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US-12617779-B2 - Self degradation-type CDK9 inhibitor prodrug and liposome encapsulating same

US12617779B2US 12617779 B2US12617779 B2US 12617779B2US-12617779-B2

Abstract

Provided is a self-degradation type CDK9 inhibitor prodrug and a liposome encapsulating the same. The present disclosure provides a compound represented by formula (1) or a pharmaceutically acceptable salt thereof: wherein R 1 is an optionally substituted C 1-6 alkyl group, R 2 and R 3 are the same or different, each independently a hydrogen atom or an optionally substituted C 1-6 alkyl group, X is CH 2 or an oxygen atom, n is 1 or 2, p is 0, 1 or 2, q is 1 or 2, and r is 0, 1 or 2, wherein, if X is an oxygen atom, q is 2.

Inventors

  • Seiji KAMIOKA
  • Naoaki Shimada
  • Makoto Matsuoka
  • Hitoshi Ban

Assignees

  • Sumitomo Pharma Co., Ltd.

Dates

Publication Date
20260505
Application Date
20220822
Priority Date
20210823

Claims (20)

  1. 1 . A compound represented by of formula (1): or a pharmaceutically acceptable salt thereof, wherein R 1 is an optionally substituted C 1-6 alkyl group, R 2 and R 3 are the same or different, each independently a hydrogen atom or an optionally substituted C 1-6 alkyl group, X is CH 2 or an oxygen atom, n is 1 or 2, p is 0, 1 or 2, q is 1 or 2, and r is 0, 1 or 2, wherein, if X is an oxygen atom, q is 2.
  2. 2 . The compound of claim 1 , which has a structure of formula (1′): or a pharmaceutically acceptable salt thereof.
  3. 3 . The compound of claim 1 , wherein the optionally substituted C 1-6 alkyl groups in R 1 , R 2 , and R 3 are each independently a C 1-6 alkyl group optionally substituted with 1 to 5 of the same or different substituents independently selected from the group consisting of: (1) a halogen atom, (2) a hydroxyl group, (3) a carboxyl group, (4) a sulfinic acid group, (5) a sulfonic acid group, (6) a phosphoric acid group, (7) an optionally substituted C 3-8 cycloalkyl group, (8) an optionally substituted C 6-10 aryl group, (9) an optionally substituted 5- to 10-membered heteroaryl group, (10) an optionally substituted C 1-6 alkoxy group, (11) an optionally substituted C 3-10 cycloalkoxy group, (12) an optionally substituted C 1-6 alkoxycarbonyl group, (13) an optionally substituted C 1-6 alkylcarbonyl group, (14) an optionally substituted 3- to 10-membered saturated heterocyclic group, (15) —NR 4 R 5 , (16) —CO 2 R 4 , (17) a guanidine group, (18) —CONR 4 R 5 , (19) —SO 2 R 4 , (20) —SO 2 NR 4 R 5 , and (21) cyano, wherein the substituents in (7), (8), (9), (10), (11), (12), (13), and (14) are groups which are optionally substituted with 1 to 5 of the same or different substituents selected from the group consisting of: (a) a halogen atom, (b) a hydroxyl group, (c) a C 1-6 alkyl group, (d) a C 1-6 alkoxy group, (e) a cyano group, (f) a carboxyl group, (g) a sulfinic acid group, (h) a sulfonic acid group, (i) a phosphoric acid group, (j) a C 1-6 alkoxycarbonyl group, (k) a C 1-6 alkylcarbonyl group, (l) —NR 4 R 5 , (m) —CO 2 R 4 , (n) a guanidine group, (o) —CONR 4 R 5 , (p) —SO 2 R 4 , and (q) —SO 2 NR 4 R 5 , and R 4 and R 5 are the same or different hydrogen atoms or C 1-6 alkyl groups, or a pharmaceutically acceptable salt thereof.
  4. 4 . The compound of claim 1 , wherein p is 0, or a pharmaceutically acceptable salt thereof.
  5. 5 . The compound of claim 1 , wherein r is 2, or a pharmaceutically acceptable salt thereof.
  6. 6 . The compound of claim 1 , wherein R 2 and R 3 are the same or different, each independently (1) a hydrogen atom, or (2) a C 1-6 alkyl group, which is optionally substituted with 1 to 3 of the same or different, each substituent is independently selected from the group consisting of a fluorine atom and C 1-6 alkoxy, or a pharmaceutically acceptable salt thereof.
  7. 7 . The compound of claim 1 , wherein R 2 and R 3 are hydrogen atoms, or a pharmaceutically acceptable salt thereof.
  8. 8 . The compound of claim 1 , wherein X is CH 2 , or a pharmaceutically acceptable salt thereof.
