Use of naphthylurea compounds in the preparation of medicaments for the treatment of pterygium

Abstract

The present invention relates to the use of a naphthylurea compound in the preparation of a medicament for treating pterygium, specifically, the use of substance A in the preparation of a medicament, wherein substance A is a naphthylurea compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystalline form thereof, or a tautomer thereof, and the medicament is used for treating pterygium. JPEG2025538351000019.jpg7855

Description

[Technical Field]

[0001] The present invention relates to the use of naphthylurea compounds in the preparation of a medicament for the treatment of pterygium. [Background technology]

[0002] Pterygium, also known as pterygium, typically manifests as a thickening of the conjunctiva in the sphenoid region of the eyelid, accompanied by a triangular proliferation of fibrovascular tissue in the bulbar conjunctiva. The head of the pterygium grows from the lateral to medial canthus, gradually enlarging and invading the corneal tissue. The enlarged pterygium tissue can cover the entire pupillary area, affecting the normal movement of the eyeball. This ophthalmic disorder causes patients to experience symptoms such as decreased vision, a foreign body sensation in the eye, and light-blocking sensation, affecting vision. Currently, the primary treatment for pterygium is surgical removal, but the postoperative recurrence rate is high. Summary of the Invention

[0003] The technical problem that the present invention aims to solve is that the existing pharmaceuticals used to treat pterygium, an ophthalmic disease, have a single structure. Therefore, the present invention provides the use of naphthylurea compounds that can be administered by eye drops for the treatment of pterygium, thereby filling the gap in this field and bringing great social and economic benefits.

[0004] The present invention provides use of substance A in the preparation of a medicament, wherein said substance A is a naphthylurea compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystalline form thereof, or a tautomer thereof, and said medicament is used for the treatment of pterygium.

[0005] [ka]

[0006] where R 1 , R 2 , R3 , R 4 and R 5 are independently selected from H, halogen, or C1-C6 alkyl; X is CH or N; R 6 is H or -O-(CH2) n -Y, Y is a 5- to 6-membered heterocycloalkyl group, a heteroatom in the 5- to 6-membered heterocycloalkyl group is N, and the number of heteroatoms is 1 to 2; n is 2, 3, 4, or 5.

[0007] In certain embodiments, in a naphthylurea compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystalline form thereof, or a tautomer thereof, certain groups are defined as follows, and undefined groups are as in any one of the above embodiments (herein referred to as "an embodiment of the present invention").

[0008] R 1 , R 2 , R 3 , R 4 or R 5 wherein the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0009] In one aspect of the present invention, R 1 , R 2 , R 3 , R 4 or R 5 In the formula, the C1-C6 alkyl may be a C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl.

[0010] In one embodiment of the present invention, the 5- to 6-membered heterocycloalkyl group in Y may be a 5- to 6-membered heterocycloalkyl group containing one N, and further may be, for example,

[0011] [ka]

[0012] is.

[0013] In one aspect of the present invention, R 6 In the formula, preferably, n is 2 or 3 (for example, 3).

[0014] In one aspect of the present invention, preferably, R 1 , R 2 , R 3 , R 4 and R 5 In the formula, 1 to 2 are independently C1 to C3 alkyl (for example, methyl), and the rest are independently halogen or H.

[0015] In one aspect of the present invention, preferably, R 1 , R 2 , R 3 , R 4 and R 5 wherein 3 to 4 are independently H, and the remaining are independently halogen (eg, fluorine) or C1 to C3 alkyl (eg, methyl).

[0016] In one embodiment of the invention, X is CH and R 6 is -O-(CH2) n -Y.

[0017] In one embodiment of the invention, X is N and R 6 is H.

[0018] In one aspect of the present invention,

[0019] [ka]

[0020] teeth

[0021] [ka]

[0022] or

[0023] [ka]

[0024] (for example,

[0025] [ka]

[0026] )

[0027] In one embodiment of the invention, X is N and R 6 If is H, then R 1 , R 2 , R 3 , R 4 and R 5 wherein 3 to 4 are independently H, and the remaining are independently halogen (eg, fluorine) or C1 to C3 alkyl (eg, methyl).

