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 ##STR00001##
Inventor(s):	Box; Philip Charles (Stevenage, GB), Coe; Diane Mary (Stevenage, GB), Looker; Brian Edgar (Stevenage, GB), Procopiou; Panayiotis Alexandrou (Stevenage, GB)
Assignee:	Glaxo Group Limited (Greenford, Middlesex, GB)
Application Number:	13/719,797
Patent Claims:	1. A compound of formula (I) ##STR00023## 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.sup.1 is selected from hydrogen, C.sub.1-6alkyl, hydroxy, halo, C.sub.1-6haloalkyl, --XC(O)NR.sup.9R.sup.10, --XNR.sup.8C(O)R.sup.9, --XNR.sup.8C(O)NR.sup.9R.sup.10, --XNR.sup.8SO.sub.2R.sup.9, --XSO.sub.2NR.sup.11R.sup.12, .[.XNR.sup.8SO.sub.2R.sup.9R.sup.10,.]. --XNR.sup.9R.sup.10, XN.sup.+R.sup.8R.sup.9R.sup.10, --XNR.sup.8C(O)OR.sup.9, --XCO.sub.2R.sup.9, --XNR.sup.8C(O)NR.sup.8C(O)NR.sup.9R.sup.10, --XSR.sup.9, XSOR.sup.9, and --XSO.sub.2R.sup.9; or R.sup.1 is selected from --X-aryl, --X-hetaryl, and --X-(aryloxy), each optionally substituted by 1 or 2 groups independently selected from hydroxy, C.sub.1-6alkoxy, halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl, --NHC(O)(C.sub.1-6alkyl), --SO.sub.2(C.sub.1-6alkyl), --SO.sub.2(aryl), --SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-6alkyl), --SO.sub.2NH(C.sub.3-7cycloalkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-6alkyl), --SO.sub.2NH(C.sub.3-7cycloalkylC.sub.1-6alkyl), --NH.sub.2, --NH(C.sub.1-6alkyl), or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, C.sub.1-6alkoxy, halo, C.sub.1-6alkyl, or C.sub.1-6haloalkyl; X is --(CH.sub.2).sub.p-- or C.sub.2-6 alkenylene; p is an integer from 0 to 6, R.sup.8 and R.sup.9 are independently selected from hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, aryl, hetaryl, hetaryl(C.sub.1-6alkyl)- and aryl(C.sub.1-6alkyl)- and R.sup.8 and R.sup.9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl, --NHC(O)(C.sub.1-6alkyl), --SO.sub.2(C.sub.1-6alkyl), --SO.sub.2(aryl), --CO.sub.2H, --CO.sub.2(C.sub.1-4alkyl), --NH.sub.2, --NH(C.sub.1-6alkyl), aryl(C.sub.1-6alkyl)-, aryl(C.sub.2-6alkenyl)-, aryl(C.sub.2-6alkynyl)-, hetaryl(C.sub.1-6alkyl)-, --NHSO.sub.2aryl, --NH(hetarylC.sub.1-6alkyl), --NHSO.sub.2hetaryl, --NHSO.sub.2(C.sub.1-6alkyl), --NHC(O)aryl, or --NHC(O)hetaryl: R.sup.10 is selected from hydrogen, C.sub.1-6alkyl and C.sub.3-7cycloalkyl; R.sup.11 and R.sup.12 are independently selected from hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, aryl, hetaryl, hetaryl(C.sub.1-6alkyl)- and aryl(C.sub.1-6alkyl)-, or R.sup.11 and R.sup.12,together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring; and .sup.R.sup.11 and R.sup.12 are each optionally substituted by one or two groups independently selected from halo, C.sub.1-6alkyl, and C.sub.1-6haloalkyl; where R.sup.1 is --XNR.sup.8C(O)NR.sup.9R.sup.10, R.sup.8 and R.sup.9 may, together with the --NC(O)N-- portion of the group R.sup.1 to which they are bonded, form a 5-, 6- or 7-membered saturated or unsaturated ring; where R.sup.1 is --XNR.sup.8C(O)OR.sup.9, R.sup.8 and R.sup.9 may, together with the --NC(O)O-- portion of the group R.sup.1 to which they are bonded, form a 5-, 6- or 7-membered saturated or unsaturated ring; where R.sup.1 is --XC(O)NR.sup.9R.sup.10 or --XNR.sup.8C(O)NR.sup.9R.sup.10, R.sup.9 and R.sup.10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring; R.sup.2 is selected from hydrogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, halo, aryl, aryl(C.sub.1-6alkyl)-, C.sub.1-6haloalkoxy, and