Azithromycin derivatives containing phosphonium ions as anticancer agents
阅读说明：本技术 作为抗癌剂的包含鏻离子的阿奇霉素衍生物 (Azithromycin derivatives containing phosphonium ions as anticancer agents ) 是由 提姆·斯裴瑞 安德鲁·拉特克利夫 戴维·哈利特 布雷特·史蒂文森 爱德华·科克伦 亚历山大 于 2018-04-20 设计创作，主要内容包括：本发明涉及可用作癌症疗法的化合物。所述化合物包含具有连接至阿奇霉素大环的鏻阳离子的阿奇霉素衍生物。本发明还涉及使用所述化合物的方法以及涉及包含所述化合物的药物制剂。所述化合物包含式(I)的离子：<Image he="589" wi="700" file="DDA0002325988320000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,Z<Sup>1</Sup>是<Image he="231" wi="677" file="DDA0002325988320000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>且Z<Sup>2</Sup>是R<Sup>4b</Sup>；或者Z<Sup>2</Sup>是<Image he="213" wi="627" file="DDA0002325988320000013.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>且Z<Sup>1</Sup>是R<Sup>2b</Sup>。(The present invention relates to compounds useful as cancer therapies. The compounds comprise an azithromycin derivative having a phosphonium cation attached to the azithromycin macrocycle. The invention also relates to methods of using said compounds and to medicaments comprising said compoundsThe preparation is prepared. The compounds comprise ions of formula (I): wherein Z is 1 Is that And Z is 2 Is R 4b (ii) a Or Z 2 Is that And Z is 1 Is R 2b 。)
1. A compound comprising an ion of formula (I):
wherein the content of the first and second substances,
Z1is that
Or Z2Is that
Z3Independently selected from H, C (O) -C1-C6-alkyl or Z3Has the structure:
Z4independently selected from H, C (O) -C1-C6-alkyl or Z4Has the structure:
-L1-is independently absent or selected from-C (O) -, -C (O) O-, -S (O)2-、-S(O)-、-C(O)NR5and-S (O)2NR5-；
-L3-independently at each occurrence is absent or selected from: -O-, -S-, -NR6-、-C(O)-、-OC(O)-、-C(O)O-、-S(O)2-、-S(O)-、-NR5C(O)-、-C(O)NR5、-NR5S(O)2-、-S(O)2NR5-、-OC(O)NR5-、-NR5C(O)O-、NR5C(O)NR5、-CR7＝CR7-and-C ≡ C-;
-L2-and-L4-each occurrence is independently-C1-C4-alkylene-, each alkylene being unsubstituted or substituted with 1 to 6 independently selected R8Substituted by groups; provided that any-L attached at each end to an atom selected from oxygen, nitrogen, sulfur or phosphorus2-or-L4The radical-C2-C4-alkylene-;
-L5-is independently absent or selected from-C (O) -and-C (O) NR5-；
n is an integer selected from 0,1, 2,3, 4 and 5;
wherein L is selected1、L2、L3、L4、L5And n such that the linker formed by these groups is from 3 to 16 atoms in length;
R1a、R1band R1cEach is unsubstituted phenyl;
R2a、R2band R2cEach independently selected from H and C1-C6-an alkyl group;
R3aindependently selected from: H. c1-C6Alkyl and C (O) -C1-C6-an alkyl group;
R3band R3cEach independently selected from: h and C (O) -C1-C6-an alkyl group;
R4aand R4bEach independently selected from: H. c1-C6Alkyl and C (O) -C1-C6-an alkyl group; or R4aAnd R4bTogether form C (O);
R5independently at each occurrence selected from H and C1-C6-an alkyl group;
R6and R11Each occurrence is independently selected from: H. c1-C6Alkyl, C (O) C1-C6Alkyl and S (O)2-C1-C6-an alkyl group;
R7independently at each occurrence selected from H, C1-C4-alkyl and halogen;
R8independently at each occurrence, is selected from: c1-C6Alkyl radical, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, OR9、SR10、NR10R11、C(O)OR10、C(O)NR10R10、NR10C(O)OR10、OR10C(O)NR10R10Halogen, cyano, nitro, C (O) R10、S(O)2OR10、S(O)2R10、S(O)R10And S: (O)2NR10R10；
R9Independently at each occurrence, is selected from: H. c1-C6-alkyl and C1-C6-a haloalkyl group;
R10independently at each occurrence, is selected from: h and C1-C6-an alkyl group;
and wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or phenyl groups is optionally chemically allowed to be independently selected from oxo, C1-C6Alkyl radical, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, ORa、NRaRb、SRa、C(O)ORa、C(O)NRaRaHalogen, cyano, nitro, C (O) Ra、S(O)2ORa、S(O)2Ra、S(O)RaAnd S (O)2NRaRaSubstituted with a group of (1); wherein R isaIndependently at each occurrence, is selected from: h and C1-C6-an alkyl group; and R isbIndependently at each occurrence, is selected from: H. c1-C6Alkyl, C (O) C1-C6Alkyl and S (O)2-C1-C6-an alkyl group.
2. The compound of claim 1, wherein Z1Is that
3. The compound of claim 2, wherein L1Selected from the group consisting of-C (O) -and-S (O)2-。
4. The compound of claim 2, wherein L1Is absent.
5. The compound of any one of claims 2 to 4, wherein R4aIs H and R4bIs H.
6. The compound of any one of claims 2 to 4, wherein R4aAnd R4bTogether form C (O).
7. The compound of claim 1, wherein Z2Is that
And Z is1Is R2bPreferably, wherein R is2bIs methyl.
8. The compound of claim 7, wherein L5is-C (O) -.
9. The compound of claim 7, wherein L5is-C (O) NR5-。
10. The compound of any one of claims 7 to 9, wherein R4aIs H.
11. The compound of any one of claims 1 to 10, wherein L3Absent at each occurrence.
12. The compound of any one of claims 1 to 11, wherein L is selected1、L2、L3、L4、L5And n such that the linker formed by these groups is 8 to 14 atoms in length.
13. The compound of any one of claims 1 to 12, wherein Z is3Is that
14. The compound of any one of claims 1 to 13, wherein R2aIs methyl and R2cIs methyl.
15. The compound of any one of claims 1 to 14, wherein R3aIs H and R3bIs H.
16. The compound of any one of claims 1 to 14, wherein R3aIs H and R3bIs C (O) CH3。
17. The compound of claim 1, wherein the cation of formula (I) is selected from:
18. the compound of any one of claims 1 to 17, wherein the compound is for medical use.
19. The compound of any one of claims 1 to 17, wherein the compound is for use in the treatment of cancer.
20. A method for treating cancer, wherein the method comprises administering a therapeutically effective amount of a compound of any one of claims 1 to 17.
21. A pharmaceutical composition, wherein the composition comprises a compound of any one of claims 1 to 17 and one or more pharmaceutically acceptable excipients.
Background
Cancer is the fourth leading cause of death in developed countries. It is predicted that over 160 million new cases of cancer will be diagnosed in the united states alone in 2016, and that cancer will result in nearly 60 million united states deaths.
Cancer is characterized by uncontrolled proliferation of cells, which destroys the function of tissue. Cell proliferation may be caused by an abnormal increase in cell yield or disruption of cell death pathways. In any event, disruptors of cell function can affect the proliferation of cells, particularly cancer cells, by reducing or inhibiting cell proliferation. For example, modulation of cancer cell metabolism can result in a reduction or inhibition of cell proliferation. Likewise, the compounds of the invention may reduce, destroy or inhibit the growth or proliferation of cancer cells, or they may induce the death of cancer cells. Thus, cancer cell metabolism and reduction of cell proliferation are potential targets for disruption of cancer growth and ultimately therapeutic approaches for cancer treatment. Accordingly, certain embodiments of the present invention contemplate compounds that modulate cancer cell metabolism and/or reduce cell proliferation. Reduction of cell proliferation can be achieved by increasing cell death or by decreasing the rate of cell growth.
It has been observed that certain compounds having antibiotic activity have beneficial effects when administered to patients suffering from cancer. The inventors have found that compounds having a phosphonium ion attached to azithromycin are capable of modulating cancer cell metabolism in cancer cell lines and thereby preventing and/or treating cancer.
"prevention" of cancer may be considered to include prevention of the formation of tumors, including primary tumors, metastatic tumors or tumors associated with the onset, resistance or recurrence of cancer. Prevention of cancer may also be considered to include prevention of progression of cancer. In this case, prevention of the development of cancer can be demonstrated by preventing an increase in the "stage" (using appropriate cancer staging methods) of a tumor that has been treated with a compound of the invention. Increased prevention of the cancer stage can be compared to the progression of an untreated tumor, or to the degree of progression expected by a clinician in the case of a tumor that is untreated.
"treatment" of cancer may be considered to include any improvement in the pathology, symptoms or prognosis achieved with respect to cancer in an individual receiving a compound of the invention. Treatment may be indicated by partial improvement of such indications or by overall improvement (e.g., no cancer following medical use of the compounds of the invention).
Thus, prevention and/or treatment as defined above is an intended object of certain embodiments of the invention. The above definitions of treating or preventing cancer apply equally to the particular form of cancer that is also contemplated.
Recent advances in cancer therapy have indicated that certain antibiotic compounds may be useful in cancer therapy. The mechanisms by which these agents, including the antibiotics azithromycin and doxycycline, exert their therapeutic effects have been explained distinctly differently. Some authors propose that these agents inhibit Matrix Metalloproteinases (MMPs) to achieve an anti-inflammatory effect, while others propose that they impair the cellular response to DNA damage, thereby increasing the effectiveness of chemotherapy or radiotherapy on large tumor cells. Still other articles indicate that antibiotics target mitochondrial function.
