Method for producing a compound and a remedy for treating skin diseases

Abstract

The present invention provides a method for easily producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione, and a method for producing the same. The present invention relates to a therapeutic agent for skin diseases, which comprises one or more compounds (a) selected from the group consisting of compounds represented by formula (I) and compounds represented by formula (II). A method for producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione, comprising a step of contacting one or more compounds (B) selected from the group consisting of betamethasone dipropionate, clobetasol propionate, betamethasone butyrate propionate, betamethasone valerate, clobetasone butyrate, and difluprednate with NaH.

Description

[Technical field]

[0001] The present invention relates to a therapeutic agent for skin diseases and a method for producing a compound having a specific structure. [Background technology]

[0002] For the treatment of skin diseases, topical medications containing various drugs are used in various dosage forms (ointments, creams, lotions, gels, foams, etc.), and topical steroids of different strengths and / or vitamin D3 medications have been widely used. However, there were not necessarily many topical medications that could achieve a therapeutic effect more quickly and in smaller doses.

[0003] For example, psoriasis, which is a representative of inflammatory keratosis, is an intractable disease in which erythema with characteristic silvery white mica-like scales is scattered on various parts of the skin of the whole body.There are more than 400,000 patients with this disease in Japan, and the incidence rate is low compared to about 120 million in Europe and the United States, but the incidence rate in Japan has recently been increasing.The male-female ratio of psoriasis patients is 2:1, and psoriasis patients are more common in men, especially in young and middle-aged people.

[0004] The cause of psoriasis is unknown, but it is believed to be based on a genetic predisposition to develop psoriasis, and psoriasis susceptibility genes such as PSORS1, IL12B, IL23R, and IL23A have been reported. Currently, it is believed that bone marrow-derived immune cells such as helper T cells and dendritic cells play a central role in the pathogenesis of psoriasis, and the involvement of IL-12, Th1 cells, IL-23, Th17 cells, etc. is important in the pathogenesis of psoriasis (Non-Patent Document 1). Factors that cause or aggravate psoriasis include focal infection, HIV infection, diabetes, metabolic syndrome, drugs (Ca antagonists, β-blockers, antimalarials, indomethacin, ACE inhibitors, tetracycline, digoxin, etc.), trauma, pregnancy, stress, etc. (Non-Patent Document 1, page 379).

[0005] Symptoms of psoriasis include red spots covered with silvery white mica-like scales, as well as various other types of red spots, wax flake phenomenon, Auspitz blood drop phenomenon, and Koebner phenomenon, and are sometimes accompanied by itching. Although symptoms tend to improve in the summer, they often go through repeated periods of relief and exacerbation. If the rash spreads within a year of onset and spreads to the nails, Achilles tendons, finger joints, etc., the prognosis is considered poor. The majority of psoriasis patients have psoriasis vulgaris.

[0006] Treatments for psoriasis vulgaris include topical therapy using steroid ointments, active vitamin D3 ointments, or combinations of these, phototherapy (PUVA therapy, narrow band UVB therapy), and combination therapy (topical therapy + phototherapy), and systemic therapy includes oral therapy using cyclosporine, etretinate, methotrexate, apremilast, JAK inhibitors, herbal medicines, and injection therapy using biological agents (Figure 1). The first choice for treating psoriasis vulgaris is topical therapy, more specifically, topical application of ointments, creams, or lotions containing steroid compounds, or ointments, creams, gels, lotions, or foams containing active vitamin D3, or topical application of these steroid compounds in combination with active vitamin D3. The effectiveness of these topical therapies varies depending on the severity of the symptoms, but even if the rash disappears, it often recurs, and there are very few cases of cure. As a result, patients' quality of life declines, and in some cases they may be driven to attempt suicide. If local treatment is ineffective and the rash worsens, systemic treatment is used; however, in severe cases, even if biological agents are used and the condition improves to the point where the rash is no longer present, complete recovery is unlikely, and maintenance treatment is necessary.

