	US 7,572,825 B2
	Ketones and reduced ketones as therapeutic agents for the treatment of bone conditions
Stuart H. Ralston, Edinburgh (United Kingdom); Iain R. Greig, Aberdeen (United Kingdom); Aymen I. I. Mohamed, Edinburgh (United Kingdom); and Robert J. Van 'T Hof, Edinburgh (United Kingdom)
Assigned to The University Court of the University of Aberdeen, Aberdeen, Aberdeenshire (United Kingdom)
Appl. No. 10/555,738 PCT Filed May 06, 2004, PCT No. PCT/GB2004/001958 § 371(c)(1), (2), (4) Date Jul. 14, 2006, PCT Pub. No. WO2004/098582, PCT Pub. Date Nov. 18, 2004.
Claims priority of application No. 0310463.5 (GB), filed on May 07, 2003; and application No. 0325259.0 (GB), filed on Oct. 29, 2003.
Prior Publication US 2007/0027112 A1, Feb. 01, 2007
Int. Cl. A61K 31/385 (2006.01); A61K 31/22 (2006.01); A61K 31/15 (2006.01); A61K 31/12 (2006.01)

U.S. Cl. 514—436 [514/546; 514/640; 514/679]

51 Claims

1. A method for the treatment of osteoporosis, rheumatoid arthritis, cancer associated bone disease, Paget's disease, or aseptic loosening of prosthetic implants, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound selected from compounds of the following formulae and pharmaceutically acceptable salts, amides, esters, and ethers thereof:

wherein:

Ar¹is independently a group of the following formula:

wherein:

q is independently an integer from 0 to 4;

r is independently an integer from 0 to 5; and

each R^Pis independently selected from: (1) carboxylic acid; (2) ester; (3) amido; (4) acyl; (5) halo; (6) cyano; (7) nitro; (8) hydroxy; (9) ether; (10) thiol; (11) thioether; (12) acyloxy; (13) amino; (14) acylamino; (15) aminoacylamino; (16) sulfonamino; (17) sulfonyl; (18) sulfonate; (19) sulfonamido; (22) C_3-20heterocyclyl; (23) C_1-7alkyl; (24) oxo; (25) imino; (26) hydroxyimino; and (27) phosphate;

R^alkis independently a C_4-8alkylene group, and is unsubstituted, or substituted with one or more substituents selected from: halogen, hydroxy, C_1-7alkoxy, amino, and amido;

—OR^O, if present, is independently —OH or —OR^K;

—OR^K, if present, is independently selected from:

—O—R^K1;

—O—C(═O)R^K2;

—O—C(═O)OR^K3;

—O—S(═O)₂OR^K4;

wherein:

each of R^K1, R^K2, R^K3, and R^K4is independently C_5-20aryl-C_1-7alkyl, C_5-20aryl, C_3-20heterocyclyl, or C_1-7alkyl, and is optionally substituted; and

each of R^K3and R^K4may additionally be —H;

Q is independently —OH or —OR^OT;

wherein:

—OR^OT, if present, is independently: —O—R^E1;

wherein:

R^E1is independently: C_5-20aryl-C_1-7alkyl, unsubstituted or substituted with one or more groups selected from (1) carboxylic acid; (2) ester; (3) amido; (4) acyl; (5) halo; (6) cyano; (7) nitro; (8) hydroxy; (9) ether; (10) thiol; (11) thioether; (12) acyloxy; (13) amino; (14) acylamino; (15) aminoacylamino; (16) sulfonamino; (17) sulfonyl; (18) sulfonate; (19) sulfonamido; (20) C_5-20aryl-C_1-7alkyl; (21) C_5-20aryl; (22) C_3-20heterocyclyl; (23) C_1-7alkyl; (24) oxo; (25) imino; (26) hydroxyimino; and (27) phosphate; C_5-20aryl, unsubstituted or substituted with one or more groups selected from (1) carboxylic acid; (2) ester; (3) amido; (4) acyl; (5) halo; (6) cyano; (7) nitro; (8) hydroxy; (9) ether; (10) thiol; (11) thioether; (12) acyloxy; (13) amino; (14) acylamino; (15) aminoacylamino; (16) sulfonamino; (17) sulfonyl; (18) sulfonate; (19) sulfonamido; (20) C_5-20aryl-C_1-7alkyl; (21) C_5-20aryl; (22) C_3-20heterocyclyl; (23) C_1-7alkyl; (24) oxo; (25) imino; (26) hydroxyimino; and (27) phosphate;

C_3-20heterocyclyl, unsubstituted or substituted with one or more groups selected from (1) carboxylic acid; (2) ester; (3) amido; (4) acyl; (5) halo; (6) cyano; (7) nitro; (8) hydroxy; (9) ether; (10) thiol; (11) thioether; (12) acyloxy; (13) amino; (14) acylamino; (15) aminoacylamino; (16) sulfonamino; (17) sulfonyl; (18) sulfonate; (19) sulfonamido; (20) C_5-20aryl-C_1-7alkyl; (21) C_5-20aryl; (22) C_3-20heterocyclyl; (23) C_1-7alkyl; (24) oxo; (25) imino; (26) hydroxyimino; and (27) phosphate; or

C_1-7alkyl, unsubstituted or substituted with one or more groups selected from (1) carboxylic acid; (2) ester; (3) amido; (4) acyl; (5) halo; (6) cyano; (7) nitro; (8) hydroxy; (9) ether; (10) thiol; (11) thioether; (12) acyloxy; (13) amino; (14) acylamino; (15) aminoacylamino; (16) sulfonamino; (17) sulfonyl; (18) sulfonate; (19) sulfonamido; (20) C_5-20aryl-C_1-7alkyl; (21) C_5-20aryl; (22) C_3-20heterocyclyl; (24) oxo; (25) imino; (26) hydroxyimino; and (27) phosphate;

wherein the group —C(═O)— in formula (1) is optionally replaced with a group selected from the following groups, wherein each R is independently C_5-20aryl-C_1-7alkyl, C_5-20aryl, C_3-20heterocyclyl, or C_1-7alkyl, and is optionally substituted:

with the proviso that if —OR^OTis —O—R^E1, then R^E1is not a phenyl group substituted with a sulfonyl group; and

with the proviso that —OR^O, if present, is other than siloxy.