However, the use of antibiotics has also been reported to increase the risk of colorectal cancer. A recent study showed that increased time to antibiotic use was significantly associated with increased risk of large bowel adenomas (Cao Y, Wu K, Mehta R et al, "Long-term use of antibiotics and isk of colonic adenoma", Gut, 2017, 0, pages 1-7).
Surprisingly, the inventors have found that compounds having a phosphonium ion attached to azithromycin have enhanced activity against certain cancer cell lines compared to azithromycin itself. This is evidenced by the reduction in cancer cell proliferation observed in the cell fusion assay.
Also provided is a method of preventing and/or treating cancer in an individual in need of such prevention and/or treatment comprising administering to the individual a therapeutically effective amount of a compound of the invention. A therapeutically effective amount of a compound of the invention may be an amount of such a compound sufficient to treat a variety of cancers, including cells that modulate cancer cells or other dysfunctional (dysfunctional) cells (e.g., tumor initiating cells, stem cell-like cancer cells, cancer stem cells, or cell populations present in tumors with stem cell-like characteristics that result in a majority of tumor cells with more differentiated phenotypes.
The same considerations described in relation to the medical use of the compounds of the invention with respect to the type of cancer to be treated and the benefits provided by treatment apply also to the treatment methods of the invention.
Disclosure of Invention
In a first aspect of the invention, there is provided a compound comprising an ion of formula (I):
wherein the content of the first and second substances,
Z1is that
Or Z2Is that
Z3Independently selected from H, C (O) -C1-C6-alkyl or Z3Has the structure:
Z4independently selected from H, C (O) -C1-C6-alkyl or Z4Has the structure:
-L1-is independently absent or selected from-C (O) -, -C (O) O-, -S (O)2-、-S(O)-、-C(O)NR5and-S (O)2NR5-；
-L3-independently at each occurrence is absent or selected from: -O-, -S-, -NR6-、-C(O)-、-OC(O)-、-C(O)O-、-S(O)2-、-S(O)-、-NR5C(O)-、-C(O)NR5、-NR5S(O)2-、-S(O)2NR5-、-OC(O)NR5-、-NR5C(O)O-、NR5C(O)NR5、-CR7＝CR7-and-C ≡ C-;
-L2-and-L4-each occurrence is independently-C1-C4-alkylene-, each alkylene being unsubstituted or substituted with 1 to 6 independently selected R8Substituted by groups; provided that any-L attached at each end to an atom selected from oxygen, nitrogen, sulfur or phosphorus2-or-L4The radical-C2-C4-alkylene-;
-L5-is independently absent or selected from-C (O) -and-C (O) NR5-；
n is an integer selected from 0,1, 2,3, 4 and 5;
wherein L is selected1、L2、L3、L4、L5And n such that the linker formed by these groups is from 3 to 16 atoms in length;
R1a、R1band R1cEach is unsubstituted phenyl;
R2a、R2band R2cEach independently selected from H and C1-C6-an alkyl group;
R3aindependently selected from: H. c1-C6Alkyl and C (O) -C1-C6-an alkyl group;
R3band R3cEach independently selected from: h and C (O) -C1-C6-an alkyl group;
R4aand R4bEach independently selected from: H. c1-C6Alkyl and C (O) -C1-C6-an alkyl group; or R4aAnd R4bTogether form C (O);
R5independently at each occurrence selected from H and C1-C6-an alkyl group;
R6and R11Each occurrence is independently selected from: H. c1-C6Alkyl, C (O) C1-C6Alkyl and S (O)2-C1-C6-an alkyl group;
R7independently at each occurrence selected from H, C1-C4-alkyl and halogen;
R8independently at each occurrence, is selected from: c1-C6Alkyl radical, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, OR9、SR10、NR10R11、C(O)OR10、C(O)NR10R10、NR10C(O)OR10、OR10C(O)NR10R10Halogen, cyano, nitro, C (O) R10、S(O)2OR10、S(O)2R10、S(O)R10And S (O)2NR10R10；
R9Independently at each occurrence, is selected from: H. c1-C6-alkyl and C1-C6-a haloalkyl group;
R10independently at each occurrence, is selected from: h and C1-C6-an alkyl group;
and wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or phenyl groups is optionally chemically allowed to be independently selected from oxo, C1-C6Alkyl radical, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, ORa、NRaRb、SRa、C(O)ORa、C(O)NRaRaHalogen, cyano, nitro, C (O) Ra、S(O)2ORa、S(O)2Ra、S(O)RaAnd S (O)2NRaRaSubstituted with a group of (1); wherein R isaIndependently at each occurrence, is selected from: h and C1-C6-an alkyl group; and R isbIndependently at each occurrence, is selected from: H. c1-C6Alkyl, C (O) C1-C6Alkyl and S (O)2-C1-C6-an alkyl group.
For the avoidance of doubt, when n is greater than 1, each-L3-L4-units independent of each other-L3-L4-a unit or a plurality of-L3-L4-the cell is selected. Thus, each of-L3-L4The units may be identical or they may be different.
For the avoidance of doubt, from L1、L2、L3、L4And L5The atomic length of the linker formed is the number of atoms in the linear chain from the phosphorus atom of the phosphonium to the oxygen or nitrogen atom via which the linker is attached to the azithromycin portion of the ion. The length does not include any substituents or branches that may be present in the chain.
To be silent, a divalent group (e.g., L) is indicated herein1、L2、L3、L4、L5Or a combination thereof) to an oxygen or nitrogen atom via which the linker is attached to the azithromycin portion of the ion, and the right-hand portion of the linker is attached directly or indirectly to the phosphorus atom of the phosphonium.
A compound comprising an ion of formula (I):
wherein the content of the first and second substances,
Z1is that
Or Z2Is that
Z3Independently selected from H, C (O) -C1-C6-alkyl or Z3Has the structure:
Z4independently selected from H, C (O) -C1-C6-alkyl or Z4Has the structure:
-L1-is independently absent or selected from-C (O) -, -C (O) O-, -S (O)2-、-S(O)-、-C(O)NR5and-S (O)2NR5-；
-L3-independently at each occurrence is absent or selected from: -O-, -S-, -NR6-、-C(O)-、-OC(O)-、-C(O)O-、-S(O)2-、-S(O)-、-NR5C(O)-、-C(O)NR5、-NR5S(O)2-、-S(O)2NR5-、-OC(O)NR5-、-NR5C(O)O-、NR5C(O)NR5、-CR7＝CR7-and-C ≡ C-;
-L2-and-L4-each occurrence is independently-C1-C4-alkylene-, each alkylene being unsubstituted or substituted with 1 to 6 independently selected R8Substituted by groups; provided that any-L attached at each end to an atom selected from oxygen, nitrogen, sulfur or phosphorus2-or-L4The radical-C2-C4-alkylene-;
-L5-is independently absent or selected from-C (O) -and-C (O) NR5-；
n is an integer selected from 0,1, 2,3, 4 and 5;
wherein L is selected1、L2、L3、L4、L5And n such that the linker formed by these groups is from 3 to 16 atoms in length;
R1a、R1band R1cEach is unsubstituted phenyl;
R2a、R2band R2cEach independently selected from H and C1-C6-an alkyl group;
R3aindependently selected from: H. c1-C6Alkyl and C (O) -C1-C6-an alkyl group;
R3band R3cEach independently selected from: h and C (O) -C1-C6-an alkyl group;
R4aand R4bEach independently selected from: H. c1-C6Alkyl and C (O) -C1-C6-an alkyl group; or R4aAnd R4bTogether form C (O);
R5independently at each occurrence selected from H and C1-C6-an alkyl group;
R6and R11Each occurrence is independently selected from: H. c1-C6Alkyl, C (O) C1-C6Alkyl and S (O)2-C1-C6-an alkyl group;
R7independently at each occurrence selected from H, C1-C4-alkyl and halogen;
R8independently at each occurrence, is selected from: c1-C6Alkyl radical, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, OR9、SR10、NR10R11、C(O)OR10、C(O)NR10R10、NR10C(O)OR10、OR10C(O)NR10R10Halogen, cyano, nitro, C (O) R10、S(O)2OR10、S(O)2R10、S(O)R10And S (O)2NR10R10；
R9Independently at each occurrence, is selected from: H. c1-C6-alkyl and C1-C6-a haloalkyl group;
R10independently at each occurrence, is selected from: h and C1-C6-an alkyl group;
and wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or phenyl groups is optionally chemically allowed to be independently selected from oxo, C1-C6Alkyl radical, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, ORa、NRaRb、SRa、C(O)ORa、C(O)NRaRaHalogen, cyano, nitro, C (O) Ra、S(O)2ORa、S(O)2Ra、S(O)RaAnd S (O)2NRaRaSubstituted with a group of (1); wherein R isaIndependently at each occurrence, is selected from: h and C1-C6-an alkyl group; and R isbIndependently at each occurrence, is selected from: H. c1-C6Alkyl, C (O) C1-C6Alkyl and S (O)2-C1-C6-an alkyl group.
In embodiments, the ion of formula (I) is an ion of formula (II):
in embodiments, the ion of formula (I) is an ion of formula (IIIa) and formula (IIIb):
in embodiments, the ion of formula (I) is an ion of formula (IVa) and formula (IVb):
in embodiments, the ion of formula (I) is an ion of formula (Va) and formula (Vb):
wherein L is6Is optionally substituted by 0 to 10R8Radical substituted C2-C15-an alkylene group.