[0007] Parapsoriasis is a general term for a chronic disease in which multiple keratotic erythema occurs on the trunk and other areas of the body, and is broadly classified into guttate parapsoriasis, plaque parapsoriasis, and lichenoid parapsoriasis. Parapsoriasis is mainly treated with topical steroid therapy and phototherapy.

[0008] Lichen planus is a disease that causes purple-red infiltrative papules and erythema on the limbs and trunk, and can also affect the lips, oral cavity (lace-like white spots), and nails. The cause of lichen planus is unknown, but it can be triggered by hepatitis C virus infection, medication, dental metal allergies, and psychological stress. It is treated with topical or oral application of steroid compounds or tacrolimus, and phototherapy.

[0009] Pustulosis is a disease that causes the formation of sterile or non-infectious pustules on the skin. Pustules are blisters that become purulent because they contain a large number of neutrophils. The cause of most cases of pustulosis is unknown. Pustulosis is classified into localized pustulosis, generalized pustulosis, and pyoderma gangrenosum.

[0010] Palmoplantar pustulosis is a representative disease of localized pustulosis, and like psoriasis, it is generally resistant to treatment. Palmoplantar pustulosis is characterized by the occurrence of multiple sterile pustules on both palms and soles or one side of the body, and follows a chronic course, with repeated improvements and exacerbations. When pustules form, lesions accompanied by erythema and scale also form. The prevalence of palmoplantar pustulosis in Japan is approximately 0.12%, and the number of patients is estimated to be approximately 136,000. The average age at onset of palmoplantar pustulosis is 55.5 years old, and the male-to-female ratio is approximately 1:2, with more women than men. Abnormal enhancement of the IL-17 signal pathway is thought to induce inflammation and neutrophil migration, contributing to the pathogenesis.

[0011] Treatment for palmoplantar pustulosis includes (1) lifestyle advice (smoking cessation, oral care), (2) removal of aggravating factors, i.e., treatment of focal infections, specifically treatment of tonsillar lesions, odontogenic lesions, and chronic sinusitis, and (3) symptomatic treatment (topical application of steroid compounds, topical application of vitamin D3, ultraviolet light exposure, granulocyte-monocyte apheresis, and biological agents).

[0012] Treatment of palmoplantar pustulosis is based on the above (1) and (2). The first choice of symptomatic treatment is topical application of steroid ointment or vitamin D3 ointment, but the effectiveness of existing topical medications is often insufficient.

[0013] There are many skin diseases, but the most common and most common are those that cause inflammatory changes in the skin, known as eczema reactions. This group of diseases undergoes a pathological condition called the eczema triangle (Figure 2, Non-Patent Document 1, p. 140), but they exhibit common clinical symptoms and tissue images in the acute phase, and their etiology and pathology are diverse, with many unknown aspects. Eczema reactions are a disease that accounts for more than one-third of skin disease patients. The basic image of eczema reactions is lymphocyte invasion of the epidermis and a spongiform state, but parakeratosis and acanthosis can also occur. They exhibit acute, subacute, and chronic tissue images. Most of them are treated mainly with topical steroid compounds, but there is always a need for topical medications that can heal this disease faster.

[0014] Acute eczema presents various symptoms such as erythema, pustules, scaling, papules, small blisters, wetness, or crusts, as shown in the eczema triangle. However, the causes and pathology are diverse, and many aspects remain unknown. When the symptoms of the eczema triangle appear, it is called acute eczema, but when it does not heal after this stage and develops into lichenification, it is called chronic eczema.

[0015] The pathological conditions shown in the eczema triangle, such as erythema, pustules, desquamation, papules, vesicles, wetting, and crusts, are symptoms of eczema whose cause is unclear, while the group of eczema / dermatitis with relatively clear causes or typical clinical symptoms includes contact dermatitis, atopic dermatitis, seborrheic dermatitis, infantile seborrheic dermatitis, nummular eczema, autosensitization dermatitis, stasis eczema, skin deficiency eczema, and shiitake dermatitis (Non-Patent Document 1).

