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CN-116583303-B - Tripterine conjugates and uses thereof

CN116583303BCN 116583303 BCN116583303 BCN 116583303BCN-116583303-B

Abstract

The present disclosure provides triptolide conjugates, methods of preparing such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat conditions/diseases, such as those associated with cancer, immunomodulation, and/or inflammation.

Inventors

  • HOU SHUJIE
  • XUE JIAN
  • ZHAO YUSHAN
  • MIAO DEZU

Assignees

  • 瑞阳公司
  • 瑞阳（上海）新药研发有限公司

Dates

Publication Date
20260512
Application Date
20210820
Priority Date
20200821

Claims (15)

  1. 1. A compound of formula I, or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, (I) Wherein the method comprises the steps of Each m 1 、m 2 、n 1 、n 2 is independently 0, 1, 2,3, or 4; R 1 、R 2 and R 3 are each independently OH, H or halo; M 1 is selected from the group consisting of bond, -C=O-, -NH (CO) -, - (CO) NH-, and-CH 2 O-; m 2 is C; X 1 、X 2 、X 3 、X 4 and X 5 are each independently a bond 、C=O、S-S、NH(CO)、(CO)NH、L 2 -NH(CO)、NH(CO)-L 2 、(CO)NH-L 2 -NH(CO)、L 2 -O、O-L 2 or unsubstituted C 1 -C 10 alkylene; Each L 2 is independently an unsubstituted C 1 -C 10 alkylene; And X 5 is attached to any of R 4 、R 5 、R 6 、R 7 and R 8 , and the remaining R 4 、R 5 、R 6 、R 7 and R 8 not attached to X 5 are each independently H, OH, O (CO) NH 2 , halo, NH (C 1 -C 10 acyl), or unsubstituted O (C 1 -C 10 alkyl).
  2. 2. The compound of claim 1, or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 and R 3 are each H.
  3. 3. The compound of claim 1, or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, wherein M 1 is-c=o-, -NH (CO) -or- (CO) NH-, and M 2 is C.
  4. 4. The compound of claim 1, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, wherein X 1 is a bond, and X 2 is NH (CO) or (CO) NH.
  5. 5. The compound of claim 1, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, wherein X 3 is O, X 4 is (CO) NH-L 2 -NH (CO), and X 5 is NH (CO) -L 2 、L 2 -(CO)NH、L 2 -O or O-L 2 .
  6. 6. The compound of claim 1, or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, wherein X 5 is attached to R 4 , and R 5 、R 6 、R 7 and R 8 are each independently OH or NH (C 1 -C 10 acyl).
  7. 7. The compound of claim 1, or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, wherein X 5 is attached to R 5 , and R 4 、R 6 、R 7 and R 8 are each independently OH or NH (C 1 -C 10 acyl).
  8. 8. The compound of claim 1, or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, wherein X 5 is attached to R 8 , and R 4 、R 5 、R 6 and R 7 are each independently OH or NH (C 1 -C 10 acyl).
  9. 9. A compound having a structure selected from any one of the following structures: 、 、 、 And , Or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof.
  10. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  11. 11. Use of a compound according to any one of claims 1 to 9, or an enantiomer, diastereomer or pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition in a subject in need thereof, wherein the disease or condition is (i) cancer selected from hepatocellular carcinoma, lung cancer, breast cancer, pancreatic cancer, biliary tract cancer, colorectal cancer and glioblastoma, or (ii) an inflammatory and/or autoimmune disease selected from membranous nephropathy, lupus nephritis, systemic lupus erythematosus, renal fibrosis, inflammatory bowel disease, crohn's disease, intestinal fibrosis, liver fibrosis, asthma, acute lung injury, pulmonary arterial hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis and psoriasis.
  12. 12. The use of claim 11, wherein the disease or disorder is a cancer selected from the group consisting of hepatocellular carcinoma, lung cancer, breast cancer, pancreatic cancer, biliary tract cancer, colorectal cancer, and glioblastoma.
  13. 13. The use according to claim 11, wherein the disease or disorder is associated with an inflammatory and/or autoimmune disease selected from membranous nephropathy, lupus nephritis, systemic lupus erythematosus, renal fibrosis, inflammatory bowel disease, crohn's disease, intestinal fibrosis, liver fibrosis, asthma, acute lung injury, pulmonary hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis and psoriasis.
  14. 14. Use of a pharmaceutical composition according to claim 10 in the manufacture of a medicament for the treatment of cancer selected from the group consisting of hepatocellular carcinoma, lung cancer, breast cancer, pancreatic cancer, biliary tract cancer, colorectal cancer and glioblastoma.
  15. 15. Use of a pharmaceutical composition according to claim 10 in the manufacture of a medicament for the treatment of inflammatory and/or autoimmune diseases selected from membranous nephropathy, lupus nephritis, systemic lupus erythematosus, renal fibrosis, inflammatory bowel disease, crohn's disease, intestinal fibrosis, liver fibrosis, asthma, acute lung injury, pulmonary arterial hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis and psoriasis.