In embodiments, the ions of formula (I) are ions of formulae (VIa) and (VIb):
wherein L is7Is optionally substituted by 0 to 10R8Radical substituted C3-C16-an alkylene group.
In embodiments, the ion of formula (I) is an ion of formula (VIIa) and formula (VIIb):
wherein L is8Is optionally substituted by 0 to 10R8Radical substituted C2-C13-an alkylene group.
The following statements apply to the compounds of any of the formulae (I) to (VIIb). These statements are independent and interchangeable. In other words, any feature described in any of the following statements may be combined (where chemically permissible) with features described in one or more other statements below. In particular, where a compound is exemplified or exemplified in this specification, any two or more statements describing the features of the compound, expressed below at any level of generality, may be combined to represent subject matter which is considered to form part of the disclosure of the invention in this specification.
In embodiments, Z1Is thatAnd Z is2Is R4b。
In embodiments, Z2Is thatAnd Z is1Is R2b。
In embodiments, Z3Is that
In embodiments, Z3Is that
In embodiments, Z3Is that
In embodiments, Z3Is H.
In embodiments, Z3Is thatWherein R is3cIs H.
In embodiments, Z3Is that
In embodiments, Z4Is that
In embodiments, Z4Is that
In embodiments, Z4Is H.
In embodiments, R2aIs C1-C6-an alkyl group.
In embodiments, R2aIs methyl.
In embodiments, R2cIs C1-C6-an alkyl group.
In embodiments, R2cIs methyl.
In embodiments, R2aIs C1-C6-alkyl and R2cIs C1-C6-an alkyl group.
In embodiments, R2aIs methyl and R2cIs methyl.
In embodiments, R2b(when present) is methyl.
In embodiments, R2aIs methyl, R2bWhen present, is methyl and R2cIs methyl.
In embodiments, R3aIs H.
In embodiments, R3bIs H or C (O) CH3。
In embodiments, R3bIs H.
In embodiments, R3bIs C (O) CH3。
In embodiments, R3cIs H.
In embodiments, R3aIs H and R3bIs H.
In embodiments, R3aIs H and R3bIs C (O) CH3。
In embodiments, R3aIs H, R3bIs C (O) CH3And R is3cIs H.
In embodiments, R3aIs H, R3bIs H and R3cIs H.
In embodiments, R4aIs H.
In embodiments, R4bIs H.
In embodiments, R4aIs H and R4bIs H.
In embodiments, R4aAnd R4bTogether form C (O).
In embodiments, Z3Is that
In embodiments, Z3Is that
In embodiments, Z3Is that
In embodiments, Z3Is thatR3cIs H, R2aIs methyl; r2cIs methyl; r3aIs H; r3bIs H, R4aIs H and R4bAnd (when present) is H.
In embodiments, Z4Is that
In embodiments, Z4Is that
In embodiments, Z4Is that
In embodiments, Z4Is that
In embodiments, Z3Is H and Z4Is H.
In embodiments, Z3Is thatAnd Z is4Is that
In embodiments, Z3Is H, R2aIs C1-C6-an alkyl group; r2bIs C1-C6-an alkyl group; r3aIs H and R3bIs H.
In embodiments, Z3Is H, R2aIs methyl; r2cIs methyl; r3aIs H and R3bIs H.
In embodiments, Z3Is H, R2aIs C1-C6-an alkyl group; r2cIs C1-C6-an alkyl group; r3aIs H; r3bIs H; r4aIs H and R4bAnd (when present) is H.
In embodiments, Z3Is H, R2aIs methyl; r2cIs methyl; r3aIs H; r3bIs H, R4aIs H and R4bAnd (when present) is H.
In embodiments, Z4Is H, R2aIs C1-C6-an alkyl group; r2bIs C1-C6-an alkyl group; r3aIs H and R3bIs H.
In embodiments, Z4Is H, R2aIs methyl; r2cIs methyl; r3aIs H and R3bIs H.
In embodiments, Z4Is H, R2aIs C1-C6-an alkyl group; r2cIs C1-C6-an alkyl group; r3aIs H; r3bIs H; r4aIs H and R4bAnd (when present) is H.
In embodiments, Z4Is H, R2aIs methyl; r2cIs methyl; r3aIs H; r3bIs H, R4aIs H and R4bAnd (when present) is H.
In embodiments, R5And at any particular occurrence is H. In embodiments, R5At each occurrence is H.
In embodiments, R5At any particular occurrence is C1-C4Alkyl groups, such as methyl. In embodiments, R5Each occurrence is C1-C4Alkyl groups, such as methyl.
In embodiments, R6And at any particular occurrence is H. In embodiments, R6At each occurrence is H.
In embodiments, R6At any particular occurrence is C1-C4Alkyl groups, such as methyl. In embodiments, R6Each occurrence is C1-C4Alkyl groups, such as methyl.
In embodiments, R7And at any particular occurrence is H. In embodiments, R7At each occurrence is H.
In embodiments, R8At any particular occurrence is C1-C4Alkyl groups, such as methyl. In embodiments, R8Each occurrence is C1-C4Alkyl groups, such as methyl.
In embodiments, R9And at any particular occurrence is H. In embodiments, R9At each occurrence is H.
In embodiments, R9At any particular occurrence is C1-C4Alkyl groups, such as methyl. In embodiments, R9Each occurrence is C1-C4Alkyl groups, such as methyl.
In embodiments, R10And at any particular occurrence is H. In embodiments, R10At each occurrence is H.
In embodiments, R10At any particular occurrence is C1-C4Alkyl groups, such as methyl. In embodiments, R10Each occurrence is C1-C4Alkyl groups, such as methyl.
In embodiments, R11And at any particular occurrence is H. In embodiments, R11At each occurrence is H.
In embodiments, R11At any particular occurrence is C1-C4Alkyl groups, such as methyl. In embodiments, R10Each occurrence is C1-C4Alkyl groups, such as methyl.
In embodiments, L is selected1、L2、L3、L4、L5And n such that the linker formed by these groups is 8 to 14 atoms in length.
In embodiments, Z1Is that
In an embodiment, L1Selected from the group consisting of-C (O) -and-S (O)2-. In an embodiment, L1is-C (O) -.
In an embodiment, L1Is absent.
In certain embodiments, L3Absent at each occurrence. Thus, the group-L2–(L3-L4)nAn alkylene linker group may be formed.
In certain embodiments, L3At each occurrence is-O-, and-L4-at each occurrence is-C2-C4-alkylene-. Thus, the group- (L)3-L4)nEther or polyether linker groups may be formed. -L4Can represent-CH at each occurrence2CH2-or-CH2CH2CH2-. Thus, the group- (L)3-L4)nEthylene glycol, polyethylene glycol, propylene glycol or polypropylene glycol linker groups may be formed.
In certain embodiments, L3At each occurrence is-NR5C(O)-、-C(O)NR5. Thus, the group- (L)3-L4)n-a peptide linker group can be formed. In these embodiments, -L4At each occurrence may be-C1-alkylene-.
In embodiments, L is selected1、L2、L3、L4And n such that the linker formed by these groups is 8 to 14 atoms in length.
In embodiments, Z1The method comprises the following steps:
whereinL6Is optionally substituted by 0 to 10R8Radical substituted C2-C15-an alkylene group. L is6May be optionally substituted with 0 to 10R8Radical substituted C7-C13-an alkylene group. L is6May be unsubstituted.
In a particular embodiment, -L1-L2-(L3-L4-)nrepresents-C (O) (CH)2)11-、-C(O)(CH2)10-、-C(O)(CH2)9-、-C(O)(CH2)8-、-C(O)(CH2)7-、-C(O)(CH2)6-or-C (O) (CH)2)5-。
In a particular embodiment, -L1-L2-(L3-L4)n-represents-C (O) NH (CH)2)8-、-C(O)NH(CH2)7-or-C (O) NH (CH)2)6-。
In embodiments, Z1The method comprises the following steps:
wherein L is7Is optionally substituted by 0 to 10R8Radical substituted C3-C16-an alkylene group. L is7May be optionally substituted with 0 to 10R8Radical substituted C8-C14-an alkylene group. L is7May be unsubstituted.
In an embodiment, L5Is absent.
In an embodiment, L5is-C (O) -.
In an embodiment, L5is-C (O) NR5-, for example-C (O) NH-.
In certain embodiments, L3Absent at each occurrence. Thus, the group-L2–(L3-L4)nAn alkylene linker group may be formed.
In certain embodiments, L3Each occurrence ofWhen it is-O-, and-L4-at each occurrence-C2-C4-alkylene-. Thus, the group- (L)3-L4)nEther or polyether linker groups may be formed. -L4Can represent-CH at each occurrence2CH2-or-CH2CH2CH2-. Thus, the group- (L)3-L4)nEthylene glycol, polyethylene glycol, propylene glycol or polypropylene glycol linker groups may be formed.
In certain embodiments, L3At each occurrence is-NR5C(O)-、-C(O)NR5. Thus, the group- (L)3-L4)n-a peptide linker group can be formed. In these embodiments, -L4At each occurrence may be-C1-alkylene-.
In embodiments, L is selected5、L2、L3、L4And n such that the linker formed by these groups is 8 to 14 atoms in length.
In embodiments Z2The method comprises the following steps:
wherein L is8Is optionally substituted by 0 to 10R8Radical substituted C2-C13-an alkylene group. L is8May be optionally substituted with 0 to 10R8Radical substituted C5-C11-an alkylene group. L is8May be unsubstituted.