C.sub.1-6 haloalkyl; R.sup.3 is selected from hydrogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, halo, aryl, aryl(C.sub.1-6alkyl)-, C.sub.1-6haloalkoxy, and C.sub.1-6haloalkyl; R.sup.4 and R.sup.5 are independently selected from hydrogen and C.sub.1-4 alkyl with the proviso that the total number of carbon atoms in R.sup.4 and R.sup.5 is not more than 4; and, R.sup.6 and R.sup.7 are independently selected from hydrogen and C.sub.1-4alkyl with the proviso that the total number of carbon atoms in .[.R.sup.4 and R.sup.5is.]. .Iadd.R.sup.6 and R.sup.7 is .Iaddend.not more than 4. 2. A compound of formula (I) ##STR00024## 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.sup.1 is selected from hydrogen, C.sub.1-6alkyl, hydroxy, halo, C.sub.1-6haloalkyl, --XC(O)NR.sup.9R.sup.10, --XNR.sup.8C(O)R.sup.9, --XNR.sup.8C(O)NR.sup.9R.sup.10, --XNR.sup.8SO.sub.2R.sup.9, --XSO.sub.2NR.sup.11R.sup.12.[.;.]..Iadd., .Iaddend.--XNR.sup.9R.sup.10, --XNR.sup.8C(O)OR.sup.9, or R.sup.1 is selected from --X-aryl, --X-hetaryl, or --X-(aryloxy), each optionally substituted by 1 or 2 groups independently selected from hydroxy, C.sub.1-6alkoxy, halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl, --NHC(O)(C.sub.1-6alkyl), --SO.sub.2(C.sub.1-6alkyl), --SO.sub.2(aryl), --SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-6alkyl), --SO.sub.2NH(C.sub.3-7cycloalkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-6alkyl), --SO.sub.2NH(C.sub.3-7cycloalkylC.sub.1-6alkyl), --NH.sub.2, --NH(C.sub.1-6alkyl), or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, C.sub.1-6alkoxy, halo, C.sub.1-6alkyl, or C.sub.1-6haloalkyl; X is --(CH.sub.2).sub.p-- or C.sub.2-6 alkenylene; p is an integer from 0 to 6.[.,.]..Iadd.; .Iaddend. R.sup.8 and R.sup.9 are independently selected from hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, aryl, hetaryl, hetaryl(C.sub.1-6alkyl)- and aryl(C.sub.1-6alkyl)- and R.sup.8 and R.sup.9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl, --NHC(O)(C.sub.1-6alkyl), --SO.sub.2(C.sub.1-6alkyl), --SO.sub.2(aryl), --CO.sub.2H, and --CO.sub.2(C.sub.1-4alkyl), --NH.sub.2, --NH(C.sub.1-6alkyl), aryl(C.sub.1-6alkyl)-, aryl(C.sub.2-6alkenyl)-, aryl(C.sub.2-6alkynyl)-, hetaryl(C.sub.1-6alkyl)-, --NHSO.sub.2aryl, --NH(hetarylC.sub.1-6alkyl), --NHSO.sub.2hetaryl, --NHSO.sub.2(C.sub.1-6alkyl), --NHC(O)aryl, or --NHC(O)hetaryl: R.sup.10 is selected from hydrogen, C.sub.1-6alkyl and C.sub.3-7cycloalkyl; R.sup.11 and R.sup.12 are independently selected from hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, aryl, hetaryl, hetaryl(C.sub.1-6alkyl)- and aryl(C.sub.1-6alkyl)-, or R.sup.11 and R.sup.12, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring; and R.sup.11 and R.sup.12 are each optionally substituted by one or two groups independently selected from halo, C.sub.1-6alkyl, and C.sub.1-6haloalkyl; where R.sup.1 is --XNR.sup.8C(O)NR.sup.9R.sup.10, R.sup.8 and R.sup.9 may, together with the portion --NC(O)N-- of the group R.sup.1 to which they are bonded, form a 5-, 6-, or 7-membered saturated or unsaturated ring; where R.sup.1 is --XNR.sup.8C(O)OR.sup.9, R.sup.8 and R.sup.9 may, together with the portion --NC(O)O-- of the group R.sup.1 to which they are bonded, form a 5-, 6-, or 7-membered saturated or unsaturated ring; where R.sup.1 is --XC(O)NR.sup.9R.sup.10 or --XNR.sup.8C(O)NR.sup.9R.sup.10, R.sup.9 