Composition for treating, ameliorating, and / or inhibiting the progression of bovine papillomavirus-induced bovine papillomatosis

Abstract

Provided are a composition for treating bovine papillomatosis caused by bovine papillomavirus and a method using the same. This composition for treating, improving, and / or preventing the progression of bovine papillomatosis caused by bovine papillomavirus contains a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. This method for treating, improving, and / or preventing the progression of bovine papillomatosis caused by bovine papillomavirus comprises administering a composition containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof to a cow.

Description

[Technical Field]

[0001] The present disclosure relates to a composition for treating, ameliorating, and / or inhibiting the progression of bovine papillomavirus (BPV)-induced bovine spleen disease, and a method for treating, ameliorating, and / or inhibiting the progression of BPV-induced bovine spleen disease in cattle using the composition. [Background technology]

[0002] Papillomatosis is a disease in which papillomaviruses (PVs) infect epithelia or mucous membranes, resulting in the formation of benign tumors (warts) called papillomas at the site of infection. Mammals known to be infected with papillomaviruses include humans, as well as cattle, horses, dogs, cats, and yaks. BPV is the most well-known PV in mammals other than humans.

[0003] BPV causes bovine milk disease by infecting the skin and certain mucous membranes of cows. Although bovine milk disease often occurs in young cows with a very high incidence rate, it is generally benign and often resolves spontaneously, so it has not been considered a major concern. However, if papilloma lesions form on the teats of dairy cows, they can interfere with milking and can cause secondary bacterial infections, leading to mastitis. In recent years, there have been reports of the effects of the spread of BPV infection, such as the spread of teat papillomas throughout a farm via dairy cow milkers.

[0004] Attempts at treating bovine milk papilloma include surgical removal, injecting ground-up, detoxified warts, feeding pigeons feed containing unhulled Job's tears, and applying wood vinegar to the affected area.

[0005] The present applicants have proposed an antiviral agent for viral infections caused by human papillomavirus (HPV) (Patent Document 1). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO2009 / 020198 Summary of the Invention [Problem to be solved by the invention]

[0007] As mentioned above, despite the problems caused by bovine milk sputum, there is no fundamental treatment for the disease. Therefore, a treatment for bovine milk sputum is desired. [Means for solving the problem]

[0008] In one aspect, the present disclosure relates to a composition for treating, ameliorating, and / or inhibiting the progression of bovine papillomavirus-induced bovine bovine papilloma, comprising, as an active ingredient, a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: [ka] In formula (I), R represents an oxygen atom or a sulfur atom.

[0009] In one aspect, the present disclosure relates to a method for treating, ameliorating, and / or inhibiting the progression of bovine papillomatosis caused by bovine papillomavirus, the method comprising administering to a cow a composition containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0010] In one aspect, the present disclosure can provide a composition capable of treating, ameliorating, and / or inhibiting the progression of bovine milk papilloma caused by BPV, and a method using the same capable of treating, ameliorating, and / or inhibiting the progression. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 shows one embodiment of the shape of the nipple cover container and the cover. [Figure 2]FIG. 2 shows an example of the results of a drug efficacy confirmation test for Compound A (N-[5-fluoro-2-(1-piperidinyl)phenyl]-4-pyridinethioamide). DETAILED DESCRIPTION OF THE INVENTION

[0012] As mentioned above, PV is a virus that is widely distributed throughout the world, with many virus types found in a variety of animals, including cattle, horses, cats, dogs, and humans. There is a wide variety of PV, and the genotype and pathology of PV vary depending on the species (host animal) that the PV infects. Furthermore, PV is generally highly species-specific, and it is generally believed that cross-species infection does not occur. In particular, BPV infects cattle, and humans cannot be infected with BPV. Furthermore, HPV cannot infect cattle.

[0013] BPV is a papillomavirus that specifically infects cattle and causes bovine papillomatosis. Treatments for BPV-induced bovine papillomatosis include surgical removal and freezing of the lesions, as well as injection of detoxified ground warts, ingestion of unhulled Job's tears, and application of wood vinegar to the affected area. However, surgical removal has a high recurrence rate, and other methods have not been found to be sufficiently effective.

[0014] The present disclosure is based on the finding that although it was thought that compounds proposed as vaccines or treatments for human cervical cancer caused by HPV, i.e., the antiviral agent for HPV disclosed in Patent Document 1, due to their high species specificity, would not be effective in treating bovine bovine uterine fibroids caused by BPV, an unexpected effect was observed against bovine bovine uterine fibroids caused by BPV.