At Z2In an embodiment of (2), -L5-L2-(L3-L4)n-represents-C (O) NH (CH)2)11-、-C(O)NH(CH2)10-、-C(O)NH(CH2)9-、-C(O)NH(CH2)8-、-C(O)NH(CH2)7-、-C(O)NH(CH2)6-or-C (O) NH (CH)2)5-。
At Z2In an embodiment of (2), -L5-L2-(L3-L4)n-represents-C (O) NH (CH)2)10-、-C(O)NH(CH2)8-or-C (O) NH (CH)2)6-。
In embodiments, n is an integer selected from 0 or 1.
In an embodiment of the invention, the ion of formula (I) is an ion selected from:
the cation of formula (I) will be associated with an anionic counterion. For administration to a subject, the cation of formula (I) will be combined with a pharmaceutically acceptable saltAssociated with the anionic counterion of (a). Accordingly, the first aspect of the invention also provides a compound comprising an ion of formula (I) and a pharmaceutically acceptable anion. The anion may have a single negative charge. For example, the anion may be selected from: halogen (e.g. Cl, Br and I), BF4、PF6、CF3C(O)O、HC(O)O、HCO3、(CF3SO2)2N、(C2F5)3PF3、HSO4、C1-C15-alkyl SO4、CH3C(O)O、CF3SO3p-toluenesulfonyl-O, C (CN)3、N(CN)2Or carboxylate anions of proteinogenic amino acids. For the avoidance of doubt, each anion listed in the previous sentence has a single negative charge. The anion may have multiple negative charges, e.g. PO4 3-Or CO3 2-. The anion may be derived from di-or tri-acids, such as glutamic acid, succinic acid, malic acid, citric acid, tartaric acid. It may be a monocarboxylic acid salt of the diacid or triacid. The remaining carboxylic acid groups may be in the form of protonated carboxylic acids, C1-C12Alkyl esters, or they may likewise be carboxylate anions. The carboxylate anions may each be accompanied by a pharmaceutically acceptable metal cation or another cation of formula (I).
The anion associated with the cation of the present invention may be quite labile. Thus, there may be cations of the invention associated with two or more different anions. Ion exchange processes can be used to control the identity of the anion associated with the cation of the present invention.
In embodiments, the anion is Cl, Br, I, PF6、CF3C (O) O or HC (O) O.
In one aspect of the invention, the compounds of the invention are for medical use.
In one aspect, the compounds of the first aspect of the invention are useful for the treatment of cancer. The compounds are also useful for reducing cellular proliferation of abnormal cells, such as cancer cells.
In one embodiment, the compounds of the first aspect of the invention are used for the treatment of solid tumors and other cancers, for example, cancers classified as non-solid tumors. The cancers that can be treated by the methods of the invention are: leukemia, lymphoma, sarcoma, or carcinoma.
In another aspect of the invention, there is provided a method for the treatment of cancer, wherein the method comprises administering a therapeutically effective amount of a compound of the first aspect of the invention. The method can also be used to reduce cell proliferation of abnormal cells, such as cancer cells.
In one embodiment, the method is used to treat solid tumors and other cancers, for example cancers classified as non-solid tumors. The cancers that can be treated by the methods of the invention are: leukemia, lymphoma, sarcoma, or carcinoma.
"treatment" of cancer may be considered to include prophylaxis. Treatment also includes any improvement in the pathology, symptoms or prognosis achieved with respect to cancer in an individual receiving a compound of the invention. Treatment may be indicated by partial improvement of such indications or by overall improvement (e.g., no cancer following medical use of the compounds of the invention).
"prevention" of cancer may be considered to include the prevention of the formation of new tumors, including new primary tumors or new metastatic tumors. Prevention of cancer may also be considered to include prevention of progression of cancer. In this case, prevention of the development of cancer can be demonstrated by preventing an increase in the "stage" (using appropriate cancer staging methods) of a tumor that has been treated with a compound of the invention. Increased prevention of the cancer stage can be compared to the progression of an untreated tumor, or to the degree of progression expected by a clinician in the case of a tumor that is untreated.
The compounds of the first aspect of the invention may be used to increase cancer cell death by another mechanism such as inhibition of cell replication or to reduce cell proliferation. For this purpose, the compounds can be used in vitro or in vivo.
The compounds of the invention may be used to modulate cancer cells or other dysfunctional cells (e.g., tumor initiating cells, stem cell-like cancer cells, cancer stem cells, or cell populations present in a tumor with stem cell-like characteristics that result in a majority of tumor cells with more differentiated phenotypes. accordingly, methods are provided for modulating cancer cells or other dysfunctional cells in vivo or in vitro by exposing cancer cells or other dysfunctional cells to the compounds of the first aspect of the invention.
In another aspect of the invention, there is provided a pharmaceutical composition, wherein said composition comprises a compound of the invention and one or more pharmaceutically acceptable excipients.
In embodiments, the pharmaceutical composition may be a combination product comprising one or more different pharmaceutically active agents. The one or more additional pharmaceutically active agents may be an anti-cancer agent as described below. The one or more pharmaceutically active agents may be independently selected from different therapeutic classes, such as antibiotics, antivirals, antiemetics, analgesics, and the like.
The present invention also contemplates the subject matter contained in the following numbered items:
1. a compound comprising an ion of formula (I):
wherein the content of the first and second substances,
Z1is that
Or Z2Is that
Z3Independently selected from H, C (O) -C1-C6-alkyl or Z3Has the structure:
Z4independently selected from H, C (O) -C1-C6-alkyl or Z4Has the structure:
-L1-is independently absent or selected from-C (O) -, -C (O) O-, -S (O)2-、-S(O)-、-C(O)NR5and-S (O)2NR5-；
-L3-independently at each occurrence is absent or selected from: -O-, -S-, -NR6-、-C(O)-、-OC(O)-、-C(O)O-、-S(O)2-、-S(O)-、-NR5C(O)-、-C(O)NR5、-NR5S(O)2-、-S(O)2NR5-、-OC(O)NR5-、-NR5C(O)O-、NR5C(O)NR5、-CR7＝CR7-and-C ≡ C-;
-L2-and-L4-each occurrence is independently-C1-C4-alkylene-, each alkylene being unsubstituted or substituted with 1 to 6 independently selected R8Substituted by groups; provided that any-L attached at each end to an atom selected from oxygen, nitrogen, sulfur or phosphorus2-or-L4The radical-C2-C4-alkylene-;
-L5-is independently absent or selected from-C (O) -and-C (O) NR5-；
n is an integer selected from 0,1, 2,3, 4 and 5;
wherein L is selected1、L2、L3、L4、L5And n such that the linker formed by these groups is from 3 to 16 atoms in length;
R1a、R1band R1cEach is unsubstituted phenyl;
R2a、R2band R2cEach of which isIndependently selected from H and C1-C6-an alkyl group;
R3aindependently selected from: H. c1-C6Alkyl and C (O) -C1-C6-an alkyl group;
R3band R3cEach independently selected from: h and C (O) -C1-C6-an alkyl group;
R4aand R4bEach independently selected from: H. c1-C6Alkyl and C (O) -C1-C6-an alkyl group; or R4aAnd R4bTogether form C (O);
R5independently at each occurrence selected from H and C1-C6-an alkyl group;
R6and R11Each occurrence is independently selected from: H. c1-C6Alkyl, C (O) C1-C6Alkyl and S (O)2-C1-C6-an alkyl group;
R7independently at each occurrence selected from H, C1-C4-alkyl and halogen;
R8independently at each occurrence, is selected from: c1-C6Alkyl radical, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, OR9、SR10、NR10R11、C(O)OR10、C(O)NR10R10、NR10C(O)OR10、OR10C(O)NR10R10Halogen, cyano, nitro, C (O) R10、S(O)2OR10、S(O)2R10、S(O)R10And S (O)2NR10R10；
R9Independently at each occurrence, is selected from: H. c1-C6-alkyl and C1-C6-a haloalkyl group;
R10independently at each occurrence, is selected from: h and C1-C6-an alkyl group;
and wherein the above alkyl group,Any of the alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or phenyl groups, where chemically permissible, is optionally independently selected from oxo, C1-C6Alkyl radical, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, ORa、NRaRb、SRa、C(O)ORa、C(O)NRaRaHalogen, cyano, nitro, C (O) Ra、S(O)2ORa、S(O)2Ra、S(O)RaAnd S (O)2NRaRa1 to 4 groups of (a); wherein R isaIndependently at each occurrence, is selected from: h and C1-C6-an alkyl group; and R isbIndependently at each occurrence, is selected from: H. c1-C6Alkyl, C (O) C1-C6Alkyl and S (O)2-C1-C6-an alkyl group.
2. The compound of item 1, wherein Z1Is that
3. The compound of claim 2, wherein L1Selected from the group consisting of-C (O) -and-S (O)2-。
4. The compound of claim 2, wherein L1Is absent.
5. The compound of any one of items 2 to 4, wherein R4aIs H and R4bIs H.
6. The compound of any one of items 2 to 4, wherein R4aAnd R4bTogether form C (O).
7. The compound of item 1, wherein Z2Is that
8. The compound of item 7, wherein L5is-C (O) -.
9. The compound of item 7, wherein L5is-C (O) NR5-。
10. The compound of any one of claims 7 to 9, wherein R4aIs H.
11. The compound of any one of items 1 to 10, wherein L3Absent at each occurrence.
12. The compound of any one of items 1 to 11, wherein L is selected1、L2、L3、L4、L5And n such that the linker formed by these groups is 8 to 14 atoms in length.