Description

Tripterine conjugates and uses thereof RELATED APPLICATIONS The present application claims priority from U.S. provisional application No. 63/068,898, filed 8/21 in 2020, the entire contents of which are incorporated herein by reference. Background Triptolide, a bioactive compound isolated from the plant of tripterygium wilfordii (Tripterygium wilfordii Hook F), is widely used in traditional Chinese medicine for the treatment of diseases or conditions associated with immunomodulation and anti-inflammatory. Triptolide has attracted research attention in recent decades due to its potential therapeutic applications in immunosuppression, anti-inflammatory, cancer therapy, neuroprotection, and the like. [ Ji Yaai S. (Ziaei S.), the immunosuppressive, anti-inflammatory and anti-cancer properties of triptolide, harabi R. (Halaby R.), micro-reviewed (Immunosuppressive, anti-inflammatory and anti-cancer properties of triptolide: A mini review.) Abamer journal of plant medicine (Avicenna, J.Phytomed.) 2016,6 (2), 149-64; the use and mechanism of triptolide in the treatment of inflammatory diseases, such as (yun k), li x (Li x), lu q (Lu q) et al-Application AND MECHANISMS of triptolide IN THE TREATMENT of inflammatory Diseases-a review (Application) pharmacological front (front. Pharmacol) 2019,10,1469; noolp (Noel p), hough d.d. (Von Hoff d.d.), sal Lu Ga a.k (Saluja a.k.), et al (Trends) in the pharmacology of triptolide and its derivatives (Triptolide AND ITS DERIVATIVES AS CANCER therapeutics) 2019,40 (5), 327-41; tongue B (Zhang B), song c (Song c), von B (Feng B), w (Fan w) triptolide as a cancer therapy by inhibiting NF- κb/PUMA signal reperfusion injury in rats and (man) in the neuronal management of (34824) is provided However, there are several drawbacks associated with the use of triptolide that limit preclinical development and clinical application, including poor aqueous solubility, narrow therapeutic index, and very short in vivo half-life. [ patulin S. (Patil S.), lis L.G. (List L.G.), shu Mahe R.J. (Schumacher R.J.) et al, phosphonooxymethyl prodrug of triptolide, synthesis of human colon and ovarian cancer xenografts, Physicochemical characterization and efficacy (Phosphonooxymethyl Prodrug of Triptolide:Synthesis,Physicochemical Characterization,and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts.) journal of pharmaceutical chemistry (j.med.chem.) 2015,58,9334-44; and Zhao y. (Zhao y.), seedling d. (Miao d.), day (Hou s.), composition of schisandra extract and its method (Compositions of Schisandra Extracts and Methods. Of.) WO2018/200143A2,2018 to solve the problem of poor water solubility of triptolide, several precursors of carboxy groups [ d. (Dai, d.), yuan h. (Yuan, h.), math j.h. (Musser, j.h.)) preparation of triptolide prodrugs with high water solubility (Preparation of triptolide prodrugs HAVING HIGH aqueous resolution.)) WO 02070472,2002] have been developed in the following chemical section Synthesis of a high water solubility triptolide prodrug for use in immunosuppression and anti-inflammatory therapy (Synthesis of triptolide prodrugs having high aqueous solubility for immunosuppressive and anti-inflammatory treatment.)WO 0012483,2000]、 phosphonooxymethyl ester [ Georg E.G., petri S.P., sa Lu Ga A.K., cuger R. (Chugh R.), vickers S.M. (Vickers S.M.) triptolide prodrug (Triptolide Prodrugs) WO2010129918A1,2010] hydroquinone derived from carboxylate [ Peng Z. (Peng Z.)), liu M. (Liu M.)), du Q (Du Q.) (Yang Y.) (Song W.), preparation of water-soluble triptolide derivatives useful as anticancer agents (Preparation of water-soluble triptolide derivatives useful as anticancer agents.)CN 110003304 A,2019]、 polyethylene glycol [ Lin Y (Lin Y), yellow x (Huang x), and severe d (yan.d.) water-soluble triptolide prodrugs using polyethylene glycol as a carrier Methods of preparation and use thereof (A water-soluble triptolide prodrug using polyethylene glycol as carrier,its preparation method and application.)CN 104629036 A,2015] or carboxylated chitosan [ once h. (Zeng h.), zhang z. (Zhang z.), yan m.). Et al, methods of preparation of triptolide-carboxylated chitosan conjugates and use thereof (Preparation method and application of triptolide-carboxylated chitosan conjugate in preparing drug for treating rheumatic arthritis,cancer and Alzheimer'sdisease.)CN 109464675 A,2019.] in the preparation of a medicament for the treatment of rheumatoid arthritis, cancer and alzheimer's disease, the aqueous solubility of these prodrugs is better, however, the therapeutic index and/or half-life is not significantly altered compared to triptolide due to the lack of targeting of the prodrug and rapid release of triptolide in the blood. In order to increase therapeutic targeting for cancer treatment, triptolide was recently delivered with glucose that would allow transport through tumors that overexpress glucose transporter [ what q. (He q.), mi En l. (Minn l.), wang q. (Wang q.