[0015] The present disclosure is based on the finding that a compound having antiviral activity and represented by the following formula: N-[5-fluoro-2-(1-piperidinyl)phenyl]-4-pyridinethioamide can be applied to bovine papillomas (warts) caused by BPV, and can exhibit excellent effects such as inhibiting the expansion of already formed papillomas (warts) and even causing the warts to disappear or reduce in size. [ka]

[0016] In one or more embodiments, "treatment, improvement, and / or inhibition of progression of papillomatosis" in the present disclosure includes inhibition of the growth of already formed papillomas (warts), disappearance of warts, or reduction in the size of warts, by administering a drug (composition) of the present disclosure to a subject.

[0017] In one or more embodiments, "bovine milk papillomatosis caused by BPV" in the present disclosure refers to a disease in which a cow is infected with BPV and a papilloma forms at the site of infection. In one or more embodiments, examples of bovine milk papillomatosis caused by BPV include bovine milk papillomatosis, cutaneous bovine milk papillomatosis, papillary bovine milk papillomatosis, and sarcoid (fibropapillosis). In one or more embodiments, examples of the site of infection (detectable lesion) include, but are not limited to, the nipple, skin, and digestive tract (such as the oral cavity and esophagus).

[0018] [Composition for treating, ameliorating, and / or inhibiting the progression of papillomatosis] In one aspect, the present disclosure provides a composition for treating, ameliorating, and / or inhibiting the progression of bovine milk disease caused by BPV, the composition comprising a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. In one or more embodiments, the compound represented by formula (I) may have anti-DNA virus activity and / or anti-RNA virus activity. [ka] In formula (I), R represents an oxygen atom or a sulfur atom.

[0019] In one or more embodiments, the compound represented by formula (I) in the present disclosure includes compounds represented by the following formulae: N-[5-fluoro-2-(1-piperidinyl)phenyl]-4-pyridinethioamide (Compound A) and N-[5-fluoro-2-(1-piperidinyl)phenyl]-4-pyridinecarboxamide (Compound B). [ka]

[0020] In one or more embodiments, the compound represented by formula (I) can be produced by known production methods or by referring to WO2009 / 020198.

[0021] In the present disclosure, a "pharmaceutically acceptable salt" refers to a pharmacologically and / or pharmaceutically acceptable salt, and examples thereof include inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, acidic amino acid salts, and basic amino acid salts. In one or more embodiments, inorganic acid salts include hydrochloride, hydrobromide, sulfate, nitrate, and phosphate. In one or more embodiments, organic acid salts include acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate, and p-toluenesulfonate. In one or more embodiments, inorganic base salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, and ammonium salt. In one or more embodiments, organic base salts include diethylamine salt, diethanolamine salt, meglumine salt, and N,N'-dibenzylethylenediamine salt. In one or more embodiments, acidic amino acid salts include aspartate and glutamate. In one or more embodiments, the basic amino acid salt may be an arginine salt, a lysine salt, or an ornithine salt.

[0022] In the present disclosure, "salts of compounds" may include hydrates that can be formed by absorbing water, and may also include solvates that can be formed by absorbing other solvents.

[0023] In one or more embodiments, the composition of the present disclosure contains the above-mentioned compound as an active ingredient, and may further contain a pharmaceutically acceptable carrier, preservative, diluent, excipient, or other pharmaceutically acceptable ingredient.

[0024] In one or more embodiments, the composition of the present disclosure can act systemically and / or locally. In one or more embodiments, the composition of the present disclosure can be administered orally, parenterally, transdermally, mucosally, nasally, buccally, rectally, lingually, dermally, or via the conjunctiva. The composition of the present disclosure is preferably administered topically, and more preferably transdermally.

[0025] In one or more embodiments, the composition of the present disclosure can be prepared into a dosage form suitable for the administration route by applying well-known formulation techniques.

[0026] In one or more embodiments, dosage forms for oral administration include tablets, capsules, granules, powders, pills, lozenges, pellets, syrups, suspensions, liquids, and aerosols.

[0027] In one or more embodiments, dosage forms for parenteral administration include ointments, creams, injections, liquids or soaks, aerosols, sprays, suppositories, patches, poultices, lotions, and liniments.

[0028] The composition of the present disclosure may be prepared into a dosage form for administration to the nipple, stored, and then used, or may be prepared immediately before use. This can be selected appropriately depending on the situation or purpose of use.

