WO2022242769A1 - 一种含杂原子环丁烷取代基的吡啶酮衍生物的应用 - Google Patents

一种含杂原子环丁烷取代基的吡啶酮衍生物的应用 Download PDF

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WO2022242769A1
WO2022242769A1 PCT/CN2022/094257 CN2022094257W WO2022242769A1 WO 2022242769 A1 WO2022242769 A1 WO 2022242769A1 CN 2022094257 W CN2022094257 W CN 2022094257W WO 2022242769 A1 WO2022242769 A1 WO 2022242769A1
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substance
pharmaceutically acceptable
formula
medicine
gel
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PCT/CN2022/094257
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English (en)
French (fr)
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李永国
陈小宁
马红岩
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广州嘉越医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the technical field of biomedicine, in particular, the invention relates to the application of a pyridone derivative containing a heteroatom cyclobutane substituent.
  • Diabetic foot is a chronic complication of diabetes. It is a general term for abnormal changes in the lower limbs caused by peripheral blood vessels and neuropathy in diabetes. Due to concurrent infection, it leads to gangrene of the extremities, which directly makes patients face disability. important cause. Because it is more common in the lower limbs, toes and soles of the feet, it is clinically called diabetic foot. The main reason is that long-term hyperglycemia has not been ideally controlled, leading to pathological changes in the large blood vessels and microvessels of the lower extremities, and then the extremities fall into a state of ischemia and hypoxia, causing the tissues to lose vitality.
  • diabetic foot The wound healing process of diabetic foot is a complex, multi-stage process, due to various complexities, insufficient angiogenesis and re-epithelialization in patients, severe inflammation is another deleterious factor caused by neutrophil infiltration. Furthermore, diabetic foot is the result of intense inflammation. Due to the increased risk of diabetic foot development in diabetic patients, resulting in reduced quality of life, loss of productivity, and a huge financial burden on the healthcare system, the direct and indirect medical costs of patients with type 2 diabetes with diabetic feet are approximately $13,561 per year .
  • the technical problem to be solved by the present invention is that the existing drug structure for treating diabetic foot is relatively single.
  • the invention provides the application of the pyridone derivative containing the heteroatom cyclobutane substituent, and the substance and the medicine containing the substance have the ability of promoting the wound healing of diabetic foot.
  • the invention provides an application of substance A in the preparation of medicines,
  • the medicine is a medicine for treating and/or preventing diabetic foot
  • the substance A is a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.
  • the medicament treats and/or prevents diabetic foot by increasing the wound healing ability of diabetic foot patients.
  • the drug comprises 1 substance A and 2 a pharmaceutically acceptable carrier.
  • the dosage form of the drug is an external preparation, such as a cream, an ointment or a gel, preferably a gel.
  • the administration frequency of the drug may be 1 time/day, 2 times/day or 3 times/day.
  • the dose of the substance A contained in the drug can be determined according to the actual therapeutic effect of the subject/patient.
  • the mass of the compound represented by formula I in the substance A accounts for 0.1-4% of the drug, such as 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6% %, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9% or 4.0%.
  • the mass fraction of the compound represented by formula I is 0.3-3%, such as 0.3%, 1% or 3%.
  • the drug is composed of 0.3-3% compound shown in formula I, 1% carbomer 940NF, 50% propylene glycol, 13% diethylene glycol monoethyl ether, 1% triethanolamine and water, Water makes up 100%.
  • the present invention also provides a method for treating and/or preventing diabetic foot, said method comprising: administering a therapeutically effective amount of substance A or medicine to a patient; said medicine comprising 1substance A and 2pharmaceutically acceptable carrier ;
  • the substance A is a compound as shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;
  • the administration frequency of the substance A or the drug may be 1 time/day, 2 times/day or 3 times/day. Each time the drug is administered, the dose of substance A contained in the drug can be determined according to the actual therapeutic effect of the subject/patient.
  • the mass of the compound represented by formula I in the substance A accounts for 0.1-4% of the drug, such as 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4% , 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, or 4.0%.
  • the drug such as 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4% , 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.
  • the mass fraction of the compound represented by formula I is 0.3-3%, such as 0.3%, 1% or 3%.
  • the medicine consists of 0.3-3% compound shown in formula I, 1% carbomer 940NF, 50% propylene glycol, 13% diethylene glycol monoethyl ether, Composed of 1% triethanolamine and water, water makes up 100%.