[0028] X is CH and R 6 -O-(CH2) n -Y, then R 1 , R 2 , R 3 , R 4 and R 5 one in is halogen (e.g., fluorine), and R 1 , R 2 , R 3 , R 4 and R 5 In the formula, one is C1-C3 alkyl (for example, methyl) and the rest are H.

[0029] In one aspect of the present invention, the naphthylurea compound of formula I is preferably selected from any one of the following compounds:

[0030] [ka]

[0031] In the above-mentioned use, the dosage form of the medicament may be eye drops.

[0032] In the eye drops, the mass concentration of the substance A is preferably 10 to 30 mg / mL.

[0033] The eye drops are sterile liquid preparations prepared from a drug and suitable ophthalmic pharmaceutical excipients, and can be divided into aqueous solution eye drops, oily solution eye drops, suspension eye drops, or emulsion eye drops.

[0034] The present invention also provides a pharmaceutical composition comprising said substance A and an ophthalmic pharmaceutical excipient.

[0035] In the present invention, the pharmaceutical composition is preferably a pharmaceutical composition for treating pterygium.

[0036] The pharmaceutical composition may be in the form of eye drops.

[0037] In the eye drops, the mass concentration of the substance A is preferably 10 to 30 mg / mL (for example, 20 mg / mL or 30 mg / mL).

[0038] The present invention also provides substance A as described above for the treatment of pterygium.

[0039] The present invention provides a method for treating pterygium in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of the substance A or the pharmaceutical composition.

[0040] In the above method, the "administration" may be in the form of eye drops.

[0041] In the method, the patient may be a mammal, such as a rabbit or a human.

[0042] In the method, the substance A or the pharmaceutical composition can be administered according to a conventional dose, and a non-limiting example range based on the substance A may be 1 mg / eye to 3 mg / eye (single dose), for example, 1 mg / eye.

[0043] In the method, the frequency of administration of the substance A or the pharmaceutical composition may be four times a day.

[0044] Unless otherwise specified, the terms used in this invention have the following meanings.

[0045] The term "pharmaceutically acceptable salt" refers to a salt prepared by using a relatively non-toxic, pharmaceutically acceptable acid or base to prepare a compound of the present invention. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a sufficient amount of a pharmaceutically acceptable base with the neutral form of the compound in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a sufficient amount of a pharmaceutically acceptable acid with the neutral form of the compound in a pure solution or in a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including, but 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 acid includes 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, acidic citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharinic acid, formic acid, ethanesulfonic acid, bishydroxynaphthoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthalenecarboxylic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base or acid addition salts.In particular, reference may be made to Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0046] The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric solvent. In a solvate, the solvent molecules exist in an ordered or disordered arrangement. Such solvents include, but are not limited to, water, methanol, ethanol, etc.

[0047] The terms "pharmaceutically acceptable salt" and "solvate" in "solvate of a pharmaceutically acceptable salt" refer to a substance formed by combining a compound of the present invention with 1) a relatively non-toxic, pharmaceutically acceptable acid or base, or 2) a stoichiometric or non-stoichiometric solvent, as described above. The "solvate of a pharmaceutically acceptable salt" includes, but is not limited to, the hydrochloride monohydrate of the compound of the present invention.

[0048] The term "tautomer" refers to a functional isomer resulting from the rapid migration of one atom in a molecule between two positions. For example, acetone and 1-propen-2-ol can change into each other by the rapid migration of a hydrogen atom on the oxygen and on the α-carbon.

[0049] The term "crystalline form" refers to a specific configuration in which ions or molecules are arranged in a strict periodic manner in three-dimensional space, with a regular pattern of periodic repetition. Due to differences in the periodic arrangement, multiple crystalline forms, i.e., polymorphic phenomena, can exist.

[0050] The term "alkyl" refers to a straight or branched chain alkyl group having the specified number of carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and similar alkyls.

[0051] The term "heterocycloalkyl" means a saturated monocyclic group having a heteroatom.

[0052] The term "ophthalmic excipients" refers to excipients or additives used in the preparation and formulation of pharmaceuticals, including all substances contained in pharmaceutical preparations other than the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 Edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0053] The term "treatment" means therapeutic therapy. When referring to a particular condition, treatment means (1) alleviating one or more biological manifestations of a disease or condition, (2) inhibiting (a) one or more points in the biological cascade that cause or contribute to the condition, or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0054] The term "therapeutically effective amount" refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient in need thereof. A "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient being treated, but can be adjusted as needed by one skilled in the art.

