5-fluorouracil compounds
阅读说明：本技术 5-氟尿嘧啶化合物 (5-fluorouracil compounds ) 是由 智林 于 2019-01-17 设计创作，主要内容包括：本文提供了5-氟尿嘧啶衍生的缩醛和半缩醛胺醚化合物、它们的制备及用途(如治疗肝脏疾病或各种类型的癌症)。(Provided herein are 5-fluorouracil-derived acetal and hemiacetal amine ether compounds, their preparation and use (e.g., in the treatment of liver disease or various types of cancer).)
1. A compound of formula I:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
R1and R2Independently selected from: H. optionally substituted C1-C10alkyl-OCH2-, optionally substituted (C)6-10Aryl) -CH2-OCH2-, optionally substituted (5-10 membered heteroaryl) -CH2-OCH2-, optionally substituted (C)6-10Aryl) -OCH2-and optionally substituted (5-10 membered heteroaryl) -OCH2Provided that R is1And R2Is not H.
2. The compound of claim 1, wherein R1Is H; and R is2Selected from: optionally substituted C1-C10alkyl-OCH2-, optionally substituted (C)6-10Aryl) -CH2-OCH2-, optionally substituted (5-10 membered heteroaryl) -CH2-OCH2-, optionally substituted (C)6-10Aryl) -OCH2-and optionally substituted (5-10 membered heteroaryl) -OCH2-。
3. The compound of claim 2, wherein R2Selected from: optionally substituted C1-C10alkyl-OCH2-, optionally substituted (C)6-10Aryl) -CH2-OCH2-and optionally substituted (5-10 membered heteroaryl) -CH2-OCH2-。
4. A compound according to claim 3, wherein R2Is C1-C6alkyl-OCH2-or phenyl-CH2-OCH2-。
5. The compound of claim 1, wherein R2Is H; and R is1Selected from: optionally substituted C1-C10alkyl-OCH2-, optionally substituted (C)6-10Aryl) -CH2-OCH2-, optionally substituted (5-10 membered heteroaryl) -CH2-OCH2-, optionally substituted (C)6-10Aryl) -OCH2-and optionally substituted (5-10 membered heteroaryl) -OCH2-。
6. The compound of claim 5, wherein R1Selected from: optionally substituted C1-C10alkyl-OCH2-, optionally substituted (C)6-10Aryl) -CH2-OCH2-and optionally substituted (5-10 membered heteroaryl) -CH2-OCH2-。
7. The compound of claim 6, wherein R1Is C1-C6alkyl-OCH2-or phenyl-CH2-OCH2-。
8. The compound of claim 1, wherein R1Is C1-C6alkyl-OCH2-or phenyl-CH2-OCH2-; and R is2Is C1-C6alkyl-OCH2-or phenyl-CH2-OCH2-。
9. The compound of claim 8, wherein R1Is phenyl-CH2-OCH2-; and R is2Is phenyl-CH2-OCH2-。
10. A compound of formula II:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
R3selected from: H. optionally substituted C1-C10alkyl-OCH2-, optionally substituted C1-C10alkyl-NHCH2-, optionally substituted C1-C10Acyl, optionally substituted C1-C10alkyl-OC (O) -, optionally substituted (C)6-10Aryl) -CH2OCH2-, optionally substituted (C)6-10Aryl) -OCH2-, optionally substituted (C)6-10Aryl) -C (O) -, optionally substituted (5-10 membered heteroaryl) -CH2OCH2-, optionally substituted (5-10 membered heteroaryl) -OCH2-, optionally substituted (C)6-10Aryl) -oc (o) -, optionally substituted (5-10 membered heteroaryl) -c (o) -and optionally substituted (5-10 membered heteroaryl) -oc (o) -;
R4and R5Independently selected from: H. optionally substituted C1-C10alkyl-OCH2-, optionally substituted C1-C10Acyl, optionally substituted (C)6-10Aryl) -CH2OCH2-, optionally substituted (C)6-10Aryl) -OCH2-, optionally substituted (C)6-10Aryl) -C (O) -, optionally substituted (5-10 membered heteroaryl) -CH2OCH2-, optionally substituted (5-10 membered heteroaryl) -OCH2Optionally substituted (5-10 membered heteroaryl) -C (O) -, optionally substituted C1-C10alkyl-NR7ACH2-, optionally substituted (C)6-10Aryl) -NR7ACH2-, optionally substituted (5-10 membered heteroaryl) -NR7ACH2-、N(R7A)2CH2-and-L-CH2-, or R4And R5Together with the atoms to which they are attached and the atoms therebetween form a 5-6 membered cyclic acetal, optionally substituted with one or more R6ASubstitution;
each R6AIndependently is C1-C10Alkyl radical, C6-10Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, each optionally substituted with 1 to 4R6AASubstitution;
each R6AAIndependently selected from: halogen, OH, optionally substituted C1-C10alkyl-OCH2O-, optionally substituted C1-C10Alkyl C (O) O-, optionally substituted C1-C10alkyl-OC (O) O-, optionally substituted C1-C10Alkyl, optionally substituted C1-C10Alkoxy, optionally substituted C3-C10Cycloalkyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted (C)6-10Aryl) -OCH2-and optionally substituted (5-10 membered heteroaryl) -OCH2-；
R7AIndependently selected from: H. optionally substituted C1-10Alkyl, optionally substituted C1-10Acyl, optionally substituted C6-10Aryl and optionally substituted 5-10 membered heteroaryl;
x is O or NR1A；
Y is O or NR1B；
R1ASelected from: H. optionally substituted C1-C10alkyl-OCH2-, optionally substituted (C)6-10Aryl) -OCH2-and optionally substituted (5-10 membered heteroaryl) -OCH2-；
R1BSelected from: optionally substituted C1-C10alkyl-OCH2-, optionally substituted C1-C10Acyl, optionally substituted C1-C10alkyl-OC (O) -, optionally substituted (C)6-10Aryl) -OCH2-, optionally substituted (C)6-10Aryl) -C (O) -, optionally substituted (5-10 membered heteroaryl) -OCH2-, optionally substituted (C)6-10Aryl) -oc (o) -, optionally substituted (5-10 membered heteroaryl) -c (o) -and optionally substituted (5-10 membered heteroaryl) -oc (o) -; and is
L is an optionally substituted nitrogen-containing 4-to 10-membered heterocycle,
with the following conditions: when R is3Is H or-X-R3is-NHC (O) O-C1-C10When alkyl is present, then R4And R5Is not H, or R4And R5Together with the atoms to which they are attached and the atoms therebetween form a 5-6 membered cyclic acetal, optionally substituted with one or more R6AAnd (4) substitution.
11. The compound of claim 10, wherein R5Is H, optionally substituted C1-C10alkyl-OCH2-or optionally substituted (C)6-10Aryl) -CH2OCH2-。
12. The compound of claim 11, wherein R5Is H.
13. The compound of claim 11, wherein R5Is C1-C10alkyl-OCH2-or phenyl-CH2OCH2-。
14. The compound according to any one of claims 10 to 13, wherein R4Is H, optionally substituted C1-C10alkyl-OCH2-or optionally substituted (C)6-10Aryl) -CH2OCH2-。
15. The compound of claim 14, wherein R4Is H.
16. The compound of claim 14, wherein R4Is C1-C10alkyl-OCH2-or phenyl-CH2OCH2-。
17. The compound of claim 10, having the structure of formula III:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein R is6Is H or R6A。
18. The compound of claim 17, wherein R6Is R6A。
19. The compound of claim 18, wherein R6AIs C1-C6Alkyl radical, C6-10Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, each optionally substituted with 1 to 4R6AAAnd (4) substitution.
