US 12,269,828 B2
Cyclic amide-containing pyridyl xanthines as A2B antagonists
Robert D Thompson, Charlottesville, VA (US)
Assigned to Adovate, LLC, Charlottesville, VA (US)
Filed by Adovate, LLC, Charlottesville, VA (US)
Filed on Oct. 16, 2023, as Appl. No. 18/487,159.
Application 18/487,159 is a division of application No. 17/663,551, filed on May 16, 2022, granted, now 11,814,387.
Claims priority of provisional application 63/201,905, filed on May 18, 2021.
Prior Publication US 2024/0124457 A1, Apr. 18, 2024
Int. Cl. C07D 473/08 (2006.01); A61P 3/10 (2006.01); A61P 9/00 (2006.01); A61P 11/06 (2006.01); A61P 25/04 (2006.01); A61P 29/00 (2006.01); A61P 35/00 (2006.01); A61P 37/00 (2006.01)
CPC C07D 473/08 (2013.01) [A61P 3/10 (2018.01); A61P 9/00 (2018.01); A61P 11/06 (2018.01); A61P 25/04 (2018.01); A61P 29/00 (2018.01); A61P 35/00 (2018.01); A61P 37/00 (2018.01)] 24 Claims
 
1. A method for treating an adenosine A2B receptor associated state in a subject, comprising: administering to the subject an effective amount of a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof:

OG Complex Work Unit Chemistry
wherein:
n is selected from 1-10, wherein the (CH2)n group is substituted with 0-1 groups selected from: C1-6 alkyl, C3-6 cycloalkyl, and —C1-3 alkylene-C3-6 cycloalkyl;
Ring A is selected from phenyl, naphthyl, and a 5-10 membered heteroaryl;
R1 is selected from: C1-6 alkyl, C3-6 cycloalkyl, —(CH2)2—OCH3, —(CH2)3—OCH3, —(CH2)4—OCH3, —(CH2)2—NH(C(O)CH3, and —C1-6 alkylene-4-10 membered cyclic amide;
R2 is selected from: C1-6 alkyl, C3-6 cycloalkyl, —(CH2)2—OCH3, —(CH2)3—OCH3,
—(CH2)4—OCH3, —(CH2)2—NH(C(O)CH3, and —C1-6 alkylene-4-10 membered cyclic amide;
R3 is a 4-10 membered cyclic amide;
R4 is selected from: H, F, Cl, Br, I, C1-6 alkyl, C3-6 cycloalkyl, —C1-3 alkylene-C3-6 cycloalkyl, OR6, SR6, —CN, NR6R7, CF3, OCF3, CO2R6, OC(O)R6, O2R6, C(O)NR6R7, OC(O)NR6R7, NR7COR6, NR7CO2R6, NR7C(O)NR6R7, and S(O)pNR6R7;
R5 is selected from: H, F, Cl, Br, I, C1-6 alkyl, C3-6 cycloalkyl, —C1-3 alkylene-C3-6 cycloalkyl, OR6, SR6, —CN, NR6R7, CF3, OCF3, CO2R6, OC(O)R6, O2R6, C(O)NR6R7, OC(O)NR6R7, NR7COR6, NR7CO2R6, NR7C(O)NR6R7, and S(O)pNR6R7;
R6 is independently selected from: H, C1-6 alkyl, C3-6 cycloalkyl, and,
—C1-3 alkylene-C3-6 cycloalkyl;
R7 is independently selected from: H, C1-6 alkyl, C3-6 cycloalkyl, and,
—C1-3 alkylene-C3-6 cycloalkyl; and,
p is independently selected from: 0, 1, and 2;
alternatively, R4 and R5 are absent, and Ring A is replicated by a group selected from: C1-6 alkyl, CF3, C3-6 cycloalkyl, —CH2—OCH3, —(CH2)2—OCH3, —CH2—O-phenyl, and
—CH2—O-pyridyl;
alternatively, —(CH2)n—R3 is selected from: C1-6 alkyl, —C1-3 alkylene-C3-6 cycloalkyl,
(CH2)2—OCH3, —(CH2)3—OCH3, and —(CH2)4—OCH3, provided that at least one of R1 and R2 is an amide-containing group independently selected from: —(CH2)2—NH(C(O)CH3 and —C1-6 alkylene-4-10 membered cyclic amide wherein the adenosine A2B receptor associated state is asthma, bronchoconstriction, pain, diabetic retinopathy, bladder cancer and breast cancer, and wherein treatment is inhibiting the adenosine A2B receptor associated state and/or relieving the adenosine A2B receptor associated state and/or ameliorating a symptom of the adenosine A2B receptor associated state.