[0029] In one or more embodiments, the composition of the present disclosure may be manufactured by a known method using additives, etc. Examples of additives include excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, diluents, etc. In addition to the above, the composition of the present disclosure may also contain additives such as surfactants and pH adjusters.

[0030] The composition of the present disclosure can be produced using a surfactant or an emulsifier, etc., as needed. When the composition of the present disclosure is made into a formulation using a solvent, such as a liquid or immersion agent, any of aqueous solvents, non-aqueous solvents, and mixed solvents of non-aqueous solvents and aqueous solvents can be used as the solvent. However, preferably, an aqueous solvent or a mixed solvent of a non-aqueous solvent mainly composed of an aqueous solvent and an aqueous solvent is used. Various aqueous and non-aqueous solvents are known, and can be appropriately selected based on the route of administration and dosage form, referring to known information. In addition, the desired formulation can be produced by using a surfactant or an emulsifier, etc., in these solvents as needed.

[0031] In one or more embodiments, the content of the compound represented by formula (I), which is an active ingredient in the composition of the present disclosure, is 0.01% by weight to 50% by weight, or 0.1% by weight to 20% by weight.

[0032] The dosage of the composition of the present disclosure can be selected as appropriate depending on the dosage form and route of administration. When administered topically, the dosage of the composition of the present disclosure can be set as appropriate depending on the size and extent of the wart, and in one or more embodiments, the composition is administered so that the amount of the active ingredient in the composition is about 0.01 mg / wart to 40 mg / wart. For example, but not limited to, when the composition of the present disclosure is applied to the nipple, the amount of the active ingredient in the composition to be applied is 0.01 mg / cm2 relative to the area of ​​the nipple surface. 2 ~40mg / cm 2 , preferably 0.1 mg / cm 2 ~20mg / cm 2 , more preferably 0.3 mg / cm 2 ~6mg / cm 2In one or more embodiments, the dosage of the composition of the present disclosure, when administered orally or by injection, is such that the amount of the active ingredient in the composition is about 0.01 mg / kg (body weight) to 100 mg / kg (body weight).

[0033] When the composition of the present disclosure is administered topically to the nipple or administered by application to the nipple, it is preferable to coat the entire nipple or the area to which the composition of the present disclosure has been administered or applied. Coating allows for more effective administration or penetration of the active ingredient into the affected area. Any material capable of covering the nipple can be used to cover the nipple, for example, a nipple coating container or coating material. Examples of nipple coating containers include, but are not limited to, nipple-shaped containers (e.g., sacks) made of elastic materials. Elastic materials can be used without particular limitation as long as they are commonly used elastic polymeric materials, but preferably materials that are less irritating to the nipple. Furthermore, to maintain the condition of the affected nipple in good condition, materials that do not leak the composition of the present disclosure but are breathable are preferred. Examples include, but are not limited to, natural rubber, silicone, and latex materials. Nipple coating materials can be used without particular limitation as long as they form a film after application to the nipple, but preferably are coating materials made of ingredients that are less irritating to the nipple. For example, but not limited to, examples include compositions (film-forming agents) consisting of natural ingredients or mixtures of such natural ingredients that can form a film when applied to the skin of the nipple, etc. These covering materials can be applied or sprayed onto the nipple to which the composition of the present disclosure has been administered or applied, thereby forming a film thereon. The film formed is preferably breathable but does not allow the composition of the present disclosure to leak out. Additionally, in one or more embodiments, the composition of the present disclosure may be administered to a cow by first applying the composition to a teat protector or dressing and then covering the teats with the composition.

[0034] One embodiment of a teat covering container and covering material is shown in Figure 1. Figure 1(a) is a diagram showing a state in which a bovine teat is covered with a cylindrical bag (finger cot-shaped) teat covering container. Figures 1(b) to 1(d) show examples of the shape of a pad (patch or sheet) teat covering material. The shape of the teat covering material may be rectangular (Figure 1(b)), anchor-shaped (Figure 1(c)), or H-shaped (Figure 1(d)). In one or more embodiments, the teat covering material can cover the teat by abutting the center of the teat covering material against the tip of the bovine teat, as shown in Figure 1(b), and then applying it so that it covers the entire teat.