13. The compound of any one of claims 1 to 12, wherein Z3Is that
14. The compound of any one of claims 1 to 13, wherein R2aIs methyl and R2cIs methyl.
15. The compound of any one of claims 1 to 14, wherein R3aIs H and R3bIs H.
16. The compound of any one of claims 1 to 14, wherein R3aIs H and R3bIs C (O) CH3。
17. The compound of any one of claims 1 to 16, wherein the compound is for medical use.
18. The compound of any one of claims 1 to 16, wherein the compound is for use in the treatment of cancer.
19. A method for treating cancer, wherein the method comprises administering a therapeutically effective amount of a compound of any one of items 1 to 16.
20. A pharmaceutical composition, wherein the composition comprises a compound of any one of items 1 to 16 and one or more pharmaceutically acceptable excipients.
Detailed Description
The following gives definitions of terms used in the present application. Any term not defined herein shall take the usual meaning as the skilled person will understand the term.
The term "halo" or "halogen" refers to an atom selected from fluorine, chlorine, bromine and iodine. "halo" or "halogen" may refer to an atom selected from Cl and F. "halo" or "halogen" may refer to fluorine.
The term "alkyl" refers to a straight or branched hydrocarbon chain. The term "C1-C8Alkyl "refers to a straight or branched hydrocarbon chain containing 1,2,3, 4,5, 6, 7, or 8 carbon atoms. The term "C1-C6Alkyl "refers to a straight or branched hydrocarbon chain containing 1,2,3, 4,5, or 6 carbon atoms. The term "C1-C6Alkyl "for example means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. An "alkyl" group may be substituted or unsubstituted with one or more substituents. The substituents for alkyl groups may be halogen (e.g. fluorine, chlorine, bromine and iodine), OH and C1-C6An alkoxy group. In addition, the alkylene group may be straight or branched and may have two junctions with the rest of the molecule.
The term "alkylene" refers to a divalent group that is a straight or branched hydrocarbon chain. In the case where an "alkylene" group is divalent, the group must form two bonds with other groups. The term "C1-C8The "alkylene group" may mean-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2CH2CH2CH2-or substituted equivalents thereof. The alkylene group may be unsubstituted or substituted by one or moreThe substituent is substituted.
The term "cycloalkyl" refers to a saturated hydrocarbon ring system. The term "C3-C8Cycloalkyl "means a saturated hydrocarbon ring system containing 3,4, 5,6, 7 or 8 carbon atoms. The ring system may be a monocyclic or bicyclic or tricyclic ring system. Where the ring system is bicyclic, one of the rings may be aromatic, for example in indane. The term "cycloalkyl" may refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and indane. The cycloalkyl group may be substituted with one or more substituents.
The term "haloalkyl" refers to a straight or branched hydrocarbon chain substituted with at least one halogen atom independently at each occurrence selected from the group consisting of fluorine, chlorine, bromine, and iodine. For example, the term "C1-C6Haloalkyl "refers to a straight or branched hydrocarbon chain containing 1,2,3, 4,5, or 6 carbon atoms. The halogen atom may be substituted at any position of the hydrocarbon chain. The term "C1-C6Haloalkyl "may refer to, for example, fluoromethyl, trifluoromethyl, chloromethyl, fluoroethyl, trifluoroethyl, chloroethyl, trichloroethyl (e.g., 1,2, 2-trichloroethyl and 2,2, 2-trichloroethyl), fluoropropyl, and chloropropyl. The haloalkyl group may be substituted with one or more substituents.
The term "alkenyl" refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond and having at least two carbon atoms. The term "C2-C6Alkenyl "means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond and having 2,3, 4,5, or 6 carbon atoms. The double bond or bonds may be either the E or Z isomers. The double bond may be present at any possible position of the hydrocarbon chain. The term "C2-C6Alkenyl "may refer to, for example, ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, and hexadienyl. The alkenyl group may be substituted or unsubstituted with one or more substituents.
The term "cycloalkenyl" refers to an unsaturated hydrocarbon ring system. The term "C3-C8-cycloalkenyl "means unsaturated containing 3,4, 5,6, 7 or 8 carbon atomsA hydrocarbon ring system. The ring may contain more than one double bond. The term cycloalkenyl can refer to, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl, and cyclooctadienyl. The cycloalkenyl group can be substituted with one or more substituents.
The term "alkynyl" refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond and having at least two carbon atoms. The term "C2-C6Alkynyl "refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond and having 2,3, 4,5, or 6 carbon atoms. The triple bond or bonds may be present at any possible position of the hydrocarbon chain. The term "C2-C6Alkynyl "may refer to, for example, ethynyl, propynyl, butynyl, pentynyl, and hexynyl. The alkynyl group may be unsubstituted or substituted with one or more substituents.
The term "heteroalkyl" refers to a straight or branched hydrocarbon chain containing at least one heteroatom selected from N, O and S, located between any possible carbon atoms in the chain or at the end of the chain. The term "C1-C6Heteroalkyl "refers to a straight or branched hydrocarbon chain containing 1,2,3, 4,5 or 6 carbon atoms and at least one heteroatom selected from N, O and S, located between any possible carbon atoms in the chain or at the end of the chain. The heteroalkyl group may be attached to another group through a heteroatom or carbon atom. The term "C1-C6Heteroalkyl "may mean, for example, -CH2NHCH3、-NHCH2CH3and-CH2CH2NH2. The heteroalkyl group may be unsubstituted or substituted with one or more substituents.
The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing at least one heteroatom selected from N, O and S in the ring system. The term "5-to 8-membered heterocycloalkyl" refers to a saturated hydrocarbon ring system having 5,6, 7, 8, 9, or 10 atoms (at least one is a heteroatom) selected from carbon, N, O, and S. A "heterocycloalkyl" group can also be represented as a "3-to 10-membered heterocycloalkyl," which is also a ring system containing 3,4, 5,6, 7, 8, 9, or 10 atoms, at least one of which is a heteroatom. The ring system may be a monocyclic or bicyclic or tricyclic ring system. The bicyclic ring system may be spiro-fused (spiro-fused), i.e. wherein the rings are connected to each other by a single carbon atom; is vicinally fused (vicinally fused), i.e. wherein the rings are connected to each other through two adjacent carbon or nitrogen atoms; or they may share a bridge end (bridgehead), i.e. the rings are connected to each other by two non-adjacent carbon or nitrogen atoms. Where the ring system is bicyclic, one of the rings may be aromatic, for example in chromanes. "heterocycloalkyl" may be bonded to the rest of the molecule through any carbon or heteroatom. "heterocycloalkyl" may have one or more, e.g., one or two, bonds to the rest of the molecule: these bonds may be through any atom in the ring. For example, "heterocycloalkyl" can be ethylene oxide, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, and chromane.
The term "heterocycloalkenyl" refers to an unsaturated hydrocarbon ring system containing at least one heteroatom selected from N, O or S. The term "C3-C8Heterocycloalkenyl "refers to an unsaturated hydrocarbon ring system containing 3,4, 5,6, 7, or 8 carbon atoms and at least one heteroatom selected from N, O or S. More than one double bond may be present. The double bond will typically be between two carbon atoms, but may be between a carbon atom and a nitrogen atom. More than 1 heteroatom may also be present. For example, 1,2 or 3 heteroatoms may be present. The ring system may be a monocyclic or bicyclic or tricyclic ring system. In the case where the ring system is bicyclic, one of the rings may be aromatic, for example in indoline and dihydrobenzofuran. The heterocycloalkenyl group may be attached to another group through any carbon or heteroatom. The term heterocycloalkenyl can refer to, for example, tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline, dihydrobenzofuran, dihydrobenzothiophene, and indoline. The heterocycloalkenyl group may be substituted with one or more substituents.
The term "aryl" refers to an aromatic hydrocarbon ring system that satisfies the aromatic rules of houcker, or an aromatic hydrocarbon ring system that comprises a ring system that satisfies the aromatic rules of houcker. Thus, the aryl group may be a monocyclic or bicyclic or tricyclic ring system. The term "aryl" may refer to, for example, phenyl, naphthyl, indane, tetralin, and anthracene. The aryl group may be unsubstituted or substituted with one or more substituents. Any aryl group may be a benzene ring.
The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom selected from N, O or S, or a ring system comprising heteroatoms and aromatic hydrocarbon rings, that satisfies the houcker' S aromaticity rule. Heteroaryl groups can be monocyclic or fused ring systems. The term "5, 6, 9 or 10 membered heteroaryl" refers to an aromatic ring system having 5,6, 9 or 10 members selected from carbon, N, O or S in a monocyclic or bicyclic ring system. The term heteroaryl can refer to, for example, imidazole, thiazole, oxazole, isothiazole, isoxazole, triazole, tetrazole, thiophene, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, indole, isoindole, quinolone, and isoquinoline.
The term "alkoxy" refers to an alkyl group attached to another group through an oxygen. The alkyl group may be linear or branched. The term "C1-C6Alkoxy "refers to an alkyl group containing 1,2,3, 4,5, or 6 carbon atoms that is attached to another group through an oxygen. Alkyl groups may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The term "C1-C6Alkoxy "may refer to, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy. The alkyl group may be substituted or unsubstituted with one or more substituents.
To be provided with
Where chemically possible and in accordance with valence requirements, a group may be substituted at any point on the group when it is substituted. A group may be substituted with one or more substituents. For example, a group may be substituted with 1,2,3 or 4 substituents. When two or more substituents are present, these substituents may be the same or different. The substituents may be, for example, halogen, CN, nitro, oxo, C1-C6Alkyl radical, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, ORa、NRaRb、SRa、C(O)ORa、C(O)NRaRaHalogen, cyano, nitro, C (O) Ra、S(O)2ORa、S(O)2RaAnd S (O)2NRaRa(ii) a Wherein R isaIndependently at each occurrence, is selected from: h and C1-C6-an alkyl group; and R isbIndependently at each occurrence, is selected from: H. c1-C6Alkyl, C (O) C1-C6Alkyl and S (O)2-C1-C6-an alkyl group.