20. The compound of claim 19, wherein R6AIs C1-C6Alkyl optionally substituted with 1 to 4R6AAAnd (4) substitution.
21. The compound of claim 18, wherein R6AIs phenyl or 4-10 membered heterocyclyl, each of which is optionally substituted with 1 to 3R6AAAnd (4) substitution.
22. The compound of claim 21, wherein R6AIs phenyl optionally substituted by 1 to 3R6AAAnd (4) substitution.
23. The compound of claim 21, wherein R6AIs a 4-10 membered heterocyclyl optionally substituted with 1 to 3R6AAAnd (4) substitution.
24. The compound of claim 21, wherein R6AIs benzo [ d][1,3]Dioxol-5-yl optionally substituted with 1 to 3R6AAAnd (4) substitution.
25. The compound of any one of claims 17 to 24, wherein each R6AAIndependently selected from:OH、C1-C6alkyl-OCH2O-、C1-C6Alkyl C (O) O-, C1-C6Alkyl radical, C1-C6Alkoxy and optionally substituted 4-10 membered heterocyclyl.
26. The compound of claim 25, wherein R6AAIs OH, methoxy or methyl.
27. The compound of claim 25, wherein R6AAIs CH3CH2OCH2O-or (CH)3)2CHC(O)O-。
28. The compound of claim 25, wherein R6AAIs a quilt C1-C6An alkyl-substituted 4-to 10-membered heterocyclic group.
29. The compound of claim 28, wherein R6AAIs a 1, 3-dioxolan-2-yl group substituted by a methyl or ethyl group.
30. A compound of formula IV or V:
or a stereoisomer or pharmaceutically acceptable salt thereof,
or a stereoisomer or pharmaceutically acceptable salt thereof,
R3selected from: H. optionally substituted C1-C10alkyl-OCH2-, optionally substituted C1-C10alkyl-NHCH2-, optionally substituted C1-C10Acyl, optionally substituted C1-C10alkyl-OC (O) -, optionally substituted (C)6-10Aryl) -CH2OCH2-, optionally substituted (C)6-10Aryl) -OCH2-, optionally substituted (C)6-10Aryl) -C (O) -, optionally substituted (5-10 membered heteroaryl) -CH2OCH2-, optionally substituted (5-10 membered heteroaryl) -OCH2-, optionally substituted (C)6-10Aryl) -oc (o) -, optionally substituted (5-10 membered heteroaryl) -c (o) -and optionally substituted (5-10 membered heteroaryl) -oc (o) -;
R4and R5Independently selected from: H. optionally substituted C1-C10alkyl-OCH2-, optionally substituted C1-C10Acyl, optionally substituted (C)6-10Aryl) -CH2OCH2-, optionally substituted (C)6-10Aryl) -OCH2-, optionally substituted (C)6-10Aryl) -C (O) -, optionally substituted (5-10 membered heteroaryl) -CH2OCH2-, optionally substituted (5-10 membered heteroaryl) -OCH2Optionally substituted (5-10 membered heteroaryl) -C (O) -, optionally substituted C1-C10alkyl-NR7ACH2-, optionally substituted (C)6-10Aryl) -NR7ACH2-, optionally substituted (5-10 membered heteroaryl) -NR7ACH2-、N(R7A)2CH2-and-L-CH2-, or R4And R5Together with the atoms to which they are attached and the atoms therebetween form a 5-6 membered cyclic acetal, optionally substituted with one or more R6ASubstitution;
R6is H or R6A；
Each R6AIndependently is C1-C10Alkyl radical, C6-10Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, each optionally substituted with 1 to 4R6AAAnd (4) substitution.
Each R6AAIndependently selected from: halogen, OH, optionally substituted C1-C10alkyl-OCH2O-, optionally substituted C1-C10Alkyl C (O) O-, optionally substituted C1-C10alkyl-OC (O) O-, optionally substituted C1-C10Alkyl, optionally substituted C1-C10Alkoxy, optionally substituted C3-C10Cycloalkyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted (C)6-10Aryl) -OCH2-and optionally substituted (5-10 membered heteroaryl) -OCH2-；
R7AIndependently selected from: H. optionally substituted C1-10Alkyl, optionally substituted C1-10Acyl, optionally substituted C6-10Aryl and optionally substituted 5-10 membered heteroaryl;
R1Aselected from: H. optionally substituted C1-C10alkyl-OCH2-, optionally substituted (C)6-10Aryl) -OCH2-and optionally substituted (5-10 membered heteroaryl) -OCH2-；
R1BSelected from: optionally substituted C1-C10alkyl-OCH2-, optionally substituted C1-C10Acyl, optionally substituted C1-C10alkyl-OC (O) -, optionally substituted (C)6-10Aryl) -OCH2-, optionally substituted (C)6-10Aryl) -C (O) -, optionally substituted (5-10 membered heteroaryl) -OCH2-, optionally substituted (C)6-10Aryl) -oc (o) -, optionally substituted (5-10 membered heteroaryl) -c (o) -and optionally substituted (5-10 membered heteroaryl) -oc (o) -; and is
L is an optionally substituted nitrogen-containing 4-to 10-membered heterocycle,
with the following conditions: when R is3When it is H, then R4And R5Is not H, or R4And R5Together with the atoms to which they are attached and the atoms therebetween form a 5-6 membered cyclic acetal, optionally substituted with one or more R6AAnd (4) substitution.
31. A compound of formula VI:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein R is3Selected from: H. optionally substituted C1-C10alkyl-OCH2-, optionally substituted C1-C10alkyl-NHCH2-, optionally substituted C1-C10Acyl, optionally substituted C1-C10alkyl-OC (O) -, optionally substituted (C)6-10Aryl) -CH2OCH2-, optionally substituted (C)6-10Aryl) -OCH2-, optionally substituted (C)6-10Aryl) -C (O) -, optionally substituted (5-10 membered heteroaryl) -CH2OCH2-, optionally substituted (5-10 membered heteroaryl) -OCH2-, optionally substituted (C)6-10Aryl) -oc (o) -, optionally substituted (5-10 membered heteroaryl) -c (o) -and optionally substituted (5-10 membered heteroaryl) -oc (o) -; and is
R7Selected from: optionally substituted C1-C20Alkyl, optionally substituted C2-C20Alkenyl, optionally substituted C3-C20Cycloalkyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C1-C10alkyl-OCH2-, optionally substituted C1-C10alkyl-CO-OCH2-, optionally substituted (C)6-10Aryl) -OCH2-, optionally substituted (5-10 membered heteroaryl) -OCH2-, optionally substituted (C)6-10Aryl) -CH2-and optionally substituted (5-10 membered heteroaryl) -CH2-；
Z is O or NR1C；
R1CSelected from: H. optionally substituted C1-C10Alkyl and optionally substituted aryl.
32. A pharmaceutical composition comprising a compound of any one of claims 1 to 31 and a pharmaceutically acceptable excipient.
33. The pharmaceutical composition of claim 32, further comprising one or more anti-cancer agents.
34. The pharmaceutical composition of claim 32, further comprising two or more anti-cancer agents.
35. The pharmaceutical composition of claim 32, further comprising an anti-cancer agent.
36. A method of treating a disease, condition, or disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 31.
37. The method of claim 36, wherein the disease, condition, or disorder is a liver disease, condition, or disorder.
38. The method of claim 36, wherein the disease, condition or disorder is a metabolic disease, cardiovascular disease, or hormonal disease, wherein the liver is involved in the production and/or homeostatic control of biochemical end products of the disease, condition or disorder.
39. The method of claim 36, wherein the disease, condition, or disorder is selected from hepatocellular carcinoma, renal cancer, colorectal cancer, breast cancer, gastric cancer, esophageal cancer, pancreatic cancer, and cervical cancer.