[0035] The composition of the present disclosure is preferably used together with a teat coating container or covering material, and by administering or applying the composition to the teat and then covering the teat with a teat coating container or covering material, the administration and penetration of the active ingredient becomes more effective. The composition of the present disclosure, which is characterized by being used together with a teat coating container or covering material, is also included in the present disclosure. The present disclosure also includes a combination of the composition of the present disclosure and a teat coating container or covering material. Such a combination can also be made into a set or kit. The composition of the present disclosure can also be administered to a cow by applying it to the inside of a teat coating container beforehand and then covering the container over the teat. Such a teat coating container with the composition of the present disclosure applied to the inside is also included in the present disclosure.

[0036] The composition of the present disclosure can be used to treat, improve, and / or inhibit the progression of bovine milk papilloma caused by BPV in cattle. When the papilloma lesion is in the nipple, in one or more embodiments, applying the composition of the present disclosure to the affected nipple may inhibit the expansion of the papilloma formed in the nipple, reduce the size of the papilloma, and / or cause the papilloma to disappear. Thus, in one or more embodiments, administering the composition of the present disclosure to dairy cows may prevent milking problems associated with the formation of papilloma in the nipple. When the lesion is in the nipple, in one or more embodiments, the composition of the present disclosure may be applied to the entire nipple where the papilloma (wart) has developed, or may be applied only to the papilloma (wart) that has developed on the nipple. However, the administration route is not limited to these, and the compound may be administered orally or by injection.

[0037] [Method for treating, improving, and / or inhibiting the progression of papillomatosis] In another aspect, the present disclosure relates to a method for treating, ameliorating, and / or inhibiting the progression of bovine bovine milk disease caused by BPV in cattle. The method of the present disclosure comprises administering to a subject cattle a composition containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0038] In this embodiment, the papillomatosis, the active ingredient, the composition, and the method of use thereof may be as described above.

[0039] The present disclosure may relate to one or more of the following embodiments. [1] The following formula (I): [ka] A composition for treating, ameliorating, and / or inhibiting the progression of bovine papillomavirus-induced bovine bovine leiomyomatosis, comprising as an active ingredient a compound represented by the formula: In formula (I), R represents an oxygen atom or a sulfur atom. [2] The compound represented by formula (I) is represented by the following formula: [ka] or a pharmaceutically acceptable salt thereof. [3] The composition described in [1] or [2], wherein the papillomatosis is papillary papillomatosis. [4] The composition according to any one of [1] to [3], which is a topical composition for application to the teats of dairy cows. [5] A method for treating, ameliorating, and / or inhibiting the progression of bovine papillomavirus-induced bovine papillomatosis, comprising: The following formula (I): [ka] A method for treating, improving, and / or inhibiting the progression of a disease comprising administering to a cow a composition containing, as an active ingredient, a compound represented by the formula: In formula (I), R represents an oxygen atom or a sulfur atom. [6] The cattle are dairy cattle, and the papillomatosis is papillary bovine papillomatosis; [5] The method described in [5], which comprises applying the composition to the teats of the dairy cow. [Example]

[0040] The present disclosure will be described in more detail below with reference to examples, but these are merely illustrative and the present disclosure is not limited to these examples. Note that the entire contents of all documents cited in this disclosure are incorporated herein as part of the present disclosure.

[0041] Example 1: Preparation of N-[5-fluoro-2-(1-piperidinyl)phenyl]-4-pyridinethioamide (Compound A) Compound A represented by the following chemical formula was prepared with reference to Reference Example 11 of WO2009 / 020198. [ka]

[0042] Preparation Example 2: Preparation of an ointment containing Compound A An ointment (3% by weight of compound A) was prepared by dissolving 120 mg of compound A in 3,880 mg of an ointment base (white petrolatum) that had been preheated to 60°C and stirring at 60°C until homogenous.

[0043] [Trial to confirm the therapeutic effect on dairy cows with papilloma] In four female dairy cows with papillomas on both front teats, an ointment containing compound A was applied once a day to the papilloma (wart) on one of the front teats (test group). After application, the teat was wrapped in dressing tape (Navis, Proshare Dressing Roll, No. 8-5965-01) to prevent contamination from the outside. The ointment was applied to the teat surface in an area of ​​1 cm. 2 Approximately 0.01g to 0.2g (equivalent to approximately 0.3mg to 6mg of active ingredient) was applied per 100ml. Treatment was continued for 4 weeks with 5 doses and 2 days off. Images of the affected area were taken once a week. The efficacy was evaluated based on the condition of the affected area (wart) 4 weeks after the start of treatment.

