WO2021119902A1 - 一种萘脲类化合物的应用 - Google Patents

一种萘脲类化合物的应用 Download PDF

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Publication number
WO2021119902A1
WO2021119902A1 PCT/CN2019/125567 CN2019125567W WO2021119902A1 WO 2021119902 A1 WO2021119902 A1 WO 2021119902A1 CN 2019125567 W CN2019125567 W CN 2019125567W WO 2021119902 A1 WO2021119902 A1 WO 2021119902A1
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substance
group
pharmaceutical composition
halogen
alkyl
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PCT/CN2019/125567
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English (en)
French (fr)
Inventor
张飞
王森
张艳宏
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苏州锐明新药研发有限公司
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Application filed by 苏州锐明新药研发有限公司 filed Critical 苏州锐明新药研发有限公司
Priority to EP19956312.3A priority Critical patent/EP4079303A4/en
Priority to CN202410576216.6A priority patent/CN118477072A/zh
Priority to PCT/CN2019/125567 priority patent/WO2021119902A1/zh
Priority to CN201980099600.9A priority patent/CN114269339A/zh
Priority to US17/785,713 priority patent/US20230062969A1/en
Priority to JP2022536628A priority patent/JP7426754B2/ja
Priority to AU2019478778A priority patent/AU2019478778B2/en
Publication of WO2021119902A1 publication Critical patent/WO2021119902A1/zh

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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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • the invention relates to an application of a naphthylurea compound.
  • the cornea is an important part of the refractive interstitium of the eye, which is transparent and avascular.
  • the clear cornea is very important for maintaining the visual function of the eye.
  • the avascular state of the cornea is based on low levels of angiogenic factors and high levels of anti-angiogenic factors. Under pathological conditions, the balance between corneal angiogenesis factors and inhibitors is broken, resulting in pathological corneal neovascularization (CNV).
  • CNV pathological corneal neovascularization
  • the technical problem to be solved by the present invention is that the existing drugs for the treatment of ophthalmic diseases related to corneal neovascularization have a single structure. For this reason, the present invention provides an application of a naphthylurea compound, which can be dripped The ophthalmic administration method treats ophthalmic diseases related to corneal neovascularization, fills the gap in this field, and has significant social and economic benefits.
  • the present invention provides an application of substance A in the preparation of medicines.
  • Said substance A is a naphthylurea compound represented by formula I, its pharmaceutically acceptable salt, its solvate, and its pharmaceutically acceptable
  • the solvate of the salt of, its crystal form or its tautomer, said drug is a drug for the treatment of corneal neovascular disease;
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from H, halogen or C 1 ⁇ C 6 alkyl;
  • X is CH or N
  • R 6 is H or -O-(CH 2 ) n -Y;
  • Y is a 5- to 6-membered heterocycloalkyl group, the heteroatom in the 5- to 6-membered heterocycloalkyl group is N, and the number of the heteroatom is 1 to 2;
  • n 2, 3, 4, or 5.
  • the halogen may be fluorine, chlorine, bromine or iodine, such as fluorine.
  • the C 1 ⁇ C 6 alkyl group may be a C 1 ⁇ C 3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl .
  • the 5- to 6-membered heterocycloalkyl group may be a 5- to 6-membered heterocycloalkyl group containing 1 N, for example
  • n is 2 or 3 (e.g., 3).
  • R 1, R 2, R 3 , R 4 and R 5 are independently C 1 ⁇ C 3 alkyl (such as methyl), and the rest are independently halogen or H.
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently H, and the rest are independently halogen (such as fluorine) or C 1 ⁇ C 3 alkyl (E.g. methyl).
  • X is CH
  • R 6 is -O-(CH 2 ) n -Y.
  • the naphthylurea compound represented by formula I its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form or its mutual variation
  • some groups are defined as follows, and undefined groups are as described in any of the previous schemes:
  • X is N and R 6 is H.
  • the naphthylurea compound represented by formula I its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form or its mutual variation
  • some groups are defined as follows, and undefined groups are as described in any of the previous schemes:
  • the naphthylurea compound represented by formula I its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form or its mutual variation
  • some groups are defined as follows, and undefined groups are as described in any of the previous schemes:
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently H, and the rest are independently halogen (such as fluorine) or C 1 ⁇ C 3 alkyl (e.g. methyl);
  • R 1 , R 2 , R 3 , R 4 and R 5 are halogen (such as fluorine), R 1 , R 2
  • R 3 , R 4 and R 5 is a C 1 -C 3 alkyl group (e.g. methyl), and the rest are H.
  • the naphthylurea compound represented by formula I is selected from any of the following structures:
  • the dosage form of the medicine can be eye drops.
  • the mass concentration of the substance A is 10-30 mg/mL (for example, 20 mg/mL).
  • the eye drops refer to a sterile liquid preparation made of drugs and suitable ophthalmic pharmaceutical auxiliary materials.
  • the eye drops can be divided into aqueous solution eye drops, oily solution eye drops, suspension eye drops or emulsion eye drops.