40. A method of treating a liver disease comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 31.
41. The method of any one of claims 36 to 40, further comprising administering to the individual in need thereof an effective amount of at least one additional therapeutic agent.
42. The method of any one of claims 36-41, wherein the individual is a mammal.
43. The method of any one of claims 36-41, wherein the individual is a human.
44. A method of inhibiting viral replication in a cell comprising contacting the cell with any one of the compounds of claims 1-31.
45. A method of stem pre-molecular pathway or modulating a target in a cell comprising contacting the cell with any one of the compounds of claims 1-31.
46. The method of claim 44 or 45, wherein the cell is in vivo.
47. The method of claim 44 or 45, wherein the cell is ex vivo.
48. The method of claim 44 or 45, wherein the cell is a hepatocyte.
49. The method of claim 44 or 45, wherein the cell is mammalian.
50. The method of claim 44 or 45, wherein the cell is human.
51. Use of a compound according to any one of claims 1 to 31 for treating a viral liver infection in an individual.
52. The use of claim 51 in combination with one or more other therapeutic agents.
53. The use of claim 52, wherein the one or more other therapeutic agents for HCC treatment are selected from sorafenib, regorafenib, immuno-oncology agents, such as PD-1 or PD-L1 checkpoint inhibitors.
54. A compound according to any one of claims 1 to 31 for use in the treatment of a liver disease or a disease or condition in which the physiological or pathogenic pathway involves the liver in a subject.
55. The compound of claim 54 in combination with one or more additional therapeutic agents.
56. Use of a compound according to any one of claims 1 to 31 in the manufacture of a medicament for the treatment of a disease or condition of the liver or a disease or condition in which the physiological or pathogenic pathway involves the liver.
Technical Field
The present disclosure relates to the fields of chemistry and medicine. More particularly, the disclosure relates to 5-fluorouracil derived compounds, including acetal and hemiacetal amine ether (hemiaminal ether) compounds, their preparation and use. In some embodiments, such compounds may be used to selectively deliver certain agents to the liver.
Background
The following description of the background art is provided to aid in understanding the present invention and is not an admission that it is prior art to the present invention or that it is prior art to the present invention.
5-fluorouracil is a synthetic analog of uracil, which is one of the four nucleobases in RNA, and has been used as a therapeutic agent for the treatment of various forms of cancer. It is one of the basic drugs in the WHO list due to its efficacy and safety, and has an intravenous form and a topical form. The mechanism of action of 5-fluorouracil is primarily as a thymidylate synthase inhibitor, which blocks the synthesis of pyrimidine thymidine, causing the cell to lack thymidine, leading to cell death. The active form of 5-fluorouracil as a thymidylate synthase inhibitor is fluorodeoxyuridine monophosphate (FdUMP) produced mainly in the liver.
5-fluorouracil has a very short biological half-life (-16 minutes), a very narrow therapeutic index, and various side effects that can be very severe. The development of new 5-fluorouracil analogue compounds with better efficacy and safety has been carried out for many years and several compounds have been put on the market. Floxuridine, also known as 5-fluorodeoxyuridine, has been used to treat colorectal cancer by continuous hepatic arterial infusion. Doxifluridine has been used as a cytostatic agent in chemotherapy in some countries. Capecitabine has been used orally for the treatment of breast, gastric and colorectal cancer. Despite advances in this area, there is a need for new compounds to further improve drug delivery efficiency or address new applications based on new technologies. For example, liver targeting compounds that can reach the liver more efficiently and are inactive outside the liver reduce the pharmacological or toxicological effects of the agent outside the target tissue. Thus, new compounds with liver targeting properties can significantly improve the therapeutic index of therapies based on the 5-fluorouracil mechanism.
Summary of The Invention
Novel 5-fluorouracil-derived acetal and hemiacetal amine ether compounds, their preparation and use are described. Some embodiments relate to novel 5-fluorouracil-derived acetal and hemiaminal ether compounds for oral delivery to the liver, which provide therapeutic benefits in the liver. Another aspect includes the use of 5-fluorouracil-derived acetal and hemiaminal ether compounds for the treatment of diseases benefiting from enhanced drug distribution to the liver and similar tissues and cells, including, but not limited to hepatocellular carcinoma (HCC), renal cancer, colorectal cancer, breast cancer, gastric cancer (stomach cancer), gastric cancer (gastic cancer), esophageal cancer, pancreatic cancer, and cervical cancer. In another aspect, the 5-fluorouracil-derived acetal and hemiacetal aminoether compounds are used to enhance the pharmacological or clinical activity of certain classes of pharmaceutical compounds, such as 5-fluorouracil-derived analog compounds. In another aspect, 5-fluorouracil-derived acetal and hemiacetal aminoether compounds are useful for reducing the potential side effects of certain classes of pharmaceutical compounds (e.g., 5-fluorouracil-derived analog compounds), particularly those that occur outside the liver. In some embodiments, the 5-fluorouracil-derived acetal and hemiaminal ether compounds are useful for more efficient oral delivery of 5-fluorouracil-derived analog compounds to the liver. Some other embodiments relate to methods of preparing 5-fluorouracil-derivatized acetal and hemiacetal amine ether compounds.
Some embodiments provided herein include compounds of formula I:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein R is1And R2Having any of the values described herein.
Some embodiments relate to compounds of formulae II, III, IV, V, and VI:
or a stereoisomer or pharmaceutically acceptable salt thereof,
or a stereoisomer or pharmaceutically acceptable salt thereof,
or a stereoisomer or pharmaceutically acceptable salt thereof,
or a stereoisomer or pharmaceutically acceptable salt thereof,
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein R is3、R4、R5、R6、R7X, Y and Z have any value described herein.
Some embodiments relate to pharmaceutical compositions comprising any of the above compounds and a pharmaceutically acceptable excipient.
Some embodiments relate to a method of treating a disease, condition, or disorder, comprising administering an effective amount of any of the above compounds.
In some embodiments, the disease, condition, or disorder is a liver disease, condition, or disorder.
In some embodiments, the disease, condition, or disorder is one in which the liver is involved in the production and/or homeostatic control (homeostatis control) of the biochemical end products of the disease, condition, or disorder.
In some embodiments, the disease, condition, or disorder is selected from hepatocellular carcinoma, renal cancer, colorectal cancer, breast cancer, gastric cancer, esophageal cancer, pancreatic cancer, and cervical cancer.
In some embodiments, the disease, condition, or disorder is a non-liver disease, condition, or disorder.
In some embodiments, the non-liver disease, condition or disorder is various types of cancer, or other diseases in which 5-fluorouracil-derived acetal and hemiacetal amine ether compounds enhance the distribution of active drugs to target tissues or cells.
Some embodiments relate to a method of treating a liver disease comprising administering to a subject in need thereof an effective amount of any of the above compounds.
Some embodiments further comprise administering to an individual in need thereof an effective amount of at least one additional therapeutic agent.
In some embodiments, the individual is a mammal.
In some embodiments, the individual is a human.
Some embodiments relate to a method of inhibiting viral replication in a cell, comprising contacting the cell with any of the above compounds.
Some embodiments relate to a method of stem pre-molecular pathway or modulating a target in a cell comprising contacting the cell with any of the above compounds.
In some embodiments, the cell is in vivo.
In some embodiments, the cell is ex vivo.
In some embodiments, the cell is a hepatocyte.
In some embodiments, the cell is a cancer cell.
In some embodiments, the cell is mammalian.
In some embodiments, the cell is human.
Some embodiments of the compounds, compositions, and methods provided herein include pharmaceutical compositions comprising any of the compounds provided herein and a pharmaceutically acceptable excipient.