[0055] The term "patient" refers to any animal, preferably a mammal, and most preferably a human, to which a compound or composition is or has been administered in accordance with embodiments of the present invention. The term "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, and humans, with humans being most preferred.

[0056] The term "pterygium" refers to an eye disease.

[0057] The above preferred conditions can be arbitrarily combined to obtain preferred examples of the present invention, provided that this does not violate common knowledge in the art.

[0058] All reagents and raw materials used in the present invention are commercially available.

[0059] The positive and progressive effect of the present invention is that the naphthylurea compounds of the present invention can treat related ophthalmic diseases such as pterygium by administration of eye drops, filling a gap in this field and bringing significant social and economic benefits.

[0060] [Specific embodiment] The present invention will be further described below with reference to the following embodiments, but the present invention is not limited to the scope of the described examples. In the following examples, experimental methods without specific conditions should be selected according to the usual methods and conditions or product specifications.

[0061] The structures of the compounds used in the following examples are as follows:

[0062] [ka]

[0063] Effect Example 1 1. Purpose of the experiment In this experiment, a pterygium model was induced in New Zealand white rabbits using NIH3T3 cells, and the compound of the present invention was topically instilled into the eyes three times daily. On day 13, the anterior segments of the animals were photographed with a slit lamp to evaluate the size of the pterygium. The inhibitory effect of the compound of the present invention on pterygium in rabbits was investigated.

[0064] 2. Testing Process Eighteen male New Zealand white rabbits were randomly divided into three groups based on body weight, with six rabbits in each group, and NIH3T3 cells and matrix membranes were injected through the bulbar conjunctiva. Models were constructed for each group of animals and surrogates. Resuscitation of NIH3T3 cells: Immediately upon receiving the cells, they were placed in a liquid nitrogen tank and stored until resuscitation. DMEM + 10% newborn bovine serum becomes ineffective after 3 months of preparation. NIH3T3 cell culture: Resuscitated cells were placed in a cell culture incubator at 5% CO2 and 37°C. The culture medium was changed twice a week, and cell passage was performed when the cell density reached 70%-75%. Passaging of NIH3T3 cells: Wash cells with PBS to obtain a final cell density of 8 x 10 6 The resulting cells and matrix membrane were mixed in an ice bath. On day 1, animals were anesthetized by intramuscular injection of a combination of xylazine (2–5 mg / kg) and ketamine (30–50 mg / kg). After the animals' corneal reflex disappeared, 20 μL of the NIH3T3 cell and matrix membrane mixture was injected into the conjunctiva of both eyes of the animals. Modeling completed. Starting on day 2 and continuing until day 12, eye drops were administered three times a day at 50 μL / eye / dose. Administration method: After visually confirming that the formulation was uniform, 50 μL of the solvent or test substance was taken up using a micropipette and dropped into the animal's conjunctival sac. The animal's eyes were gently closed several times to ensure uniform distribution of the solvent or test substance. To ensure uniformity of the formulation, the formulation in the container can be turned upside down and vortexed appropriately as necessary. Solvent: 0.1% (w / v) poloxamer 188 and 2.4% (w / v) glycerin were dissolved in sterile water for injection to form a solvent. RMP-A01 eye drop test sample: 20 mg / mL of RMP-A01 was dissolved in a solvent. RMP-A03 eye drop test sample: 30 mg / mL of RMP-A03 was dissolved in a solvent. Examination items: 13 days after modeling, the anterior segment of the animal's eye was photographed using a slit lamp, and the size of the pterygium was evaluated and its area was measured. The results are shown in Table 1.

[0065] [Table 1]

[0066] On day 13, the area of ​​pterygium was reduced in both the RMP-A01 eye drop test group and the RMP-A03 eye drop test group compared to the vehicle control group.

[0067] 3. Experimental Conclusion Under the conditions of this experiment, NIH3T3 can successfully induce a rabbit pterygium model. Under the conditions of this experiment, compounds of the present invention tend to reduce the area of ​​pterygium under the administration conditions of the test.

[0068] In summary, the novel compound of formula I disclosed in the present invention provides the potential for the use of a novel medicine for the clinical treatment of pterygium disease.

