US 12,473,302 B2
4-phenylpiperidines, their preparation and use
Konstantin Petrukhin, New Windsor, NY (US); Christopher Cioffi, Albany, NY (US); Graham Johnson, Sanbornton, NH (US); Nicoleta Dobri, New York, NY (US); Emily Freeman, Albany, NY (US); Ping Chen, Albany, NY (US); Michael Conlon, Albany, NY (US); and Lei Zhu, Albany, NY (US)
Assigned to THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, New York, NY (US)
Filed by The Trustees of Columbia University in the City of New York, New York, NY (US)
Filed on Feb. 9, 2024, as Appl. No. 18/437,702.
Application 17/320,158 is a division of application No. 16/151,019, filed on Oct. 3, 2018, granted, now 11,028,098, issued on Jun. 8, 2021.
Application 16/151,019 is a division of application No. 14/775,532, granted, now 10,273,243, issued on Apr. 30, 2019, previously published as PCT/US2014/026813, filed on Mar. 13, 2014.
Application 18/437,702 is a continuation of application No. 17/320,158, filed on May 13, 2021, granted, now 11,919,913.
Claims priority of provisional application 61/785,187, filed on Mar. 14, 2013.
Prior Publication US 2024/0287092 A1, Aug. 29, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 498/04 (2006.01); A61K 31/437 (2006.01); A61K 31/4375 (2006.01); A61K 31/454 (2006.01); A61K 31/4545 (2006.01); A61K 31/497 (2006.01); A61K 31/501 (2006.01); A61K 31/5025 (2006.01); A61K 31/506 (2006.01); A61P 27/02 (2006.01); C07D 401/06 (2006.01); C07D 405/14 (2006.01); C07D 409/06 (2006.01); C07D 471/04 (2006.01); C07D 487/04 (2006.01); C07D 491/052 (2006.01); C07D 495/04 (2006.01)
CPC C07D 498/04 (2013.01) [A61K 31/437 (2013.01); A61K 31/4375 (2013.01); A61K 31/454 (2013.01); A61K 31/4545 (2013.01); A61K 31/497 (2013.01); A61K 31/501 (2013.01); A61K 31/5025 (2013.01); A61K 31/506 (2013.01); A61P 27/02 (2018.01); C07D 401/06 (2013.01); C07D 405/14 (2013.01); C07D 409/06 (2013.01); C07D 471/04 (2013.01); C07D 487/04 (2013.01); C07D 491/052 (2013.01); C07D 495/04 (2013.01)] 20 Claims
 
1. A method of lowering a retinal concentration of a bisretinoid in a mammal, the method comprising administering to the mammal an effective amount of a compound having the structure:

OG Complex Work Unit Chemistry
wherein
R1, R2, R3, and R4 are each independently H, halogen, CF3 or C1-C4 alkyl;
R5 is CF3;
R6 is H;
B has the structure:

OG Complex Work Unit Chemistry
wherein
n is 1;
R7 is H, C1-C4 alkyl, or oxetane;
Y1, Y2 and Y4 are CH2 or C(CH3)2; and
Y3 is O, SO2, or N—R10,
wherein
R10 is H, C1-C4 alkyl, C1-C4 cycloalkyl, (C1-C4 alkyl)-CF3, (C1-C4 alkyl)-OCH3, (C1-C4 alkyl)-halogen, SO2—(C1-C4 alkyl), SO2—(C1-C4 alkyl)-CF3, SO2—(C1-C4 alkyl)-OCH3, SO2—(C1-C4 alkyl)-halogen, C(O)—(C1-C4 alkyl), C(O)—(C1-C4 alkyl)-CF3, C(O)—(C1-C4 alkyl)-OCH3, C(O)—(C1-C4 alkyl)-halogen, C(O)—NH—(C1-C4 alkyl), C(O)—N(C1-C4 alkyl)2, C1-C4 alkyl)-C(O)OH, or oxetane; or
wherein
n is 2;
R7 is H, C1-C4 alkyl, or oxetane;
Y1, Y3, and each occurrence of Y4 are each CH2 or C(CH3)2; and
Y2 is O, SO2, or N—R10,
wherein
R10 is H, C1-C4 alkyl, C3-C6 cycloalkyl, (C1-C4 alkyl)-CF3, (C1-C4 alkyl)-OCH3, (C1-C4 alkyl)-halogen, SO2—(C1-C10alkyl), SO2—(C1-C4 alkyl)-CF3, SO2—(C1-C4 alkyl)-OCH3, SO2—(C1-C4 alkyl)-halogen, C(O)—(C1-C10 alkyl), C(O)—(C1-C4 alkyl)-CF3, C(O)—(C1-C4 alkyl)-OCH3, C(O)—(C1-C4 alkyl)-halogen, C(O)—NH—(C1-C4 alkyl), C(O)—N(C1-C4 alkyl)2, (C3-C4 alkyl)-C(O)OH, C(O)—NH2 or oxetane.