[0016] Atopic dermatitis and seborrheic dermatitis are classified as eczema or dermatitis in a group of skin diseases that cause inflammatory changes, and are skin diseases in which the cause is relatively clear or which present a typical clinical picture.

[0017] Atopic dermatitis is a disease characterized by pruritic eczema as the main lesion, and is subject to repeated exacerbations and remissions. Most patients with atopic dermatitis have a predisposition to atopy. There is no treatment that can cure atopic dermatitis in a short time, but topical treatments include steroid compounds, tacrolimus, delgocitinib, and difamilast. In recent years, phosphodiesterase 4 (PDE4) inhibitors have also been used for topical treatment. In addition to oral and dietary treatments, biological agents have been developed in recent years, and the therapeutic effect has increased, but from the patient's perspective, more effective topical medications are essential.

[0018] Seborrheic dermatitis (synonymous with seborrheic eczema) is an intractable inflammatory disease that causes erythematous lesions accompanied by light brown scales on seborrheic and intertriginous areas (head, face, armpits, pubic area, etc.). In adults, the disease manifests as an increase in pityriasis-like scales on the head, erythematous lesions at the hairline, erythematous lesions accompanied by scales on the eyebrows and nasolabial folds, and sometimes erythematous lesions with macerated scales on the armpits, under the breasts, and pubic area. In some infants, the disease is indistinguishable from atopic dermatitis. The symptoms of seborrheic dermatitis are subject to repeated remission and exacerbation over a long period of time. The fungus Malassezia has also been noted as a cause of seborrheic dermatitis. It has been pointed out that the inflammation-inducing mechanism of Malassezia involves the activation of complement and increased production of cytokines such as IL-6 and IL-8. Treatment for seborrheic dermatitis involves topical application of steroid compounds, topical application of ketoconazole, etc.

[0019] Looking only at the existing topical steroid compounds, there are 25 types, ranging from strongest to weakest, and the degree of effectiveness of each on each skin disease has been established in clinical practice. The details of the 25 steroid compounds will be described later, but they range from very effective to almost ineffective.

[0020] There are more than 20 types of steroid compounds that are commonly used for the treatment of psoriasis. Steroid compounds classified as strongest improve the rash more quickly in most cases with short-term application, but they recur when application is discontinued, and repeated resumption of application causes thinning of the skin and does not result in recovery. If the strength of the steroid compound is reduced, the degree of improvement of the rash decreases in proportion to the strength of the compound, the time required for improvement increases, patient satisfaction decreases, so-called compliance decreases, and the treatment effect decreases. In addition, topical vitamin D3 medications, either alone or in combination with steroid compounds, which are commonly used to treat psoriasis, are often as effective as or even more effective than topical steroid compounds alone, but because they require long-term application, side effects such as hypercalcemia (e.g., fatigue, lethargy, impaired consciousness, excessive drinking, excessive urination, shortened QT interval, nausea, and vomiting) may occur.

[0021] There are many skin diseases other than psoriasis that are difficult to treat, and the topical steroid compounds used to treat them have the side effect of thinning the skin because they are used for a long period of time. Side effects of topical steroid compounds can also occur in eczema and dermatitis that are not difficult to treat, so there is always a need for topical medications that work faster.

[0022] On the other hand, 11β-hydroxy-4-androstene-3,17-dione has been reported as a therapeutic agent for autoimmune diseases, and its derivatives such as 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione have been disclosed (Patent Document 1). However, the effect of 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione has not been disclosed.

