Use of WS635 in medicine

Abstract

The present invention relates to a method of inducing or accelerating the wound healing process in a subject in need thereof, the method comprising the step of administering to the subject a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharma-ceutically acceptable salt, or prodrug thereof. [Case 1] JPEG2024541690000006.jpg83122

Description

[Technical Field]

[0001] The present invention belongs to the field of medicine. Specifically, the present invention relates to the use of (3S,6S,9S,12R,15S,18S,21S,24S,27R,30S,33S)-27-((2-(dimethylamino)ethyl)thio)-30-ethyl-33-((1R,2R,E)-1-hydroxy-2-methylhexyl-4-en-1-yl)-24-(2-hydroxy-2-methylpropyl)-6,9,1 The present invention relates to the use of 8-triisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecanone (I) (also known as WS635, SCY-635) and pharmaceutical compositions thereof. [Background technology]

[0002] The skin forms an important physical barrier to prevent microbial invasion and maintain temperature and fluid balance. Skin trauma can temporarily disrupt this barrier, posing a significant health challenge. Wound healing is a complex process characterized by dynamic changes in the wound microenvironment, recruiting and guiding different types of participating cells. The overall process is typically divided into four sequentially overlapping phases: hemostasis, inflammation, proliferation, and remodeling. During the hemostasis phase, bleeding is controlled by sympathetic nerve-induced vasoconstriction and thrombus formation. Cells in damaged tissue release alarm signals, chemokines, and growth factors, which recruit immune cells from the blood circulation, stimulate the proliferation of resident cells within the tissue, and accumulate immune cells at the wound site. The proliferative phase is characterized by the formation of granulation tissue, which consists of neovasculature, immune cells, and fibroblasts and can migrate epidermal cells into the tissue during wound re-epithelialization. During scar tissue formation, dermal and epidermal fibroblasts deposit new extracellular matrix to strengthen the repaired tissue. Different species have different skin structures and compositions, leading to different healing rates.

[0003] Currently, most treatments for wound healing are topical and include functional dressings (e.g., interactive dressings and bioactive dressings), biomaterials (e.g., xenogeneic decellularized dermal matrix and tissue-engineered skin), and negative pressure therapy techniques. Most existing oral medications target supportive aspects of wound care, such as pain management, infection relief, and nutrition, leaving a significant lack of oral medications that directly promote wound healing. Because oral formulations are easy to use and can shorten healing time, increasing the number of oral formulations that effectively heal wounds would be extremely beneficial in the field of wound care.

[0004] According to the research report, the area of ​​open wounds in the skin of rats injected with growth factors was reduced compared to the control group. Microscopic observation showed that in the wounds injected with growth factors, the levels of vascular endothelial growth factor, fibroblast growth factor, and insulin growth factor increased, promoting epithelial cell growth and angiogenesis, and accelerating fibrosis and the deposition of type I collagen, thereby accelerating wound healing.

[0005] In another study, the results of ex vivo vascular remodeling evaluation of the aortas of WT and CypD KO mice showed that CypD KO mice had earlier onset and significantly faster wound closure, which was associated with increased vascularity around the wound 14 days after ear resection.

[0006] WS635 (compound of formula (I)) is a non-immunosuppressive derivative of cyclosporin A (CsA) with double substitution at the 3,4 positions, which binds to procyclin D (CypD) and inhibits mPTP opening. Therefore, WS635 merits further investigation as a novel mPTP inhibitor. Summary of the Invention [Problem to be solved by the invention]

[0007] The following summarizes only some aspects of the present invention, and the present invention is not limited to these aspects. These aspects and other parts will be described more fully later. All references in this specification are incorporated herein by reference. If there is any difference between the disclosure of this specification and the cited reference, the disclosure of this specification shall prevail.

