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CN-121987633-A - Heterocyclic compounds and their use in complexes with pharmaceutically acceptable acids

CN121987633ACN 121987633 ACN121987633 ACN 121987633ACN-121987633-A

Abstract

The present invention provides for the use of heterocyclic compounds and complexes thereof with pharmaceutically acceptable acids. In particular to application of a compound shown in a formula I-3B or a compound thereof in preparing a medicament for treating and/or preventing inflammatory bowel disease, wherein the compound is a compound formed by the compound shown in the formula I-3B and pharmaceutically acceptable acid. The compound shown in the formula I-3B or the compound thereof provided by the invention can obviously improve IBD symptoms and tissue injury, and has good safety; 。

Inventors

  • ZHANG XUEJUN
  • LIU LIFEI
  • AN DAN
  • YIN SHANSHAN
  • ZHOU YUAN
  • TONG ZEXIN
  • LI QUN
  • Zong qiao

Assignees

  • 湖北生物医药产业技术研究院有限公司

Dates

Publication Date
20260508
Application Date
20251107
Priority Date
20241107

Claims (10)

  1. 1. Use of a compound of formula I-3B or a complex thereof for the manufacture of a medicament for the treatment and/or prophylaxis of inflammatory bowel disease; ; Wherein, the The compound is a compound formed by a compound shown in a formula I-3B and pharmaceutically acceptable acid; the inflammatory bowel disease is Crohn's disease or ulcerative colitis, wherein the Crohn's disease is selected from one or more of ileal colitis, ileitis, gastroduodenal type Crohn's disease, jejunum ileitis and Crohn's disease granulomatous colitis; ulcerative colitis is selected from one or more of ulcerative proctitis, ulcerative proctositis, left-handed colitis, and complete colitis.
  2. 2. Use according to claim 1, characterized in that it fulfils one or more of the following conditions: (1) The pharmaceutically acceptable acid is hydrochloric acid, phosphoric acid, fumaric acid, tartaric acid, malic acid, ethanedisulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid or oxalic acid, preferably fumaric acid; and (2) the compound represented by the formula I-3B or a complex thereof is amorphous or a crystal form thereof.
  3. 3. Use according to claim 1, characterized in that it fulfils one or more of the following conditions: (1) The inflammatory bowel disease is an inflammatory bowel disease suffered by teenagers, young and middle-aged people or the elderly; (2) The Crohn's disease is a disease having one or more of the terminal ileum, colon, lesions involving both the terminal ileum and colon and upper digestive tract, preferably colon or involving both terminal ileum and colon; (3) The Crohn's disease has lesions behaviors of non-stenotic, non-penetrating, stenotic, penetrating, or perianal lesions; (4) The Crohn's disease is acute or non-acute Crohn's disease, e.g., acute Crohn's disease, further e.g., TNBS-induced acute Crohn's disease; (5) The ulcerative colitis is ulcerative colitis of the rectal, left-half colon, wide colon or ileal colon type, preferably ulcerative colitis of the left-half colon, wide colon or ileal colon type; (6) The ulcerative colitis is acute or non-acute ulcerative colitis, for example acute ulcerative colitis, further for example DSS-induced acute ulcerative colitis; and (7) the inflammatory bowel disease is a high-expression inflammatory bowel disease of interleukin-6, tumor necrosis factor-alpha, chemokine-2, and interferon-gamma.
  4. 4. Use according to claim 1, characterized in that it fulfils one or more of the following conditions: (1) The medicine further comprises pharmaceutical excipients; (2) In the medicine, the content of the compound shown in the formula I-3B or the compound thereof is 0.01% -90%, preferably 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%, wherein the percentage is the mass ratio of the compound shown in the formula I-3B or the compound thereof to the medicine; (3) The medicament is administered by stomach administration or by enema, for example, orally; (4) The single administration dosage of the medicine is 0.1mg-40mg based on the mass of the compound shown in the formula I-3B or the compound thereof; (5) The medicament is administered in a long-period administration or a short-period administration, for example, a long-period administration; and (6) the frequency of administration of the drug is 1-3 times/0.5-2 days, preferably 1 time/day.
  5. 5. The use according to claim 1, wherein the compound is a compound of formula I-3B and fumaric acid compound, the molar ratio of fumaric acid to compound of formula I-3B is 1:1, preferably the compound of formula I-3B and fumaric acid compound are co-crystals.
  6. 6. Use according to claim 1, characterized in that it fulfils one or more of the following conditions: the compound is a crystal form of a fumaric acid compound shown in a formula I-3B, and an X-ray powder diffraction pattern expressed by a2 theta angle by using Cu-K alpha radiation has diffraction peaks at 20.5+/-0.2 o, 15.9+/-0.2 o, 26.6+/-0.2 o, 18.9+/-0.2 o and 22.5+/-0.2 o; Preferably, the molar ratio of the compound of formula I-3B to fumaric acid is 1:1; Further preferably, the compound fumaric acid compound shown in the formula I-3B is in a crystal form of a compound fumaric acid eutectic shown in the formula I-3B.