  • the present invention also provides a pharmaceutical composition, which comprises the above-mentioned substance A and ophthalmic pharmaceutical excipients.
  • the pharmaceutical composition is a pharmaceutical composition for treating corneal neovascular disease.
  • the dosage form of the pharmaceutical composition can be eye drops.
  • the mass concentration of the substance A is 10-30 mg/mL (for example, 20 mg/mL).
  • the present invention also provides a substance A for treating corneal neovascular disease, and the substance A is as described above.
  • the present invention provides a method for treating corneal neovascular disease in a patient in need, which comprises: administering a therapeutically effective amount of the above-mentioned substance A or the above-mentioned pharmaceutical composition to the patient in need.
  • the "administration" can be administered in the form of eye drops.
  • the patient can be a mammal, such as a rabbit or a human.
  • the substance A or the pharmaceutical composition can be administered according to a conventional dosage, and based on the substance A, a non-limiting example range can be 1 mg/eye-3 mg/eye ( Single dose), for example 1 mg/eye.
  • the frequency of administration of the substance A or the pharmaceutical composition may be four times a day.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • the compound of the present invention contains a relatively acidic functional group, it can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt.
  • the acid addition can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.
  • a pharmaceutically acceptable acid include inorganic acids, and the inorganic acids include, but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
  • the pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , Tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e.
  • solvate refers to a substance formed by combining the compound of the present invention with a stoichiometric or non-stoichiometric solvent.
  • the solvent molecules in the solvate can exist in an ordered or non-ordered arrangement.
  • the solvents include but are not limited to: water, methanol, ethanol and the like.
  • pharmaceutically acceptable salt solvate and “solvate” in the term “pharmaceutically acceptable salt” and “solvate” are as described above, and mean that the compound of the present invention is combined with 1, and relatively non-toxic, pharmaceutically acceptable 2.
  • solvate of a pharmaceutically acceptable salt includes, but is not limited to, the hydrochloric acid monohydrate of the compound of the present invention.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in a molecule at two positions. For example, acetone and 1-propene-2-ol can be converted into each other by the rapid movement of hydrogen atoms on oxygen and ⁇ -carbon.
  • crystal form means that the ions or molecules are arranged strictly and periodically in a three-dimensional space in a certain way, and have the regularity of periodic recurrence at a certain distance; due to the above-mentioned periodic arrangement, there may be multiple Crystal form, that is, polymorphism.
  • alkyl refers to a straight or branched chain alkyl group having the specified number of carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and similar alkyl groups.
  • heterocycloalkyl refers to a saturated monocyclic group with heteroatoms.
  • ophthalmic pharmaceutical excipients refers to excipients and additives used in the production of drugs and formulating prescriptions, and are all substances contained in pharmaceutical preparations except for active ingredients. Please refer to the Fourth Edition of the Pharmacopoeia of the People's Republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition)
  • treatment refers to therapeutic therapy.
  • treatment refers to: (1) alleviating one or more biological manifestations of the disease or disease, (2) interfering with (a) one or more points in the biological cascade causing or causing the disease, or (b) ) One or more biological manifestations of the disease, (3) improving one or more symptoms, effects or side effects related to the disease, or one or more symptoms, effects or side effects related to the disease or its treatment, Or (4) to slow down the development of the disease or one or more biological manifestations of the disease.
  • terapéuticaally effective amount refers to an amount of a compound that is sufficient to effectively treat the diseases or conditions described herein when administered to a patient in need thereof.
  • the “therapeutically effective amount” will vary according to the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted by those skilled in the art as needed.
  • patient refers to any animal that is about to or has received administration of the compound or composition according to an embodiment of the present invention, mammals are preferred, and humans are preferred.
  • 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 the most preferred.
  • corneal neovascularization refers to ophthalmic diseases caused by corneal neovascularization.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the naphthylurea compounds of the present invention can treat corneal neovascular disease by means of eye drops, fill the gap in this field, and have significant social and economic benefits.
  • Age and weight 4-6 months old, weighing 2.305-3.280kg at the time of modeling;
  • the main inspection contents include the general state of the animal, weight measurement, eye examination and corneal fluorescence staining.
  • the animals included in the formal experiment were healthy animals with no abnormalities in the ocular surface.
  • the IACUC number for this experiment is IACUC-B2019030-P001-01.
  • the method used in this animal experiment is to use a highly recognized operating method after consulting a large amount of literature. During the experiment, the animals experienced short-term, slight pain or discomfort, and local anesthetics were appropriately given to relieve the symptoms.
  • Breeding cage type stainless steel rabbit cage (L ⁇ W ⁇ H: 550mm ⁇ 550mm ⁇ 400mm);
  • Humidity relative humidity 45.44 ⁇ 72.40%
  • Lighting artificial lighting, 12/12 hours day and night alternately.
  • Feed type rabbit growth and breeding feed; Beijing Keyao Xieli Feed Co., Ltd.
  • Feed production license Beijing Feed Certificate (2014) 06054;
  • Feeding method free intake.
