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CN-122011091-A - Polypeptide compound, preparation method, pharmaceutical composition and application thereof

CN122011091ACN 122011091 ACN122011091 ACN 122011091ACN-122011091-A

Abstract

The application relates to the technical field of polypeptide compound medicines, in particular to a polypeptide compound, a pharmaceutical composition and application thereof. The application discloses a polypeptide compound which has a structural formula (XX), shows good in-vitro osteogenesis activity and has good pharmacokinetic properties, and the polypeptide compound has potential application value in osteoporosis treatment.

Inventors

  • XU ANCHAO
  • YAO WEI
  • CAI YONGLONG
  • CHEN JIWEI

Assignees

  • 中山莱博瑞辰生物医药有限公司

Dates

Publication Date
20260512
Application Date
20251111
Priority Date
20241111

Claims (16)

  1. 1. A polypeptide compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof, characterized by comprising the following structural formula (XX); ; r 1 is independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; r 2 is independently selected from the group consisting of C1-C6 alkyl, H, halogen, C1-C6 alkoxy, and C1-C6 haloalkyl; Y 1 -Y 4 is independently selected from amino acid residues; x is selected from CH 3 、COOH、SO 3 H or OH; m, n, q, w in the subscript is independently selected from any one of values 0-6; o in the subscript is selected from any one of values 1-4; r in the subscript is selected from any one of values 0 to 2; P in the subscript is selected from any one of values 10-20.
  2. 2. The polypeptide compound of claim 1, wherein Y 4 is selected from the group consisting of citrulline residues, Lysine residue, homoccitrulline residue, leucine residue, (N-methyl) leucine residue, isoleucine residue, norleucine residue, (N-methyl) isoleucine residue and homophenylalanine residue, Y 3 is selected from glutamic acid residue, glutamine residue, aspartic acid residue or asparagine residue, Y 2 is selected from serine residue, threonine residue, tyrosine residue or cysteine residue, and Y 1 is selected from valine residue, isoleucine residue, leucine residue, methionine residue or norleucine residue.
  3. 3. The polypeptide compound of claim 1, wherein Selected from the group consisting of 。
  4. 4. The polypeptide compound of claim 1, wherein Selected from the group consisting of ,m=0-2,n=0-2,o=4,r=2。
  5. 5. The polypeptide compound of claim 1, comprising the following structural formula (I); ; In the structural formula (I), n is any one value of 0, 1, 2, 3, 4, 5 and 6, m is any one value of 0, 1, 2, 3, 4, 5 and 6, p is any one value of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, and X is selected from CH 3 、COOH、SO 3 H or OH.
  6. 6. A pharmaceutical composition comprising a polypeptide compound of any one of claims 1-5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof, and one or more pharmaceutically acceptable excipients or carriers.
  7. 7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable salt thereof comprises any one or more of sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, and ammonium salt.
  8. 8. The pharmaceutical composition of claim 6, comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.
  9. 9. A kit product comprising a) a container, b) at least one compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof, and c) optionally, packaging and/or instructions.
  10. 10. A drug conjugate comprising a compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof.
  11. 11. A method for preventing, treating or alleviating osteoporosis and promoting fracture healing comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 5, or a stereoisomer, or a pharmaceutically acceptable salt thereof, or a deuterated compound, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound, or a metabolite thereof, or a prodrug thereof, a pharmaceutical composition according to claims 6-8, a kit of parts according to claim 9, or a pharmaceutical conjugate according to claim 10.
  12. 12. A method of promoting bone formation comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof, a pharmaceutical composition of claims 6-8, a kit of parts of claim 9, or a pharmaceutical conjugate of claim 10.
  13. 13. Use of the polypeptide compound of any one of claims 1-5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof, or the pharmaceutical composition of claims 6-8, the kit product of claim 9, or the pharmaceutical conjugate of claim 10, for the preparation of a medicament for activating cell signaling in osteoprogenitor cells, thereby promoting bone formation.
  14. 14. Use of the polypeptide compound of any one of claims 1-6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof, or the pharmaceutical composition of claims 6-8, the kit of parts of claim 9, or the pharmaceutical conjugate of claim 10, for the manufacture of a medicament for the prevention, treatment or alleviation of osteoporosis.
  15. 15. A pharmaceutical composition for preventing, treating or alleviating osteoporosis, promoting fracture healing, comprising a compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof, a pharmaceutical composition according to claims 6-8, a kit product according to claim 9, or a pharmaceutical conjugate according to claim 10.
  16. 16. A pharmaceutical composition for promoting bone formation, comprising a compound of any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof, a pharmaceutical composition of claims 6-8, a kit product of claim 9, or a pharmaceutical conjugate of claim 10.