  7. 7. Use according to claim 6, characterized in that it fulfils one or more of the following conditions: (1) The crystal form of the fumaric acid compound shown in the formula I-3B also has diffraction peaks at one or more of 22.3+/-0.2 o, 26.4+/-0.2 o, 10.8+/-0.2 o, 17.4+/-0.2 o and 17.5+/-0.2 o in an X-ray powder diffraction pattern expressed in terms of a 2 theta angle by using Cu-K alpha radiation; Preferably, the crystalline form of the fumaric acid complex of the compound of formula I-3B has an X-ray powder diffraction pattern expressed in terms of 2 theta using Cu-K alpha radiation with diffraction peaks at 20.5.+ -. 0.2, 15.9.+ -. 0.2, 26.6.+ -. 0.2, 18.9.+ -. 0.2, 22.5.+ -. 0.2, 22.3.+ -. 0.2 and 26.4.+ -. 0.2; further preferably, the crystalline form of the fumaric acid complex of the compound of formula I-3B has a diffraction peak at 20.5.+ -. 0.2o, 15.9.+ -. 0.2o, 26.6.+ -. 0.2o, 18.9.+ -. 0.2o, 22.5.+ -. 0.2o, 22.3.+ -. 0.2o, 26.4.+ -. 0.2o, 10.8.+ -. 0.2o, 17.4.+ -. 0.2o and 17.5.+ -. 0.2o using Cu-K alpha radiation in X-ray powder diffraction pattern expressed in terms of 2 theta angle; for example, the crystalline form of the fumaric acid complex of the compound of formula I-3B, which uses Cu-K alpha radiation, has an X-ray powder diffraction pattern expressed in terms of 2 theta angles with diffraction peaks as shown in the following table: ; ; Further for example, the crystalline form of the fumaric acid complex of the compound of formula I-3B, using Cu-K alpha radiation, has an X-ray powder diffraction pattern substantially as shown in FIG. 2; (2) The differential scanning calorimetric curve of the crystal form of the fumaric acid compound shown as the formula I-3B has a starting point of an endothermic peak at 165.2+/-3 ℃ and/or reaches the peak value of the endothermic peak at 167.2 +/-3 ℃; for example, the differential scanning calorimetry curve of the crystalline form of the fumaric acid complex of the compound of formula I-3B is substantially as shown in figure 3; (3) The thermogravimetric analysis curve of the crystalline form of the fumaric acid complex of the compound of formula I-3B loses weight by about 0.36% in the temperature range of 26.2+ -3 ℃ to 120+ -3 ℃; For example, the thermogravimetric analysis of the crystalline form of the fumaric acid complex of the compound of formula I-3B is substantially as shown in FIG. 3.
  8. 8. Use according to claim 5 or 6, characterized in that it fulfils one or more of the following conditions: The crystal forms of the fumaric acid compound shown in the formula I-3B have the following unit cell parameters of orthorhombic system, space group P2 1 2 1 2 1 , a= 6.4400 (4) A, alpha=90 DEG, b= 11.9376 (8) A, beta=90 DEG, c= 33.139 (2) A, gamma=90 DEG, unit cell volume= 2547.7 (3) A 3 , asymmetric unit number Z=4 in unit cell and crystal density of 1.451 mg/m 3 ; (2) The crystal form of the compound fumaric acid compound shown in the formula I-3B is a single crystal of the compound fumaric acid compound shown in the formula I-3B.
  9. 9. The use according to claim 1 or 6, wherein the fumaric acid complex of the compound of formula I-3B is prepared by the following method 1 or method 2: the method 1 comprises the following steps of mixing the good solvent solution of the compound shown as the formula I-3B with fumaric acid to enable the fumaric acid to be fully dissolved and devitrified to prepare the fumaric acid compound shown as the formula I-3B, Wherein the good solvent is ethanol; The method 2 comprises the following steps of sequentially mixing the good solvent solution of the compound shown as the formula I-3B with fumaric acid and a poor solvent, crystallizing to prepare the fumaric acid compound of the compound shown as the formula I-3B, Wherein the good solvent is acetone or ethanol, the poor solvent is n-heptane, and the ratio of the volume ratio of the poor solvent to the good solvent is more than 1.
  10. 10. Use according to claim 1 or 6, characterized in that it fulfils one or more of the following conditions: (1) The medicine is administered at a single dose of 0.01mg/kg-10mg/kg, such as 2.5 mg/kg, 5 mg/kg, 1.2 mg/kg, 0.6 mg/kg or 2.4 mg/kg, based on the mass of the compound of formula I-3B or a complex thereof, preferably the administration subject is a rat; (2) The medicine is administered at a single dose of 0.001mg/kg-2mg/kg, such as 0.1-1mg/kg, preferably 0.2 mg/kg, 0.1 mg/kg, 0.4 mg/kg, 0.42 mg/kg, 0.83 mg/kg or 1.2 mg/kg, based on the mass of the compound of formula I-3B or a complex thereof, preferably the administration subject is human; (3) The complex has a solubility of greater than 5mg/mL, preferably a1 hour solubility of 5.1 mg/mL-6.7 mg/mL and above after administration; (4) The DAI score after administration of the compound of formula I-3B or a complex thereof is 35.65 or less; (5) Substantially equivalent therapeutic effects, e.g., equivalent colon weight/length ratio, are achieved when the compound of formula I-3B or a complex thereof is administered at a dose of 4% mesalamine; (6) After administration of the compound of formula I-3B or a complex thereof, the colon weight/length ratio is 13.95 or less; (7) After administration of the compound of formula I-3B or a complex thereof, (CW/CL) x 10 is below 2.26, CL represents colon length, CW represents intestinal weight; (8) After administration of the compound of formula I-3B or a complex thereof, (CW/CL/BW) ×1000 is below 1.39, CL represents colon length, CW represents intestinal weight, BW represents body weight.

