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EP-4741395-A1 - NOVEL COMPOUND SENSITIVE TO NITROGEN MONOXIDE AND PHARMACEUTICAL COMPOSITION COMPRISING SAME

EP4741395A1EP 4741395 A1EP4741395 A1EP 4741395A1EP-4741395-A1

Abstract

The present disclosure relates to a compound in which a nitrogen monoxide scavenger is conjugated to a low-molecular-weight compound having pharmaceutical activity, and a pharmaceutical composition sensitive to nitrogen monoxide including the same. The compound is designed such that a nitrogen monoxide scavenger is separated while removing nitrogen monoxide only in a diseased area such as an inflammatory area with high concentration of nitrogen monoxide, so that a low-molecular-weight compound in an inactivated state exhibits pharmaceutical activity. The compound is activated only in a diseased area, thereby minimizing side effects of existing medicines and simultaneously securing the effect of pharmaceutical activity of the low-molecular-weight compound and the effect of removing nitrogen monoxide, and can be used in preventing or treating diseases associated with nitrogen monoxide generation.

Inventors

  • KIM, WON JONG
  • YOON, JOO BYOUNG
  • KWON, BO SUNG
  • JU, Jae Eun
  • KANG, BYUNG YOON
  • LEE, JI YOUN
  • JEON, SO YEON

Assignees

  • Omniamed Co. Ltd

Dates

Publication Date
20260513
Application Date
20240705

Claims (10)