[0023] A method for producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione has been reported in which betamethasone is dissolved in dioxane, sodium hydroxide is added, the mixture is heated to 80° C., and the mixture is allowed to react for 5 hours (Non-Patent Document 2). [Prior art documents] [Patent documents]

[0024] [Patent Document 1] Japanese Patent Application Publication No. 9-151197 [Non-patent literature]

[0025] [Non-Patent Document 1] Original author: Kenichi Ueno, editors: Fujio Otsuka and Manabu Fujimoto, Dermatology, 11th Edition, Kinpodo Co., Ltd., published in June 2022 [Non-Patent Document 2] Tetsuro Hidaka et al., "Study on Betamethasone: Behavior of Betamethasone under Mild Conditions of Acid, Alkaline, Light Irradiation and Oxidizing Agents," Pharmaceutical Journal, 1980, 100(1), pp. 72-80 Summary of the Invention [Problem to be solved by the invention]

[0026] The present invention provides a more effective therapeutic agent for skin diseases, and a method for easily producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione. [Means for solving the problem]

[0027] The present inventors have conducted extensive research to solve the above problems, and as a result have found that the above problems can be solved by providing the following configuration, which has led to the completion of the present invention. The present invention relates to, for example, the following aspects [1] to

[11] . [1] A therapeutic agent for skin diseases, comprising one or more compounds (a) selected from the group consisting of compounds represented by the following formula (I) and compounds represented by the following formula (II):

[0028] [ka]

[0029] [ka] [In formula (I) and formula (II), X 1 is a fluorine atom or a chlorine atom, and X 2 is a fluorine atom, a chlorine atom or a hydrogen atom, and X 3 is a methyl group or a hydrogen atom. [2] The drug for treating a skin disease according to [1], wherein the compound (a) is a compound represented by the following formula (I-1):

[0030] [ka] [3] The method for treating a skin disease according to [1] or [2], wherein the skin disease is inflammatory keratosis. [4] The drug for treating a skin disease according to [3], wherein the inflammatory keratosis is one or more selected from the group consisting of psoriasis, parapsoriasis, and lichen planus. [5] The method for treating a skin disease according to [1] or [2], wherein the skin disease is pustulosis. [6] The drug for treating a skin disease according to [5], wherein the pustulosis is palmoplantar pustulosis. [7] The therapeutic agent for skin diseases according to [1] or [2], wherein the skin disease is a disease group that causes inflammatory changes. [8] The therapeutic drug for skin diseases according to [7], wherein the disease group causing inflammatory changes is eczema / dermatitis group. [9] The therapeutic agent for skin diseases according to [7], wherein the group of diseases causing inflammatory changes is one or more selected from the group consisting of atopic dermatitis and seborrheic dermatitis.

[10] A method for producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione, comprising a step of contacting one or more compounds (B) selected from the group consisting of betamethasone dipropionate, clobetasol propionate, betamethasone butyrate propionate, betamethasone valerate, clobetasone butyrate, and difluprednate with NaH.

[11] The method according to

[10] , wherein the compound (B) is betamethasone dipropionate. Effect of the Invention

[0031] According to the present invention, a more effective therapeutic drug for skin diseases can be provided. The therapeutic drug for skin diseases of the present invention is more effective than existing topical drugs containing steroids and vitamin D3, particularly for psoriasis vulgaris, and has no side effects due to vitamin D. The therapeutic drug for skin diseases of the present invention is equally or more effective than existing topical drugs containing steroids and vitamin D3, particularly for palmoplantar pustulosis, and has no side effects due to vitamin D. The therapeutic drug for skin diseases of the present invention is equally or more effective than existing topical drugs containing steroids or phosphodiesterase 4 (PDE4) inhibitors, particularly for atopic dermatitis. The therapeutic drug for skin diseases of the present invention is also highly effective against seborrheic dermatitis. The therapeutic drug for skin diseases of the present invention is also highly effective against chronic eczema.

[0032] According to the present invention, a method for easily producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione can be provided. [Brief description of the drawings]