  • the compound or drug represented by formula I treats and/or prevents diabetic foot by increasing the wound healing ability of diabetic foot patients.
  • the dosage form of the drug is an external preparation, such as cream, ointment or gel, preferably gel.
  • the present invention also provides a pharmaceutical composition, which includes substance A and a pharmaceutically acceptable carrier; said substance A is a compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutical A solvate of an acceptable salt; the mass fraction of the compound shown in formula I is 0.1-4%;
  • the mass fraction of the compound represented by formula I is 0.3-3%, such as 0.3%, 1% or 3%.
  • composition is composed of 0.3-3% of the compound shown in formula I, 1% of carbomer 940NF, 50% of propylene glycol, 13% of diethylene glycol monoethyl ether, 1% of triethanolamine and water. 100%.
  • the composition is used for treating and/or preventing diabetic foot.
  • the present invention also provides an external composition, which includes substance A and a pharmaceutically acceptable carrier; said substance A is a compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutical Solvates of acceptable salts above;
  • the mass fraction of the compound shown in formula I is 0.1-4%; preferably, the mass fraction of the compound shown in formula I is 0.3-3%, such as 0.3 %, 1% or 3%.
  • the pharmaceutically acceptable carrier is a conventional carrier of this type of external composition in the art; preferably, the pharmaceutically acceptable carrier is at least carbomer, propylene glycol, diethylene glycol Alcohol monoethyl ether, triethanolamine and water.
  • the carbomer is selected from one or more of carbomer 940NF, carbomer 934, carbomer 974, carbomer 981 or carbomer 1342.
  • the dosage form of the external composition may be a cream, an ointment or a gel, such as a gel.
  • the external composition can be used for treating and/or preventing diabetic foot.
  • composition for external use is composed of 0.3-3% of the compound shown in formula I, 1% carbomer 940NF, 50% propylene glycol, 13% diethylene glycol monoethyl ether, 1% triethanolamine and water, water Make up 100%.
  • the present invention also provides a gel, which includes substance A and a pharmaceutically acceptable carrier; said substance A is a compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutical Solvates of acceptable salts above;
  • the mass fraction of the compound shown in formula I is 0.1-4%; preferably, the mass fraction of the compound shown in formula I is 0.3-3%, such as 0.3 %, 1% or 3%.
  • the pharmaceutically acceptable carrier is a conventional carrier for this gel in the art; preferably, the pharmaceutically acceptable carrier is carbomer, propylene glycol, diethylene glycol mono Ethyl ether, triethanolamine and water.
  • the gel in terms of mass percentage, the gel includes 0.3-3% of the compound shown in formula I, 1% of the carbomer 940NF, 50% of the propylene glycol, 13% of the diethylene glycol Glycol monoethyl ether, 1% of said triethanolamine, made up 100% by water.
  • the external composition can be used for treating and/or preventing diabetic foot.
  • the gel consists of 0.3-3% of the compound shown in formula I, 1% carbomer 940NF, 50% propylene glycol, 13% diethylene glycol monoethyl ether, 1% triethanolamine and water, water Make up 100%.
  • the mass fraction of the compound shown in the formula I mentioned in the present invention refers to the mass corresponding to the structure of the compound shown in the formula I in the total mass of the drug or composition, for example, when the compound shown in the formula I is When the salt form exists, the mass proportion is calculated based on its anion.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier refers to any preparation or carrier medium capable of delivering an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient.
  • Representative carriers include water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity builders, skin penetration enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. Additional information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • treatment refers to therapeutic therapy.
  • treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.
  • prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound which, when administered to a patient, is sufficient to effectively treat the diseases or conditions described herein.
  • a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by those skilled in the art.
  • patient refers to any animal, preferably a mammal, and most preferably a human, that is about to or has received the administration of the compound according to the embodiments of the present invention.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is: the present invention provides a kind of application of substance A in the preparation of medicine, and said substance A is the compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutical acceptable salt.
  • the substance A according to the invention or the medicament comprising substance A has good activity in diabetic foot patients.
