阅读说明：本技术 含取代脒基结构的2,3-双加氧酶抑制剂及其制备方法和用途 (2,3-dioxygenase inhibitor containing substituted amidino structure and preparation method and application thereof ) 是由 董肖椿 夏志锋 刘唱 南艳阳 赵伟利 鞠佃文 于 2019-03-14 设计创作，主要内容包括：本发明属药物合成领域,涉及通式(Ⅰ)所示的含有取代脒基的1,2,5-噁二唑类化合物及其药学上可接受的盐,及其制备方法和在医学上的应用。本发明所述化合物、其立体异构体或其药学上可接受盐或其药物组合与抗CTLA-4抗体、抗PD-1抗体、抗PD-L1抗体,抗病毒剂、化疗剂、免疫抑制剂、辐射、抗肿瘤疫苗、抗病毒疫苗、细胞因子疗法或酪氨酸激酶抑制剂进行联合用药,调节吲哚胺2,3-双加氧酶活性,可用于治疗或预防癌症或肿瘤、病毒感染、抑郁症、神经变性病症、创伤、年龄相关白内障、器官移植排斥或自身免疫疾病。<Image he="402" wi="605" file="DDA0001994908410000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,<Image he="64" wi="700" file="DDA0001994908410000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>X＝NH或SR<Sub>1</Sub>＝CN或NO<Sub>2</Sub><Image he="116" wi="542" file="DDA0001994908410000013.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>。(The invention belongs to the field of drug synthesis, and relates to a 1,2, 5-oxadiazole compound containing substituted amidino group shown in a general formula (I)And pharmaceutically acceptable salts thereof, and a preparation method and medical application thereof. The compound, the stereoisomer or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof is combined with an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an antiviral agent, a chemotherapeutic agent, an immunosuppressant, radiation, an anti-tumor vaccine, an antiviral vaccine, cytokine therapy or a tyrosine kinase inhibitor to regulate the activity of indoleamine 2,3-dioxygenase, and can be used for treating or preventing cancers or tumors, viral infections, depression, neurodegenerative diseases, wounds, age-related cataract, organ transplant rejection or autoimmune diseases. Wherein the content of the first and second substances, x is NH or SR 1 CN or NO 2 。)

1. A2, 3-dioxygenase inhibitor containing a substituted amidino structure is characterized in that the inhibitor contains a substituted amidino 1,2, 5-oxadiazole compound with a structure in a general formula (I) and pharmaceutically acceptable salts thereof,

wherein the content of the first and second substances,

x is NH or S

R₁CN or NO₂

2. The 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1, wherein the 1,2, 5-oxadiazole compound of a substituted amidino structure is compound 1 of the following structure,

3. the 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1, wherein the 1,2, 5-oxadiazole compound of a substituted amidino structure is compound 2 of the following structure,

4. the 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1, wherein the 1,2, 5-oxadiazole compound of a substituted amidino structure is compound 3 of the following structure,

5. the 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1, wherein the 1,2, 5-oxadiazole compound of a substituted amidino structure is compound 4 of the following structure,

6. the 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1, wherein the 1,2, 5-oxadiazole compound of a substituted amidino structure is compound 5 of the following structure,

7. the 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1, wherein the 1,2, 5-oxadiazole compound of a substituted amidino structure is compound 6,

8. the 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1, wherein the 1,2, 5-oxadiazole compound of a substituted amidino structure is compound 7 of the following structure,

9. the 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1, wherein the 1,2, 5-oxadiazole compound of a substituted amidino structure is compound 8 of the following structure,

10. the 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1, wherein the 1,2, 5-oxadiazole compound of a substituted amidino structure is compound 9 of the following structure,

11. the 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1, wherein the 1,2, 5-oxadiazole compound of a substituted amidino structure is compound 10 of the following structure,

12. the 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1, wherein the 1,2, 5-oxadiazole compound of a substituted amidino structure is compound 11 of the following structure,

13. the 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1, wherein the 1,2, 5-oxadiazole compound of a substituted amidino structure is compound 12,

14. the process for preparing a 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1, which comprises preparing a compound represented by the following formula,

15. use of a 2,3-dioxygenase inhibitor containing a substituted amidino structure according to claim 1 for the preparation of a pharmaceutical composition for the prevention and/or treatment of diseases characterized by pathologies of the tryptophan metabolic pathway mediated by IDO.

16. The use according to claim 15, wherein the disease is cancer or a tumor, a viral infection, depression, a neurodegenerative disorder, trauma, age-related cataract, organ transplant rejection or an autoimmune disease.

17. The use according to claim 16, wherein said cancer or tumor is selected from the group consisting of lung cancer, bone cancer, stomach cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, rectal cancer, colon cancer, cancer of the anal region, breast cancer, and esophageal cancer.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (i) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is administered in combination with an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an antiviral agent, a chemotherapeutic agent, an immunosuppressive agent, radiation, an anti-tumor vaccine, an antiviral vaccine, cytokine therapy, or a tyrosine kinase inhibitor.

Technical Field

The invention belongs to the field of drug synthesis, relates to a 2,3-dioxygenase inhibitor, and particularly relates to a 2,3-dioxygenase inhibitor containing a substituted amidino structure, and a preparation method and application thereof.

Background

Disclosure of Invention

The invention aims to provide a novel IDO inhibitor based on the current state of the prior art, relates to a 2,3-dioxygenase inhibitor containing a substituted amidino structure, and particularly relates to a high-efficiency IDO enzyme inhibitor of 1,2, 5-oxadiazole compounds containing substituted amidino, and a preparation method and application thereof.

It is a further object of the present invention to provide a process for producing the above substituted amidino group-containing 1,2, 5-oxadiazole compound.

The inhibitor contains 1,2, 5-oxadiazole compounds of substituted amidino shown in a general formula (I) and pharmaceutically acceptable salts thereof,

wherein the content of the first and second substances,

x is NH or S

R₁CN or NO₂

In the present invention, preferred compounds have the following structures of compounds 1,2, 3, 4,5, 6, 7, 8, 9, 10, 11, and 12:

in the present invention, compound 3 is taken as an example, and the preparation process of the compound of the present invention is as follows:

the invention provides application of a compound for inhibiting IDO, wherein the compound is used for preparing a pharmaceutical composition for preventing and/or treating diseases with pathological characteristics of IDO mediated tryptophan metabolic pathway.

The compound can be added with pharmaceutically acceptable carriers to prepare common pharmaceutical preparations, such as tablets, capsules, powder, syrup, liquid, suspension injection and the like. The clinical administration mode of the compound of the invention can adopt oral administration, injection and the like.

In another aspect, the present invention provides a method of modulating indoleamine 2,3-dioxygenase activity comprising administering a therapeutically effective amount of a compound of the foregoing, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination with an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an antiviral agent, a chemotherapeutic agent, an immunosuppressive agent, radiation, an anti-tumor vaccine, an antiviral vaccine, cytokine therapy, or a tyrosine kinase inhibitor.

The medicament of the invention is used for treating or preventing cancer or tumor, virus infection, depression, neurodegenerative disease, trauma, age-related cataract, organ transplant rejection or autoimmune disease; preferably, wherein the cancer or tumor is selected from lung cancer, bone cancer, stomach cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, rectal cancer, colon cancer, cancer of the anal region, breast cancer, esophageal cancer, and the like.

Drawings

FIG. 1 shows that Compound 3 of the present invention has a good in vivo inhibitory activity against Lewis lung cancer and a strong in vivo antitumor activity at a dose of 100mg/kg (bid, ig).

Detailed Description