  • Water supply method drinking water for laboratory animals; drinking water bottle for free ingestion.
  • Preparation method In a biological safety cabinet, fully shake A01, A02, A03, and B01 eye drops, separate them into 1.8ml test samples, and distribute them directly;
  • Preparation frequency 1 time/day
  • Labeling method after preparation The A01, A02, A03, and B01 administered preparations issued are marked with green, blue, red, and yellow labels, and the test number, test substance name, storage conditions, expiration date, responsible person, and finished product are indicated. Number and date of issuance;
  • Temporary storage conditions and validity period after preparation and packaging sealed and stored at room temperature, and used within the same day.
  • Group design model control group, A01 group, A02 group, A03 group, B01 group. See Table 5 for specific grouping information.
  • Grouping method use the PRISTIMA data system to randomly group the rabbits by sex according to their body weight;
  • the first digit of the animal number represents the group (1, 2, 3, 4, and 5 respectively represent the model control group, A01 group, A02 group, A03 group, and B01 group).
  • the second letter represents gender (M is male, F is female), and the third, fourth, and fifth digits represent the animal serial number.
  • Japanese big-eared rabbits were anesthetized with pentobarbital sodium for the first time (25 mg/kg, intravenous injection at the ear edge), disinfected the periphery of the eye with 0.5% povidone iodine, covered with a special wound towel for ophthalmology, opened the upper and lower eyelids with a eyelid opener to expose eyeball.
  • antibiotics were given to the eyes, 3 times a day, for three days.
  • Dosing frequency start dosing on the 2nd day after modeling, 4 times/day each time interval is not less than 4 hours, continuous dosing for 14 days;
  • Dosing volume 50 ⁇ L/eye
  • Method of administration Lift the lower eyelid of the animal, expose the conjunctival sac, directly instill the test or reference substance into the rabbit conjunctival sac, and lightly close the eyelid for about 8-10 seconds;
  • Test personnel Observe at least once a day during the administration period. If toxic symptoms occur, increase the number of observations;
  • Veterinarian/veterinary technician at least once a week.
  • Test personnel and veterinarians including but not limited to local reactions in rabbit eyes (with or without congestion, edema, increased secretions, etc.), physical signs, coat, general behavior, mental status, glandular secretion, skin and mucous membrane color, respiratory status , Stool traits, genitals, death, and other toxic symptoms.
  • Inspection time check once before administration and 2, 4 and 7 days after administration respectively;
  • Inspection method Use a slit lamp microscope to examine the anterior segment of the eye, namely conjunctiva, cornea, anterior chamber, iris, lens and other structures, focusing on observation of abnormal conditions such as ocular inflammation, such as corneal turbidity and ulcers.
  • Inspection time 1 inspection each 7 and 14 days after administration
  • Measurement method use a digital camera connected to the slit lamp to collect images of corneal neovascularization, and then use image analysis software to analyze the images;
  • Detection indicators corneal neovascularization area, the percentage of corneal neovascularization area to corneal area.
  • Anatomical animals 4 in the model control group and 4 in each administration group;
  • Anesthesia and dissection method Anesthetize with pentobarbital sodium according to body weight (intravenous injection about 30mg/kg, the dose can be adjusted according to animal health), abdominal aorta or femoral artery bloodletting is euthanized, and unilateral eyeball is removed and stored in modified Davidson ′S fixed solution for storage.
  • the rabbits in each group were in good mental condition after the model was made to the end of the experiment, their autonomous activities were normal, the skin and coat were clean, and there were no abnormal reactions in eating or feces. Among them, the rabbit with the number 2M004 in group A01 had an accident during the operation, and there was no data on this animal.
  • the model control group, A01 group, A02 group, A03 group and B01 group had corneal sutures in place and mild corneal and conjunctival edema, indicating that the model was successful.
  • the area of corneal neovascularization showed a gradually increasing trend, 3.5 ⁇ 1.6mm 2 and 7.6 ⁇ 2.5mm 2 respectively , and the percentage of corneal neovascularization was 6.7 ⁇ 3.0% and 15.2 ⁇ 7.1%, respectively.
  • the area of corneal neovascularization gradually increased to 0.6 ⁇ 1.1mm 2 and 4.0 ⁇ 3.4mm 2 respectively , and the percentage of corneal neovascularization was 1.2 ⁇ 2.5% and 8.2 ⁇ 7.0%, respectively.
  • the area of corneal neovascularization and its percentage were statistically significant (P ⁇ 0.05).
  • the area of corneal neovascularization gradually increased to 0.7 ⁇ 1.2mm 2 and 3.1 ⁇ 2.1mm 2 respectively.
  • the percentage of corneal neovascularization was 1.3 ⁇ 2.3% and 6.4 ⁇ 4.4%, respectively.
  • the area of corneal neovascularization and its percentage at 7 days after the administration was statistically significant (P ⁇ 0.05), and the area of corneal neovascularization at 14 days after the administration was significantly different from the model control group (P ⁇ 0.05).
