US 12,391,711 B2
Tetrahydrocannabinol derivatives, preparation method thereof and use thereof
Jing Zhang, Chengdu (CN); Xuezhen Xu, Chengdu (CN); Yonggang Wei, Chengdu (CN); Hongzhu Chu, Chengdu (CN); Fuqiang Zhao, Chengdu (CN); Guizhuan Su, Chengdu (CN); Meiwei Wang, Chengdu (CN); and Yi Sun, Chengdu (CN)
Assigned to Chengdu Baiyu Pharmaceutical Co., Ltd., Chengdu (CN)
Appl. No. 17/772,993
Filed by CHENGDU BAIYU PHARMACEUTICAL CO., LTD., Sichuan (CN)
PCT Filed Jan. 7, 2021, PCT No. PCT/CN2021/070729
§ 371(c)(1), (2) Date Apr. 28, 2022,
PCT Pub. No. WO2021/139740, PCT Pub. Date Jul. 15, 2021.
Claims priority of application No. 202010016989.0 (CN), filed on Jan. 8, 2020.
Prior Publication US 2023/0227482 A1, Jul. 20, 2023
Int. Cl. C07F 9/655 (2006.01)
CPC C07F 9/65522 (2013.01) [C07B 2200/05 (2013.01)] 7 Claims
 
1. A compound represented by general formula (I), or stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or cocrystals thereof:

OG Complex Work Unit Chemistry
wherein:
R1 is C1-6 alkyl;
R2 is

OG Complex Work Unit Chemistry
R3 is selected from the group consisting of methyl, C3-8 carbocyclic group, —CH2OH, carboxyl, —C(═O)OC1-6 alkyl and —C(═O)NRb1Rb2;
R4 and R5 are each independently selected from the group consisting of H, halogen and carboxyl;
Ra is selected from the group consisting of H and C1-6 alkyl;
Rb and Rc are each independently selected from the group consisting of H, C1-6 alkyl, amino acid side chain, —C1-6 alkylene-C3-12 carbocyclic ring and —C1-6 alkylene-C3-12 heterocyclic ring; the C3-12 heterocyclic ring contains 1 to 4 heteroatoms selected from the group consisting of N, O and S; the C1-6 alkylene, the C1-6 alkyl, the C3-12 carbocyclic ring and the C3-12 heterocyclic ring are optionally further substituted by 0 to 3 substituents selected from the group consisting of hydroxyl, carboxyl, halogen, cyano, ═O, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, —NRb1Rb2, —C(═O)OC1-6 alkyl, —C(═O)Nb1Rb2, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C6-12 aryl or C5-12 heteroaryl; and the C1-6 alkyl, the C1-6 heteroalkyl, the C2-6 alkenyl or the C2-6 alkynyl are optionally further substituted by one or more groups selected from the group consisting of hydroxyl, carboxyl, cyano, halogen, —O—Rb1, —NRb1Rb2, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C6-12 aryl and C5-12 heteroaryl; when the amino acid side chain contains hydroxyl, mercapto or carboxyl, the hydroxyl, the mercapto or the carboxyl is optionally esterified;
Rb1 and Rb2 are each independently selected from the group consisting of H, C1-6 alkyl, —C(═O)Rb3 and —C(═O)NRb4Rb5, wherein the C1-6 alkyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxyl, halogen, C1-6 alkyl, C1-6 alkoxy, C6-12 aryl, C5-12 heteroaryl, C3-12 cycloalkyl and C3-12 heterocycloalkyl;
Rb3 is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy and C6-12 aryl;
Rb4 and Rb5 are each independently selected from the group consisting of H and C1-6 alkyl; or Rb4 and Rbs together with N atom form a 3 to 12 membered heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O and S;
or, Rb and Rc together with the atom to which they are attached form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, the 3 to 6 membered carbocyclic ring or the 3 to 6 membered heterocyclic ring is optionally further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxyl, carboxyl and amino, wherein the 3 to 6 membered heterocyclic ring contains 1 to 4 heteroatoms selected from the group consisting of N, O and S;
Rd is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclic ring, 3 to 10 membered heterocyclic ring, —C1-6 alkylene-C3-10 carbocyclic ring, —C1-6 alkylene-3 to 10 membered heterocyclic ring, —C1-6 alkylene-O—C1-6 alkylene-C3-10 carbocyclic ring, —C1-6 alkylene-O—C1-6 alkylene-3 to 10 heterocyclic ring and —C1-6 alkylene-O—C1-4 alkyl; the C1-6 alkylene, the C2-6 alkenyl, the C2-6 alkynyl, the C1-6 alkyl, the C3-10 carbocyclic ring and the 3 to 10 membered heterocyclic ring are optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, hydroxyl, carboxyl, amino, 1-cyclopropylethyl, C1-4 alkyl, C1-4 alkoxy, —OC(═O)ORd1 and —OC(═O)Rd2, wherein the 3 to 10 membered heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of N, O and S;
Rd1 and Rd2 are each independently selected from the group consisting of C1-4 alkyl, C3-10 carbocyclic ring and 3 to 10 membered heterocyclic ring, the C1-4 alkyl, the C3-10 carbocyclic ring or the 3 to 10 membered heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, hydroxyl, carboxyl, C1-4 alkyl, C1-4 alkoxy, C3-10 carbocyclic ring and 3 to 10 membered heterocylic ring, wherein the 3 to 10 membered heterocylic ring contains 1 to 6 heteroatoms selected from the group consisting of N, O and S;
R6 is selected from the group consisting of C1-12 alkyl, C1-12 heteroalkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkylene, C3-12 carbocyclic group, C3-12 heterocyclic group, —C1-6 alkylene-C3-12 carbocyclic group, —C1-6 alkylene-C3-12 heterocyclic group, —NRb1Rb2, —C1-6 alkylene-C(═O)OC1-6 alkyl and —C1-6 alkylene-C(═O)Nb1Rb2, wherein the C1-12 alkyl, the C1-12 heteroalkyl, the C2-12 alkenyl, the C2-12 alkynyl, C1-12 alkylene, the C3-12 carbocyclic group and the C3-12 heterocyclic group are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, carboxyl, halogen, cyano, ═O, C1-6 alkyl, —NRb1Rb2, C3-12 carbocyclic group, C3-12 heterocyclic group, C2-6 alkenyl, C2-6 alkynyl, —C(═O)OC1-6 alkyl, —C(═O)C1-6 alkyl, —C(═O)NRb1Rb2, —S(═O)C1-6 alkyl and —S(═O)2C1-6 alkyl, wherein as substituents, the C1-6 alkyl, the C3-12 carbocyclic group and the C3-12 heterocyclic group are optionally further substituted with one or more substituents selected from the group consisting of ═O, hydroxyl, carboxyl, halogen, cyano, —C(═O)OC1-6 alkyl and —C(═O)C1-6 alkyl;
custom character is a single bond or a double bond;
or, the general formula (I) is optionally substituted with one or more D atoms.