  • Fig. 1 is the effect of compound I gel topical administration on fasting blood sugar in diabetic rats
  • Fig. 2 is the effect of Compound I topical administration on the wound opening rate of diabetic rats for 11 days;
  • Figure 3 is the representative photographs of the wound healing of each experimental group on the 1st day and the 11th day.
  • Test substance Compound I was prepared as a gel containing 0.3% of Compound I by mass fraction, 1% by mass fraction of Compound I and 3% by mass fraction of Compound I; Gel is example, and the mass fraction of its each composition is as shown in table 1 below:
  • Compound I accounts for 0.3% and 1% mass fraction of the gel, and the preparation method of the above-mentioned compound I accounts for 3% of the gel is only different in the mass fraction of Compound I, and the mass fraction of the changed part is made up to 100% with water .
  • Compound I is provided by Guangzhou Jiayue Pharmaceutical Technology Co., Ltd., and can also be prepared according to Example 2 in WO2017177974A1;
  • Administration method direct administration of 50 mg per wound.
  • Jinyin peptide (recombinant human epidermal growth factor external use solution) specification: 2000IU/mL, 15mL/bottle
  • Example 1 Making a full-thickness back skin defect model and drug efficacy evaluation after STZ-induced diabetes in rats;
  • STZ diabetic rats were used to simulate type I diabetes, and another 8 normal rats were used as a control group (normal blank gel control group (no STZ)).
  • STZ diabetic rats were modeled as follows: male Wistar rats were weighed and intraperitoneally injected with streptozotocin (STZ, freshly prepared, dissolved in 0.1M citrate buffer (pH4.5)) at a dose of 80 mg/kg .
  • streptozotocin STZ, freshly prepared, dissolved in 0.1M citrate buffer (pH4.5)
  • a total of two intraperitoneal injections of streptozotocin were performed in STZ, 5 days apart.
  • the fasting blood glucose level > 250mg/dl was defined as a diabetic model rat, and the skin wound healing study could be carried out 1 week to 8 weeks after the successful modeling of diabetic rats.
  • Diabetic model rats used a stamp to mark the back skin, and a full-thickness excision resulted in a standard area of wound.
  • the day of full-thickness skin resection was set as the first day of the experiment.
  • the specific operation process is as follows:
  • All experimental groups received topical medication. Rinse the wound with normal saline before using the medicine, blot the residual water with a sterile cotton swab, and then apply the medicine.
  • the Jinyin peptide group solution was evenly applied to the wound and the surrounding skin, and the dressing was changed twice a day.
  • the gel samples of the remaining groups were applied from the periphery to the inside, first mainly on the edge of the lesion, and then covered inward, and the dressing was changed twice a day.
  • the medicine was applied immediately after the wound model was made, and the medicine was used continuously for 18 days in each group. See Table 2 for specific dosing information.
  • a ruler was placed near the wound as a reference scale, and a digital camera was used to keep it fixed on the 1st day, the 4th day, the 8th day, the 11th day, the 14th day, and the 18th day Under the conditions of focal length and pixel, the back wounds of rats were photographed, and the obtained images were processed by software to measure the wound area.
  • the drug was administered on the day after the operation, and the drug was applied to the wound twice a day, and the drug was used until the 18th day after the operation or until the wound was completely healed.
  • the wound opening rate of the reference drug Jinyin peptide group was significantly lower than that of the model blank gel control group (22.43% ⁇ 1.37% vs. 27.99% ⁇ 2.31%, P ⁇ 0.05), suggesting that Jinyin peptide has Promoting role in diabetic wound healing.
  • 1% and 3% compound I also significantly reduced the wound opening rate on the 11th day of administration (19.66% ⁇ 1.93% vs. 27.99% ⁇ 2.31%, P ⁇ 0.01; 22.23% ⁇ 0.87 % vs.