  • the area of corneal neovascularization gradually increased to 0.4 ⁇ 0.8mm 2 and 3.4 ⁇ 2.4mm 2 respectively.
  • the percentage of corneal neovascularization was 0.8 ⁇ 1.4% and 5.9 ⁇ 4.2%, respectively.
  • the area and percentage of corneal neovascularization were statistically significant (P ⁇ 0.05).
  • the area of corneal neovascularization gradually increased to 1.1 ⁇ 1.0mm 2 and 7.8 ⁇ 4.5mm 2 respectively.
  • the percentage of corneal neovascularization was 2.4 ⁇ 2.3% and 16.2 ⁇ 11.4%, respectively.
  • the area of corneal neovascularization and its percentage were statistically significant (P ⁇ 0.05).

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Abstract

本发明提供了一种物质A在制备药物中的应用。所述的物质A为如式I所示的萘脲类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、其晶型或其互变异构体，所述的药物为用于治疗眼角膜新生血管病的药物。本发明的萘脲类化合物可以通过滴眼的给药方式治疗眼角膜新生血管病。

Description

一种萘脲类化合物的应用 技术领域
本发明涉及一种萘脲类化合物的应用。
背景技术
角膜是眼屈光间质的重要组成部分，具有透明性、无血管性。透明角膜对维持眼视光功能十分重要。角膜的无血管状态是以低水平的血管生成因子和高水平的抗血管生成因子为基础。在病理情况下，角膜血管生成因子和抑制因的平衡被打破，从而产生病理性角膜新生血管(corneal neovascularization，CNV)。
在药物研究领域，同一种作用机理虽然原理上一样，但不一定对该原理有关的所以疾病都有作用，药物对不同部位的作用因为不同的给药方式、吸收、代谢、浓度和环境等具体作用的情况不同。
发明内容
本发明所要解决的技术问题是现有的、用于治疗角膜新生血管有关的眼科疾病的药物的结构单一，为此，本发明提供了一种萘脲类化合物的应用，该类化合物可以通过滴眼的给药方式治疗角膜新生血管有关的眼科疾病，填补该领域的空白，具有重大的社会效益和经济效益。
本发明提供了一种物质A在制备药物中的应用，所述的物质A为如式I所示的萘脲类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、其晶型或其互变异构体，所述的药物为用于治疗眼角膜新生血管病的药物；
Figure PCTCN2019125567-appb-000001
其中，R 1、R 2、R 3、R 4和R 5独立地选自H、卤素或C 1～C 6烷基；
X为CH或N；
R 6为H或-O-(CH 2) n-Y；
Y为5～6元杂环烷基，所述的5～6元杂环烷基中杂原子为N，所述的杂原子的个数为1～2个；
n为2、3、4或5。
R 1、R 2、R 3、R 4或R 5中，所述的卤素可为氟、氯、溴或碘，例如氟。
R 1、R 2、R 3、R 4或R 5中，所述的C 1～C 6烷基可为C 1～C 3烷基，例如甲基、乙基、正丙基或异丙基。
Y中，所述的5～6元杂环烷基可为含1个N的5～6元杂环烷基，再例如为
Figure PCTCN2019125567-appb-000002
R 6中，较佳地，n为2或3(例如3)。
本发明中，较佳地，R 1、R 2、R 3、R 4和R 5中有1～2个独立地为C 1～C 3烷基(例如甲基)，其余独立地为卤素或H。
本发明中，较佳地，R 1、R 2、R 3、R 4和R 5中有3～4个独立地为H，其余独立地为卤素(例如氟)或C 1～C 3烷基(例如甲基)。
在某一方案中，如式I所示的萘脲类化合物某些基团的定义如下，未定义的基团如前任一方案所述：
X为CH，R 6为-O-(CH 2) n-Y。
在某一方案中，如式I所示的萘脲类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、其晶型或其互变异构体中，某些基团的定义如下，未定义的基团如前任一方案所述：
X为N，R 6为H。
在某一方案中，如式I所示的萘脲类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、其晶型或其互变异构体中，某些基团的定义如下，未定义的基团如前任一方案所述：
Figure PCTCN2019125567-appb-000003
为
Figure PCTCN2019125567-appb-000004
(例如
Figure PCTCN2019125567-appb-000005