[0033] [Figure 1] Figure 1 is a diagram explaining psoriasis treatment options, modified from Hajime Iizuka, J Visual Dematol 16(9):850-851,2017. [Diagram 2] Figure 2 is a diagram explaining the eczema triangle. [Diagram 3] FIG. 3 is an IR chart of compound (I-1-1). [Figure 4] FIG. 4 is a 1H NMR chart of compound (I-1-1). [Diagram 5] FIG. 5 is a 13C NMR chart of compound (I-1-1). [Figure 6] FIG. 6 shows the results of automated single crystal X-ray structure analysis of compound (I-1-1). [Figure 7] FIG. 7 shows the results of automated single crystal X-ray structure analysis of compound (I-1-1). [Figure 8] FIG. 8 shows a summary of the analysis results of compound (I-1-1) and the chemical structural formula of compound (I-1-1) (9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione). [Figure 9] FIG. 9 is a photograph of the anterior lower leg before the start of topical application of a cream containing compound (I-1-1) in Example 1. [Figure 10] FIG. 10 is a photograph of the anterior lower leg 4 months after the start of topical application of a cream containing compound (I-1-1) in Example 1. [Figure 11] FIG. 11 is a photograph of the left temporal region before the start of topical application of a cream containing compound (I-1-1) in Example 2. [Figure 12] FIG. 12 is a photograph of the left temporal region in Example 2, taken 28 days after the start of topical application of a cream containing compound (I-1-1).

[0034] [Figure 13] FIG. 13 is a photograph of the front hair line before the start of topical application of a cream containing compound (I-1-1) in Example 3. [Figure 14] FIG. 14 is a photograph of the frontal hairline on day 14 after the start of topical application of a cream containing compound (I-1-1) in Example 3. [Figure 15] FIG. 15 is a photograph of the anterior right lower leg before the start of topical application of a cream containing compound (I-1-1) in Example 4. [Figure 16] FIG. 16 is a photograph of the anterior right lower leg on the 52nd day after the start of topical application of a cream containing compound (I-1-1) in Example 4. [Figure 17] FIG. 17 is a photograph of both palms before the start of topical application of a cream containing compound (I-1-1) in Example 5. [Figure 18] FIG. 18 is a photograph of the palms of both hands three weeks after the start of topical application of a cream containing compound (I-1-1) in Example 5. [Figure 19] FIG. 19 is a photograph of the back hair line before the start of topical application of a cream containing compound (I-1-1) in Example 6. [Figure 20] FIG. 20 is a photograph of the back hairline on the 28th day after the start of topical application of a cream containing compound (I-1-1) in Example 6. [Figure 21] FIG. 21 is a photograph of both cubital fossae and both popliteal fossae before the start of external application in Example 7.

[0035] [Figure 22] FIG. 22 shows photographs of both cubital fossae and both popliteal fossae on the 15th day after the start of external application in Example 7. [Diagram 23] FIG. 23 is a photograph of both cubital fossae before the start of external application in Example 8. [Figure 24] FIG. 24 is a photograph of both cubital fossae in Example 8, taken 14 days after the start of external application. [Diagram 25] FIG. 25 is a photograph of both thighs before the start of external application in Example 9. [Figure 26] FIG. 26 is a photograph of both thighs on the 14th day after the start of external application in Example 9. [Figure 27] FIG. 27 is a photograph of the soles of both feet before the start of external application in Example 10. [Figure 28] FIG. 28 is a photograph of the soles of both feet on the 29th day after the start of external application in Example 10. [Figure 29] FIG. 29 is a photograph of the medial edge of the right plantar surface before the start of external application in Example 11. [Diagram 30] FIG. 30 is a photograph of the medial edge of the right plantar fascia in Example 11, taken 12 days after the start of external application. [Diagram 31] FIG. 31 is a photograph of the sacrum area before the start of external application in Example 12. [Diagram 32] FIG. 32 is a photograph of the sacrum area 6 and a half months after the start of external application in Example 12. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Next, the present invention will be specifically described. Note that, unless otherwise specified, the description "A to B" regarding a numerical range means A or more and B or less. For example, the description "1 to 5%" means 1% or more and 5% or less.

[0037] [Dermatological treatment] <Compound (a)> The therapeutic agent for skin diseases of the present invention contains compound (a). The compound (a) contained in the skin disease therapeutic agent of the present invention may be one type or two or more types.

[0038] The compound (a) is one or more compounds selected from the group consisting of compounds represented by the following formula (I) and compounds represented by the following formula (II).