  • Wound opening rate open wound area (O)/initial wound area (I)*100%

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Abstract

公开了一种含杂原子环丁烷取代基的吡啶酮衍生物的应用。公开了一种物质A在制备药物中的应用，所述物质A为如式Ⅰ所示化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；所述药物为治疗和/或预防糖尿病足的药物。公开的的物质A或包含物质A的药物对糖尿病足病人具有良好的活性。

Description

一种含杂原子环丁烷取代基的吡啶酮衍生物的应用
本申请要求申请日为2021年5月20的中国专利申请2021105610935和2022年5月6日的中国专利申请2022105321130优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及生物医药技术领域，具体地，本发明涉及一种含杂原子环丁烷取代基的吡啶酮衍生物的应用。
背景技术
糖尿病足是伴随糖尿病发生的一种慢性并发症，为糖尿病周围血管、神经病变所造成的下肢发生异常改变的一种总称，由于并发感染，导致肢端坏疽，这也是直接使患者面临残疾的一个重要诱因。由于其多见于下肢、足趾以及足底部，所以被临床叫做是糖尿病足。主要是由于长时间的处于高血糖状态下，没有得到理想的控制，导致下肢大血管与微血管发生病理性的改变，继而肢端陷入到缺血、缺氧的状态下，使组织丧失掉活力。
糖尿病足创面愈合过程是一个复杂的、多阶段的过程，由于各种复杂性，患者血管生成和再上皮化不足，严重炎症是中性粒细胞浸润引起的另一个有害因素。此外，糖尿病足是剧烈炎症的结果。由于糖尿病患者发生糖尿病足的风险增加，导致生活质量下降，生产力损失，也给医疗系统带来了巨大的经济负担，患有糖尿病足的2型糖尿病患者每年的直接和间接医疗费用约为13561美元。有证据表明导致伤口愈合延迟的各种因素包括血糖水平升高、胰岛素抵抗增加、血管生成和胶原沉积减少、浸润反应延迟、伤口部位血液供应受阻、颗粒组织形成减少和血液黏度增加。尽管在过去的几十年里对糖尿病足的研究取得了巨大的突破，但有效地治疗糖尿病足仍然是一个挑战。
发明内容
本发明所要解决的技术问题是现有治疗糖尿病足的药物结构较为单一。本发明提供了含杂原子环丁烷取代基的吡啶酮衍生物的应用，该物质及包含该物质的药物具有促进糖尿病足伤口愈合的能力。
本发明提供了一种物质A在制备药物中的应用，
Figure PCTCN2022094257-appb-000001
所述药物为治疗和/或预防糖尿病足的药物；
所述物质A为如式Ⅰ所示化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
所述应用中，所述药物通过增加糖尿病足病人的伤口愈合能力治疗和/或预防糖尿病足。
所述应用中，所述药物包含①物质A和②药学上可接受的载体。
所述应用中，所述药物的剂型为外用制剂，例如乳膏剂、软膏剂或凝胶剂，优选为凝胶剂。
所述应用中，所述药物的施用频率可为1次/日、2次/日或3次/日。每次施用所述药物时，所述药物所含有的所述物质A的剂量可根据受试者/患者的实际治疗效果来确定。较佳地，所述应用中，所述物质A中的如式Ⅰ所示化合物的质量占所述药物的0.1-4％，例如0.1％、0.2％、0.3％、0.4％、0.5％、0.6％、0.7％、0.8％、0.9％、1.0％、1.1％、1.2％、1.3％、1.4％、1.5％、1.6％、1.7％、1.8％、1.9％、2.0％、2.1％、2.2％、2.3％、2.4％、2.5％、2.6％、2.7％、2.8％、2.9％、3.0％、3.1％、3.2％、3.3％、3.4％、3.5％、3.6％、3.7％、 3.8％、3.9％或4.0％。
所述应用中，所述如式Ⅰ所示化合物的质量分数为0.3-3％，例如0.3％、1％或3％。
所述应用中，所述药物由0.3-3％如式Ⅰ所示化合物、1％卡波姆940NF、50％丙二醇、13％二乙二醇单乙基醚、1％三乙醇胺和水组成，水补足100％。
本发明还提供了一种治疗和/或预防糖尿病足的方法，所述方法包括：通过向患者施用治疗有效量的物质A或药物；所述药物包含①物质A和②药学上可接受的载体；所述物质A为如式Ⅰ所示化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
