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US-12617805-B2 - Codrug that disintegrates in intestine, preparation therefor, and use thereof

US12617805B2US 12617805 B2US12617805 B2US 12617805B2US-12617805-B2

Abstract

The present invention relates to a codrug that cleaved in the gut, preparation therefor, and a use thereof. Specifically, provided is a codrug compound in formula I. Also provided are a method of using the present compound for the treatment of gastrointestinal tract autoimmune diseases, inflammatory diseases, and cancers, as well as a method and an intermediate for preparing the present compound.

Inventors

  • Jianyong Shou
  • XIANG AO
  • Lei Jiang
  • Shengyang LIU
  • XUDONG MAO
  • Zhi Qiao
  • Xiaoping Xie
  • Jianhua Zhang

Assignees

  • ENNOVABIO (ZHEJIANG) PHARMACEUTICALS CO., LTD.
  • SHANGHAI ENNOVABIO PHARMACEUTICALS CO., LTD.

Dates

Publication Date
20260505
Application Date
20210719
Priority Date
20200717

Claims (14)

  1. 1 . A codrug compound of formula I, wherein the codrug compound is formed by coupling the first drug molecule, the second drug molecule and a linker precursor: D 1 -linker-D 2 ; I wherein, D 1 is a first drug group; and the first drug group is a structural fragment in the first drug molecule which can be connected to the linker, and the first drug group is a berberine analog of formula II, formula III, or formula IV: wherein Ro, Rp, Rq, Rr, Rs and Rt are each independently selected from the group consisting of H, substituted or unsubstituted C 1 -C 4 alkyl, and substituted or unsubstituted C 1 -C 4 alkoxy; or two of Ro, Rp, Rq, Rr, Rs and Rt on two adjacent atoms together with the atoms to which they are attached form a 5-7 membered heterocyclic ring; wherein substituted means that one or more hydrogen atoms of the group is independently replaced by a substituent selected from the group consisting of halogen, C 1 -C 4 alkyl and phenyl; D 2 is a second drug group; and the second drug group is a structural fragment in the second drug molecule which can be connected to the linker, wherein the second drug molecule is a JAK family inhibitor selected from the group consisting of Tofacitinib, Ruxolitinib, Oclacitinib, Baricitinib, Peficitinib, Abrocitinib, Filgotinib, Upadacitinib, Delgocitinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, AZD-4205, ASN-002, BMS-986165, PF-06700841, PF-06651600, R-348, INCB-52793, ATI-501, ATI-502, NS-018, KL-130008, and deuterated derivatives of any of the foregoing, or the second drug molecule is selected from the group consisting of: and the linker has a structure of (a), (b), or (c), wherein in each formula, J 1 connects to the first drug group, and J 2 connects to the second drug group; Glu has a structure selected from the group consisting of: wherein the A ring is selected from the group consisting of C 6 -C 10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclic group; wherein, R 4 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyoxy-C 1-4 alkylene-C 3-12 cycloalkyl, and C 3-12 cycloalkyl-C 1-4 alkylene-; wherein the B-ring and C-ring are independently selected from the group consisting of C 6 -C 10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclic group; in the above formulas (a), (b) and (c), J 1 and J 2 are each independently —(Y) z —, and each Y is selected from the group consisting of —NH—, —C(O)—, —CH═CH—, —NH(CH 2 )—, —NHC(O)—, —CH 2 —, —OCH 2 CH 2 O—, —O—, —S—, —P(O) 2 O—, —S(O) 2 —, —S(O)—, —C(O)NH—, and —N═N—; and each Y can independently be substituted by one or more R, with the proviso that the combination of each Y forms a chemically stable structure; each L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is independently selected from the group consisting of C 1 -C 8 alkylene, C 1-6 alkylene-O—C 1-4 alkylene (—CH 2 —O—CH 2 —), C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6 -C 10 arylidene, 5-10 membered heteroarylidene, 3-12 membered heterocyclylene group, —NH—, —C(O)—, —CH═CH—, —NH(CH 