[0039] [ka]

[0040] [ka] [In formula (I) and formula (II), X 1 is a fluorine atom or a chlorine atom, and X 2 is a fluorine atom, a chlorine atom or a hydrogen atom, and X 3 is a methyl group or a hydrogen atom.

[0041] Since the effectiveness of skin disease treatment drugs will be stronger, 1 is preferably a fluorine atom. Since the effectiveness of skin disease treatment drugs will be stronger, 2 is preferably a fluorine atom or a hydrogen atom, and more preferably a hydrogen atom. Since the effectiveness of skin disease treatment drugs will be stronger, 3 is preferably a methyl group.

[0042] The compound represented by formula (I) is X shown in Table 1 below. 1 , X 2 , and X 3The compounds Nos. 1 to 12 each having the above combination are exemplified.

[0043] [Table 1]

[0044] The compound represented by formula (II) is X shown in Table 2 below. 1 , X 2 , and X 3 Compounds No. 13 to 24 having the above combinations are exemplified. Compound No. 2 and Compound No. 14, Compound No. 4 and Compound No. 16, Compound No. 6 and Compound No. 18, Compound No. 8 and Compound No. 20, Compound No. 10 and Compound No. 22, and Compound No. 12 and Compound No. 24 are the same compound.

[0045] [Table 2]

[0046] Since the effect of the skin disease treatment drug is stronger, compound (a) is preferably compound Nos. 1, 2, 5, 6, and 13, more preferably compound Nos. 1, 2, 5, and 13, even more preferably compound Nos. 1, 2, and 5, particularly preferably compound Nos. 1 and 5, and even more preferably compound No. 5, in other words, the compound represented by the following formula (I-1) (9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione).

[0047] [ka]

[0048] The content of compound (a) in the skin disease therapeutic agent is preferably 0.0001 to 5 mass %, more preferably 0.001 to 1 mass %, further preferably 0.01 to 0.5 mass %, and particularly preferably 0.05 to 0.2 mass %. When the content of compound (a) is within the above range, sufficient effects are obtained, and the irritation to the skin is low and the feeling of use is good.

[0049] The method for producing compound (a) is not particularly limited, and can be produced by known methods.The compound represented by formula (I-1) (9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione) can be obtained, for example, by the method described in Tetsuro Hidaka et al., "Betamethasone Research: Behavior of Betamethasone in Acid, Alkaline, Light Irradiation and Oxidizing Agents Under Weak Conditions", Yakugaku Zasshi, 1980, 100(1), pp. 72-80, or the method described in the examples below.

[0050] The compound represented by formula (I-1) (9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione) may be a commercially available product, and its CAS registration number is 3109-01-1.

[0051] Considering the stability to light, compound (a) is preferably stored in a light-shielded location.

[0052] Topical steroids have a history of being developed in 1952 by Sulzberger in the form of an ointment, and hydrocortisone acetate was the first topical steroid approved in Japan in 1953. Since then, many topical steroids have been developed, and the following 25 types are currently in common use, all of which share a common chemical structure. Group I (Strongest): Dermovate (clobetasol propionate ester), Diacort (diflorasone acetate ester) Group II (very strong): Flumeta (mometasone furoate), Antebate (betamethasone butyrate propionate), Topsym (fluocinonide), Rinderon DP (betamethasone dipropionate), Visderm (amcinonide), Nerisona, Texmetin (diflucortolone valerate), Pandel (hydrocortisone butyrate propionate), Myser (difluprednate)

[0053] Group III (strong): Boala (dexamethasone valerate), Betnetabate, Linderone V, Linderone VG (betamethasone valerate), Flucort (fluocinolone acetonide), Flucort F (fluocinolone acetonide), Eclar (deprodone propionate), Methaderm (dexamethasone propionate) Group IV (medium): Lidomex (prednisolone valerate acetate), Ledacort (triamcinolone acetonide), Almeta (alclometasone propionate), Kindabate (clobetasone butyrate), Locoid (hydrocortisone butyrate), Eurasone (dexamethasone, glimethasone) Group V (weak): Prednisolone, Terra-Cortril (hydrocortisone), Exalbe (mixed killed bacteria suspension and hydrocortisone) The structural formula of prednisolone, a representative topical steroid medication, is shown below in formula (P).