If this is chemically possible, the cyclic substituent may be substituted on the group to form a spiro ring.
Substituents are only present at positions where they are chemically possible and the skilled person is able to determine (experimentally or theoretically) which substitutions are chemically possible and which are not without undue effort.
Ortho, meta and para substitution are terms well known in the art. For the avoidance of doubt, "ortho" substitution is a substitution pattern in which adjacent carbon atoms bear substituents, whether simple groups (e.g. fluoro groups in the examples below), or other parts of the molecule (e.g. by bond ends)
"meta" substitution is a substitution pattern in which two substituents are on carbons that are one carbon apart from each other, i.e., there is a single carbon atom between the carbons being substituted. In other words, one substituent is located on a second atom spaced from the atom bearing the other substituent. For example, the following groups are meta-substituted.
"para" substitution is a substitution pattern in which two substituents are located on carbons that are two carbons apart from each other, i.e., there are two carbon atoms between the substituted carbons. In other words, one substituent is located on a third atom spaced from the atom bearing the other substituent. For example, the following groups are para-substituted.
The cation of formula (I) will be associated with a pharmaceutically acceptable anionic counterion for administration to a subject. However, where the cationic or anionic counterions of formula (I) comprise basic or acidic groups, those groups may themselves be protonated or deprotonated and associated with suitable counterions.
Suitable acid addition salts are formed from acids which form non-toxic salts, for example, acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, salicylate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate (naphylate), 1, 5-naphthalenedisulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate (pamoate), Phosphate/hydrogen phosphate/dihydrogen phosphate, sugar acid salt, stearate, succinate, tartrate, tosylate and trifluoroacetate.
Suitable base salts are formed from bases which form non-toxic salts and include, for example, aluminum, arginine, benzathine, calcium, choline, diethylamine, dialcohol, glycine, lysine, magnesium, meglumine, alkanolamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed. A review of suitable Salts is found in Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and use" (Wiley-VCH, Weinheim, Germany, 2002).
The salts may be acid addition salts.
The salt may be a formate or a hydrochloride.
Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of the following methods:
(i) reacting a compound of formula (I) with a desired acid or base;
(ii) removing acid-or base-labile protecting groups from suitable precursors of compounds of formula (I), or by ring-opening a suitable cyclic precursor (e.g. a lactone or lactam) using a desired acid or base; or
(iii) One salt of the compound of formula (I) is converted to another salt by reaction with a suitable acid or base or with the aid of a suitable ion exchange column.
The above reaction is usually carried out in solution, and the resulting salt may be precipitated and collected by filtration, or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from fully ionized to almost unionized.
The compounds may exist in unsolvated as well as solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" is used when the solvent is water.
Complexes are contemplated, such as clathrates, drug-host clathrates, where the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to the solvates described above. Pharmaceutical complexes comprising two or more organic and/or inorganic components that may be stoichiometric or non-stoichiometric are also contemplated. The resulting complex may be ionized, partially ionized or not. An overview of such complexes is found in J Pharm Sci,64(8),1269-1288(August 1975) by Haleblian.
The compounds and salts described in this specification may be isotopically labeled (or "radiolabeled"). Thus, one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of radionuclides that may be incorporated include2H (also written as "D" for deuterium)3H (also written as "T" for tritium),11C、13C、14C、15O、17O、18O、18f, and the like. The radionuclide used will depend on the particular application of the radiolabeled derivative. For example, for in vitro competition assays,3h or14C is generally useful. For the application of radio imaging,11c or18F is generally useful. In some embodiments, the radionuclide is3H. In some embodiments, the radionuclide is14C. In some embodiments, the radionuclide is11C. And in some embodiments the radionuclide is18F。
Hereinafter, all references to compounds of any general formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
The compounds include a number of general formulas as defined herein, including all polymorphs and crystal habits thereof as defined below, prodrugs and isomers thereof (including optical isomers, geometric isomers and tautomers), as well as isotopically labeled compounds of the present invention.
Prior to purification, the compounds may exist as a mixture of enantiomers depending on the synthetic method used. Enantiomers may be separated by conventional techniques known in the art. Thus, the compounds encompass individual enantiomers and mixtures thereof.
For certain steps of the process for preparing compounds of formula (I), it may be necessary to protect potentially reactive functional groups which are not desired to react and thus cleave the protecting group. In this case, any compatible protecting group may be used. In particular, protection and deprotection methods such as those described in T.W.Greene (Protective Groups in organic Synthesis, A.Wiley-lnterference Publication,1981) or P.J.Kocienski (Protective ggroups, Georg Thieme Verlag,1994) can be used. All of the above reactions and preparations of the novel starting materials used in the foregoing processes are conventional, and reagents and reaction conditions suitable for their performance or preparation, as well as methods for isolating the desired products, are well known to those skilled in the art in the context of the reference precedents, as well as the examples and preparations herein.
In addition, the compounds and intermediates for their preparation may be purified according to various well-known methods, such as crystallization or chromatography.
The therapeutic methods or compounds for the treatment of solid tumors, leukemias, lymphomas, sarcomas or carcinomas as defined above can be used as monotherapy or in combination therapy with other active agents.
In addition to the compounds of the present invention, therapeutic methods or compounds for the treatment of solid tumors, leukemias, lymphomas, sarcomas, or carcinomas can also include conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following classes of anti-cancer agents:
(i) antiproliferative/antineoplastic agents and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustine (bendamustine), melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, e.g., fluoropyrimidines such as 5 fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, and hydroxyurea); antibiotics (e.g., anthracycline antibiotics such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin, and mithramycin); antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes such as paclitaxel and taxotere and paul kinase (polokinase) inhibitors); proteasome inhibitors, such as carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (e.g., podophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, mitoxantrone, and camptothecin);
(ii) cytostatics, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene (iodoxyfene)), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, voprazole and exemestane) and 5 α -reductase inhibitors such as finasteride;
(iii) anti-invasion agents, such as dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, or heparanase antibodies;
(iv) growth factor function inhibitors: for example, such inhibitors include growth factor antibodies and growth factor receptor antibodies, e.g., the anti-erbB 2 antibody trastuzumab [ Herceptin ]TM]anti-EGFR antibodies panitumumab, anti-erbB 1 antibody cetuximab, tyrosine kinase inhibitors, e.g., inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib, and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) -quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); hepatocyte growth factorInhibitors of the subfamily; inhibitors of the insulin growth factor family; modulators of apoptosis protein modulators (e.g., Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family, such as imatinib and/or nilotinib (AMN 107); inhibitors of serine/threonine kinases (e.g., Ras/Raf signal inhibitors such as farnesyl transferase inhibitors, e.g., sorafenib, tipifarnib, and lonafarnib), cellular signaling through MEK kinases and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptors, kinase inhibitors; ordokinase inhibitors and cyclin dependent kinase inhibitors, such as CDK2 inhibitors and/or CDK4 inhibitors;
(v) anti-angiogenic agents, e.g. those inhibiting the action of vascular endothelial growth factor, e.g. the anti-vascular endothelial growth factor antibody bevacizumab (Avastin)TM) (ii) a Thalidomide; lenalidomide; and for example VEGF receptor tyrosine kinase inhibitors such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;
(vi) gene therapy methods, including, for example, methods of replacing an abnormal gene such as abnormal p53 or abnormal BRCA1 or BRCA 2;
(vii) immunotherapy, including checkpoint inhibitors of targets such as PD-1, PD-L1 and CTCLA-4, e.g. antibody therapy, e.g. alemtuzumab, rituximab, ibritumomab tiuxetan
(viii) cytotoxic agents, e.g. fludarabine (fludarabine), cladribine, pentostatin (Nipent)TM)；
(ix) Steroids, such as corticosteroids, including glucocorticoids and mineralocorticoids, such as beclomethasone (aclometasone), alclomethasone dipropionate, aldosterone (aldosterone), amcinonide (amcinonide), beclomethasone (beclomethasone), betamethasone (betamethasone), betamethasone dipropionate (betamethasone), sodium betamethasone phosphate (betamethasone sodium phosphate), betamethasone valerate (betamethasone), budesonide (budesonide), clobetasone (clobetasone), sodium clobetasone butyrate (clobetamethasone butyrate), dexamethasone (dexamethasone acetate), sodium clobetamethasone (dexamethasone acetate), dexamethasone acetate (sodium phosphate), dexamethasone acetate (dexamethasone acetate), dexamethasone acetate (dexamethasone acetate), and/or dexamethasone acetate (dexamethasone acetate), or dexamethasone acetate, or (dexamethasone acetate, or dexamethasone acetate, Diflucortolone (diflucortolone), fluchloroolone (fluxolone), flumethasone (fluethasone), flunisolide (fluisolalide), fluocinolone (fluocinolone), fluocinonide (fluocinolone acetate), fluocinonide (fluocidin butyl), flucortisone (fluocirtisone), fluocinolone (fluxolone acetonide), fluocinonide (fluxolone hexanoate), fluocinonide (fluocinolone propionate), fluocinolone pivalate (fluocinolone pivalate), fluorometholone (fluoromethasone), flunisolone (flunisolone), fluprednilnide (fluprednilnide), fluprednilone acetate (flunisolone acetate), fludroxyolone (flunisolone), flunisolone (fluxolone propionate), fluxolone propionate (fluxolone propionate), hydrocortisone acetate (hydrocortisone), hydrocortisone acetate (hydrocortisone), hydrocortisone (hydrocortisone), flunisolone (flunisolone) and the like, Methylprednisolone (meprednisone), methylprednisolone (methylprednisone), mometasone furoate (mometasone Parathasone), mometasone furoate (mometasone furoate monohydranate), prednisone carbonate (prednicarbate), prednisolone (prednisone), prednisone (prednisone), tixocortisone (tixocortol), tixocortol pivalate (tixocortol pivalate), triamcinolone (triamcinolone), triamcinolone acetonide (triamcinolone acetonide), triamcinolone alcohol (triamcinolone alcohol), and their respective pharmaceutically acceptable derivatives. Combinations of steroids may be used, for example combinations of two or more steroids mentioned in this paragraph;
(x) Targeted therapies, such as PI3K δ inhibitors, e.g., idelalisib and piperacillin.
