 — link.

13. A compound of formula (I) according to claim 3 wherein R 1 represents a substituent other than hydrogen, attached to the meta-position relative to the —OCR 6 R 7 — link, and R 2 and R 3 each represent hydrogen.

14. A compound of formula (I) according to claim 1 wherein R 1 represents hydrogen and R 2 and R 2 each represent a substituent at least one of which is other than hydrogen, and R 2 and R 3 are each independently attached to the ortho- or meta-positions relative to the —OCR 6 R 7 — link.

15. A compound of formula (I) according to claim 1 wherein R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, hydroxy, halo, C 1-6 haloalkyl, —XNR 8 (C)OR 9 , —XNR 8 C(O)NR 9 R 10 , —XNR 8 SO 2 R 9 , —XSO 2 NR 11 R 12 , —XNR 9 R 10 , —XNR 8 C(O)OR 9 , XSR 9 , XSOR 9 , XSO 2 R 9 , X-aryl, X-hetaryl and X-aryloxy.

16. A compound of formula (I) according to claim 1 wherein X is (CH 2 ) p and p is zero.

17. A compound of formula (I) according to claim 1 wherein R 1 is selected from the group consisting of hydrogen, c 1-4 alkyl, is selected from the group consisting of C 1-4 alkyl, hydroxy, halo, —NR 8 C(O)NR 9 R 10 , and —NR 8 SO 2 R 9 .

18. A compound of formula (I) according to claim 1 , wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, haloC 1-6 alkyl, C 1-6 alkyl, phenyl, and substituted phenyl.

19. A compound of formula (I) according to claim 1 , wherein R 4 and R 5 are independently selected from the group consisting of hydrogen, and methyl.

20. A compound of formula (I) according to claim 1 , wherein R 6 and R 7 are independently selected from the group consisting of hydrogen, and methyl.

21. A compound of formula (I) according to claim 1 , wherein m is 4, 5, or 6, and n is 2 or 3.

22. An inhalation device comprising the compound according to claim 1 .

23. An inhalation device according to claim 22 , wherein the compound is present in particles ranging in size from 1 μm to 10 μm.

24. An inhalation device according to claim 22 , wherein the compound is present in a dry powder pharmaceutical formulation.

25. An inhalation device according to claim 22 , wherein the compound is present in an aerosol pharmaceutical formulation.

26. A compound which is selected from the group consisting of:

N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}ethoxy)methyl]phenyl}-N′-phenylurea;

4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol; and

salts thereof.

27. A compound which is selected from the group consisting of:

4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;

N-(3-{[({3-[(2-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}ethoxy)methyl]phenyl}amino)carbonyl]amino}phenyl)pyridine-3-carboxamide; and

salts thereof.

28. A compound which is selected from the group consisting of:

4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;

4-{(1R)-1-Hydroxy-2-[(6-{2-[(3-hydroxybenzyl)oxy]ethoxy}hexyl)amino]ethyl}-2-(hydroxymethyl)phenol; and

salts thereof.

29. A compound which is selected from the group consisting of:

4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;

4-{(1R)-2-[(6-{2-[(3,5-Dimethylbenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol; and

salts thereof.

30. A compound which is selected from the group consisting of:

4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;

N-{3-[(2-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)pentyl]oxy}ethoxy)methyl]phenyl}-N′-phenylurea; and

salts thereof.