[0008] During research and development, the inventors unexpectedly discovered that WS635 can significantly promote angiogenesis in rats. Further research by the inventors showed that WS635 can be used to promote wound healing. As an active ingredient in a wound healing therapeutic agent, WS635 has low toxicity, and in a toxicity test using repeated oral administration to rats for 9 days, the no-obvious-adverse-effect level (NOAEL) was 80 mg / kg / day. Furthermore, WS635 has better stability, pharmacokinetics, etc., and has been proven to be more effective in wound healing. [Means for solving the problem]

[0009] Specifically, in one aspect, the present invention relates to a method of promoting the wound healing process in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof. [ka]

[0010] During the course of research and development, the inventors unexpectedly discovered that WS635 can significantly promote angiogenesis in rats. According to an embodiment of the present invention, the compound represented by formula I can promote angiogenesis and thereby promote wound healing.

[0011] In one embodiment, the wound is a surgical wound.

[0012] In one embodiment, the wound is a skin wound.

[0013] In one embodiment, the compound is administered to the subject after wounding.

[0014] In one embodiment, the compound is administered to the subject within 14 days of wound formation.

[0015] In one embodiment, the compound is administered to the subject within seven days of wound formation.

[0016] In one embodiment, the compound is administered in a daily dosage of less than about 1000 mg.

[0017] In one embodiment, the compound is administered in a daily dosage of between about 30 mg and about 1000 mg.

[0018] In one embodiment, the compound is administered in a daily dosage of between about 500 mg and about 700 mg.

[0019] In one embodiment, the compound is administered once daily.

[0020] In one embodiment, the compound is administered in a single dose once daily.

[0021] In one embodiment, the compound is administered orally.

[0022] In one embodiment, the compound is administered as a tablet, capsule, or injection.

[0023] In one embodiment, the compound is administered in combination with one or more other agents, different from the compound of formula I, for inducing or accelerating the wound healing process.

[0024] In another aspect, the present invention provides the use of a compound of Formula I, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, in promoting the wound healing process in a subject in need thereof. [ka]

[0025] In one embodiment, the wound is a surgical wound.

[0026] In one embodiment, the wound is a skin wound.

[0027] In one embodiment, the compound is administered to the subject after wounding.

[0028] In one embodiment, the compound is administered to the subject within 14 days of wound formation.

[0029] In one embodiment, the compound is administered to the subject within seven days of wound formation.

[0030] In one embodiment, the compound is administered in a daily dosage of less than about 1000 mg.

[0031] In one embodiment, the compound is administered in a daily dosage of between about 30 mg and about 1000 mg.

[0032] In one embodiment, the compound is administered in a daily dosage of between about 500 mg and about 700 mg.

[0033] In one embodiment, the compound is administered once daily.

[0034] In one embodiment, the compound is administered in a single dose once daily.

[0035] In one embodiment, the compound is administered orally.

[0036] In one embodiment, the compound is administered as a tablet, capsule, or injection.

[0037] In one embodiment, the compound is administered in combination with one or more other agents, different from the compound of formula I, for inducing or accelerating the wound healing process.

[0038] Any embodiment disclosed in this specification can be combined with any other embodiment, even if described in different aspects of the present invention, as long as these embodiments are not inconsistent with each other. Furthermore, any technical feature in one embodiment can be applied to a corresponding technical feature in another embodiment, even if these embodiments are described in different aspects of the present invention, as long as they are not inconsistent with each other.

[0039] The foregoing summarizes only some aspects disclosed herein, and is not meant to be limiting in nature. These and other aspects and embodiments are described more fully below. [Brief explanation of the drawings]

[0040] [Figure 1] These results demonstrate that WS635 significantly promotes wound healing, and its effect is comparable to that of rb-bFGF. [Figure 2] WS635 enhances the rate of wound healing in a time-dependent manner. DETAILED DESCRIPTION OF THE INVENTION

[0041] Definitions and General Terms

[0042] Some embodiments of the present invention are described in detail below, examples of which are shown in the accompanying structures and formulas. The present invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the present invention, as defined by the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is not limited to the methods and materials described herein. If one or more of the cited documents, patents, and similar materials differ from or contradict the present invention, including but not limited to defined terms, term usage, described techniques, etc., the present invention shall be the basis.

[0043] Although, for purposes of clarity, some features of the invention are described in the context of separate embodiments, it should also be understood that these features may also be provided in combination in a single embodiment. Rather, various features of the invention that are, for brevity's sake, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0044] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications mentioned herein are incorporated by reference in their entirety.

