阅读说明：本技术 核苷抗代谢物的伊班膦酸盐缀合物 (Ibandronate conjugates of nucleoside antimetabolites ) 是由 A·卡佩斯基 S·金宁 于 2018-01-05 设计创作，主要内容包括：本申请提供了核苷抗代谢物及其类似物与伊班膦酸盐的缀合物、包含一种或多种所述缀合物的药物组合物、其合成方法以及使用其治疗疾病和/或病症的方法。(Provided herein are conjugates of nucleoside antimetabolites and analogs thereof with ibandronate, pharmaceutical compositions comprising one or more of the conjugates, methods of synthesizing the same, and methods of treating diseases and/or disorders using the same.)

1. A compound, or a pharmaceutically acceptable acid addition salt thereof, said compound comprising:

wherein X is an anticancer compound and Y is selected from the group consisting of H, alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

2. The compound of claim 1, wherein X is a nucleoside antimetabolite having the structure:

wherein

B is a natural or modified nucleic acid base,

r4 ═ H, and

r2 and R3 are independently selected from H, OH, F and Cl.

3. The compound of claim 1, wherein X is a nucleoside antimetabolite having the structure:

B is a natural or modified nucleobase, and

r2 and R3 are independently selected from H, OH, F and Cl.

4. A compound, or a pharmaceutically acceptable acid addition salt thereof, said compound comprising:

wherein X is an anticancer compound and Y is selected from the group consisting of H, alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

5. The compound of claim 4, wherein X is a nucleoside antimetabolite having the structure:

B is a natural or modified nucleic acid base,

r2 and R3 are independently selected from H, OH, F and Cl.

6. The compound of any one of claims 1 to 5, wherein X is selected from cytarabine, gemcitabine, clofarabine, cladribine, Vidamia (vidaza), dake, fludarabine, floxuridine, nelarabine, and pentostatin.

7. A pharmaceutical composition comprising a compound of any one of claims 1-6 and a pharmaceutically acceptable carrier or diluent.

8. A method of treating a bone disease caused by cancer or a primary bone cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 6 or a pharmaceutical composition comprising a compound of any one of claims 1 to 6.

9. A method of delivering a nucleoside antimetabolite to bone or surrounding tissue comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 6 or a pharmaceutical composition comprising a compound of any one of claims 1 to 6.

10. A method of preventing bone metastasis, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 6 or a pharmaceutical composition comprising a compound of any one of claims 1 to 6.

11. A method of treating a bone disease caused by cancer or a primary bone cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 6 or a pharmaceutical composition comprising a compound of any one of claims 1 to 6.

12. The method of claim 11, wherein the compound is administered in combination with one or more therapeutic agents.

13. The method of claim 11, wherein the compound or the pharmaceutical composition is administered subcutaneously, intravenously, intradermally, intramuscularly, intranasally, or orally.

14. A method of treating or ameliorating at least one symptom of, or reducing the frequency or severity of at least one symptom of a bone cancer or a bone disease caused by cancer, comprising administering to a subject in need thereof a compound of any one of claims 1 to 6 or a pharmaceutical composition comprising a compound of any one of claims 1 to 6.

15. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for use in the treatment or amelioration of at least one symptom of a bone disease caused by a bone cancer or cancer, or a reduction in the frequency or severity of at least one symptom of a bone disease caused by a bone cancer or cancer, wherein the improvement or severity of a bone disease caused by a bone cancer or cancer is reduced, or pain associated with a bone disease caused by a bone cancer or cancer is prevented, ameliorated or reduced in severity.

16. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the manufacture of a medicament for treating or ameliorating at least one symptom of a bone cancer or bone disease caused by cancer, or for reducing the frequency or severity of at least one symptom of a bone cancer or bone disease caused by cancer, wherein the bone cancer or bone disease caused by cancer is ameliorated or reduced in severity, or pain associated with the bone cancer or bone disease caused by cancer is prevented, ameliorated or reduced in severity.

17. A method of synthesizing a nucleoside antimetabolite-ibandronate conjugate, the method comprising reacting nucleoside-5 ' -phosphate ester or nucleoside-2 ' -or 3' -phosphate ester with trifluoroacetic anhydride in the presence of a tertiary amine base in an organic solvent, followed by addition of a nucleophilic catalyst, followed by addition of ibandronate, followed by addition of water, and purification by ion exchange or reverse phase chromatography.

18. The method of claim 17, wherein the tertiary amine is selected from triethylamine, dimethylaniline, and pyridine.

19. The method of claim 17, wherein the nucleophilic catalyst is selected from the group consisting of dimethylaminopyridine and N-methylimidazole.

20. The method of claim 17, wherein the organic solvent is selected from the group consisting of acetonitrile, pyridine, dimethylformamide, and dimethylacetamide.

Technical Field

Provided herein are compounds and methods of using them that relate to the fields of chemistry, biochemistry, and medicine. More specifically, disclosed herein are conjugates of nucleoside antimetabolites and analogs thereof with ibandronate, pharmaceutical compositions comprising one or more of the conjugates, methods of synthesizing the same, and methods of treating diseases and/or disorders using the same.

Background

The active compounds are typically delivered to a patient in need thereof by systemic administration (e.g., via intravenous or oral routes). While drugs are only needed in specific areas of the body, such systemic delivery also exposes healthy cells and tissues to the drugs. As a result, the drug may adversely affect healthy cells and tissues, and significantly higher concentrations of the drug are required to deliver pharmacologically relevant amounts to the site in need of treatment.

The compositions and methods provided herein solve this and other problems in the art.

Summary of The Invention

Provided herein are compounds, compositions comprising those compounds, methods of making those compounds, and methods of using those compounds.

One aspect relates to a compound of formula I or a pharmaceutically acceptable salt thereof.

Another aspect relates to a compound of formula II or a pharmaceutically acceptable salt thereof.

Further disclosed herein are methods of synthesizing the compounds of formula I and II.

Further disclosed herein are methods of delivering nucleoside antimetabolites and analogs thereof to bone by conjugating the compounds to ibandronate.

Also disclosed herein are pharmaceutical compositions comprising one or more compounds of formula I and/or II, one or more pharmaceutically acceptable carriers, diluents, excipients, or a combination thereof.

Some aspects of the methods disclosed herein relate to treating a disease and/or ameliorating the symptoms of a disease, including but not limited to cancer, bone disease caused by cancer, primary bone cancer, bone metastasis and pain, by administering to a patient in need thereof a therapeutically effective amount of one or more compounds of formula I and/or II or a pharmaceutical composition comprising the compounds. These compounds can be used for the manufacture of medicaments for the treatment of said diseases. These compounds are useful in the treatment of a variety of diseases.

Brief Description of Drawings

FIG. 1 provides a Kaplan-Meier survival curve: a mouse model with mouse breast cancer treated with saline, gemcitabine-ibandronate conjugate (GEM-IB), or gemcitabine-etidronate conjugate (GEM-ET).

Figure 2 shows an image analysis of a model of bone disease caused by prostate cancer untreated (saline) or treated with gemcitabine-ibandronate (2mg/kg, five days per week).

FIG. 3 shows metastasis in a mouse model of prostate cancer-induced bone disease.

Mice were treated with saline or an equimolar dose of ibandronate (Iband), gemcitabine (Gem), gemcitabine-etidronate conjugate (Gem-Eti), or gemcitabine-ibandronate conjugate 5 (Gem-Ibad).

Examples