Description

Polypeptide compound, preparation method, pharmaceutical composition and application thereof Technical Field The application relates to the technical field of polypeptide compound medicines, in particular to a polypeptide compound, a preparation method, a pharmaceutical composition and application thereof. Background Osteoporosis (Osteoporosis, OP) is a systemic bone disease that is prone to fracture due to reduced bone density, reduced bone mass, damaged bone microstructure, and increased bone fragility, among many reasons. Osteoporosis generally occurs in postmenopausal women and aged men, and seriously affects the physical health and quality of life of patients, even shortens the life span, increases the burden of families, and has become one of the important social concerns. The bone tissue is always in the process of bone remodeling/bone conversion of old bone replaced by new bone, the cytological basis of bone remodeling/bone conversion is the balance of "coupling" between the bone formation of osteoblasts (Osteoblast, OB) and the bone resorption of osteoclasts (Osteoclast, OC), which is the guarantee of maintaining the normal bone mass and the integrity of bone structure of bone tissue, and the occurrence and development of osteoporosis is mainly the result of "imbalance" in the process of bone remodeling/bone conversion consisting of osteoblastic bone formation and osteoclastic bone resorption. Currently, most osteoporosis treatments are those that inhibit bone resorption, such as bisphosphonates and monoclonal antibodies, denosumab. Although there are several osteoporosis therapeutic drugs for inhibiting osteoclast formation clinically, most of the drugs still have limited effects on osteoporosis, and some of the drugs have large toxic and side effects and many adverse reactions. For example, bisphosphonates have low bioavailability, are easy to cause gastrointestinal reactions, and are easy to cause esophagus cancer, mandibular necrosis and the like after long-term use, and denosemab (denosemab, deshu monoclonal antibody) is limited in use due to price. The now osteogenic drugs include recombinant human parathyroid hormone drugs such as hPTH (1-34) (teriparatide) and PTHrp (abamectin), bone sclerostin mab Evenity (romosozumab), which have all been FDA approved for use in the treatment of OP. However, as hormonal agents, clinical implications are that there is a risk of inducing osteosarcoma, such as long-term use of teriparatide and abaclotide, while it is not recommended to use teriparatide and abaclotide in patients with a history of radiation, primary or secondary hyperparathyroidism. Evenity (romosozumab) is a fully humanized monoclonal antibody which acts by inhibiting the activity of osteopetron (Sclerostin) and in the ARCH test Evenity shows a stronger potency than the existing OP drug alendronate, the vertebral and non-vertebral fracture rates are reduced, but group Evenity (romosozumab) shows a certain risk of cardiovascular side effects. There is therefore an urgent need to find new osteogenic anabolic drugs for the associated treatment of osteoporosis, promoting fracture healing. Disclosure of Invention The embodiment of the application aims to provide a polypeptide compound, a pharmaceutical composition and application, wherein the polypeptide compound has a structural formula XX, and the polypeptide compound has good in-vitro osteogenesis activity, good pharmacokinetic properties and great application value in bone repair and osteoporosis treatment. In order to solve the technical problems, the application is realized as follows: A first object of the present application is to provide a polypeptide compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or a prodrug thereof, comprising the following structural formula (XX); ; In the structural formula (XX), R 1 is independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl, R 2 is independently selected from C1-C6 alkyl, H, halogen, C1-C6 alkoxy and C1-C6 haloalkyl, Y 1-Y4 is independently selected from amino acid residues, X is selected from CH 3、COOH、SO3 H or OH; m, n, q, w is independently selected from any one of values 0 to 6; Subscript o is selected from any one of values 1-5; Subscript r is selected from any one of values 0-3; subscript p is selected from any one of values 10-20. In some embodiments, R 1 is independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; in some embodiments, R 2 is independently selected from the group consisting of C1-C6 alkyl, H, halogen, C1-C6 alkoxy, and C1-C6 haloalkyl; In some embodiments, Y 4 is selected from the group consisting of a citrulline residue, Lysine residue, homocamptothecin residue, leucine residue, (N-meth