)。
在某一方案中，如式I所示的萘脲类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、其晶型或其互变异构体中，某些基团的定义如下，未定义的基团如前任一方案所述：
当X为N，R 6为H时，R 1、R 2、R 3、R 4和R 5中有3～4个独立地为H，其余独立地为卤素(例如氟)或C 1～C 3烷基(例如甲基)；
当X为CH、R 6为-O-(CH 2) n-Y时，R 1、R 2、R 3、R 4和R 5中有1个为卤素(例如氟)，R 1、R 2、R 3、R 4和R 5中有1个为C 1～C 3烷基(例如甲基)，其余为H。
本发明中，较佳地，所述的如式I所示的萘脲类化合物选自如下任一结构：
Figure PCTCN2019125567-appb-000006
Figure PCTCN2019125567-appb-000007
在所述的应用中，所述的药物的剂型可以为滴眼剂。
所述的滴眼剂中，较佳地，所述的物质A的质量浓度为10～30mg/mL(例如20mg/mL)。
所述的滴眼剂是指由药物与适宜的眼用药物辅料制成的无菌液体制剂。所述的滴眼剂可分为水性溶液滴眼剂、油性溶液滴眼剂、混悬液滴眼剂或乳状液滴眼剂。
本发明还提供了一种药物组合物，所述的药物组合物包括上述的物质A和眼用药用辅料。
本发明中，较佳地，所述的药物组合物为用于治疗眼角膜新生血管病的药物组合物。
所述的药物组合物的剂型可以为滴眼剂。
所述的滴眼剂中，较佳地，所述的物质A的质量浓度为10～30mg/mL(例如20mg/mL)。
本发明还提供了一种用于治疗眼角膜新生血管病的物质A，所述的物质A如上所述。
本发明提供了一种在有需要的患者中治疗眼角膜新生血管病的方法，其包括：向有需要的患者施用治疗有效量的上述的物质A或上述的药物组合物。
在所述的方法中，所述的“施用”的方式可为以滴眼剂的形式施用。
在所述的方法中，所述的患者可以为哺乳动物，例如兔或人类。
在所述的方法中，所述的物质A或所述的药物组合物可根据常规剂量来施用，以所述的物质A计，非限制性的实例范围可以为1mg/眼-3mg/眼(单次剂量)，例如1mg/眼。
在所述的方法中，所述的物质A或所述的药物组合物的施用频次可以为一天四次。
如无特别说明，本发明所用术语具有如下含义：
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于：水、甲醇、乙醇等。
术语“药学上可接受的盐的溶剂合物”中的“药学上可接受的盐”和“溶剂合物”如上所述，是指本发明化合物与1、与相对无毒的、药学上可接受的酸或碱制备得到的2、与化学计量或非化学计量的溶剂结合形成的物质。所述的“药学上可接受的盐的溶剂合物”包括但不限于本发明化合物的盐酸一水合物。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。例如，丙酮和1-丙烯-2-醇可以通过氢原子在氧上和α-碳上的迅速移动而互相转变。
术语“晶型”是指其中的离子或分子是按照一种确定的方式在三维空间作严格周期性排列，并具有间隔一定距离周期重复出现规律；因上述周期性排列的不同，可存在多种晶型，也即多晶型现象。
术语“烷基”是指具有指定的碳原子数的直链或支链烷基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基及其类似烷基。
术语“杂环烷基”是指具有杂原子的饱和的单环基团。
术语“眼用药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009 Sixth Edition)
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“治疗有效量”是指在给予有需要的患者时足以有效治疗本文所述的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或组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。
术语“眼角膜新生血管病”是指由角膜新生血管引起的眼科疾病。
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：本发明的萘脲类化合物可以通过滴眼的给药方式治疗眼角膜新生血管病，填补该领域的空白，具有重大的社会效益和经济效益。
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的实施例范围之中。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。
下述实施例所使用的化合物的结构如下：
化合物IV：
Figure PCTCN2019125567-appb-000008
化合物III：
Figure PCTCN2019125567-appb-000009
化合物V：
Figure PCTCN2019125567-appb-000010
化合物VI：
Figure PCTCN2019125567-appb-000011
效果实施例1 对兔角膜新生血管的抑制试验
1 试验材料
1.1 实验系统
1.1.1 实验动物
种属及等级：日本大耳白兔，普通级；
数量和性别：购入24只，雄性，造模时选用20只；