  1. A compound of the following Chemical Formula 1, or a solvate, a hydrate, a stereoisomer or a pharmaceutically acceptable salt thereof: wherein, in Chemical Formula 1, X is a low-molecular-weight compound including an amine group or a hydroxyl group in the molecular structure of the compound and having pharmaceutical activity; Y is selected from the group consisting of hydrogen, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a hydroxyl group, a nitro group, an amino group, halogen, a thiol group, a cyano group and Z is selected from the group consisting of and n and m are each independently an integer of 0 to 4; R 1 and R 2 are each independently selected from the group consisting of a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a hydroxyl group, a nitro group, an amino group, halogen, a thiol group, a cyano group, a C 3 -C 14 aryl group, a C 3 -C 14 heteroaryl group, -NR 11 R 12 , -NR 12 C(=O)R 12 , -C(=O)R 11 and - C(=O)OR 11 ; R 11 and R 12 are each independently selected from the group consisting of hydrogen, halogen, CF 3 , a C 1 -C 6 alkyl group, a C 3 -C 14 aryl group and a C 3 -C 14 heteroaryl group; the aryl group or the heteroaryl group is each independently unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, a hydroxyl group, a thiol group, a cyano group, a C 1 -C 6 alkyl group and a C 1 -C 6 alkoxy group; when there are two or more R 1 s and R 2 s, each independently, these are the same as or different from each other, and two adjacent R 1 s or R 2 s optionally bond to each other to form a fused ring or not form a fused ring; and R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, a hydroxyl group, a thiol group, a cyano group, a C 1 -C 6 alkyl group and a C 1 -C 6 alkoxy group, or R 3 and R 4 bond to form a fused ring.
  2. The compound, or a solvate, a hydrate, a stereoisomer or a pharmaceutically acceptable salt thereof of claim 1, wherein X is a kinase inhibitor, an anticancer agent or an anti-inflammatory agent.
  3. The compound, or a solvate, a hydrate, a stereoisomer or a pharmaceutically acceptable salt thereof of claim 2, wherein the kinase inhibitor is selected from the group consisting of netarsudil, fostamatinib, belumosudil, tofacitinib, upadacitinib, baricitinib, filgotinib, abrocitinib, delgocitinib, oclacitinib, peficitinib, and ruxolitinib.
  4. The compound, or a solvate, a hydrate, a stereoisomer or a pharmaceutically acceptable salt thereof of claim 2, wherein the anticancer agent is selected from the group consisting of doxorubicin, cyclophosphamide, cisplatin, oxaliplatin, 5-fluorouracil (5-Fu), gemcitabine, paclitaxel, docetaxel, irinotecan, monomethyl auristatin E (MMAE), crizotinib, osimertinib, sorafenib, ibrutinib, ruxolitinib, vemurafenib, ceritinib, alectinib, brigatinib, lorlatinib, capmatinib, gefitinib, erlotinib, lapatinib, icotinib, afatinib, neratinib, dacomitinib, almonertinib, tucatinib, midostaurin, gilteritinib, quizartinib, pexidartinib, sunitinib, pazopanib, vandetanib, axitinib, cabozantinib, regorafenib, apatinib, lenvatinib, tivozanib, fruquintinib, nintedanib, anlotinib, erdafitinib, pemigatinib, avapritinib, ripretinib, pralsetinib, larotrectinib, entrectinib, imatinib, dasatinib, nilotinib, bosutinib, radotinib, ponatinib, acalabrutinib, zanubrutinib, fedratinib, dabrafenib, encorafenib, trametinib, cobimetinib, binimetinib, selumetinib, palbociclib, ribociclib, abemaciclib, idelalisib, copanlisib, duvelisib, alpelisib, tazemetostat, vorinostat belinostat, tucidinostat, panobinostat, enasidenib, ivosidenib, venetoclax, vismodegib, sonidegib, glasdegib, bortezomib, carfilzomib, ixazomib, olaparib, rucaparib, niraparib, talazoparib, umbralisib, trilaciclib, infigratinib, mobocertinib, asciminib, futibatinib, pacritinib, and everolimus.
  5. The compound, or a solvate, a hydrate, a stereoisomer or a pharmaceutically acceptable salt thereof of claim 2, wherein the anti-inflammatory agent is selected from the group consisting of dexamethasone, methotrexate, cyclosporine, acetaminophen, etodolac, piroxicam, and aceclofenac.
  6. The compound, or a solvate, a hydrate, a stereoisomer or a pharmaceutically acceptable salt thereof of claim 1, which is selected from the group consisting of the following Chemical Formulae 2 to 6: wherein, in Chemical Formulae 2 to 6, X, R 1 , R 2 , R 3 , R 4 , R 11 , R 12 , n and m have the same definitions as in Chemical Formula 1.
  7. The compound, or a solvate, a hydrate, a stereoisomer or a pharmaceutically acceptable salt thereof of claim 1, which is selected from the group consisting of the following Compounds (1) to (35):
  8. A pharmaceutical composition for preventing and treating a disease associated with nitrogen monoxide generation, the composition comprising the compound, or a solvate, a hydrate, a stereoisomer or a pharmaceutically acceptable salt thereof of claim 1.
  9. The pharmaceutical composition of claim 8, wherein the disease associated with nitrogen monoxide generation includes: an inflammatory disease selected from the group consisting of inflammatory diseases caused by viral infection, inflammatory diseases caused by bacterial infection, sepsis and degenerative inflammatory diseases; a neurological disorder selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and stroke; a cardiovascular disease, which is hypertension or heart failure; an autoimmune disease selected from the group consisting of rheumatoid arthritis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, psoriasis, multiple sclerosis and juvenile idiopathic arthritis; an allergic disease selected from the group consisting of asthma, rhinitis and atopic dermatitis; cancer selected from the group consisting of lung cancer, breast cancer, colorectal cancer, gastric cancer, liver cancer, brain cancer, pancreatic cancer, thyroid cancer, skin cancer, bone marrow cancer, lymphoma, uterine cancer, cervical cancer, ovarian cancer, renal cancer and melanoma; obesity; myelofibrosis; or hepatic encephalopathy.
  10. The pharmaceutical composition of claim 8, which is administered orally, intraarticularly, intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, intrapulmonarily or rectally.