Figure PCTCN2022094257-appb-000002
所述治疗和/或预防糖尿病足的方法中，所述物质A或药物的施用频率可为1次/日、2次/日或3次/日。每次施用所述药物时，所述药物所含有的物质A的剂量可根据受试者/患者的实际治疗效果来确定。较佳地，所述物质A中的如式Ⅰ所示化合物的质量占所述药物的0.1-4％，例如0.1％、0.2％、0.3％、0.4％、0.5％、0.6％、0.7％、0.8％、0.9％、1.0％、1.1％、1.2％、1.3％、1.4％、1.5％、1.6％、1.7％、1.8％、1.9％、2.0％、2.1％、2.2％、2.3％、2.4％、2.5％、2.6％、2.7％、2.8％、2.9％、3.0％、3.1％、3.2％、3.3％、3.4％、3.5％、3.6％、3.7％、3.8％、3.9％或4.0％。
所述治疗和/或预防糖尿病足的方法中，所述如式Ⅰ所示化合物的质量分数为0.3-3％，例如0.3％、1％或3％。
所述治疗和/或预防糖尿病足的方法中，所述药物由0.3-3％如式Ⅰ所示化合物、1％卡波姆940NF、50％丙二醇、13％二乙二醇单乙基醚、1％三乙醇胺 和水组成，水补足100％。
所述治疗和/或预防糖尿病足的方法中，所述如式Ⅰ所示化合物或药物通过增加糖尿病足病人的伤口愈合能力治疗和/或预防糖尿病足。
所述治疗和/或预防糖尿病足的方法中，所述药物的剂型为外用制剂，例如乳膏剂、软膏剂或凝胶剂，优选为凝胶剂。
本发明还提供了一种药物组合物，其包括物质A和药学上可接受的载体；所述物质A为如式Ⅰ所示化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；所述如式Ⅰ所示化合物的质量分数为0.1-4％；
Figure PCTCN2022094257-appb-000003
所述组合物中，较佳地，所述如式Ⅰ所示化合物的质量分数为0.3-3％；例如0.3％、1％或3％。
所述组合物由0.3-3％所述如式Ⅰ所示化合物、1％卡波姆940NF、50％丙二醇、13％二乙二醇单乙基醚、1％三乙醇胺和水组成，水补足100％。
所述组合物中，较佳地，所述组合物用于治疗和/或预防糖尿病足。
本发明还提供了一种外用组合物，其包括物质A和药学上可接受的载体；所述物质A为如式Ⅰ所示化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
Figure PCTCN2022094257-appb-000004
所述外用组合物中，较佳地，所述如式Ⅰ所示化合物的质量分数为0.1-4％；优选地，所述如式Ⅰ所示化合物的质量分数为0.3-3％，例如0.3％、1％或3％。
所述外用组合物中，所述药学上可接受的载体为本领域此类外用组合物常规的载体；较佳地，所述药学上可接受的载体至少为卡波姆、丙二醇、二乙二醇单乙基醚、三乙醇胺和水。
本发明中，所述卡波姆选自卡波姆940NF、卡波姆934、卡波姆974、卡波姆981或卡波姆1342中的一种或多种。
所述外用组合物中，所述外用组合物的剂型可为乳膏剂、软膏剂或凝胶剂，例如凝胶剂。
所述外用组合物中，较佳地，所述外用组合物可用于治疗和/或预防糖尿病足。
所述外用组合物由0.3-3％所述如式Ⅰ所示化合物、1％卡波姆940NF、50％丙二醇、13％二乙二醇单乙基醚、1％三乙醇胺和水组成，水补足100％。本发明还提供了一种凝胶剂，其包括物质A和药学上可接受的载体；所述物质A为如式Ⅰ所示化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
Figure PCTCN2022094257-appb-000005
所述凝胶剂中，较佳地，所述如式Ⅰ所示化合物的质量分数为0.1-4％；优选地，所述如式Ⅰ所示化合物的质量分数为0.3-3％，例如0.3％、1％或3％。
所述凝胶剂中，所述药学上可接受的载体为本领域此凝胶剂常规的载体；较佳地，所述药学上可接受的载体为卡波姆、丙二醇、二乙二醇单乙基醚、三乙醇胺和水。
所述凝胶剂中，用质量百分数计，所述凝胶剂包括0.3-3％如式Ⅰ所示化合物、1％所述卡波姆940NF、50％所述丙二醇、13％所述二乙二醇单乙基醚、1％所述三乙醇胺，由水补足100％。
所述凝胶剂中，较佳地，所述外用组合物可用于治疗和/或预防糖尿病足。