2 )—, —NHC(O)—, —CH 2 —, —OCH 2 CH 2 O—, —O—, —S—, —P(O) 2 O—, —S(O) 2 —, —S(O)—, —C(O)NH—, —N═N—, and —C(O)NH(CH 2 )(1-4)-NHC(O)—; with the proviso that the combination of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 forms a stable divalent structure; each Y, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is independently optionally substituted by one or more R, wherein each R is independently selected from the group consisting of —OH, C 1 -C 4 alkyl, halogen, cyano, nitro, —OR 4 , C 1-6 haloalkyl, sulfonate group, formyl, carboxyl, and —COOR 4 ; with the proviso that each Y, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 together form a chemically stable structure; m, n, p, q, r, s and t are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; and z is 0, 1, 2, 3, 4, 5 or 6.
  2. 2 . The codrug compound of claim 1 , wherein the second drug molecule is Tofacitinib, Ruxolitinib, Oclacitinib, Baricitinib, Peficitinib, Abrocitinib, Filgotinib, Upadacitinib, Delgocitinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, AZD-4205, ASN-002, BMS-986165, PF-06700841, PF-06651600, R-348, INCB-52793, ATI-501, ATI-502, NS-018, KL-130008, or a deuterated derivative of any of the foregoing.
  3. 3 . The codrug compound of claim 1 , wherein the first drug group is selected from the group consisting of: or the first drug group is a group formed by losing one hydrogen atom in a drug molecular selected from the group consisting of:
  4. 4 . The codrug compound of claim 1 , wherein the first drug group has the structure shown in the following formula:
  5. 5 . The codrug compound of claim 1 , wherein the second drug group is selected from the group consisting of:
  6. 6 . The codrug compound of claim 1 , wherein the second drug group is selected from the group consisting of:
  7. 7 . The codrug compound of claim 1 , wherein the linker is selected group (A), (B), or (C): Group (A) has a structure of -L a -L-, where L a has a structure selected from the group consisting of: and L has the structure shown below, wherein * is the connection site of L to L a : Group (B): Group (C):
  8. 8 . The compound of formula I according to claim 1 , wherein the compound is selected from the following group: No. Structure 1 2 3 4A 4B 5 6 7 8 9 10 11 12 13 14 15 16 17 18
  9. 9 . A pharmaceutical composition, comprising a therapeutically effective amount of a compound of claim 1 , or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
  10. 10 . The pharmaceutical composition of claim 9 , wherein the pharmaceutical composition is an enteric-coated preparation.
  11. 11 . A method of treating a disease, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 9 to a subject in need thereof, wherein the disease is selected from the group consisting of: gastrointestinal inflammatory diseases, gastroenteritis caused by radiotherapy or chemotherapy, gastrointestinal autoimmune diseases, peptic ulcer, irritable bowel syndrome, gastric cancer, esophageal cancer, and colon cancer.
  12. 12 . A method of treating a gastrointestinal functional disorder comprising administering to a subject in need thereof a codrug compound or a pharmaceutically acceptable salt thereof according to claim 1 , or a pharmaceutical composition of claim 9 , wherein the gastrointestinal functional disorder is gastrointestinal inflammatory disease.
  13. 13 . The method of claim 12 , wherein the gastrointestinal functional disorder is selected from the group consisting of ulcerative colitis, Crohn's disease, and colitis associated with immune checkpoint inhibitor therapy.
  14. 14 . The method of claim 11 , wherein the disease is selected from the group consisting of: ulcerative colon inflammation, Crohn's disease, colitis associated with immune checkpoint inhibitor therapy, collagenous colitis, lymphocytic colitis, pouchitis, acute/chronic gastritis, acute/chronic appendicitis, graft-versus-host disease, celiac sprue, and autoimmune bowel disease.