  9. 9 . The compound of claim 8 , which has a structure of formula (1A): or a pharmaceutically acceptable salt thereof.
  10. 10 . The compound of claim 9 , which has a structure of formula (1A′): or a pharmaceutically acceptable salt thereof.
  11. 11 . The compound of claim 1 , wherein R 1 is a C 1-6 alkyl group, which is optionally substituted with 1 to 3 of the same or different, each substituent is independently selected from the group consisting of a halogen atom, a C 6-10 aryl group, a hydroxyl group, a carboxyl group, a sulfinic acid group, a sulfonic acid group, a phosphoric acid group, C 1-6 alkoxy, —NR 4 R 5 , —CO 2 R 4 , —CONR 4 R 5 , —SO 2 R 4 , and —SO 2 NR 4 R 5 , or a pharmaceutically acceptable salt thereof.
  12. 12 . The compound of claim 1 , wherein R 1 is an ethyl group, or a pharmaceutically acceptable salt thereof.
  13. 13 . The compound of claim 1 , which is 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl ethyl {[(2S)-piperidin-2-yl]methyl}carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl ethyl {[(2R)-piperidin-2-yl]methyl}carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl methyl {[(2S)-piperidin-2-yl]methyl}carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl methyl {[(2R)-piperidin-2-yl]methyl}carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl {[(2S)-piperidin-2-yl]methyl}propylcarbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl {[(2R)-piperidin-2-yl]methyl}propylcarbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl ethyl[(piperidin-2-yl)methyl]carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl methyl[(piperidin-2-yl)methyl]carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl[(piperidin-2-yl)methyl]propylcarbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl[(piperidin-2-yl)methyl]propan-2-ylcarbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl (2-fluoroethyl) [(piperidin-2-yl)methyl]carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl (2-methoxyethyl) [(piperidin-2-yl)methyl]carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl[(piperidin-2-yl)methyl](3,3,3-trifluoropropyl) carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl[(piperidin-2-yl)methyl](4,4,4-trifluorobutyl) carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl benzyl[(piperidin-2-yl)methyl]carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl ethyl[2-(piperidin-2-yl)ethyl]carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl methyl {[(3R)-morpholin-3-yl]methyl}carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl ethyl[(pyrrolidin-2-yl)methyl]carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl methyl {1-[(2R)-piperidin-2-yl]ethyl}carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl methyl {1-[(2S)-piperidin-2-yl]ethyl}carbamate, 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl ethyl[(piperidin-3-yl)methyl]carbamate, or 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl ethyl[(pyrrolidin-3-yl)methyl]carbamate, or a pharmaceutically acceptable salt thereof.
  14. 14 . The compound of claim 1 , which is 2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxo-4H-1-benzopyran-7-yl ethyl {[(2S)-piperidin-2-yl]methyl}carbamate, or a pharmaceutically acceptable salt thereof.
  15. 15 . A composition, comprising: the compound of claim 1 or a pharmaceutically acceptable salt thereof.
  16. 16 . A liposome, comprising: the compound of claim 1 or a pharmaceutically acceptable salt thereof.
  17. 17 . A composition, comprising: a liposome encapsulating the compound of claim 1 or a pharmaceutically acceptable salt thereof.
  18. 18 . The composition of claim 17 , wherein the liposome comprises a phospholipid, and the compound of claim 1 or a pharmaceutically acceptable salt thereof.
  19. 19 . The composition of claim 18 , wherein the phospholipid comprises at least one selected from the group consisting of phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, soybean lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin.
  20. 20 . The composition of claim 17 , wherein the liposome further comprises a sterol.