年龄和体重：4～6月龄，造模时体重2.305～3.280kg；
来源：四川省实验动物专委会养殖场，生产许可证号：SCXK(川)2018－14。质量合格证颁发、印制单位：四川省科技厅。
入室后环境适应期：主要检查内容包括动物一般状态、体重测定、眼科检查及角膜荧光染色。最终所纳入正式试验的动物均为健康且眼表无异常的 动物。
动物福利：本实验IACUC编号为，IACUC-B2019030-P001-01。本动物试验所用的方法是查阅大量文献资料后，采用认可度较高的一种操作方法。试验过程中动物出现短暂的、轻微的疼痛或不适，已适当给予局麻药缓解症状。
1.1.2 饲养地点和条件
成都华西海圻医药科技有限公司普通动物房中小区(第1栋)(实验动物使用许可证号：SYXK(川)2013-123)。
饲养笼种类：不锈钢兔笼(L×W×H：550mm×550mm×400mm)；
饲养密度：1只/笼。
饲养环境条件标准：中华人民共和国国标GB14925-2010；
温度：室温22.62-24.97℃(日温差0.57-1.56℃)；
湿度：相对湿度45.44～72.40％；
光照：人工照明，12/12小时昼夜明暗交替。
饲料种类：兔生长繁殖饲料；北京科澳协力饲料有限公司。饲料生产许可证：京饲证(2014)06054；
给料方法：自由摄取。
供水方法：实验动物饮用水；饮水瓶盛装，自由摄取。
1.1.3 动物标识方法
环境适应期：采用耳牌号和笼卡作为动物的识别标记；
分组后：采用耳牌号及笼卡作为动物识别标记。
1.2 供试品
1.2.1 基本信息
供试品1
名称或代号：A01滴眼液；
来源：苏州锐明新药研发有限公司；
主要成分如表1所示：
表1
Figure PCTCN2019125567-appb-000012
性状：肤色混悬液；
规格：20mg/mL；批号：201906001；pH：7.4；渗透压：未知；
有效期：2019年12月3日；
保存条件及注意事项：常温密封保存；
保存地点：本机构供试品管理部；
防护措施：常规(口罩、手套、工作服)。
供试品2
名称或代号：A02滴眼液；
来源：苏州锐明新药研发有限公司；
主要成分如表2所示：
表2
Figure PCTCN2019125567-appb-000013
Figure PCTCN2019125567-appb-000014
性状：肤色混悬液；
规格：20mg/mL；批号：201906001；pH：7.4；渗透压：未知；
有效期：2019年12月3日；
保存条件及注意事项：常温密封保存；
保存地点：本机构供试品管理部；
防护措施：常规(口罩、手套、工作服)。
供试品3
名称或代号：A03滴眼液；
来源：苏州锐明新药研发有限公司；
主要成分如表3所示：
表3
Figure PCTCN2019125567-appb-000015
性状：淡红色混悬液；
规格：20mg/mL；批号：201906001；pH：7.4；渗透压：未知；
有效期：2019年12月3日；
保存条件及注意事项：常温密封保存；
保存地点：本机构供试品管理部；
防护措施：常规(口罩、手套、工作服)。
供试品4
名称或代号：B01滴眼液；
来源：苏州锐明新药研发有限公司；
主要成分如表4所示：
表4
Figure PCTCN2019125567-appb-000016
性状：类白色混悬液；
规格：20mg/mL；批号：201906001；pH：7.4；渗透压：未知；
有效期：2019年12月3日；
保存条件及注意事项：常温密封保存；
保存地点：本机构供试品管理部；
防护措施：常规(口罩、手套、工作服)。
1.2.2 给药制剂配制
配制方法：在生物安全柜内，充分摇匀A01、A02、A03和B01滴眼液，分别分装1.8ml供试品，分装后直接发放；
配制频率：1次/天；
配制后标识方法：所发放的A01、A02、A03和B01给药制剂分别以绿、蓝、红、黄色标签标识，并注明试验编号、试验物质名称、保存条件、有效期、责任人、制剂成品编号及发放日期；
配制分装后暂存条件及有效期：常温密封保存，当日内使用。
2 试验方法和观察指标
2.1 动物分组
组别设计：模型对照组、A01组、A02组、A03组、B01组。具体分组信息见表5。
动物数量及性别：4只/组，雄性；
分组方法：采用PRISTIMA数据系统根据兔体重分性别随机分组；
剩余动物处置：分组后剩余动物移交实验动物管理部。
表5
Figure PCTCN2019125567-appb-000017
备注：动物编号的首位数字代表组别(1、2、3、4、5分别代表模型对照组、A01组、A02组、A03组、B01组)。第二位字母代表性别(M为雄性，F为雌性)，第三、四、五位数值代表动物序列号。
2.2 造模方法
日本大耳白兔经戊巴比妥钠首次麻醉(25mg/kg，耳缘静脉注射)，用0.5％聚维酮碘消毒眼外周，眼科专用创巾覆盖，开睑器撑开上下眼睑，暴露眼球。双眼滴1～2滴盐酸奥布卡因滴眼液局部麻醉，应用龙胆紫放射状标记角膜上1/4，于平行角膜缘约1.5mm处将第一行角膜缝线缝合于角膜基质，长度约为3.8mm；第二行缝线缝合于平行距离第一行缝线1.5mm处，长度约为3mm；将最后一根缝线缝合于距离第二排缝线1.5mm的三角形顶点位置。双眼造模。
术后抗生素点眼，3次/天，持续三天。
2.3 给药剂量设计及给药