Some embodiments of the compounds, compositions, and methods provided herein include methods of treating a disease or disorder in the liver of a subject comprising administering to a subject in need thereof an effective amount of any of the compounds provided herein.
Some embodiments further comprise administering to an individual in need thereof an effective amount of one or more additional therapeutic agents.
In some embodiments, the individual is a mammal.
In some embodiments, the individual is a human.
Some embodiments of the compounds, compositions, and methods provided herein include the use of any of the compounds provided herein for treating a liver disease or a disease or condition in which a physiological or pathogenic pathway involves the liver in an individual.
Some embodiments also include the use of any of the compounds provided herein in combination with other therapeutic agents.
Some embodiments of the compounds, compositions, and methods provided herein include any of the compositions provided herein for use in the preparation of a medicament for treating a liver disease or disorder or a disease or disorder in which a physiological or pathogenic pathway involves the liver.
Detailed Description
This embodiment relates to compositions and methods related to novel 5-fluorouracil-derived acetal and hemiaminal ether compounds, their preparation, and uses. In some embodiments, the novel 5-fluorouracil-derived acetal and hemiacetal amine ether compounds facilitate the delivery of 5-fluorouracil-derived therapeutic agents, such as 5-fluorouracil, doxifluridine, 5-fluorouridine monophosphate (5-fluorouridine monophosphate), and/or 5-fluorodeoxyuridine monophosphate (5-fluorodeoxyuridine).
These 5-fluorouracil-derived acetal and hemiacetal amine ether compounds, and stereoisomers and pharmaceutically acceptable salts thereof, are represented by formulas I, II, III, IV, V, and VI:
or a stereoisomer or pharmaceutically acceptable salt thereof,
or a stereoisomer or pharmaceutically acceptable salt thereof,
or a stereoisomer or pharmaceutically acceptable salt thereof,
or a stereoisomer or pharmaceutically acceptable salt thereof,
or a stereoisomer or pharmaceutically acceptable salt thereof,
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein R is1、R2、R3、R4、R5、R6、R7X, Y and Z have any value described herein.
In some embodiments, R1And R2Independently selected from: H. optionally substituted C1-C10alkyl-OCH2-, optionally substituted (C)6-10Aryl) -CH2-OCH2-, optionally substituted (5-10 membered heteroaryl) -CH2-OCH2-, optionally substituted (C)6-10Aryl) -OCH2-and optionally substituted (5-10 membered heteroaryl) -OCH2-; provided that R is1And R2Is not H.
In some embodiments, R3Selected from: H. optionally substituted C1-C10alkyl-OCH2-, optionally substituted C1-C10alkyl-NHCH2-, optionally substituted C1-C10Acyl, optionally substituted C1-C10alkyl-OC (O) -, optionally substituted (C)6-10Aryl) -CH2OCH2-, optionally substituted (C)6-10Aryl) -OCH2-, optionally substituted (C)6-10Aryl) -C (O) -, optionally substituted (5-10 membered heteroaryl) -CH2OCH2-, optionally substituted (5-10 membered heteroaryl) -OCH2-, optionally substituted (C)6-10Aryl) -oc (o) -, optionally substituted (5-10 membered heteroaryl) -c (o) -and optionally substituted (5-10 membered heteroaryl) -oc (o) -.
In some embodiments, R4And R5Independently selected from: H. optionally substituted C1-C10alkyl-OCH2-, optionally substituted C1-C10Acyl, optionally substituted (C)6-10Aryl) -CH2OCH2-, optionally substituted (C)6-10Aryl) -OCH2-, optionally substituted (C)6-10Aryl) -C (O) -, optionally substituted (5-10 heteroaryl) -CH2OCH2-, optionally substituted (5-10 membered heteroaryl) -OCH2Optionally substituted (5-10 membered heteroaryl) -C (O) -, optionally substituted C1-C10alkyl-NR7ACH2-, optionally substituted (C)6-10Aryl) -NR7ACH2-, optionally substituted (5-10 membered heteroaryl) -NR7ACH2-、N(R7A)2CH2-and-L-CH2-；R7AIndependently selected from: H. optionally substituted C1-10Alkyl, optionally substituted C1-10Acyl, optionally substituted C6-10Aryl and optionally substituted 5-10 membered heteroaryl; x is O or NR1A(ii) a Y is O or NR1B；R1ASelected from: H. optionally substituted C1-C10alkyl-OCH2-, optionally substituted (C)6-10Aryl) -OCH2-and optionally substituted (5-10 membered heteroaryl) -OCH2-；R1BIndependently selected from: optionally substituted C1-C10alkyl-OCH2-, optionally substituted C1-C10Acyl, optionally substituted C1-C10alkyl-OC (O) -, optionally substituted (C)6-10Aryl) -OCH2-, optionally substituted (C)6-10Aryl) -C (O) -, optionally substituted (5-10 membered heteroaryl) -OCH2-, optionally substituted (C)6-10Aryl) -oc (o) -, optionally substituted (5-10 membered heteroaryl) -c (o) -and optionally substituted (5-10 membered heteroaryl) -oc (o) -; and L is an optionally substituted 4-10 membered nitrogen containing heterocycle with the provisos that: when R is3Is H or-X-R3When it is-NHC (O) O-alkyl, R4And R5At least one of which is not H.
In some embodiments, R6Is H or R6A；R6AIs C1-C10Alkyl radical, C6-10Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, each optionally substituted with 1 to 4R6AASubstitution; each R6AAIndependently selected from: halogen, OH, optionally substituted C1-C10alkyl-OCH2O-, optionally substituted C1-C10Alkyl C (O) O-, optionally substituted C1-C10alkyl-OC (O) O-, optionally substituted C1-C10Alkyl, optionally substituted C1-C10Alkoxy, optionally substituted C3-C10Cycloalkyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted (C)6-10Aryl) -OCH2-and optionally substituted (5-10 membered heteroaryl) -OCH2-。
In some embodiments, R7Selected from: optionally substituted C1-C20Alkyl, optionally substituted C3-C20Cycloalkyl, optionally substituted C2-C20Alkenyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C1-C10alkyl-OCH2-, optionally substituted C1-C10alkyl-CO-OCH2-, optionally substituted (C)6-10Aryl) -OCH2-, optionally substituted (5-10 membered heteroaryl) -OCH2-, optionally substituted (C)6-10Aryl) -CH2-and optionally substituted (5-10 membered heteroaryl) -CH2-。
In some embodiments, X is O or NR1A(ii) a And R is1ASelected from: H. optionally substituted C1-C10alkyl-OCH2-, optionally substituted (C)6-10Aryl) -OCH2-and optionally substituted (5-10 membered heteroaryl) -OCH2-。
In some embodiments, Y is O or NR1B(ii) a And R is1BSelected from: optionally substituted C1-C10alkyl-OCH2-, optionally substituted C1-C10Acyl, optionally substituted C1-C10alkyl-OC (O) -, optionally substituted (C)6-10Aryl) -OCH2-, optionally substituted (C)6-10Aryl) -C (O) -, optionally substituted (5-10 membered heteroaryl) -OCH2-, optionally substituted (C)6-10Aryl) -oc (o) -, optionally substituted (5-10 membered heteroaryl) -c (o) -and optionally substituted (5-10 membered heteroaryl) -oc (o) -.
In some embodiments, Z is O or NR1C(ii) a And R is1CSelected from: H. optionally substituted C1-C10Alkyl and optionally substituted aryl.
In some embodiments, the 5-fluorouracil-derived acetal and hemiacetal amine ether compounds of formulae I, II, III, IV, V, and VI are substrates for liver enzymes such as cytochrome p450 isoenzymes CYP3As (monooxygenase family), dehydrogenases, esterases, and amidases.
