Phenethanolamine derivative for the treatment of respiratory diseases

A compound of formula (Ia):

• or a salt, solvate, or physiologically functional derivative thereof, wherein:
• m is an integer of from 2 to 8;
• and
• n is an integer of from 3 to 11;
• with the proviso that m+n is 5 to 19;
• R1 is SR6, SOR6, or SO2R6,
• wherein R6 is a C3-7cycloalkyl or C3-7cycloalkenyl group;
• R2 and R3 are independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, halo, phenyl, and C1-6haloalkyl;
• and
• R4 and R5 are independently selected from hydrogen and C1-4alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4.

A compound selected from the group consisting of:

• 4-{(1R)-2-[(6-{4-[3-(Cyclopentylsulfinyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;
• 4-{(1R)-2-[(6-{4-[3-(Cyclopentylsulfinyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol (Isomer 1);
• 4-{(1R)-2-[(6-{4-[3-(Cyclopentylsulfinyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol (Isomer 2);
• 4-{(1R)-2-[(6-{4-[3-(Cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;
• 4-{(1R)-2-[(6-{4-[4-(Cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;
• 4-((1R)-2-{[6-({4-[3-(Cyclohexylsulfonyl)phenyl]butyl}oxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;
• 4-((1R)-2-{[6-({4-[3-(3-Cyclopenten-1-ylsulfonyl)phenyl]butyl}oxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;
• 4-((1R)-2-{[6-({5-[3-(Cyclopentylsulfonyl)phenyl]pentyl}oxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;
• 4-((1R)-2-{[7-({3-[3-(Cyclopentylsulfonyl)phenyl]propyl}oxy)heptyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;
• 4-((1R)-2-{[6-({4-[3-(Cyclopentylsulfonyl)-5-methylphenyl]butyl}oxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;
• N-[5-((1R)-2-{[6-({4-[3-(Cyclopentylsulfonyl)phenyl]butyl}oxy)hexyl]amino}-1-hydroxyethyl)-2-hydroxyphenyl]methanesulfonamide;
• 4-((1R)-2-{[6-({4-[3-(Cyclopentylsulfonyl)phenyl]butyl}oxy)hexyl]amino}-1-hydroxyethyl)-2-fluorophenol;
• 6-{2-[(6-{4-[3-(Cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)pyridin-3-ol;
• 5-{(1R)-2-[(6-{4-[3-(Cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-8-hydroxy-3,4-dihydroquinolin-2(1H)-one;
• 5-{(1R)-2-[(6-{4-[3-(Cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-hydroxyphenylformamide;
• salts thereof, solvates thereof, and physiologically functional derivatives thereof.

A method for the treatment of a clinical condition in a mammal for which a selective β2-adrenoreceptor agonist is indicated, which comprises administering a therapeutically effective amount of a compound of formula (I):

• or a salt, solvate, or physiologically functional derivative thereof, wherein:
• m is an integer of from 2 to 8;
• and
• n is an integer of from 3 to 11;
• with the proviso that m+n is 5 to 19;
• R1 is SR6, SOR6, or SO2R6,
• wherein R6 is a C3-7cycloalkyl or C3-7cycloalkenyl group;
• R2 and R3 are independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, halo, phenyl, and C1-6haloalkyl;
• R4 and R5 are independently selected from hydrogen and C1-4alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4;
• Ar is a group selected from
• wherein R8 represents hydrogen, halogen, —(CH2)qOR11, —NR11C(O)R12, —NR11SO2R12,
• —SO2NR11R12, —NR11R12, —OC(O)R13 or OC(O)NR11R12,
• and R7 represents hydrogen, halogen, or C1-4 alkyl;
• or R8 represents —NHR14 and R7 and —NHR14 together form a 5- or 6-membered heterocyclic ring;
• R9 represents hydrogen, halogen, —OR11 or —NR11R12;
• R10 represents hydrogen, halogen, haloC1-4 alkyl, —OR11, NR11R12, —OC(O)R13 or OC(O)NR11R12;
• R11 and R12 each independently represents hydrogen or C1-4 alkyl, or in the groups —NR11R12, —SO2NR11R12 and —OC(O)NR11R12, R11 and R12 independently represent hydrogen or C1-4 alkyl or together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered nitrogen-containing ring,
• R13 represents an aryl group which may be unsubstituted or substituted by one or more substituents selected from halogen, C1-4 alkyl, hydroxy, C1-4 alkoxy or halo C1-4 alkyl;
• and
• q is zero or an integer from 1 to 4.