Such combination therapy may be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment. Such combination products may be administered so as to provide the combination in a therapeutically effective amount, e.g., the compounds of the invention may be administered within a therapeutically effective dosage range as described herein, and the other pharmaceutically active agents may be administered in an amount less than or within their allowable dosage range.
According to a further aspect of the present invention there is provided a pharmaceutical product comprising a compound of the first aspect of the present invention or a pharmaceutically acceptable salt thereof as defined herein and a further active agent. The additional active agent may be a cancer therapy as defined above for the combination treatment of cancer.
According to another aspect of the present invention there is provided a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, simultaneously, sequentially or separately with an additional anti-cancer agent as defined above.
According to another aspect of the present invention there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer simultaneously, sequentially or separately with an additional anti-cancer agent as defined herein.
According to another aspect of the invention there is provided the use of a compound of the invention in combination with an anti-cancer agent (such as those described above). The compounds of formula (I) may be used simultaneously, sequentially or separately with additional anti-cancer agents. Can be used in a single combination product comprising the compound of the present invention and an anticancer agent. The additional anti-cancer agent may be another compound of the first aspect of the invention.
According to another aspect, there is provided a method of providing a combination product, wherein the method comprises providing a compound of the invention simultaneously, sequentially or separately with an anti-cancer agent as defined above. The method may comprise combining a compound of the invention and an anti-cancer agent in a single dosage form. Alternatively, the method may comprise providing the anti-cancer agent as a separate dosage form.
The compounds of the invention may be present in single crystal form or as a mixture of crystal forms, or they may be amorphous. Thus, the compounds of the present invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They can be obtained, for example, in the form of solid plugs, powders or films by methods such as precipitation, crystallization, freeze drying or spray drying or evaporation drying. Microwave or radio frequency drying may be used for this purpose.
For the above compounds of the invention, the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the condition being indicated. For example, if a compound of the invention is administered orally, the daily dose of the compound of the invention may be from 0.01 micrograms per kilogram of body weight (μ g/kg) to 100 milligrams per kilogram of body weight (mg/kg).
The compounds of the invention or pharmaceutically acceptable salts thereof may be used alone, but are generally administered in the form of a pharmaceutical composition in which the compound of the invention or pharmaceutically acceptable salt thereof is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional methods for selecting and preparing suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals-the science of Dosage Form Designs", m.e. ulton, churchlill Livingstone, 1988.
Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition for administering the compounds of the invention will preferably comprise 0.05% w to 99% w (by weight) of the compounds of the invention, more preferably 0.05% w to 80% w of the compounds of the invention, still more preferably 0.10% w to 70% w of the compounds of the invention, even more preferably 0.10% w to 50% w of the compounds of the invention, all weight percentages being based on the total composition.
The pharmaceutical compositions may be administered topically (e.g., to the skin) in the form of, for example, a cream, gel, lotion, solution, suspension, or may be administered systemically by oral administration in the form of a tablet, capsule, syrup, powder, or granule; or by parenteral administration in the form of sterile solutions, suspensions or emulsions for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); administration by rectal administration in the form of suppositories; or in aerosol form by inhalation.
For oral administration, the compounds of the invention may be mixed with: adjuvants or carriers, such as lactose, sucrose, sorbitol, mannitol; starches, such as potato starch, corn starch or amylopectin; a cellulose derivative; binders, such as gelatin or polyvinylpyrrolidone; and/or lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin wax, and the like, and then compressed into tablets. If coated tablets are desired, the cores prepared as described above may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talc and titanium dioxide. Alternatively, the tablets may be coated with a suitable polymer dissolved in a volatile organic solvent.
For the preparation of soft gelatin capsules, the compounds of the invention may be mixed with, for example, vegetable oils or polyethylene glycols. Hard gelatin capsules may contain granules of the compound using any of the above excipients for tablets. Liquid or semisolid formulations of the compounds of the present invention may also be filled into hard gelatin capsules. Liquid preparations for oral administration may be in the form of syrups or suspensions, for example, solutions containing the compounds of the invention, the remainder being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid formulations may contain coloring agents, flavoring agents, sweetening agents (such as saccharin), preservatives, and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in the art.
For intravenous (parenteral) administration, the compounds of the invention may be administered as a sterile aqueous or oily solution.
The size of the dose of the compound of the present invention for therapeutic purposes will naturally vary according to well-known principles of medicine, depending on the nature and severity of the disease, the age and sex of the animal or patient and the route of administration.
It is contemplated that the dosage level, frequency of dosage, and duration of treatment of the compounds of the invention will vary with the formulation and the clinical indication, age, and co-morbid medical condition of the patient.
Throughout the description and claims of this specification, the words "comprise" and "contain," and variations thereof, mean "including but not limited to," and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular forms "a", "an", and "the" include plural referents unless the context requires otherwise. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.
The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.
Method for synthesizing compounds
Certain ions of the present invention can be synthesized according to or similar to the methods described in the following general schemes and/or by other techniques known to those of ordinary skill in the art. Certain ions of the invention may be synthesized according to or similar to the methods described in the examples.
Certain compounds of formula (II) may be prepared by scheme a.
Scheme A
Amide bond formation between N-desmethyl-azithromycin (1) and phosphonium carboxylic acid (2) can provide phosphonium amide (3). The reaction may be carried out by standard peptide coupling agents such as HATU or TATU or 1, 3-Dicyclohexylcarbodiimide (DCC) in the presence of a base such as N, N-Diisopropylethylamine (DIEA) in an organic solvent such as DCM at a temperature of 25 ℃ to 40 ℃. The phosphonium carboxylic acids (2) can be prepared from halides (4) (X ═ Cl or Br) and phosphines PR1aR1bR1c(7) The reaction of (1). The reaction may be accomplished by heating at a temperature of 50 ℃ to 80 ℃ in an organic solvent (e.g., MeCN).
Certain compounds of formula (II) may be prepared by scheme B.
Scheme B
Reaction of N-demethyl-azithromycin (1) with a halogenated sulfonic acid (5) (where X ═ Cl or Br) can provide the halogenated sulfonamide (6). The reaction may be carried out at a temperature of from 20 ℃ to 60 ℃ using SOCl in an organic solvent such as DMF or DCM2The process is carried out. Reaction of the phosphine (7) with the halo sulfonamide (6) can provide the phosphonium sulfonamide (8). The reaction may be carried out in an organic solvent (e.g., M)eCN) at a temperature of from 50 ℃ to 80 ℃.
Certain compounds of formula (II) may be prepared by scheme C.
Scheme C
Reaction of N-desmethyl-azithromycin (1) with phosphonium chlorocarbonate (9) can provide phosphonium carbamate (10). The reaction can be carried out at a temperature of from 0 ℃ to room temperature in an organic solvent (e.g., DCM) in the presence of a base (e.g., pyridine). Phosphonium chloroacetate (9) can be synthesized from phosphonium alcohol (11) by treatment with triphosgene in the presence of a base such as N, N-Diisopropylethylamine (DIEA) in an organic solvent such as THF at a temperature of-5 ℃ to 5 ℃. Phosphonium alcohols (11) can be synthesized from halohydrins (12) (where X ═ Cl or Br) and phosphines (7). The reaction may be accomplished by heating in an organic solvent (e.g., MeCN) at a temperature of 50 ℃ to 80 ℃.
Certain compounds of formula (II) may be prepared by scheme D.
Scheme D
Reductive amination of N-demethyl-azithromycin (1) with aldehyde (13) may provide amine (14), wherein LG represents a leaving group, such as Cl, Br, I, tosyl or mesylate, and L2aRatio L2One carbon shorter. The reaction may be carried out at a temperature of from 25 ℃ to 80 ℃ in an organic solvent (e.g. DMF) in an acid source (e.g. CH)3COOH) in the presence of a suitable reducing agent (e.g., NaBH)3CN) is finished. (14) Substitution of LG in (2) with phosphine (7) can provide phosphonium amine (15). The reaction may be carried out at a temperature of 50 ℃ to 90 ℃ in an organic solvent (e.g. MeCN). Where LG is not I, the adaptive addition of a metal iodide (e.g., NaI or KI) may facilitate the in situ formation of I as a potentially more effective LG.
Certain compounds of formula (II) may be prepared by scheme E.
