Claims for Patent: RE44874

Summary for Patent: RE44874

Title:	Phenethanolamine derivatives for treatment of respiratory diseases
Abstract:	The present invention relates to novel compounds of formula (I), to a process for their manufacture, to pharmaceutical compositions containing them, and to their use in therapy, in particular their use in the prophylaxis and treatment of respiratory diseases
Inventor(s):	Philip Charles Box, Diane Mary Coe, Brian Edgar Looker, Panayiotis Alexandrou Procopiou
Assignee:	Glaxo Group Ltd
Application Number:	US13/719,797
Patent Claims:	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; R1 is selected from hydrogen, C1-6alkyl, hydroxy, halo, C1-6haloalkyl, —XC(O)NR9R10, —XNR8C(O)R9, —XNR8C(O)NR9R10, —XNR8SO2R9, —XSO2NR11R12, XNR8SO2R9R10, —XNR9R10, XN+R8R9R10, —XNR8C(O)OR9, —XCO2R9, —XNR8C(O)NR8C(O)NR9R10, —XSR9, XSOR9, and —XSO2R9; or R1 is selected from —X-aryl, —X-hetaryl, and —X-(aryloxy), each optionally substituted by 1 or 2 groups independently selected from hydroxy, C1-6alkoxy, halo, C1-6alkyl, C1-6haloalkyl, —NHC(O)(C1-6alkyl), —SO2(C1-6alkyl), —SO2(aryl), —SO2NH2, —SO2NH(C1-6alkyl), —SO2NH(C3-7cycloalkyl), —CO2H, —CO2(C1-6alkyl), —SO2NH(C3-7cycloalkylC1-6alkyl), —NH2, —NH(C1-6alkyl), or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, C1-6alkoxy, halo, C1-6alkyl, or C1-6haloalkyl; X is —(CH2)p— or C2-6 alkenylene; p is an integer from 0 to 6, R8 and R9 are independently selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, hetaryl, hetaryl(C1-6alkyl)- and aryl(C1-6alkyl)- and R8 and R9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, C1-6alkyl, C1-6haloalkyl, —NHC(O)(C1-6alkyl), —SO2(C1-6alkyl), —SO2(aryl), —CO2H, —CO2(C1-4alkyl), —NH2, —NH(C1-6alkyl), aryl(C1-6alkyl)-, aryl(C2-6alkenyl)-, aryl(C2-6alkynyl)-, hetaryl(C1-6alkyl)-, —NHSO2aryl, —NH(hetarylC1-6alkyl), —NHSO2hetaryl, —NHSO2(C1-6alkyl), —NHC(O)aryl, or —NHC(O)hetaryl: R10 is selected from hydrogen, C1-6alkyl and C3-7cycloalkyl; R11 and R12 are independently selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, hetaryl, hetaryl(C1-6alkyl)- and aryl(C1-6alkyl)-, or R11 and R12,together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring; and R 11 and R12 are each optionally substituted by one or two groups independently selected from halo, C1-6alkyl, and C1-6haloalkyl; where R1 is —XNR8C(O)NR9R10, R8 and R9 may, together with the —NC(O)N— portion of the group R1 to which they are bonded, form a 5-, 6- or 7-membered saturated or unsaturated ring; where R1 is —XNR8C(O)OR9, R8 and R9 may, together with the —NC(O)O— portion of the group R1 to which they are bonded, form a 5-, 6- or 7-membered saturated or unsaturated ring; where R1 is —XC(O)NR9R10 or —XNR8C(O)NR9R10, R9 and R10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring; R2 is selected from hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, halo, aryl, aryl(C1-6alkyl)-, C1-6haloalkoxy, and C1-6 haloalkyl; R3 is selected from hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, halo, aryl, aryl(C1-6alkyl)-, C1-6haloalkoxy, and C1-6haloalkyl; R4 and R5 are independently selected from hydrogen and C1-4 alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4; and, R6 and R7 are independently selected from hydrogen and C1-4alkyl with the proviso that the total number of carbon atoms in R4 and R5is R6 and R7 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; R1 is selected from hydrogen, C1-6alkyl, hydroxy, halo, C1-6haloalkyl, —XC(O)NR9R10, —XNR8C(O)R9, —XNR8C(O)NR9R10, —XNR8SO2R9, —XSO2NR11R12;, —XNR9R10, —XNR8C(O)OR9, or R1 is selected from —X-aryl, —X-hetaryl, or —X-(aryloxy), each optionally substituted by 1 or 2 groups independently selected from hydroxy, C1-6alkoxy, halo, C1-6alkyl, C1-6haloalkyl, —NHC(O)(C1-6alkyl), —SO2(C1-6alkyl), —SO2(aryl), —SO2NH2, —SO2NH(C1-6alkyl), —SO2NH(C3-7cycloalkyl), —CO2H, —CO2(C1-6alkyl), —SO2NH(C3-7cycloalkylC1-6alkyl), —NH2, —NH(C1-6alkyl), or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, C1-6alkoxy, halo, C1-6alkyl, or C1-6haloalkyl; X is —(CH2)p— or C2-6 alkenylene; p is an integer from 0 to 6,; R8 and R9 are independently selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, hetaryl, hetaryl(C1-6alkyl)- and aryl(C1-6alkyl)- and R8 and R9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, C1-6alkyl, C1-6haloalkyl, —NHC(O)(C1-6alkyl), —SO2(C1-6alkyl), —SO2(aryl), —CO2H, and —CO2(C1-4alkyl), —NH2, —NH(C1-6alkyl), aryl(C1-6alkyl)-, aryl(C2-6alkenyl)-, aryl(C2-6alkynyl)-, hetaryl(C1-6alkyl)-, —NHSO2aryl, —NH(hetarylC1-6alkyl), —NHSO2hetaryl, —NHSO2(C1-6alkyl), —NHC(O)aryl, or —NHC(O)hetaryl: R10 is selected from hydrogen, C1-6alkyl and C3-7cycloalkyl; R11 and R12 are independently selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, hetaryl, hetaryl(C1-6alkyl)- and aryl(C1-6alkyl)-, or R11 and R12, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring; and R11 and R12 are each optionally substituted by one or two groups independently selected from halo, C1-6alkyl, and C1-6haloalkyl; where R1 is —XNR8C(O)NR9R10, R8 and R9 may, together with the portion —NC(O)N— of the group R1 to which they are bonded, form a 5-, 6-, or 7-membered saturated or unsaturated ring; where R1 is —XNR8C(O)OR9, R8 and R9 may, together with the portion —NC(O)O— of the group R1 to which they are bonded, form a 5-, 6-, or 7-membered saturated or unsaturated ring; where R1 is —XC(O)NR9R10 or —XNR8C(O)NR9R10, R9 and R10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring; R2 is selected from hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, halo, aryl, aryl(C1-6alkyl)-, C1-6haloalkoxy, and C1-6 haloalkyl; R3 is selected from hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, halo, aryl, aryl(C1-6alkyl)-, C1-6haloalkoxy, and C1-6haloalkyl; R4 and R5 are independently selected from hydrogen and C1-4 alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4; and, R6 and R7 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. 3. A compound according to claim 1 of formula (Ia) or a salt, solvate, or physiologically functional derivative thereof, wherein R1, R2, R3, R6 and R7 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 β2-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 R4, R5, R6, R7, m, and n are as defined for the compound of formula (I) or (Ia), and R1α, R2α, and R3α R1a, R2a, and R3a are each independently either the same as R1, R2, and R3 respectively as defined for the compound of formulae (I) or (Ia) or a precursor for said group R1, R2, or R3, and R13, R14, and R15 are each independently either hydrogen or a protecting group provided that at least one of R13, R14, and R15 is a protecting group, and R19 is hydrogen or a protecting group; (B) alkylating an amine of formula (XIX): wherein R13, R14, R15 and R19 are as hereinbefore defined, with a compound of formula (VI): wherein L1 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 R4, R6, R7, R1α, R2α, and R3α R1a, R2a, R3a, 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 R1α, R2α, and/or R3αR1a, R2a and/or R3a to a group R1, R2 and/or R3 respectively. 11. A compound of formula (I) according to claim 1 wherein the group R1 is attached to the meta-position relative to the —OCR6R7—link. 12. A compound of formula (I) according to claim 1, wherein the groups R2 and R3 are each independently attached to the ortho position relative to the —OCR6R7— link. 13. A compound of formula (I) according to claim 3 wherein R1 represents a substituent other than hydrogen, attached to the meta-position relative to the —OCR6R7— link, and R2 and R3 each represent hydrogen. 14. A compound of formula (I) according to claim 1 wherein R1 represents hydrogen and R2 and R2 each represent a substituent at least one of which is other than hydrogen, and R2 and R3 are each independently attached to the ortho- or meta-positions relative to the —OCR6R7— link. 15. A compound of formula (I) according to claim 1 wherein R1 is selected from the group consisting of hydrogen, C1-6alkyl, hydroxy, halo, C1-6haloalkyl, —XNR8(C)OR9, —XNR8C(O)NR9R10, —XNR8SO2R9, —XSO2NR11R12, —XNR9R10, —XNR8C(O)OR9, XSR9, XSOR9, XSO2R9, X-aryl, X-hetaryl and X-aryloxy. 16. A compound of formula (I) according to claim 1 wherein X is (CH2)p and p is zero. 17. A compound of formula (I) according to claim 1 wherein R1 is selected from the group consisting of hydrogen, c 1-4alkyl, is selected from the group consisting of C1-4alkyl, hydroxy, halo, —NR8C(O)NR9R10, and —NR8SO2R9. 18. A compound of formula (I) according to claim 1, wherein R2 and R3 are independently selected from the group consisting of hydrogen, halogen, haloC1-6alkyl, C1-6alkyl, phenyl, and substituted phenyl. 19. A compound of formula (I) according to claim 1, wherein R4 and R5 are independently selected from the group consisting of hydrogen, and methyl. 20. A compound of formula (I) according to claim 1, wherein R6 and R7 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.