Description

TECHNICAL FIELD The present disclosure relates to prodrugs of the CDK9 inhibitor Alvocidib, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof. The present disclosure also relates to pharmaceutical compositions comprising the same, and the like. BACKGROUND ART Cyclin-dependent kinases (CDKs) are important regulatory factors that regulate cell cycle progression and the like, and selective CDK inhibitors are useful chemotherapeutic agents. Alvocidib (flavopiridol) is a synthetic flavone having the following structure: Alvocidib is a potent and selective inhibitor of CDK, has anti-tumor activity against various tumor cell lines, including human lung cancer and breast cancer, and inhibits tumor growth in tumor-bearing mouse models. Alvocidib inhibits polymerase II-driven transcription through CDK9 inhibition. Treatment with Alvocidib inhibits positive transcription elongation factors, or CDK9, which forms part of a complex known as P-TEFb, and decreases the expression of important oncogenes such as MYC and important anti-apoptotic proteins such as MCL1. Therefore, Alvocidib is an attractive cancer therapeutic agent, and is currently in clinical development for use in blood cancers. On the other hand, while Alvocidib has excellent pharmacological activity, it has been reported to cause many side effects such as diarrhea and neutropenia in clinical trials, which may limit its clinical application. In clinical trials to date, long-term intravenous administration of Alvocidib (for example, 24-hour or 72-hour continuous administration) has been investigated with the aim of reducing side effects, but no clear improvement in side effects has been achieved (Non-Patent Document 1). CITATION LIST Patent Documents [Patent Document 1]: WO 2016/187316[Patent Document 2]: WO 2018/094275[Patent Document 3]: WO 2019/059344 Non-Patent Documents [Non-Patent Document 1]: Suoping Zhai et al. The Annals of Pharmacotherapy 36: 905-911. (2002)[Non-Patent Document 2]: Atiar M. Rahman et al. International Journal of Nanomedicine 2(4): 567-583. (2007)[Non-Patent Document 3]: Yechezkel (Chezy) Barenholz. Journal of Controlled Release 160: 117-134. (2012)[Non-Patent Document 4]: Xiaojuan Yang et al. International Journal of Pharmaceutics 365; 170-174. (2009) SUMMARY OF THE INVENTION Means of Solving the Problems The present disclosure provides Alvocidib derivatives as having excellent pharmacological activity. The Alvocidib derivatives of the present disclosure have anti-tumor activity. The Alvocidib derivatives of the present disclosure do not have side effects that limit their clinical application. The Alvocidib derivatives of the present disclosure can be released from liposomes in a sustained release manner. The present disclosure provides Alvocidib prodrugs that are highly efficiently encapsulated in liposomes by a remote loading method, are released from the liposomes in a sustained release manner, and are efficiently converted to Alvocidib in the in vivo environment after release. In recent years, liposomal formulations in which compounds are encapsulated in liposomes have been used clinically. These liposomal formulations have been reported to alter the biodistribution of compounds and improve their retention in vivo, compared to conventional direct administration of low-molecular-weight compounds (Non-Patent Document 2). Remote loading methods that utilize the principle of solubility gradient are often used to encapsulate compounds in liposomes. The remote loading method generally has the advantage of being able to encapsulate compounds with high efficiency (Non-Patent Document 3), but in order to use the remote loading method, the compound needs to have high water solubility and exhibit a pH- or ion concentration-dependent solubility gradient. Therefore, the compounds to which the remote loading method is applicable are limited. It is extremely important if compounds can be encapsulated in liposomes with high efficiency because loss of compounds during the liposome formulation stage will be reduced. Non-Patent Document 4 discloses that Alvocidib is encapsulated in liposomes by a remote loading method. However, there is no disclosure or suggestion regarding the concentration of the prepared liposome solution. Furthermore, the half-life (T1/2β) of liposomal Alvocidib in mice is 340 minutes, which is longer than that of Alvocidib alone, but its efficacy is insufficient. Similarly, the AUC of liposomal Alvocidib was only 10.8 min μmol/L compared to Alvocidib alone (3.4 min μmol/L) (both at 2.5 mg/kg administration), which does not show ideal pharmacokinetics. Patent Document 1 describes the following compound as a phosphate-type prodrug of Alvocidib. wherein one of R1, R2 and R3 is —P(═O)(OH)2, and the other two are each a hydrogen atom. Patent Document 2 describes the following compound as a prodrug of Alvocidib. wherein R1, R2 and R3 are independently a hydrogen atom, or —C(═O)Ra or the like, and Ra is an o