本试验设A01组、A02组、A03组、B01组，分别给予A01、A02、A03和B01给药制剂。另设模型对照组，给予0.1％氯化钠灭菌注射用水。各组动物于建模后第2天开始给药。剂量设计如表6所示：
表6 剂量设计表
Figure PCTCN2019125567-appb-000018
给药途径：双眼滴眼给药；
给药途径选择理由：与临床拟用途径一致；
给药频率：建模后第2天开始给药，4次/天每次间隔不小于4小时，连续给药14天；
给药体积：50μL/眼；
给药方法：提起动物下眼睑，暴露眼结膜囊，将供试品或对照品直接滴 入兔眼结膜囊内，轻合眼睑约8～10秒；
2.4 观察指标
2.4.1 一般状态观察
2.4.1.1 观察时间与频率
动物饲养人员：每天1次；
试验人员：给药期每天至少观察1次。若出现毒性症状，可增加观察次数；
兽医/兽医技术员：每周至少1次。
2.4.1.2 观察动物及内容
观察动物：各组所有存活兔；
观察内容：
动物饲养人员：死亡及摄食、饮水；
试验人员及兽医：包括但不限于兔眼局部反应(有无充血、水肿、分泌物增多等)、外观体征、被毛、一般行为活动、精神状态、腺体分泌、皮肤和粘膜颜色、呼吸状态、粪便性状、生殖器、死亡等情况及其它毒性症状。
2.4.2 裂隙灯检查
检查时间：分别于造模后给药前及给药后2、4、7天各检查1次；
检查动物：所有存活各组动物；
检查方法：以裂隙灯显微镜检查眼前节即结膜、角膜、前房、虹膜、晶状体等结构，重点观察眼炎症等异常情况，如：角膜浑浊和溃疡等情况。
2.4.3 角膜新生血管面积测量
检查时间：分别于给药后7、14天各检查1次；
检查动物：所有存活各组动物；
测量方法：应用连接于裂隙灯的数码照相机采集角膜新生血管的图像，再应用图像分析软件对图像进行分析；
检测指标：角膜新生血管面积，角膜新生血管面积所占角膜面积的百分 比。
2.4.4 大体解剖
检查时间：给药后14天；
解剖动物：模型对照组4只，各给药组4只；
麻醉及解剖方法：根据体重以戊巴比妥钠麻醉(静脉注射约30mg/kg，可根据动物健康状况调整剂量)，腹主动脉或股动脉放血安乐死，取下单侧眼球保存于改良的Davidson′s固定液中固定保存。
3 结果
3.1 一般状况
各组兔造模后至试验结束均精神状况良好，自主活动正常，皮肤被毛清洁，摄食、粪尿均未见异常反应。其中，A01组编号为2M004的兔在手术过程出现意外，缺少该动物的数据。
3.2 造模情况及裂隙灯检查
造模后第2天，模型对照组、A01组、A02组、A03组和B01组角膜缝线在位、角膜结膜轻度水肿，提示造模成功。
模型对照组，A01组、A02组、A03组和B01组在给药后7、14天，裂隙灯检查可见角膜缝线在位，缝线部位角膜轻度水肿，角膜新生血管由角膜缘向角膜顶点生长，新生血管生长随时间变化增长。
3.3 角膜新生血管面积检查
表7 日本大耳兔角膜新生血管面积个体数据(mm 2)
Figure PCTCN2019125567-appb-000019
Figure PCTCN2019125567-appb-000020
Figure PCTCN2019125567-appb-000021
表8 日本大耳兔角膜新生血管面积占角膜百分比个体数据(％)
Figure PCTCN2019125567-appb-000022
Figure PCTCN2019125567-appb-000023
模型对照组给药后7、14天，角膜新生血管面积呈逐渐上升趋势，分别3.5±1.6mm 2、7.6±2.5mm 2，角膜新生血管面积百分比分别为6.7±3.0％、 15.2±7.1％。
A01组给药后7、14天，角膜新生血管面积逐渐上升，分别为0.6±1.1mm 2、4.0±3.4mm 2，角膜新生血管面积百分比分别为1.2±2.5％、8.2±7.0％，其中给药后7天角膜新生血管面积及其百分比与模型对照组相比差异有统计学意义(P≤0.05)。
A02组给药后7、14天，角膜新生血管面积逐渐上升，分别为0.7±1.2mm 2、3.1±2.1mm 2，角膜新生血管面积百分比分别为1.3±2.3％、6.4±4.4％，其中给药后7天角膜新生血管面积及其百分比与模型对照组相比差异有统计学意义(P≤0.05)，给药后14天角膜新生血管面积与模型对照组相比差异有统计学意义(P≤0.05)。
A03组给药后7、14天，角膜新生血管面积逐渐上升，分别为0.4±0.8mm 2、3.4±2.4mm 2，角膜新生血管面积百分比分别为0.8±1.4％、5.9±4.2％，其中给药后7、14天角膜新生血管面积及其百分比与模型对照组相比差异有统计学意义(P≤0.05)。
B01组给药后7、14天，角膜新生血管面积逐渐上升，分别为1.1±1.0mm 2、7.8±4.5mm 2，角膜新生血管面积百分比分别为2.4±2.3％、16.2±11.4％，其中给药后7天角膜新生血管面积及其百分比与模型对照组相比差异有统计学意义(P≤0.05)。
4 结论
综上所述，本试验用日本大耳白兔通过角膜缝线诱导角膜新生血管，经滴眼给予A01、A02、A03和B01 4mg/眼/天治疗，在第2、4、7天进行眼部裂隙灯检查，在第7、14天记录角膜新生血管面积。
结果显示，4mg/眼/天(1mg/眼/次)的A03对兔角膜新生血管抑制作用明显，4mg/眼/天(1mg/眼/次)的A02对兔角膜新生血管有一定的抑制作用，4mg/眼/天(1mg/眼/次)的A01对兔角膜新生血管有抑制的趋势，4mg/眼/天(1mg/眼/次)的B01对第7天角膜新生血管的抑制作用明显，但对第14天 (晚期)角膜新生血管的抑制作用不明显。也即，上述各化合物在该模型中，对兔角膜新生血管具有不同程度的抑制作用。