Description

FIELD OF THE INVENTION The invention relates to a codrug compound that is cleaved in gut. The invention also relates to pharmaceutical compositions comprising such compounds; methods of using such compounds for treating gastrointestinal autoimmune diseases, inflammatory diseases and cancers; and methods and intermediates for the preparation of such compounds. BACKGROUND OF THE INVENTION JAK family (JAK1, JAK2, JAK3 and TYK2) inhibitors such as tofacitinib have been approved for the treatment of certain patients suffering from moderate to severe active rheumatoid arthritis (RA) and moderate to severe ulcerative colitis (UC). In many clinical trials of JAK family inhibitors, a large number of adverse events mediated by systemic drug exposure have been reported, including severe infections, opportunistic infections, and laboratory abnormalities, such as lymphopenia, neutropenia, elevated liver enzymes, elevated lipid and elevated serum creatinine. All of JAK inhibitors currently approved in the market carry black-box warnings of safety risks such as serious infections, malignancies, and thrombosis. Therefore, development of next generation of safer JAK family inhibitor drugs may require limiting their systemic exposure in the treatment of local inflammatory diseases. For example, increasing the distribution of the JAK family inhibitors in the gastrointestinal tract, while minimizing the systemic exposure of drugs in the treatment of UC. Berberine, also known as berberinum, is an isoquinoline alkaloid extracted from plants such as Coptis chinensis. Berberine is well documented and has been used in the traditional Chinese medicine for more than a thousand years. It is of low bioavailability. Berberine is mainly used in the treatment of gastrointestinal diseases in clinical practice, such as diarrhea and intestinal infection. Studies in recent years have also found certain therapeutic potential of berberine for cardiovascular diseases, as well as glucose and lipid metabolism regulation. Berberrubine is the major in vivo metabolite of berberine. Studies in animal models have shown that berberrubine have similar therapeutic effects to berberine in ulcerative colitis. However, up to date, there has been no effective way to improve the therapeutic effect of berberine or its analogs in the art. Inflammation bowel disease (IBD) mainly includes ulcerative colitis and Crohn's disease. These chronic intestinal inflammatory diseases have long-term disease course, recurrent attacks, and excessive chronic inflammation which may raise the risk of cancers. The incidence rate of IBD has been on the rise in recent years. It is currently believed that the pathogenesis of IBD may relate to genetic, environmental, immunity, and microorganisms, but the exact etiology has not been fully understood. Current clinical treatment mainly involves the use of salicylic acid derivatives, adrenal glucocorticoids and immunosuppressants, all of which have certain adverse effects such as gastrointestinal discomfort and anaphylaxes. Our previous work has shown that the combination of JAK inhibitors and berberine analogs can achieve synergistic effects and lead to better treatment for gastrointestinal inflammatory diseases. In the present invention, a codrug compound linking berberine analog and JAK inhibitor is designed, it will be cleaved into two effective molecules in intestine and enrich within gastrointestinal tract, while reducing the systemic exposure in the whole body to achieve a better safety profile. The synergistic effects of the two drug molecules would provide better therapeutic effects. SUMMARY OF THE INVENTION In one aspect, the present invention provides a codrug which is formed by a berberine analog as a first therapeutic agent (preferably Berberrubine) linked to a JAK family inhibitor (preferably Tofacitinib, Upadacitinib, SHR0302) as a second therapeutic agent, via a covalent linkage which can be cleaved. The codrug is designed to release the JAK family inhibitor and the first therapeutic agent in the gastrointestinal tract, thereby increasing the content of JAK family inhibitor and the first therapeutic agent in the inflammation site of gastrointestinal tract, and minimize the systemic exposure in the whole body. In the first aspect of the present invention, a codrug compound shown in the formula I is provided. The codrug compound is formed by the first drug molecule, the second drug molecule and a linker precursor: D1-linker-D2;  I wherein, D1 is the first drug group; and the first drug group is a structural fragment in the first drug molecule which can be connected to the linker (i.e., the fragment of the first drug molecule can be attached to the linker through coupling or condensing reactions with the linker precursor, and the linker moiety is not included this fragment);D2 is the second drug group; and the second drug group is the structural fragment in the second drug molecule which can be connected to the linker (i.e.,