CYP3A4 is expressed in the liver at levels much higher than other tissues (DeWaziers et al, J Pharm Exp Ther253:387 (1990)). 5-fluorouracil-derived acetal and hemiaminal ether compounds of formulae I, II, III, IV, V and VI are activated in the liver primarily by CYP3A 4. In some embodiments, the compounds of formulae I, II, III, IV, V, and VI have high efficiency in liver targeting by selective delivery of the bioactive agent to the liver. In some embodiments, the acetal and hemiaminal compounds are used to increase the therapeutic index of a drug because the compounds of formulas I, II, III, IV, V, and VI may be inactive or less active outside the liver.
In some embodiments, due to the liver targeting properties of the 5-fluorouracil-derived acetal and hemiacetal amine ether compounds of formulas I, II, III, IV, V, and VI, the compounds are useful in the treatment of diseases that benefit from enhanced drug distribution to the liver and similar tissues and cells, including but not limited to liver diseases (e.g., hepatocellular carcinoma).
In some embodiments, the disclosed compounds are used to improve pharmacokinetic properties (e.g., prolong half-life or enhance absorption of the drug). In addition, the disclosed methods can be used to achieve sustained delivery of active therapeutic agents. Due to the enhanced pharmacokinetic properties of the 5-fluorouracil derived acetal and hemiacetal amine ether compounds of formulae I, II, III, IV, V and VI, the compounds are useful for treating diseases that benefit from enhanced drug properties, including but not limited to diseases such as various types of cancer. In some embodiments, methods of making these compounds are described.
Certain compounds of formulae I, II, III, IV, V and VI have asymmetric centers that may not specify stereochemistry, and the present invention includes diastereomeric mixtures of these compounds, as well as the individual stereoisomers when referring generally to compounds of formulae I, II, III, IV, V and VI.
Some embodiments of the compounds, compositions, and methods provided herein include pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable carrier.
Some embodiments further comprise administering to a subject in need thereof an effective amount of a second therapeutic agent or agents in combination with a compound provided herein.
In some embodiments, the individual is a mammal.
In some embodiments, the individual is a human.
Some embodiments of the compounds, compositions, and methods provided herein include methods of testing a compound in a cell, the method comprising contacting the cell with the disclosed compound.
Some embodiments of the compounds, compositions, and methods provided herein include the use of the compounds provided herein in the treatment of liver disease.
Some embodiments include the use of a compound provided herein in combination with one or more other therapeutic agents for the treatment of liver disease.
Some embodiments of the compounds, compositions, and methods provided herein include the use of the compounds provided herein to treat a disease or disorder by interfering with a molecular pathway in the liver.
Some embodiments include the use of a compound provided herein in combination with one or more other therapeutic agents to treat a disease or disorder by intervening in a molecular pathway in the liver.
Some embodiments of the compounds, compositions, and methods provided herein include the use of the compounds provided herein in the treatment of non-liver diseases (such as various types of cancer).
Some embodiments include the use of a compound provided herein in combination with one or more other therapeutic agents for the treatment of non-liver diseases (such as various types of cancer).
When the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers (including racemates). The isolation of the individual isomers and the selective synthesis of the individual isomers is carried out by applying various methods well known to those skilled in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included within the scope of the compounds disclosed herein, including any polymorphic form. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included within the scope of the compounds disclosed herein.
One skilled in the art will recognize that some of the structures described herein may be resonance forms or tautomers of a compound, which may be clearly represented by other chemical structures, even kinetically; those skilled in the art recognize that such structures may represent only a very small fraction of a sample of such compounds. Such compounds are considered to be within the scope of the depicted structures, although such resonance forms or tautomers are not represented herein.
Isotopes may be present in the compounds. Each chemical element as represented in the compound structure may include any isotope of the element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood as being present in the compound. In any position of the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, unless the context clearly indicates otherwise, all possible isotopic forms are encompassed by the compounds referred to herein.
Definition of
In light of the present disclosure and as used herein, the following terms are defined with the following meanings unless explicitly stated otherwise. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" as well as other forms, such as "includes" and "included", is not limiting.
As used herein, ranges and amounts can be expressed as "about" a particular value or range. "about" also includes the exact amount. Thus, "about 10%" means "about 10%" and "10%".
As used herein, "optional" or "optionally/optionally present" means that the subsequently described event or circumstance occurs or does not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, an optionally substituted group means that the group is unsubstituted or substituted.
As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing "a therapeutic agent" includes a composition having one or more therapeutic agents.
As used herein, "C" isaTo Cb"or" Ca-b"(wherein" a "and" b "are integers) refers to the number of carbon atoms in the specified group. That is, the group may contain "a" to "b" (inclusive) carbon atoms. Thus, for example, "C1-C4Alkyl "or" C1-4Alkyl "refers to all alkyl groups having 1-4 carbons, i.e., CH3-、CH3CH2-、CH3CH2CH2-、(CH3)2CH-、CH3CH2CH2CH2-、CH3CH2CH(CH3) -and (CH)3)3C-。
As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., does not contain double or triple bonds). An alkyl group can have 1 to 20 carbon atoms (as long as it appears herein, a numerical range (e.g., "1 to 20") refers to each integer in the given range; e.g., "1 to 20 carbon atoms" refers to an alkyl group that can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also encompasses the term "alkyl" where no numerical range is specified"occurrence). The alkyl group may also be a medium size alkyl group having 1 to 9 carbon atoms. The alkyl group may also be a lower alkyl group having 1 to 4 carbon atoms. The alkyl group may be designated as "C1-C4Alkyl "or the like. By way of example only, "C1-C4Alkyl "means that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
As used herein, a substituted group is derived from an unsubstituted parent group in which there is an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is considered "substituted" it means that the group is substituted with one or more groups independently selected from: c1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C7Carbocyclyl (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy), C3-C7-carbocyclyl-C1-C6Alkyl (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy), 3-10 membered heterocyclyl (optionally substituted with halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy substituted), 3-10 membered heterocyclyl-C1-C6Alkyl (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy), aryl (optionally substituted by halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Halogenoalkoxy substituted), aryl (C)1-C6) Alkyl (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy substituted), 5-to 10-membered heteroaryl (C)1-C6) Alkyl (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy substituted), halogen, cyano, hydroxy, C1-C6Alkoxy radical, C1-C6Alkoxy (C)1-C6) Alkyl (i.e. ether), aryloxy (optionally with halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy), C3-C7Carbocyclyloxy (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy), 3-10 membered heterocyclyl-oxy (optionally substituted with halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy), 5-10 membered heteroaryl-oxy (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy), C3-C7-carbocyclyl-C1-C6Alkoxy (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy substituted), 3-10 membered heterocyclyl-C1-C6Alkoxy (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Halogenoalkoxy substituted), aryl (C)1-C6) Alkoxy (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy substituted), 5-to 10-membered heteroaryl (C)1-C6) Alkoxy (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy), sulfhydryl (mercapto), halo (C)1-C6) Alkyl (e.g., -CF)3) Halo (C)1-C6) Alkoxy (e.g., -OCF)3)、C1-C6Alkylthio, arylthio (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy), C3-C7Carbocyclylthio (optionally substituted by halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy), 3-10 membered heterocyclyl-thio (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy), 5-10 membered heteroaryl-thio (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy), C3-C7-carbocyclyl-C1-C6Alkylthio (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl andC1-C6haloalkoxy substituted), 3-10 membered heterocyclyl-C1-C6Alkylthio (optionally substituted by halogen, C)1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Halogenoalkoxy substituted), aryl (C)1-C6) Alkylthio (optionally substituted by halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Haloalkoxy substituted), 5-to 10-membered heteroaryl (C)1-C6) Alkylthio (optionally substituted by halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl and C1-C6Substituted by haloalkoxy), amino (C)1-C6) Alkyl, nitro, O-carbamoyl, N-amidoformyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amidoyl, N-amidoyl, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato (cyanato), isocyanato (isocyanato), thiocyanato (thiocyanato), isothiocyanato (thiocyanato), sulfinyl, sulfonyl and oxo (═ O). When a group is described as "optionally substituted," the group may be substituted with the substituents described above.