[0045] As used herein, the grammatical articles "a," "an," "the," and "said" are intended to include "at least one" or "one or more," unless otherwise explained herein or clearly contradicted by context. Thus, the articles used herein refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an embodiment" refers to one or more embodiments.

[0046] The term "comprises" is an open expression and means to include what is disclosed herein but not to exclude other content.

[0047] As used herein, the term "pharmaceutically acceptable" means a compound, material, composition and / or dosage form that is, within the scope of reasonable medical judgment, suitable for contact with the tissues of a patient, without significant toxicity, irritation, allergic response or other problem or complication, and that is effective for the expected use, with reasonable benefit / risk implications.

[0048] The term "prodrug" refers to a compound that is converted to a compound of Formula (I) in the body. For example, such conversion can be achieved by hydrolysis of the prodrug form in the blood or by facilitating conversion to the parent form by enzymes in the blood or tissues. Prodrugs of the compounds disclosed herein can be, for example, esters. Esters used as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonate esters, carbamates, and amino acid esters. For example, a hydroxy-containing compound disclosed herein is acylated at that position in its prodrug form. Other prodrug forms include phosphates, such as phosphate compounds derived from hydroxyphosphorylation on the parent compound. Detailed discussions of prodrugs are provided in the following documents: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and S. J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, which are incorporated herein by reference.

[0049] A "metabolite" is a product produced by metabolism in the body of a particular compound or its salt. Metabolites of a compound can be identified using routine techniques known in the art, and their activity can be confirmed using the tests described herein. Such products can be produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds disclosed herein, including metabolites produced by contacting the compounds disclosed herein with a mammal for a sufficiently long period of time.

[0050] "Pharmaceutically acceptable salt" refers to an organic or inorganic salt of a compound disclosed herein. Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19, which is incorporated herein by reference. Some non-limiting examples of pharmaceutically acceptable and non-toxic salts include salts of an amino group with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid), or salts formed using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogensulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucopyranate, glyceryl phosphate, gluconate, hemisulfate, heptanoate, caproate, hydrogen iodate, 2-hydrogen iodide, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-methyl-N ... + (C 1-4 The present invention also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Such quaternization may result in water- or oil-soluble or dispersible products. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Optionally, other pharmaceutically acceptable salts may be used, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 These include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as sulfonate or arylsulfonate.

[0051] The term "solvate" refers to an association or complex of one or more solvent molecules with a compound disclosed herein. Examples of solvents that form solvates include, but are not limited to, water, isopropyl alcohol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, and mixtures thereof. The term "hydrate" refers to a complex where the solvent molecule is water.

[0052] When the solvent is water, the term "hydrate" can be used. In one embodiment, one water molecule is associated with one molecule of a compound disclosed herein, such as a hydrate. In another embodiment, one or more water molecules are associated with one molecule of a compound disclosed herein, such as a dihydrate. In another embodiment, not more than one water molecule can be associated with one molecule of a compound disclosed herein, such as a hemihydrate. It should be noted that all solvates of the present invention retain the biological effectiveness of the non-hydrate forms of the compounds disclosed herein.

[0053] As used herein, the term "therapeutically effective amount" or "therapeutically effective dosage" refers to an amount of a compound disclosed herein that elicits a biological or medical response (e.g., reducing or inhibiting the activity of an enzyme or protein, ameliorating symptoms, alleviating a disturbance, slowing the progression of a disease, etc.).

[0054] Uses of the Compounds and Drug Compositions

[0055] The compound WS635 or pharmaceutical composition disclosed herein can effectively promote wound healing.

[0056] An "effective amount," "therapeutically effective amount," or "effective dosage" of a compound disclosed herein, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, or a pharmaceutically acceptable composition thereof, is an amount that effectively promotes wound healing. The compound and pharmaceutically acceptable composition can be effectively administered within a fairly wide dosage range. For example, the daily dosage per person is about 30 mg to about 1000 mg, and the compound or pharmaceutically acceptable composition can be administered in a single dose or in several divided doses per day. According to the methods disclosed herein, the compound and composition can be administered in any amount and by any route of administration that effectively promotes wound healing. The exact amount required will vary from subject to subject, depending on the type, age, and general condition of the subject, the severity of the infection, the particular drug, and its method of administration, among other factors.