and R.sup.10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring; R.sup.2 is selected from hydrogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, halo, aryl, aryl(C.sub.1-6alkyl)-, C.sub.1-6haloalkoxy, and C.sub.1-6 haloalkyl; R.sup.3 is selected from hydrogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, halo, aryl, aryl(C.sub.1-6alkyl)-, C.sub.1-6haloalkoxy, and C.sub.1-6haloalkyl; R.sup.4 and R.sup.5 are independently selected from hydrogen and C.sub.1-4 alkyl with the proviso that the total number of carbon atoms in R.sup.4 and R.sup.5 is not more than 4; and, R.sup.6 and R.sup.7 are independently selected from hydrogen and C.sub.1-4alkyl with the proviso that the total number of carbon atoms in R.sup.4 and R.sup.5 is not more than 4. 3. A compound according to claim 1 of formula (Ia) ##STR00025## or a salt.[., solvate, or physiologically functional derivative.]. thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.6 and R.sup.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 .Iadd.the group consisting of.Iaddend.: 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-hydroxyet- hyl}-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)py- ridine-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-hydroxyet- hyl}-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 .Iadd.selected from the group consisting of .Iaddend.a PDE4 inhibitor, a corticosteroid .[.or.]. .Iadd.and .Iaddend.an anti-cholinergic agent. 8. A combination according to claim 7 wherein the additional therapeutic ingredient is 6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11 .beta.-hydroxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carboth- ioic acid S-fluoromethyl ester. 9. A method for the .[.prophylaxis or.]. treatment of a clinical condition in a mammal, for which a selective .beta..sub.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.]. .Iadd.claim 1.Iaddend., wherein said process is one of (A), (B).Iadd., .Iaddend.or (C): (A) deprotecting a protected intermediate of formula (II): ##STR00026## or a salt .[.or solvate.]. thereof, wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, m, and n are as defined for the compound of formula (I) or (Ia), and .[.R.sup.1.alpha., R.sup.2.alpha., and R.sup.3.alpha..]. .Iadd.R.sup.1a, R.sup.2a, and R.sup.3a.Iaddend. are each independently either the same as R.sup.1, R.sup.2, and R.sup.3 respectively as defined for the compound of formulae (I) or (Ia) or a precursor for said group R.sup.1, R.sup.2, or R.sup.3, and R.sup.13, R.sup.14, and R.sup.15 are each independently either hydrogen or a protecting group provided that at least one of R.sup.13, R.sup.14, and R.sup.15 is a protecting group, and R.sup.19 is hydrogen or a protecting group; (B) alkylating an amine of formula (XIX): ##STR00027## wherein R.sup.13, R.sup.14, R.sup.15 and R.sup.19 are as hereinbefore defined, with a compound of formula (VI): ##STR00028## wherein L.sup.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): ##STR00029## wherein R.sup.4, R.sup.6, R.sup.7, .[.R.sup.1.alpha., R.sup.2.alpha., and R.sup.3.alpha..]. .Iadd.R.sup.1a, R.sup.2a, R.sup.3a, .Iaddend. 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.[...]..Iadd.; .Iaddend. (iv) converting a group .[.R.sup.1.alpha., R.sup.2.alpha., and/or R.sup.3.alpha..]..Iadd.R.sup.1a, R.sup.2a and/or R.sup.3a.Iaddend. to a group R.sup.1, R.sup.2 and/or R.sup.3 respectively. 11. A compound .