A pharmaceutical formulation comprising a compound of formula (I):

• or a salt, solvate, or physiologically functional derivative thereof, wherein:
• m is an integer of from 2 to 8;
• and
• n is an integer of from 3to 11;
• with the proviso that m+n is 5 to 19;
• R1 is SR6, SOR6, or SO2 R6,
• wherein R6 is a C3-7cycloalkyl or C3-7cycloalkenyl group;
• R2 and R3 are independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, halo phenyl, and C1-6haloalkyl;
• R4 and R5 are independently selected from hydrogen and C1-4alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4;
• Ar is a group selected from
• wherein R8 represents hydrogen, halogen, —(CH2)qOR11, —NR11C(O)R12, —NR11SO2R12,
• —SO2NR11R12 —NR11R12, —OC(O)R13 or OC(O)NR11R12,
• and R7 represents hydrogen, halogen, or C1-4 alkyl;
• or R8 represents —NHR14 and R7 and —NHR14 together form a 5- or 6-membered heterocyclic ring;
• R9 represents hydrogen, halogen, —OR11 or —NR11R12;
• R10 represents hydrogen, halogen, haloC1-4 alkyl, —OR11, —NR11R12, —OC(O)R13 or OC(O)NR11R12;
• R11 and R12 each independently represents hydrogen or C1-4 alkyl, or in the groups —NR11R12, —SO2NR11R12 and —OC(O)NR11R12, R11 and R12 independently represent hydrogen or C1-4 alkyl or together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered nitrogen-containing ring,
• R13 represents an aryl group which may be unsubstituted or substituted by one or more substituents selected from halogen, C1-4 alkyl, Hydroxy, C1-4 alkoxy or halo C1-4 alkyl;
• and
• q is zero or an integer from 1 to 4, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.

A combination comprising a compound of formula (I):

• or a salt, solvate, or physiologically functional derivative thereof, wherein:
• m is an integer of from 2 to 8;
• and
• n is an integer of from 3to 11;
• with the proviso that m+n is 5 to 19;
• R1 is SR6, SOR6, or SO2R6, wherein R6 is a C3-7cycloalkyl or C3-7cycloalkenyl group;
• R2 and R3 are independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, halo, phenyl, and C1-6haloalkyl;
• R4 and R5 are independently selected from hydrogen and C1-4alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4;
• Ar is a group selected from
• wherein R8 represents hydrogen, halogen, —(CH2)qOR11, —NR11C(O)R12, —NR11SO2R12,
• —SO2NR11R12, —NR11R12, —OC(O)R13 or OC(O)NR11R12,
• and R7 represents hydrogen, halogen, or C1-4 alkyl;
• or R8 represents —NHR14 and R7 and —NHR14 together form a 5- or 6-membered heterocyclic ring;
• R9 represents hydrogen, halogen, —OR11 or NR11R12;
• R10 rerpresents hydrogen, halogen, haloC1-4 alkyl, —OR11, —NR11R12, —OC(O)R13 or OC(O)NR11R12;
• R11 and R12 each independently represents hydrogen or C1-4 alkyl, or in the groups —NR11R12, —SO2NR11R12 and —OC(O)NR11R12, R11 and R12 independently represent hydrogen or C1-4 alkyl or together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered nitrogen-containing ring,
• R13 represents an aryl group which may be unsubstituted or substituted by one or more substituents selected from halogen, C1-4 alkyl, hydroxy, C1-4 alkoxy or halo C1-4 alkyl;
• and
• q is zero or an integer from 1 to 4 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and one or more other therapeutic ingredients.