所述凝胶剂由0.3-3％所述如式Ⅰ所示化合物、1％卡波姆940NF、50％丙二醇、13％二乙二醇单乙基醚、1％三乙醇胺和水组成，水补足100％。
本发明中提及到的所述如式Ⅰ所示化合物的质量分数是指式所述Ⅰ所示化合物的结构对应的质量占药物或组合物的总质量，例如当所述Ⅰ所示化合物以盐形式存在时，以其阴离子计算质量占比。
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领 域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“治疗有效量”是指在给予患者时足以有效治疗本文所述疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，但可由本领域技术人员根据需要进行调整。
术语“患者”是指根据本发明的实施例，即将或已经接受了该化合物给药的任何动物，哺乳动物为优，人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明提供了一种物质A在制备药物中的应用，所述物质A为如式Ⅰ所示化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐。本发明的物质A或包含物质A的药物对糖尿病足病人具有良好的活性。
附图说明
图1为化合物Ⅰ凝胶局部用药对糖尿病大鼠禁食血糖的影响；
图2为化合物Ⅰ局部用药11天对糖尿病大鼠创面开放率的影响；
图3为各实验组第1天和第11天创面愈合代表性照片。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
1.下述实施例中的化合物Ⅰ是指
Figure PCTCN2022094257-appb-000006
2.实验材料：
1)受试物：将化合物Ⅰ制备为分别含有质量分数0.3％的化合物Ⅰ、质量分数1％的化合物Ⅰ和质量分数3％的化合物Ⅰ的凝胶剂；以质量分数3％的化合物Ⅰ的凝胶剂为例，其各成分的质量分数如下表1所示：
表1
原辅料占比 (w/w)％
化合物Ⅰ 3.0
卡波姆940NF 1.0
丙二醇 50.0
二乙二醇单乙基醚 13.0
三乙醇胺 1.0
水 32.0
合计 100.0
化合物I占比0.3％和1％质量分数的凝胶剂，与上述化合物I占比3％的凝胶剂的制备方法区别仅在于化合物Ⅰ的质量分数不同，变化部分的质量分 数用水补足100％。
供应方：化合物Ⅰ由广州嘉越医药科技有限公司提供，也可按照WO2017177974A1中实施例2制备得到；
给药方式：每个创面50mg直接给药。
2)阳性对照品：
金因肽(重组人表皮生长因子外用溶液)规格：2000IU/mL，15mL/支
供应方：珠海亿胜生物制药有限公司
实施例1 STZ诱导大鼠糖尿病后制作全层背部皮肤缺损模型及药效评价；
1.动物：Wistar大鼠，雄性，15-16周，体重约220g；供应商：上海西普尔-必凯实验动物有限公司；
本研究中使用50只STZ糖尿病大鼠，模拟I型糖尿病，另有8只正常大鼠作为对照组(正常空白凝胶对照组(无STZ))。STZ糖尿病大鼠建模方式如下：雄性Wistar大鼠，称重后按照80mg/kg剂量腹腔注射链脲佐菌素(STZ，新鲜配制，溶于0.1M柠檬酸盐缓冲液(pH4.5))。STZ共计腹腔注射注射链脲佐菌素两次，时隔5天进行。第二次STZ注射3天后空腹血糖水平＞250mg/dl定义为糖尿病模型大鼠，糖尿病大鼠建模成功后1周至8周均可进行皮肤创口愈合研究。
2.给药组别及给药方案如表2。
表2
Figure PCTCN2022094257-appb-000007
Figure PCTCN2022094257-appb-000008
a：若有伤口未愈合的动物，将延长给药至伤口愈合
3.背部全层皮肤缺损模型制备
糖尿病模型大鼠使用印章标记背部皮肤，全层切除造成标准面积创口。皮肤全层切除手术日定为实验的第1天。具体手术过程如下：
1)手术前，动物2-5％异氟烷麻醉，背部进行脱毛备皮，手术区域使用碘伏消毒，并用75％酒精脱碘消毒；
2)所有动物使用带有圆形的印章标记大鼠背部皮肤，在大鼠背中线做一个圆形的全层皮肤切除，深至筋膜层，每个切口直径约为1.5cm。每只动物手术部位基本保持一致；
3)术后每8-12小时在伤口处皮下注射8mg/kg的布比卡因(生理盐水稀释至0.25％)。所有的动物都将受到密切监控，直到它们恢复意识。每天对动物进行监测，如果疼痛症状持续存在，动物将继续接受疼痛药物治疗。