[.of formula (I).]. according to claim 1 wherein the group R.sup.1 is attached to the meta-position relative to the --OCR.sup.6R.sup.7--link. 12. A compound .[.of formula (I).]. according to claim 1, wherein the groups R.sup.2 and R.sup.3 are each independently attached to the ortho position relative to the --OCR.sup.6R.sup.7-- link. 13. A compound .[.of formula (I).]. according to claim 3 wherein R.sup.1 represents a substituent other than hydrogen, attached to the meta-position relative to the --OCR.sup.6R.sup.7-- link, and R.sup.2 and R.sup.3 each represent hydrogen. 14. A compound .[.of formula (I).]. according to claim 1 wherein R.sup.1 represents hydrogen and R.sup.2 and R.sup.2 each represent a substituent at least one of which is other than hydrogen, and R.sup.2 and R.sup.3 are each independently attached to the ortho- or meta-positions relative to the --OCR.sup.6R.sup.7-- link. 15. A compound .[.of formula (I).]. according to claim 1 wherein R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-6alkyl, hydroxy, halo, C.sub.1-6haloalkyl, --XNR.sup.8(C)OR.sup.9, --XNR.sup.8C(O)NR.sup.9R.sup.10, --XNR.sup.8SO.sub.2R.sup.9, --XSO.sub.2NR.sup.11R.sup.12, --XNR.sup.9R.sup.10, --XNR.sup.8C(O)OR.sup.9, XSR.sup.9, XSOR.sup.9, XSO.sub.2R.sup.9, X-aryl, X-hetaryl and X-aryloxy. 16. A compound .[.of formula (I).]. according to claim 1 wherein X is (CH.sub.2).sub.p and p is zero. 17. A compound .[.of formula (I).]. according to claim 1 wherein R.sup.1 .[..sup.is selected from the group consisting of hydrogen, c.sub.1-4alkyl,.]. .Iadd.is selected from the group consisting of C.sub.1-4alkyl, .Iaddend.hydroxy, halo, --NR.sup.8C(O)NR.sup.9R.sup.10, and --NR.sup.8SO.sub.2R.sup.9. 18. A compound .[.of formula (I).]. according to claim 1, wherein R.sup.2 and R.sup.3 are independently selected from the group consisting of hydrogen, halogen, haloC.sub.1-6alkyl, C.sub.1-6alkyl, phenyl, and substituted phenyl. 19. A compound .[.of formula (I).]. according to claim 1, wherein R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen.[.,.]. and methyl. 20. A compound .[.of formula (I).]. according to claim 1, wherein R.sup.6 and R.sup.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 .mu.m to 10 .mu.m. 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. .Iadd.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-hydroxyet- hyl}-2-(hydroxymethyl)phenol; and salts thereof. .Iaddend. .Iadd.27. A compound which is selected from the group consisting of: 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet- hyl}-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)py- ridine-3-carboxamide; and salts thereof. .Iaddend. .Iadd.28. A compound which is selected from the group consisting of: 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet- hyl}-2-(hydroxymethyl)phenol; 4-{(1R)-1-Hydroxy-2-[(6-{2-[(3-hydroxybenzyl)oxy]ethoxy}hexyl)amino]ethyl- }-2-(hydroxymethyl)phenol; and salts thereof. .Iaddend. .Iadd.29. A compound which is selected from the group consisting of: 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet- hyl}-2-(hydroxymethyl)phenol; 4-{(1R)-2-[(6-{2-[(3,5-Dimethylbenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet- hyl}-2-(hydroxymethyl)phenol; and salts thereof. .Iaddend. .Iadd.30. A compound which is selected from the group consisting of: 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet- hyl}-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. .Iaddend.