[0057] In some embodiments, a compound described herein is administered to a subject within 14 days of wound formation, for example, within 14 days of wound formation. The compound described herein can be administered at a daily dose of less than about 1000 mg, for example, at a daily dose of about 30 mg to about 1000 mg, or at a daily dose of about 500 mg to about 700 mg. The compound can be administered once daily, or in a single dose once daily.

[0058] WS635 and compositions thereof can be used in the treatment of humans as well as in the veterinary treatment of animals, including companion animals, exotic animals, and farm mammals. In other embodiments, animals disclosed herein include horses, dogs, and cats. As used herein, the compounds disclosed herein include pharmaceutically acceptable derivatives thereof.

[0059] Example

[0060] Materials and Methods

[0061] Eighteen 6-week-old male SD rats were randomly divided into three groups: a model group, a test group, and a positive control group, each consisting of six rats. After anesthesia, surgery for skin wound formation was performed, and oral administration began 2 hours after the skin wound was formed. All rats were housed in the same cage. The surgical details were as follows: all animals were anesthetized with an intraperitoneal injection of 10% hydrochloraldehyde solution (3 ml / kg), hair was removed from the back with a pet shaving knife, a 2-cm diameter circular marker was created, the skin was disinfected with alcohol, and full-thickness skin was excised along the marker line with surgical scissors. The wound surface was then compressed for hemostasis. The model group was orally gavaged with 10% DMSO in corn oil, the test group was orally gavaged with 52.8 mg / kg of WS635 (corn oil dissolved in 10% DMSO), and the positive control group was topically administered 262.5 IU / cm. 2 (i.e., 62.5 μl / cm 2 A topical solution of recombinant bovine basic fibroblast growth factor (rb-bFGF) was administered once daily for seven consecutive days. Digital photographs of the wounds of each rat were taken under the same conditions. The wounds were traced with transparent plastic paper, and the wound area was scanned using Image J software. Based on the wound area, the wound healing rate (%) was calculated as follows: (Area after administration - Area before administration) / Area before administration x 100%.

[0062] result

[0063] Compared with the model group, the wound areas of the WS635 group and the positive control group (rb-bFGF) were significantly smaller on days 3 and 7 (P<0.05, P<0.01). There was no significant difference between WS635 and rb-bFGF (P>0.05). Within the administration cycle, the wound healing rates of the WS635 and rb-bFGF groups improved with increasing administration time. The results indicate that oral administration of WS635 can significantly promote wound healing in a wound healing model in SD rats. The results are shown in Figures 1 and 2.

Claims

1. 1. A therapeutic agent for promoting the wound healing process in a subject in need thereof, said therapeutic agent comprising a compound of formula I or a solvate or pharmaceutically acceptable salt thereof. 【Chemistry 1】

2. The therapeutic agent of claim 1 , wherein the wound is a surgical wound.

3. The therapeutic agent of claim 1 , wherein the wound is a skin wound.

4. The method of claim 1 , wherein the compound is administered to the subject after the wound is formed.

5. The method of claim 1, wherein the compound is administered to the subject within 14 days after the wound is formed.

6. The method of claim 1, wherein the compound is administered to the subject within seven days after the wound is formed.

7. The method of claim 1 , wherein the compound is administered in a daily dosage of less than about 1000 mg.

8. The method of claim 1, wherein the compound is administered in a daily dosage of between about 30 mg and about 1000 mg.

9. The method of claim 1, wherein the compound is administered in a daily dosage of between about 500 mg and about 700 mg.

10. The method of claim 1 , wherein the compound is administered once daily.

11. The method of claim 1, wherein the compound is administered in a single dose once daily.

12. The therapeutic agent of claim 1 , wherein the compound is administered orally.

13. The therapeutic agent of claim 1 , wherein the compound is administered in a tablet, capsule, or injection.

14. 10. The method of claim 1, wherein the compound is administered in combination with one or more other agents for inducing or accelerating the wound healing process, different from the compound of formula I.

15. 20. Use of a compound of formula I, or a solvate or pharmaceutically acceptable salt thereof, in the preparation of a medicament for promoting the wound healing process in a subject in need thereof. 【Chemistry 2】

Images