Scheme E
Phosphonium amides (3) with Ac2The reaction of O can selectively acylate a hydroxyl group in the desosaminyl sugar to give the acylated phosphonium amide (16). The reaction can be carried out at room temperature in the presence of an organic solvent (e.g., DCM) in the presence of a base (e.g., Et)3N) is completed in the presence of a catalyst. Para (16) with Carbonyldiimidazole (CDI) at a temperature of 25 ℃ to 70 ℃ in a base such as Et3N), followed by treatment with a strong base (e.g., NaOH) in an organic solvent (e.g., THF) at a temperature of 0 to 25 deg.C, followed by sequential treatments of heat in MeOH at a temperature of 40 deg.C to 65 deg.C, can provide phosphonium carbonate (17).
Certain compounds of formula (VIIb) may be prepared by scheme F.
Scheme F
(18) The carbamate (19) can be provided by reaction of (prepared by the method described in European Journal of Medicinal Chemistry 40, 2011, 5196) with a strong base (such as NaOH) in the presence of a solvent (such as THF) at a temperature of 0 ℃ to 25 ℃, followed by ring opening of the carbonate with the phosphonium amine (20). The carbonate ring-opening reaction can be accomplished at room temperature in pyridine in the presence of a non-nucleophilic base (e.g., DBU). Removal of acetate esters from the desosaminyl sugars may be accomplished by heating in MeOH at temperatures of 40 ℃ to 65 ℃ to afford the phosphonium carbamate (21).
Phosphonium amines (20) can be provided by scheme G.
Scheme G
Reaction of a halogenated isoindoline-1, 3-dione (22) (where X ═ Cl or Br) with phosphine (7) can provide phosphonium isoindoline-1, 3-dione (23). The reaction may be carried out by heating at a temperature of 50 ℃ to 80 ℃ in an organic solvent (e.g., MeCN). Reaction of phosphonium isoindoline-1, 3-dione (23) with hydrazine hydrate in an alcohol solvent (e.g., EtOH) at a temperature of 50 ℃ to 75 ℃ can provide phosphonium amine (20).
Certain compounds of formula (II) may be prepared by scheme H.
Scheme H
Removal of cladinosyl sugar (24) from the phosphonium amide (3) to give (24) may be accomplished by treatment with a mineral acid (e.g. HCl) in a solvent (e.g. MeOH) at room temperature.
Substitution of amine (25) (prepared as described in WO 2011116312) for amine (1) in scheme a can give phosphonium amide (26).
Experiment of
Analytical method
NMR spectra were obtained on 400MHz Bruker AV III
UPLC/MS Using Waters Acquity QDa Mass Detector and method A, G or Waters SQ Mass Detector and method B, C, D, E, F, H
Method A
Column: waters Acquity UPLC CSH C18, 1.7 μm, 2.1 × 30 mm; gradient eluent: 5-95% MeCN/H with 0.1% HCOOH2O; time: 0-10 min
Method B
Column: waters Acquity UPLC CSH C18, 1.7 μm, 2.1 × 50 mm; gradient eluent: 2-98% MeCN/H with 0.02% HCOOH2O; time: 0-4.5 minutes
Method C
Column: waters Acquity UPLC CSH C18, 1.7 μm, 2.1 × 50 mm; gradient eluent: contains 0.035% TFA/H containing 0.05% TFA2MeCN 2-98% of O; time: 0-4.5 minutes
Method D
Column: waters Acquity UPLC CSH C18, 1.7 μm, 2.1 × 100 mm; gradient eluent: contains 0.035% TFA/H containing 0.05% TFA2MeCN 2-98% of O; time: 0-15 minutes
Method E
Column: waters Acquity UPLC BEH C18, 1.7 μm, 2.1 × 30 mm; gradient eluent: containing 10mM (NH)4)2CO35-95% of MeCN/H2O; time: 0-3 minutes
Method F
Column: waters Acquity UPLC CSH C18, 1.7 μm, 2.1 × 50 mm; gradient eluent: contains 0.035% TFA/H containing 0.05% TFA2MeCN of 2-100% of O; time: 0-3 minutes
Method G
Column: waters Acquity UPLC BEH C18, 1.7 μm, 2.1 × 30 mm; gradient eluent: containing 10mM (NH)4)2CO35-95% of MeCN/H2O; time: 0-3 minutes
Method H
Column: waters Acquity UPLC BEH C18, 1.7 μm, 2.1 × 30 mm; gradient eluent: containing 10mM (NH)4)2CO35-95% of MeCN/H2O; time: 0-15 minutes
Method I
Column: waters Acquity UPLC BEH C18, 1.7 μm, 2.1 × 30 mm; gradient eluent: 5-95% MeCN/H with 0.1% HCOOH2O; time: 0-3 minutes
Preparative HPLC using ZQ Mass Spectroscopy and method A or Gilson PLC2020 and method B, C
Method A
Waters X-Select Prep-C18, 5 μm, 19X 50mm, using MeCN/H2O/0.1% HCOOH elution
Method B
Gemini NX-C18, 10 μm, 30X 250mm, using MeCN/0.035% TFA and H2Elution with a mixture of O/0.05% TFA
Method C
Gemini NX-C18, 10 μm, 50X 300mm using MeCN/H2Elution with a mixture of O/0.1% TFA
General scheme for amide coupling (scheme A)
A1-to a stirred solution of N-desmethyl-azithromycin (1 equivalent), the corresponding phosphonium acid (1.1 equivalent) and HATU (1.2 equivalent) in DCM (10mL) was added N, N-Diisopropylethylamine (DIEA) (2 equivalents). After stirring at room temperature for 16 to 20 hours, the reaction mixture was concentrated and the resulting residue was taken up in 7M NH3MeOH diluted and stirred for 16 to 20 hours more. The reaction mixture was then concentrated under reduced pressure and diluted with EtOAc. The organic phase is successively treated with saturated NaHCO3Aqueous solution, NH4Aqueous Cl and brine. Subjecting the organic matter to Na2SO4Drying and concentration under reduced pressure gives the crude product, which is purified by chromatography to give the desired final product.
A2-to a stirred solution of N-desmethyl-azithromycin (1 equivalent), the corresponding phosphonium acid (1.1 equivalent) and HATU (1.2 equivalent) in DCM (10mL) was added N, N-Diisopropylethylamine (DIEA) (2 equivalents). After stirring at room temperature for 16 to 20 hours, the reaction mixture was concentrated under reduced pressure and diluted with EtOAc. Saturated NaHCO for organic matter3Washing with aqueous solution over Na2SO4Dried and concentrated under reduced pressure. The resulting residue was diluted with MeOH, and the stirred solution was heated at 50 ℃ for 16 to 20 hours. After cooling, the reaction mixture was concentrated under reduced pressure and diluted with EtOAc. The organic phase is successively treated with saturated NaHCO3Aqueous solution, NH4Aqueous Cl and brine. Passing organic matter through Na2SO4Drying and concentration under reduced pressure gave the crude product, which was purified by chromatography. Passing organic matter through Na2SO4Drying and concentration under reduced pressure gives the crude product, which is purified by chromatography to give the desired final product.
General scheme for reductive amination (scheme D)
Step 1-to N-demethyl-azithromycin (1 equivalent), LG-L2a-CHO (wherein LG represents a leaving group; L2aOne carbon shorter than L2) (3.5 equivalents) and CH3To a stirred solution of COOH (10 equivalents) in DMF (10mL) was added NaBH3CN (2 whenAmount). The resulting mixture was heated at 75 ℃ for 90 minutes to 16 hours. After cooling, the reaction is taken off in H2O, saturated NaHCO3The aqueous solution was quenched and diluted with DCM. The aqueous layer was further extracted with DCM and the combined organics were extracted with saturated NaHCO3Aqueous solution and brine. Through Na2SO4After drying, the organics were passed through a phase separator and concentrated under reduced pressure to give the crude product, which was purified by chromatography and used in step 2.
Step 2-the purified product obtained in step 1 was dissolved in MeCN (10mL) and treated with the corresponding phosphine (3 equiv.) and NaI (3 equiv.). After heating at 70 ℃ to 85 ℃ for 16 to 20 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by chromatography to give the final desired product. As an adaptation, the reaction can be carried out under microwave conditions at 100 ℃ for 2 to 6 hours.
General scheme for the formation of phosphonium carboxylic acids (2)
Towards HOOC-L2-(L3-L4) To a solution of n-Br (1 eq) in MeCN (10mL) was added phosphine (3 eq). After heating at 60 ℃ for 16 to 20 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford the desired phosphonium carboxylic acid product.
The following abbreviations have been used throughout the description and examples: dichloromethane (DCM), Tetrahydrofuran (THF), Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 4-Dimethylaminopyridine (DMAP), N, N, Diisopropylethylamine (DIEA), trifluoroacetic acid (TFA), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1-hydroxy-7-azabenzotriazole (HOAT), O- (7-azabenzotriazol-1-yl) N, N, N ', N' -tetramethyluronium tetrafluoroborate (TATU), (1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide Hexafluorophosphate) (HATU).
Example 1- {14- [ (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -11- { [ (2S,3R,4S,6R) -4- (dimethylamino) -3-hydroxy-6-methyltetrahydropyran-2-yl ] oxy } -2-ethyl-3, 4, 10-trihydroxy-13- { [ (2R,4R,5S,6S) -5-hydroxy-4-methoxy-4, 6-dimethyltetrahydropyran-2-yl ] oxy } -3,5,8,10,12, 14-hexamethyl-15-oxo-1-oxa-6-azacyclopenta-6-yl ] -14-oxotetradecyl } triphenylphosphonium hexafluorophosphate (V )
Prepared according to amide coupling procedure A1 using (13-carboxytridecyl) triphenylphosphonium bromide. The title compound was isolated as a white solid.
LC-MS (method G)1206[ M]+(ii) a RT 2.09 min
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