4.给药
所有实验组局部用药。用药前用生理盐水冲洗伤口，用无菌棉签吸干残留水分，然后涂抹药物。金因肽组溶液均匀涂抹在伤口及周围皮肤，每天换药两次。其余组的凝胶样品从外周向内涂抹，先主要涂抹在病变的边缘，然后往内覆盖，每天换药两次。伤口造模后立即涂药，各组连续用药18天。具体给药信息见表2。
5.药效评价指标
1)血糖监测：所有动物均采用尾静脉采血的方式获得血液样品，采用血糖仪在第0/9/18天测定各动物的空腹血糖含量；
2)伤口闭合的评价：
用异氟烷麻醉大鼠后，把直尺摆放在伤口附近作为参考标尺,采用数码相机在第1天，第4天，第8天，第11天，第14天，第18天保持固定焦距、像素条件下对大鼠背部创面进行拍照，获得的图像使用软件处理测量创面面积。
6.统计分析
实验数据用均数±标准误表示(mean±S.E.M.)。数据由Graphpad Prism或SPSS采用相应的统计方法分析。p<0.05认为有显著性差异。
7.结果
1)禁食血糖
表3受试物化合物Ⅰ局部用药对糖尿病大鼠禁食血糖水平的影响
Figure PCTCN2022094257-appb-000009
注：***，p<0.001，与正常空白凝胶对照组相比。
实验期间，分别在第0/9/18天检测动物禁食血糖，从图1和表3可以看出，与正常空白凝胶对照组G6比较，所有糖尿病模型组G1-5动物血糖显著升高，并在实验过程中稳定维持在400mg/dL以上。与模型空白凝胶对照组G1比较，各给药物组药物处理对动物血糖没有显著的影响。
2)创面开放率
本实验在术后当天开始治疗给药，每日两次在创面涂抹药物，用药时间 至术后第18天或至伤口完全愈合。在局部用药11天后，参比药物金因肽组的创面开放率显著低于模型空白凝胶对照组(22.43％±1.37％vs.27.99％±2.31％,P<0.05)，提示金因肽具有促进糖尿病伤口愈合的作用。与模型空白凝胶对照组相比，1％和3％化合物Ⅰ在用药第11天时亦显著降低创面开放率(19.66％±1.93％vs.27.99％±2.31％,P<0.01；22.23％±0.87％vs.27.99％±2.31％,P<0.05)，提示化合物Ⅰ在1％和3％浓度下均有促进糖尿病创口愈合作用(表4和图2)。在局部用药14天后，也观察到受试物化合物Ⅰ凝胶在1％和3％浓度水平下，创面开放率有减小的趋势，但无统计学差异(表4)。各实验组第1天和第11天创面愈合代表性照片如图3所示。
表4受试物化合物Ⅰ局部用药对糖尿病大鼠创面开放率的影响
Figure PCTCN2022094257-appb-000010
Figure PCTCN2022094257-appb-000011
注：*，p<0.05，**，p<0.01，与模型空白凝胶对照组相比。
创面开放率＝开放创面面积(O)/创面初始面积(I)*100％
结论：采用STZ诱导大鼠糖尿病后制作全层背部皮肤缺损模型，受试物每天两次局部给药持续18天，与模型空白凝胶对照组相比，1％和3％化合物Ⅰ凝胶及对照品金因肽在给药后第11天显著降低伤口创面开放率，结果显示1％和3％化合物Ⅰ促进伤口愈合。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理 解，这些仅是举例说明，在不违背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (10)

  1. 一种物质A在制备药物中的应用，其特征在于，所述物质A为如式Ⅰ所示化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；所述药物为治疗和/或预防糖尿病足的药物；
    Figure PCTCN2022094257-appb-100001
  2. 如权利要求1所述物质A在制备药物中的应用，其特征在于，所述药物通过增加糖尿病足病人的伤口愈合能力治疗和/或预防糖尿病足；
    和/或，所述药物包含①物质A和②药学上可接受的载体；
    和/或，所述药物的施用频率为1次/日、2次/日或3次/日；
    和/或，所述药物的剂型为外用制剂；
    和/或，所述物质A中的如式Ⅰ所示化合物的质量占所述药物的0.1-4％。
  3. 如权利要求2所述物质A在制备药物中的应用，其特征在于，所述药物的剂型为乳膏剂、软膏剂或凝胶剂，优选为凝胶剂；