[0069] While specific embodiments of the present invention have been described above, it should be understood by those skilled in the art that these are merely examples and that various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Accordingly, the scope of the present invention is defined by the appended claims.

Claims

1. 1. Use of substance A in the preparation of a medicament, wherein said substance A is a naphthylurea compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystalline form thereof, or a tautomer thereof, and said medicament is used for the treatment of pterygium. 【Chemistry 1】 (where R １ , R ２ , R ３ , R ４ and R ５ are independently 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 heteroatoms is 1 to 2; n is 2, 3, 4 or 5.

2. R １ , R ２ , R ３ , R ４ or R ５ wherein the halogen is fluorine, chlorine, bromine or iodine; and / or R １ , R ２ , R ３ , R ４ or R ５ In the above, １ ~C ６ Alkyl is C １ ~C ３ is alkyl, and / or, in Y, the 5- to 6-membered heterocycloalkyl group is a 5- to 6-membered heterocycloalkyl group containing one N; and / or R ６ 2. The use of substance A in the preparation of a medicament according to claim 1, wherein n is 2 or 3.

3. R １ , R ２ , R ３ , R ４ or R ５ wherein the halogen is fluorine; and / or R １ , R ２ , R ３ , R ４ or R ５ In the above, １ ~C ６ alkyl is methyl, ethyl, n-propyl or isopropyl; and / or, in Y, the 5- to 6-membered heterocycloalkyl group is 【Chemistry 2】 and and / or R ６ 3. The use of substance A in the preparation of a medicament according to claim 2, wherein n is 3.

4. R １ , R ２ , R ３ , R ４ and R ５ In the formula, one or two of the １ ~C ３ alkyl, and the remainder are independently halogen or H; １ ~C ３ Alkyl is preferably methyl; and / or R １ , R ２ , R ３ , R ４ and R ５ In the formula, 3 to 4 are independently H, and the remaining are independently halogen or C. １ ~C ３ alkyl, wherein the halogen is preferably fluorine, １ ~C ３ 2. Use of substance A in the preparation of a medicament according to claim 1, characterized in that alkyl is preferably methyl.

5. X is CH and R ６ is -O-(CH ２ ) ｎ -Y, or X is N and R ６ is H, and / or 【Transformation 3】 teeth 【Chemistry 4】 or 【Transformation 5】 and preferably 【Transformation 6】 teeth 【Transformation 7】 2. Use of substance A in the preparation of a medicament according to claim 1, characterized in that it is

6. X is N and R ６ is H, then R １ , R ２ , R ３ , R ４ and R ５ In the formula, 3 to 4 are independently H, and the remaining are independently halogen or C. １ ~C ３ alkyl, wherein the halogen is preferably fluorine, １ ~C ３ Alkyl is preferably methyl; X is CH and R ６ -O-(CH ２ ) ｎ -Y, then R １ , R ２ , R ３ , R ４ and R ５ one of the groups is halogen, and R １ , R ２ , R ３ , R ４ and R ５ One of them is C １ ~C ３ alkyl, the remainder being H, wherein said halogen is preferably fluorine, and said C １ ~C ３ 2. Use of substance A in the preparation of a medicament according to claim 1, characterized in that alkyl is preferably methyl.

7. The use of substance A in the preparation of a medicament according to claim 1, characterized in that the naphthylurea compound of formula I is selected from any one of the following compounds: 【Transformation 8】

8. the pharmaceutical formulation is an eye drop, and the eye drop is preferably an aqueous solution eye drop, an oily solution eye drop, a suspension eye drop, or an emulsion eye drop; The use of substance A in the preparation of a medicament according to claim 1, characterized in that in the eye drops, the mass concentration of substance A is 10-30 mg / mL.

9. A pharmaceutical composition comprising substance A according to any one of claims 1 to 8 and an ophthalmic pharmaceutical excipient.

10. The pharmaceutical composition is an eye drop formulation, and in the eye drop formulation, the mass concentration of the substance A is preferably 10 to 30 mg / mL, and further preferably 20 mg / mL or 30 mg / mL; And / or the pharmaceutical composition according to claim 9, characterized in that the pharmaceutical composition is a pharmaceutical composition for the treatment of pterygium.

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