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 (12)

  1. 一种物质A在制备药物中的应用，其特征在于，所述的物质A为如式I所示的萘脲类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、其晶型或其互变异构体，所述的药物为用于治疗眼角膜新生血管病的药物；
    Figure PCTCN2019125567-appb-100001
    其中，R 1、R 2、R 3、R 4和R 5独立地选自H、卤素或C 1～C 6烷基；
    X为CH或N；
    R 6为H或-O-(CH 2) n-Y；
    Y为5～6元杂环烷基，所述的5～6元杂环烷基中杂原子为N，所述的杂原子的个数为1～2个；
    n为2、3、4或5。
  2. 如权利要求1所述的物质A在制备药物中的应用，其特征在于，R 1、R 2、R 3、R 4或R 5中，所述的卤素为氟、氯、溴或碘；较佳地，所述的卤素为氟；
    和/或，R 1、R 2、R 3、R 4或R 5中，所述的C 1～C 6烷基为C 1～C 3烷基；较佳地，所述的C 1～C 6烷基为甲基、乙基、正丙基或异丙基；
    和/或，Y中，所述的5～6元杂环烷基为含1个N的5～6元杂环烷基；较佳地，所述的5～6元杂环烷基为为
    Figure PCTCN2019125567-appb-100002
    和/或，R 6中，n为2或3，较佳地，n为3。
  3. 如权利要求1～2中至少一项所述的物质A在制备药物中的应用，其特征在于，R 1、R 2、R 3、R 4和R 5中有1～2个独立地为C 1～C 3烷基，其余独立地为卤素或H，其中，所述卤素较佳地为氟，所述C 1～C 3烷基较佳地为甲基；
    和/或，R 1、R 2、R 3、R 4和R 5中有3～4个为H，其余独立地为卤素或C 1～C 3烷基，其中，所述卤素较佳地为氟，所述C 1～C 3烷基较佳地为甲基。
  4. 如权利要求1～3中至少一项所述的物质A在制备药物中的应用，其特征在于，X为CH，R 6为-O-(CH 2) n-Y；
    或，X为N，R 6为H；
    或，
    Figure PCTCN2019125567-appb-100003
    为
    Figure PCTCN2019125567-appb-100004
    较佳地，
    Figure PCTCN2019125567-appb-100005
    为
    Figure PCTCN2019125567-appb-100006
  5. 如权利要求1～4中至少一项所述的物质A在制备药物中的应用，其特征在于，当X为N，R 6为H时，R 1、R 2、R 3、R 4和R 5中有3～4个独立地为H，其余独立地为卤素或C 1～C 3烷基；
    当X为CH、R 6为-O-(CH 2) n-Y时，R 1、R 2、R 3、R 4和R 5中有1个为卤素，R 1、R 2、R 3、R 4和R 5中有1个为C 1～C 3烷基，其余为H。
  6. 如权利要求1～5中至少一项所述的物质A在制备药物中的应用，其特征在于，所述的如式I所示的萘脲类化合物选自如下任一结构：
    Figure PCTCN2019125567-appb-100007
  7. 如权利要求1～6中至少一项所述的物质A在制备药物中的应用，其特征在于，所述的药物的剂型为滴眼剂；
    较佳地，所述的滴眼剂中，所述的物质A的质量浓度为10～30mg/mL，进一步为20mg/mL。
  8. 一种用于治疗眼角膜新生血管病的物质A，所述的物质A如权利要求1～7中至少一项所述。
  9. 一种药物组合物，其特征在于，所述的药物组合物包括如权利要求1～7中至少一项所述的物质A和眼用药用辅料。
  10. 如权利要求9所述的药物组合物，其特征在于，所述的药物组合物的剂型为滴眼剂；较佳地，所述的滴眼剂中，所述的物质A的质量浓度为10～30mg/mL，进一步为20mg/mL；
    和/或，所述的药物组合物为用于治疗眼角膜新生血管病的药物组合物。
  11. 一种在有需要的患者中治疗眼角膜新生血管病的方法，其特征在于，包括：向有需要的患者施用治疗有效量的如权利要求1～8中至少一项所述的 物质A或如权利要求9～10中至少一项所述的药物组合物。
  12. 如权利要求11所述的在有需要的患者中治疗眼角膜新生血管病的方法，其特征在于，所述的“施用”的方式为以滴眼剂的形式施用；
    和/或，所述的患者为哺乳动物，较佳地为兔或人类；
    和/或，以所述的物质A计，所述的物质A或所述的药物组合物的单次剂量范围为1mg/眼-3mg/眼；
    和/或，所述的物质A或所述的药物组合物的施用频次为一天四次。
PCT/CN2019/125567 2019-12-16 2019-12-16 一种萘脲类化合物的应用 WO2021119902A1 (zh)

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