As used herein, "acyl" refers to — C (═ O) R, where R is hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl and acryloyl (acryl).
"heteroacyl" refers to-C (═ O) R, where R is C1-6A heteroalkyl group.
"Alkoxymethylene" means-CH2OR, wherein R is C1-6Alkyl or heteroalkyl, each of which is optionally substituted.
An "O-carboxy" group refers to an "-OC (═ O) R" group, wherein R is selected from hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.
A "C-carboxy" group refers to a "C (═ O) OR" group, where R is selected from hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. Non-limiting examples include carboxyl (i.e., -C (═ O) OH).
A "cyano" group refers to a "-CN" group.
A "cyanato" group is an "-OCN" group.
An "isocyanato" group refers to an "-NCO" group.
"thiocyanato" group refers to the "-SCN" group.
An "isothiocyanato" group is intended to mean an "-NCS" group.
A "sulfinyl" group refers to a "-S (═ O) R" group, where R is selected from hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.
"sulfonyl" group means "-SO2R' group, wherein R is selected from hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.
"S-sulfonylamino" group means "-SO2NRARB"group, wherein RAAnd RBEach independently selected from hydrogen and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.
The "N-sulfonylamino" group refers to "-N (R)A)SO2RB"group, wherein RAAnd RbEach independently selected from hydrogen and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.
An "O-carbamoyl" group means "-OC (═ O) NRARB"group, wherein RAAnd RBEach independently selected from hydrogen and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.
An "N-carbamoyl" group refers to "-N (R)A)C(＝O)ORB"group, wherein RAAnd RBEach independently selected from hydrogen and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.
An "O-thiocarbamoyl" group is intended to mean "-OC (═ S) NRARB"group, wherein RAAnd RBEach independently selected from hydrogen and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.
An "N-thiocarbamoyl" group is intended to mean "-N (R)A)C(＝S)ORB"group, wherein RAAnd RBEach independently selected from hydrogen and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.
A "C-amido" group is intended to mean the radical-C (═ O) NRARB"group, wherein RAAnd RBEach independently selected from hydrogen and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as described hereinEach of which is optionally substituted with one or more groups selected from: -OH, C1-6Alkyl radical, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, optionally substituted with C1-6Alkoxy or-OH substituted C1-6Alkyl, and optionally substituted by C1-6Alkoxy or-OH substituted C1-6An alkoxy group.
An "N-amido" group is intended to mean "-N (R)A)C(＝O)RB"group, wherein RAAnd RBEach independently selected from hydrogen and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, each of which is optionally substituted with one or more groups selected from: -OH, C1-6Alkyl radical, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, optionally substituted with C1-6Alkoxy or-OH substituted C1-6Alkyl, and optionally substituted by C1-6Alkoxy or-OH substituted C1-6An alkoxy group.
An "amino" group is intended to mean the radical-NRARB"group, wherein RAAnd RBEach independently selected from hydrogen and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Carbocyclyl, C6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. Non-limiting examples include free amino (i.e., -NH)2)。
An "aminoalkyl" group refers to an amino group attached through an alkylene group.
An "alkoxyalkyl" group refers to an alkoxy group attached through an alkylene group (e.g., "C2-8Alkoxyalkyl groups ", etc.).
The term "acyloxy" refers to-OC (O) R, where R is alkyl.
The term "alkoxy" OR "alkyloxy" refers to OR, wherein R is alkyl OR heteroalkyl, each of which is optionally substituted.
The term "carboxy" refers to C (O) OH.
The term "oxo" refers to an ═ O group.
The term "halogen" or "halo" refers to F (fluorine), Cl (chlorine), Br (bromine) and I (iodine).
The term "haloalkyl" refers to an alkyl group containing at least one halogen (in another aspect, 1 to 3 halogen atoms). Suitable halogen atoms include F, Cl and Br.
The term "haloacyl" refers to-C (O) -haloalkyl.
The term "alkenyl" refers to unsaturated groups having 2 to 12 atoms and containing at least one carbon-carbon double bond, including straight chain, branched chain, and cyclic groups. The alkenyl group may be optionally substituted. Suitable alkenyl groups include allyl.
The term "alkynyl" refers to unsaturated groups having 2 to 12 atoms and containing at least one carbon-carbon triple bond, including straight chain, branched chain, and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl.
As used herein, "aryl" refers to an aromatic ring or ring system containing only carbon in the ring backbone (i.e., two or more fused rings that share two adjacent carbon atoms). When the aryl group is a ring system, each ring in the system is aromatic. Aryl groups may have from 6 to 18 carbon atoms, but the present definition also covers occurrences of the term "aryl" where no numerical range is specified. In some embodiments, aryl has 6 to 10 carbon atoms. The aryl group may be designated as "C6-10Aryl group "," C6Or C10Aryl "or the like. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.
As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contains one or more heteroatoms (i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur) in the ring backbone. When the heteroaryl group is a ring system, each ring in the system is aromatic. Heteroaryl groups may have from 5 to 18 ring members (i.e., the number of atoms making up the ring backbone, including carbon and heteroatoms), but the present definition also encompasses those in which the term "heteroaryl" is not specified to a numerical rangeAnd occurs. In some embodiments, heteroaryl has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as a "5-7 membered heteroaryl" or a "5-10 membered heteroaryl" or similar designation. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C's containing one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms3-8Heterocyclyl groups, as well as their substituted derivatives and benzo-and pyrido-fused derivatives, for example, attached via one of the ring-forming carbon atoms. In some embodiments, heteroaryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, cyano, nitro, alkylamido, acyl, C1-6-alkoxy, C1-6Alkyl radical, C1-6-hydroxyalkyl, C1-6Aminoalkyl radical, C1-6-alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfamoyl or trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, the following unsubstituted groups or mono-or di-substituted derivatives thereof: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2, 3-oxadiazole, 1,2, 3-thiadiazole, 1,2, 4-thiadiazole, triazole, benzotriazole, pteridine, benzoxazole (phenoxazole), oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline and quinoxaline. In some embodiments, the substituent is halogen, hydroxy, cyano, O-C1-6Alkyl radical, C1-6-alkyl, hydroxy-C1-6Alkyl and amino C16-an alkyl group.
As used herein, "cycloalkyl" refers to a fully saturated carbocyclic ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl groups may have 3 to 10 carbon atoms (as long as it appears herein, a numerical range (e.g., "3 to 10") means that each and every one within the given range is meantAn integer). Cycloalkyl groups may be designated as "C3-C8Cycloalkyl "or the like. By way of example only, "C3-C8Cycloalkyl "means the presence of 3 to 8 carbon atoms in the carbocyclic ring or ring system.