Description

Technical Field This application claims priority to and the benefit of Korean Patent Application No. 10-2023-0086949 filed in the Korean Intellectual Property Office on July 5, 2023, the entire contents of which are incorporated herein by reference. The present disclosure relates to a pharmaceutical composition sensitive to nitrogen monoxide. The pharmaceutical composition includes a nitrogen monoxide scavenger moiety that senses and removes nitrogen monoxide and a low-molecular-weight compound having separate pharmaceutical activity, and, whereas activity of the low-molecular-weight compound having pharmaceutical activity is minimized in a normal tissue with low nitrogen monoxide concentration, the nitrogen monoxide scavenger is separated from the low-molecular-weight compound as it removes nitrogen monoxide only in the inflammatory disease-affected area with a high nitrogen monoxide concentration, thereby allowing the low-molecular-weight compound to exhibit pharmaceutical activity locally and selectively only in the target area and thus minimizing side effects and maximizing efficacy. Accordingly, the pharmaceutical composition may be useful in preventing or treating all diseases associated with nitrogen monoxide. Background Art Nitrogen monoxide (nitric oxide) is a highly reactive radical molecule having a short half-life of less than about 5 seconds, and is associated with various diseases such as inflammatory diseases, cancer growth and metastasis by acting as a major mediator of cell signaling. Specifically, inflammatory-related diseases include rheumatoid arthritis, osteoarthritis, asthma, ulcerative colitis and Crohn's disease, inflammatory diseases caused by bacterial infection, inflammatory diseases caused by viral infection, inflammatory diseases caused by parasitic infection, septic shock and the like, and as neurological disorders, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and stroke are associated with nitrogen monoxide. In addition, cardiovascular diseases such as hypertension and heart failure, and diseases such as cancer, obesity and hepatic encephalopathy are also known to be associated with nitrogen monoxide. DISCLOSURE Technical Problem The present disclosure is directed to providing a pharmaceutical composition for preventing or treating all diseases associated with nitrogen monoxide in which a pharmaceutical composition sensitive to nitrogen monoxide removes nitrogen monoxide locally and selectively only in a diseased area with a high nitrogen monoxide concentration and releases a low-molecular-weight compound having pharmaceutical activity, thereby minimizing side effects and toxicity of the low-molecular-weight compound, and maximizing its efficacy. However, problems to be resolved by the present disclosure are not limited to the above-mentioned problem, and other problems not mentioned will be clearly understood by those skilled in the art from the following description. Technical Solution All combinations of various elements disclosed in the present disclosure fall within the scope of the present disclosure. In addition, the scope of the present disclosure should not be construed as being limited by the following detailed description. In view of the above, the present disclosure provides a pharmaceutical composition for preventing or treating all diseases associated with nitrogen monoxide, the pharmaceutical composition comprising a low-molecular-weight compound conjugated to a nitrogen monoxide scavenger as an active ingredient. The compound according to the present disclosure is a material in which a nitrogen monoxide scavenger and a pharmaceutically active low-molecular-weight compound are conjugated, and an amine group or a hydroxyl group present in the low-molecular-weight compound and the nitrogen monoxide scavenger may be conjugated using an organic synthesis reaction. One embodiment of the present disclosure provides a compound represented by the following Chemical Formula 1, or a solvate, a hydrate or a stereoisomer thereof, or pharmaceutically acceptable salts thereof: in Chemical Formula 1, X is a low-molecular-weight compound including an amine group or a hydroxyl group in the molecular structure of the compound and having pharmaceutical activity, and examples thereof may include kinase inhibitors, particularly Janus kinase inhibitors (JAK inhibitors), and in addition thereto, anticancer agents, anti-inflammatory agents, and the like. The kinase inhibitor may include netarsudil (ROCK1/2, therapeutic agent for glaucoma), fostamatinib (Syk, therapeutic agent for thrombocytopenia), belumosudil (ROCK2, therapeutic agent for graft-versus-host disease), and the like. The Janus kinase inhibitor may be selected from the group consisting of tofacitinib, upadacitinib, baricitinib, filgotinib, abrocitinib, delgocitinib, oclacitinib, peficitinib, ruxolitinib, and the like. The anticancer agent may be selected from the group consi