[0044] As a control, an ointment base not containing compound A was applied to the wart on the other nipple that was not used as the test group (control group).

[0045] [Evaluation method 1] The changes in the warts after 4 weeks of medication (shrinkage / disappearance, no change, and enlargement / development) were scored on a 3-point scale as follows. Note that "no change" can include suppression of enlargement and no effect. "Development" refers to new warts that developed during the 4 weeks of medication. Shrinkage / disappearance = +1, no change = 0, expansion / appearance = -1 The results are shown in Table 1 below. [Table 1]

[0046] Furthermore, the scores for each individual cow were added up, and the medication effect for each individual cow was judged according to the following criteria. Effective: Test area > Control area Invalid: Test area ≦ Control area The results are shown in Table 2 below. [Table 2]

[0047] In Table 1 above, the combined score of the test group was +1 and the combined score of the control group was -8, so the effect of the ointment containing compound A was confirmed in the test group. In Table 2 above, when evaluated on an individual basis, 3 out of 4 cases were effective, demonstrating the effectiveness of the ointment containing compound A. Figure 2 shows images of the affected areas in the test group (examples in which the warts disappeared) from before the start of medication to the end of medication.

[0048] After four weeks of administration, administration was continued for another four weeks under the same conditions. As a result, four more warts in the test group shrank (two of them disappeared).

[0049] [Evaluation method 2] When only small warts are targeted, the expansion or contraction of the warts becomes more pronounced, making it easier to assess the effect of Compound A. For this reason, only warts that were less than 5 mm in size before application of the ointment were extracted from the test and control groups in the above confirmation test, and the percentage of warts that shrank / disappeared was calculated. As a result, of the warts analyzed (14 in the test group and 15 in the control group), the percentage of warts that shrank / disappeared in the test group was 28.6%, while it was 0% in the control group. Therefore, the clear effectiveness of the ointment containing Compound A against papillomas occurring in cows was confirmed.

Claims

1. The following formula (I): 【Chemistry 1】 A composition for treating, ameliorating, and / or inhibiting the progression of bovine papillomavirus-induced bovine bovine ovarian disease, comprising, as an active ingredient, a compound represented by the formula: In formula (I), R represents an oxygen atom or a sulfur atom.

2. The compound represented by formula (I) is represented by the following formula: 【Chemistry 2】 The composition according to claim 1, wherein the compound is a compound represented by the formula:

3. The composition according to claim 1 or 2, wherein the papillomatosis is papillary papillomatosis.

4. 4. The composition of any one of claims 1 to 3, which is a topical composition for application to the teats of dairy cows.

5. The compound or a pharmaceutically acceptable salt thereof is administered at a concentration of 0.01 mg / cm 2 ~40 mg / cm 2 5. The composition of claim 4, wherein the composition is applied to the nipple where the papilloma is present.

6. The composition according to claim 4 or 5, which is used together with a nipple covering container or covering material capable of covering the nipple, so that the nipple is covered by the nipple covering container or covering material after the composition is applied to the nipple.

7. 7. The composition according to claim 6, wherein the nipple-coating container or coating material is a container that covers the nipple or a coating material that can form a film when applied to the nipple.

8. A method for treating, ameliorating, and / or inhibiting the progression of bovine papillomavirus-induced bovine papillomatosis, comprising: The following formula (I): 【Transformation 3】 A method for treating, improving, and / or inhibiting the progression of a disease comprising administering to a cow a composition containing, as an active ingredient, a compound represented by the formula: In formula (I), R represents an oxygen atom or a sulfur atom.

9. The compound represented by formula (I) is represented by the following formula: 【Chemistry 4】 The method according to claim 8, wherein the compound is a compound represented by the formula:

10. the cattle are dairy cattle, and the papillomatosis is papillary bovine papillomatosis; 10. The method of claim 8 or 9, comprising applying the composition to the teats of the dairy cow.

11. The compound or a pharmaceutically acceptable salt thereof is administered at a concentration of 0.01 mg / cm 2 ~40 mg / cm 2 The method according to claim 10, wherein the composition is applied to the nipple where the papilloma is present.

12. The method according to claim 10 or 11, further comprising covering the applied site with a nipple covering container or covering material after applying the compound or a pharmaceutically acceptable salt thereof to the nipple.

13. The method according to claim 12, wherein the nipple-covering container or covering material is a container that covers the nipple or a covering material that can form a film by applying it to the nipple.

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