As used herein, "heterocyclyl" means a non-aromatic or cyclic ring structure that is fully or partially saturated and contains at least one heteroatom selected from nitrogen, oxygen, and sulfur in the ring backbone. The heterocyclyl group may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Heteroatoms may be present in non-aromatic or aromatic rings in the ring system. Heterocyclyl groups may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon and heteroatoms), but the present definition also encompasses occurrences of the term "heterocyclyl" where no numerical range is specified. Heterocyclyl may also be a medium-sized heterocyclyl having 3 to 10 ring members. The heterocyclic group may also be a heterocyclic group having 3 to 6 ring members. Heterocycloalkyl can be designated as "3-15 membered heterocycloalkyl", "4-10 membered heterocycloalkyl", "3-15 membered C2-14Heterocycloalkyl group and 5-to 9-membered C4-8Heterocycloalkyl group, 5-to 10-membered C4-9Heterocycloalkyl group and 5-membered C3-4Heterocycloalkyl group and 6-membered C4-5Heterocycloalkyl group and 7-membered C5-6Heterocycloalkyl "," bicyclic or tricyclic 9-15 membered C8-14Heterocycloalkyl "," monocyclic or bicyclic 3-to 10-membered C2-9Heterocycloalkyl and bicyclic 8-10-membered C4-9Heterocycloalkyl and bicyclic 8-to 10-membered C5-9Heterocycloalkyl and monocyclic 4-to 7-membered C3-6-Heterocycloalkyl "," monocyclic 5-to 6-membered C3-5Heterocycloalkyl "or the like. Heterocyclyl can also be C having 3 to 10 ring members having 1 to 3O (oxygen), N (nitrogen) or S (sulfur))2-C9A heterocyclic group. The heterocyclyl group may be designated as "3-10 membered C2-C9Heterocyclyl "or similar designations. In a preferred six-membered monocyclic heterocyclic group, the heteroatom is selected from 1 to 3 heteroatoms selected from O (oxygen), N (nitrogen) or S (sulfur), and in a preferred five-membered monocyclic heterocyclic group, the heteroatom is selected from 1 to 2 heteroatoms selected from O (oxygen), N (nitrogen) or S (sulfur). Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinylCarbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl (oxapanyl), thiepanyl (thiepanyl), piperidyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolindionyl (pyrrolidinoyl), 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1, 3-dioxinyl, 1, 3-dioxanyl, 1, 4-dioxinyl, 1, 4-dioxanyl, 1, 3-oxathianyl (oxathianyl), 1, 4-oxathianyl (oxathianyl), 2H-1, 2-oxazinyl, trioxocyclohexyl, hexahydro-1, 3, 5-triazinyl, 1, 3-dioxacyclopentadienyl (dioxanyl), 1, 3-dioxolanyl, 1, 3-dithiocyclopentadienyl (dithioly), 1, 3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidonyl, thiazolinyl, thiazolidinyl, 1, 3-oxathiolanyl (oxathiolanyl), indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydro-1, 4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolinyl and tetrahydroquinoline.
As used herein, "cyclic acetal" refers to a cyclic group containing the following moieties, wherein two oxygens form part of the ring backbone:
it is to be understood that the naming convention for certain radicals may include mono-radicals or di-radicals, depending on the context. For example, when a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a diradical. For example, substituents identified as alkyl groups requiring two points of attachment include diradicals (e.g., -CH)2-、-CH2CH2-、-CH2CH(CH3)CH2-etc.). Other radical naming conventions clearly indicate that the radical is a diradical (e.g., "alkylene" or "alkenylene").
When two R groups are said to be "attached to" the atomWhen taken together to "form a ring (e.g., a carbocyclic, heterocyclic, aryl, or heteroaryl ring), it is meant that the atoms and the collective unit of the two R groups are the ring in question. When considered individually, the ring is not otherwise limited by the definition of each R group. For example, when the following substructure is present:and R is1And R2Is defined as being selected from alkyl and aryl, or R1And R2When taken together with the oxygen to which they are each attached to form a heterocyclic group, it means R1And R2May be selected from alkyl or aryl groups, or the substructure has the following structure:wherein ring A is a heterocycle containing the indicated oxygen.
Similarly, when two "adjacent" R groups are said to "form a ring with the atom to which they are attached," it is meant that the atom, the intervening bonds, and the collective units of the two R groups are the ring. For example, when the following substructure is present:and R is1And R2Is defined as being selected from hydrogen and alkyl, or R1And R2When taken together with the atom to which they are attached to form an aryl or carbocyclyl group, it refers to R1And R2May be selected from hydrogen or alkyl, or the substructure has the following structure:wherein A is an aryl ring or carbocyclyl containing the indicated double bond.
Wherever a substituent is described as a diradical (i.e., having two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise specified. Thus, for example, described as-AE-or
The phrase "therapeutically effective amount" refers to an amount of a compound or combination of compounds that partially or completely ameliorates, reduces or eliminates one or more symptoms of a particular disease or disorder, or prevents, ameliorates or delays the onset of one or more symptoms of a particular disease or disorder. Such amounts may be administered as a single dose or may be administered according to an effective regimen. Repeated administrations may be required to achieve a desired result (e.g., treatment of a disease and/or disorder).
The term "pharmaceutically acceptable salts" includes salts of the compounds of formulae I, II and III derived from a combination of a compound of the present embodiment with an organic or inorganic acid or base. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts may be derived include, for example, acetic acid, adipic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, (+) -7, 7-dimethyl-2-oxobicyclo [2.2.1 ] sulfonic acid]Heptane-1-methanesulfonic acid, 1, 2-ethanedisulfonic acid, dodecylsulfonic acid, salicylic acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloride hemiglycolic acid, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, methylbromic acid, methylsulfuric acid, 2-naphthalenesulfonic acid, oleic acid, 4' -methylenebis- [ 3-hydroxy-2-naphthoic acid]Polygalacturonic acid, stearic acid, sulfosalicylic acid, tannic acid, terephthalic acid, and the like. Inorganic bases from which salts can be derived include, for example, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. In some embodiments, treatment of a compound disclosed herein with an inorganic base results in the loss of labile hydrogen from the compound to provide a composition comprising an inorganic cation (e.g., Li)+、Na+、K+、Mg2+And Ca2+Etc.) salt forms. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine, among others.
Where the number of any given substituent is not specified (e.g., "haloalkyl"), one or more substituents may be present. For example, "haloalkyl" may comprise one or more of the same or different halogens. For example, "haloalkyl" includes the substituent CF3、CHF2And CH2And F.
The term "patient" refers to the animal being treated and includes mammals (e.g., dogs, cats, cows, horses, sheep, and humans). In some embodiments, the patient is a male or female mammal. In some embodiments, the patient is a human being, male or female.
The term "prodrug" as used herein refers to any compound that, when administered to a biological system, produces a biologically active compound as a result of a spontaneous chemical reaction, an enzymatically catalyzed chemical reaction, and/or a metabolic chemical reaction, or a combination of various reactions. Standard prodrugs are formed using groups attached to functional groups, such as HO-, HS-, HOOC-, HOOPR2-, associated with the drug, which are cleaved in vivo. Standard prodrugs include, but are not limited to, carboxylic acid esters (where the groups are alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl) and esters of hydroxy, thiol and amine (where the attached group is acyl, alkoxycarbonyl, aminocarbonyl, phosphate or sulfate). The groups illustrated are exemplary, non-exhaustive, and one skilled in the art can prepare other known classes of prodrugs. Prodrugs must undergo some form of chemical transformation to produce a compound that is biologically active or a precursor of the biologically active compound. In some cases, prodrugs are biologically active, which is generally less than the drug itself, and enhance the therapeutic efficacy or safety of the drug through improved oral bioavailability, pharmacodynamic half-life, and the like. Prodrug forms of the compounds may be used, for example, to improve bioavailability, improve individual acceptability (e.g., by masking or reducing unpleasant characteristics (e.g., bitter taste or gastrointestinal irritation)), alter solubility (e.g., for intravenous use), provide extended or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compounds.
The term "stereoisomer" refers to the relative or absolute spatial relationship of the R group attached to the stereocenter of a carbon or phosphorus atom, and refers to an individual isomer or any combination of individual isomers (e.g., racemic and diastereomeric mixtures). When a compound has two stereocenters, there are 4 possible stereoisomers.