    和/或，所述物质A中的如式Ⅰ所示化合物的质量占所述药物的0.1％、0.2％、0.3％、0.4％、0.5％、0.6％、0.7％、0.8％、0.9％、1.0％、1.1％、1.2％、1.3％、1.4％、1.5％、1.6％、1.7％、1.8％、1.9％、2.0％、2.1％、2.2％、2.3％、2.4％、2.5％、2.6％、2.7％、2.8％、2.9％、3.0％、3.1％、3.2％、3.3％、3.4％、3.5％、3.6％、3.7％、3.8％、3.9％或4.0％。
  4. 一种治疗和/或预防糖尿病足的方法，其特征在于，所述方法包括：通过向患者施用治疗有效量的物质A或药物；所述药物包含①物质A和②药学上可接受的载体；所述物质A为如式Ⅰ所示化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
    Figure PCTCN2022094257-appb-100002
  5. 如权利要求4所述治疗和/或预防糖尿病足的方法，其特征在于，所述物质A或药物的施用频率为1次/日、2次/日或3次/日；
    和/或，所述物质A或药物过增加糖尿病足病人的伤口愈合能力治疗和/或预防糖尿病足；
    和/或，所述药物的剂型为外用制剂；
    和/或，所述物质A中的如式Ⅰ所示化合物的质量占所述药物的0.1-4％。
  6. 如权利要求5所述治疗和/或预防糖尿病足的方法，其特征在于，所述药物的剂型为乳膏剂、软膏剂或凝胶剂，优选为凝胶剂；
    和/或，所述物质A中的如式Ⅰ所示化合物的质量占所述药物的0.1％、0.2％、0.3％、0.4％、0.5％、0.6％、0.7％、0.8％、0.9％、1.0％、1.1％、1.2％、1.3％、1.4％、1.5％、1.6％、1.7％、1.8％、1.9％、2.0％、2.1％、2.2％、2.3％、2.4％、2.5％、2.6％、2.7％、2.8％、2.9％、3.0％、3.1％、3.2％、3.3％、3.4％、3.5％、3.6％、3.7％、3.8％、3.9％或4.0％。
  7. 一种药物组合物，其特征在于，其包括物质A和药学上可接受的载体；所述物质A为如式Ⅰ所示化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；所述如式Ⅰ所示化合物的质量分数为0.1-4％；
    Figure PCTCN2022094257-appb-100003
    较佳地，所述如式Ⅰ所示化合物的质量分数为0.3-3％，例如0.3％、1％或3％。
  8. 一种外用组合物，其特征在于，其包括物质A和药学上可接受的载体；所述物质A为如式Ⅰ所示化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
    Figure PCTCN2022094257-appb-100004
    较佳地，所述如式Ⅰ所示化合物的质量分数为0.1-4％；优选地，所述如式Ⅰ所示化合物的质量分数为0.3-3％，例如0.3％、1％或3％；
    和/或，所述药学上可接受的载体至少为卡波姆、丙二醇、二乙二醇单乙基醚、三乙醇胺和水；所述卡波姆优选自卡波姆940NF、卡波姆934、卡波姆974、卡波姆981或卡波姆1342中的一种或多种；
    和/或，所述外用组合物中，所述外用组合物的剂型为乳膏剂、软膏剂或凝胶剂，例如凝胶剂。
  9. 一种凝胶剂，其特征在于，其包括物质A和药学上可接受的载体；所述物质A为如式Ⅰ所示化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
    Figure PCTCN2022094257-appb-100005
    较佳地，所述如式Ⅰ所示化合物的质量分数为0.1-4％；优选地，所述如式Ⅰ所示化合物的质量分数为0.3-3％，例如0.3％、1％或3％；
    和/或，所述凝胶剂为外用制剂；
    和/或，所述药学上可接受的载体至少为卡波姆、丙二醇、二乙二醇单乙基醚、三乙醇胺和水。
  10. 如权利要求9所述的凝胶剂，其特征在于，所述凝胶剂中，用质量百分数计，所述凝胶剂包括0.3-3％如式Ⅰ所示化合物、1％所述卡波姆940NF、50％所述丙二醇、13％所述二乙二醇单乙基醚、1％所述三乙醇胺，由水补足100％。
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