Description

Heterocyclic compounds and their use in complexes with pharmaceutically acceptable acids The present application claims priority from China patent application 2024115879138 with application date 2024/11/07. The present application incorporates the entirety of the above-mentioned chinese patent application. Technical Field The invention relates to the field of medicines, in particular to a heterocyclic compound and application of a compound formed by the heterocyclic compound and pharmaceutically acceptable acid. Background Prostaglandin E2 (prostaglandin E, PGE 2) is one of prostaglandins, and has biological effects of regulating blood pressure, inflammatory reaction, and promoting cell proliferation and differentiation. In vivo, cell membrane phospholipids produce arachidonic acid (arachidonic acid, AA) under the action of phospholipase A2 (phospholipase A2, PLA 2), after which AA is catalyzed by cyclooxygenase 1/2 (cyclooxygenase, COX 1/2) to produce prostaglandin intermediate prostaglandin G2 (prostaglandin G, PGG 2), after which PGG2 is rapidly reduced to prostaglandin H2 (prostaglandin H, PGH 2) and PGH2 is metabolized to PGE2 by prostaglandin synthase type E (prostaglandin E SYNTHASE, PGES). A large number of researches show that PGE2 can promote stem cell proliferation by activating a downstream EPs receptor and exert the tissue injury repair effect, but the clinical use of PGE2 is limited due to the short half-life period of PGE2 in blood. Therefore, by increasing the endogenous PGE2 content in tissue cells, the proliferation of tissue stem cells is promoted, and the method is an ideal mode for playing the function of PGE2 tissue repair. 15-prostaglandin dehydrogenase (15-PGDH) is an important metabolic enzyme of intracellular PGE2, and can promote degradation and inactivation of PGE2, thereby blocking downstream signal paths, and can increase the intracellular PGE2 content by inhibiting 15-PGDH, thereby promoting stem cell proliferation. However, because the 15-PGDH is widely expressed in the whole body, the too high PGE2 in the tissues may bring about corresponding adverse reactions, such as fever, inflammation injury and the like, and often cannot play a role in treatment because the 15-PGDH cannot be directionally expressed at focus positions, so that the target tissue distribution proportion of the medicine is improved, the system exposure is reduced, the medicine effect is effectively improved, and the use risk is reduced. Inflammatory Bowel Disease (IBD), a idiopathic intestinal inflammatory disease involving the ileum, rectum, colon, manifests as diarrhea, abdominal pain, and possibly even bloody stool, including Ulcerative Colitis (UC) and Crohn's Disease (CD). The existing therapy mainly relieves IBD symptoms from the aspects of anti-inflammation and immunoregulation, and has the defects of high treatment failure rate, poor tolerance and the like. The development of a drug which can be effectively used for treating inflammatory bowel disease, so as to improve the intestinal tissue distribution of the drug, improve the safety of the drug and reduce the side effects of the drug has important research value. Disclosure of Invention The invention provides a heterocyclic compound and application of a compound formed by the heterocyclic compound and pharmaceutically acceptable acid, which are used for solving the defects in the prior art. In order to achieve the above purpose, the present invention adopts the following technical scheme: the invention provides an application of a compound shown in a formula I-3B or a compound thereof in preparing a medicament for treating and/or preventing inflammatory bowel disease; ; Wherein, the The compound is a compound formed by a compound shown in a formula I-3B and pharmaceutically acceptable acid; The inflammatory bowel disease is Crohn's disease or ulcerative colitis, wherein the Crohn's disease is selected from one or more of Crohn's disease (Ileocolitis), ileitis (Ileitis), gastroduodenal Crohn's disease (Gastroduodenal Crohn's), jejunum ileitis (Jejunoileitis) and Crohn's granulomatous colitis (Crohn's (granulomatous) colitis); ulcerative colitis is selected from one or more of ulcerative proctitis (Ulcerative proctitis), ulcerative proctositis (Proctosigmoiditis), left-side colitis (Left-side colitis), and complete colitis (Pancolitis). In the present invention, the pharmaceutically acceptable acid is, for example, hydrochloric acid, phosphoric acid, fumaric acid, tartaric acid, malic acid, ethanedisulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid or oxalic acid, preferably fumaric acid. In the present invention, the compound represented by the formula I-3B or a complex thereof may be amorphous or a crystalline form thereof. In the invention, the compound can be a compound shown in the formula I-3B and fumaric acid compound, the molar ratio of fumaric acid to the compound shown in the formula I-3B is 1:1, and the eute