The term "liver" refers to the liver organ.
The term "liver-specific" refers to the following ratios as measured in animals treated with the drug or prodrug:
[ drug or drug metabolite in liver tissue ] -based on the liver tissue
[ drugs or drug metabolites in blood or other tissues ]
The ratio may be determined by measuring the tissue level at a particular time, or the AUC (area under the curve) may be expressed based on values measured at three or more time points.
The term "increased or enhanced liver specificity" refers to an increase in the liver specificity ratio of an animal treated with a prodrug relative to an animal treated with the parent drug.
The term "enhanced oral bioavailability" refers to an increase in absorption of at least about 50% of a reference drug dose. In another aspect, the increase in oral bioavailability of the compound (as compared to a reference drug) is at least about 100%, or the absorption is doubled. Measurement of oral bioavailability generally refers to the measurement of a prodrug, drug, or drug metabolite in blood, plasma, tissue, or urine after oral administration as compared to the measurement after parenteral administration.
The term "therapeutic index" refers to the ratio of the dose of a drug or prodrug that produces a therapeutically beneficial response to the dose that produces an undesirable response (e.g., death, elevated marker indicative of toxicity, and/or pharmacological side effects).
The term "sustained delivery" refers to an increase in the period in which the therapeutically effective drug level is prolonged due to the presence of the prodrug.
The term "treating" or "treatment" of a disease includes inhibiting the disease (slowing or arresting or partially arresting its development), preventing the disease, alleviating the symptoms or side effects of the disease (including palliative treatment), and/or relieving the disease (causing regression).
The term "biological agent" refers to a compound (e.g., a compound carrying a radioisotope or heavy atom) that has biological activity or molecular properties useful for therapeutic or diagnostic purposes.
The term "molecular pathway" refers to a series of molecular events in a tissue (e.g., receptor regulatory sequences, enzyme regulatory sequences, or biosynthetic sequences, which are involved in the physiological or pathophysiological functions of a living animal).
Administration and pharmaceutical compositions
The disclosed compounds can be used alone or in combination with other therapies. When used in combination with other agents, these compounds may be administered as a daily dose or as an appropriate fraction of a daily dose (e.g., twice daily). The compound can be administered after a course of treatment with another agent, during a course of treatment with another agent, as part of a treatment regimen, or can be administered prior to treatment with another agent during the course of treatment.
Examples of pharmaceutically acceptable salts include acetate, adipate, benzenesulfonate, bromide, camphorsulfonate, chloride, citrate, edisylate, etonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hexoate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, methanesulfonate, methylbromide, methylsulfate, naphthalenesulfonate, nitrate, oleate, palmitate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate, and triethyliodide (triethiodode).
The composition containing the active ingredient may be in any form suitable for the intended method of administration. In some embodiments, the compounds of the methods and/or compositions described herein can be provided via oral, rectal, transmucosal, enteral (enteral), topical, transdermal, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular, and/or parenteral administration.
When the compounds are administered orally, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide palatable preparations. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents (such as calcium or sodium carbonate, lactose, calcium or sodium phosphate); granulating and disintegrating agents (e.g., corn starch or alginic acid); binding agents (e.g., starch, gelatin, or acacia); and lubricating agents (such as magnesium stearate, stearic acid or talc). Tablets may be uncoated or they may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material (such as glyceryl monostearate or glyceryl distearate) may be employed alone or with a wax.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain, for example, antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Injectable solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
In some embodiments, the unit dose formulation contains a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of the drug. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed; the age, weight, general health, sex, and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have been previously administered; and the severity of the particular disease being treated, as will be well understood by those skilled in the art.
The actual dosage of the compounds described herein depends on the particular compound and the condition being treated; the selection of an appropriate dosage is well within the knowledge of one skilled in the art. In some embodiments, the daily dose may be from about 0.1mg/kg to about 100mg/kg or more, from about 0.25mg/kg or less to about 50mg/kg, from about 0.5mg/kg or less to about 25mg/kg, from about 1.0mg/kg to about 10mg/kg of body weight. Thus, for a 70kg human, the dosage will range from about 7 mg/day to about 7000 mg/day, from about 35 mg/day or less to about 2000 mg/day or more, from about 70 mg/day to about 1000 mg/day.
Method of treatment
Some embodiments of the invention include methods of treating a disease, condition, or disorder selected from the group consisting of: hepatitis, liver cancer, liver fibrosis, fatty liver, malaria, viral infection, parasitic infection, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia, hormonal disorders, HIV, and various types of cancer. Some methods comprise administering to a subject in need thereof a compound, composition, pharmaceutical composition described herein. In some embodiments, the subject may be an animal, e.g., a mammal, a human. In some embodiments, the subject is a human.
Additional embodiments include administering to a subject in need thereof a combination of compounds. The combination may comprise a compound, composition, pharmaceutical composition, and other agent described herein.
Some embodiments include co-administration of a compound, composition, and/or pharmaceutical composition described herein with other agents or other therapeutic agents. By "co-administered" is meant that two or more agents may be found in the bloodstream of a patient at the same time, regardless of the time or manner of actual administration. In one embodiment, multiple agents are administered simultaneously. In one such embodiment, co-administration is achieved by combining multiple agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered by the same route (e.g., orally). In another embodiment, the agents are administered by different routes (e.g., oral and intravenous).
Examples of other drugs include therapeutic agents selected from other types of chemotherapeutic agents (e.g., cyclophosphamide, methotrexate, doxorubicin, docetaxel, cisplatin, epirubicin, oxaliplatin, and folinic acid); and other targeted anti-tumor agents (e.g., HDAC inhibitors). In some embodiments, the other therapeutic agent for HCC treatment may be one or more of sorafenib, regorafenib, an immunotumor agent (such as a PD-1 or PD-L1 checkpoint inhibitor).
To further illustrate the invention, the following examples are included. Of course, these examples should not be construed as specifically limiting the present invention. Variations of these embodiments within the scope of the claims are within the ability of those skilled in the art and are considered to be within the scope of the invention described and claimed herein. The reader will recognize that those skilled in the art and having possession of this disclosure will be able to make and use the invention without exhaustive enumeration of the examples.
Synthesis of Compounds
The following procedures for preparing the novel compounds illustrate general procedures for preparing the 5-fluorouracil-derived acetal and hemiacetal amine ether compounds.
Route I describes a general strategy for synthesizing compounds of formula I. 5-Fluorouracil (1) is reacted with an alkylating agent of structure 2 in the presence of a base to provide a product of structure 3, which can be further reacted with a second alkylating agent of structure 4 in the presence of a base to provide a final product of structure 5. Alternatively, if both alkylating agents are the same, fluorouracil can be double alkylated in one step to produce the final product of structure 5.
Route I
The compounds of formula II and IV were synthesized in a similar manner to scheme I using doxifluridine as starting material. Scheme II describes a general strategy for the synthesis of compounds of formulae III and V. The condensation of doxifluridine (6) with an aldehyde of structure 7 in the presence of an acid catalyst under standard conditions to produce a ketal product of structure 8, which can be further reacted with an alkylating or acylating agent of structure 9 to give the final product of structure 10.
Route II
Scheme III describes a general synthesis of compounds of formula VI. Fluorouridine (11) is reacted with phosphine diamine (12) in the presence of 4, 5-dicyanoimidazole to give the cyclic product of structure 13, and the crude reaction mixture is then treated with an oxidizing agent such as t-butyl hydroperoxide to give the final product of structure 14.
Route III
Examples
Some of the compounds of formulas I, II, III, IV, V, and VI were prepared as follows.
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