[0054] [ka]

[0055] The 25 types of topical steroids currently in common use have common molecular structural characteristics as shown below and exert their pharmacological effects. (1) C3 is a ketone group. (2) When the bond between C1 and C2 is a double bond, the anti-inflammatory effect is enhanced. (3) The double bond between C4 and C5 is essential for enhancing glucocorticoid activity. (4) When C6 and C9 have halogen atoms, the medicinal effect is enhanced. (5) It is essential for C11 to have an OH group (hydroxyl group) or a C=O group (ketone group) in order to exert an anti-inflammatory effect. (6) The α-OH group of C17 is important for the anti-inflammatory effect. (7) When the OH groups (hydroxyl groups) of C17 and C21 are esterified, their affinity to the skin increases.

[0056] Compound (a) is significantly different in structure from the above-mentioned 25 kinds of steroid compounds in that C17 is a C=O group (ketone group). Considering the above (6), it is expected that compound (a) will have a lower affinity to the skin, but as shown in the examples described below, this is not the case. Rather, it is suggested that if C17 is a C=O group (ketone group), the pharmacological effect will be enhanced. Furthermore, compound (a) has a molecular weight of 318.4 to 383.4, which is relatively small for a steroid compound. In particular, the molecular weight of the compound represented by formula (I-1) (9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione) is 332.4, which is smaller than any of the above-mentioned 25 kinds of steroid compounds (the largest is flumetha (mometasone furoate, molecular weight 521.43) and the smallest is terra-cortril (hydrocortisone, molecular weight 362.46)). It is a well-known fact that the smaller the molecular weight of a steroid compound (500 or less), the higher its percutaneous absorption (Maruho Medical Professionals' Site, Topical Ointment Knowledge, Chapter 2, Main Component and Percutaneous Absorption: Characteristics of Main Component That Easily Passes Through the Skin). This percutaneous absorption can also be said to be in an inverse exponential relationship.

[0057] Generally, a low melting point of a compound is considered to be advantageous for enhancing transdermal absorbability. The melting point of the compound represented by formula (I-1) (9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione) is as high as 278 to 280°C, and is expected to be disadvantageous in terms of transdermal absorbability. However, as shown in the examples described below, the transdermal absorbability of the compound represented by formula (I-1) is sufficiently high, and the effect of the small molecular weight is considered to outweigh the disadvantage of the high melting point.

[0058] For these reasons, compound (a) is considered to be effective in treating skin diseases at lower doses and for a shorter period of time than existing topical steroid medications, without significant side effects, and more safely (mainly because it is less likely to cause skin thinning).

[0059] <Dermatological treatment> The therapeutic agent for skin diseases of the present invention contains one or more compounds (a) selected from the group consisting of the compounds represented by the above formula (I) and the compounds represented by the formula (II). The skin disease therapeutic drug of the present invention is not particularly limited in terms of its properties or dosage form, so long as it contains compound (a). The form of the skin disease therapeutic agent may be, for example, a solid, semi-solid, liquid, emulsion, cream, gel, or foam (mousse), and is preferably an emulsion, cream, gel, or foam (mousse).

[0060] The skin disease treatment drug can be an external medicine such as a dermatological medicine, eye drops, nasal drops, ear drops, oral medicine, or suppository; or an injectable medicine, but an external medicine is preferable, and an external medicine is more preferable. Examples of dosage forms of topical medications include solid preparations for topical use such as powders for topical use; liquid preparations for topical use such as liniments and lotions; sprays (sprays) such as aerosols and pump sprays; ointments such as oily ointments and water-soluble ointments; creams (emulsion base) such as oil-in-water creams and water-in-oil creams; gels such as aqueous gels and oily gels; and patches such as poultices and tapes. Of these, sprays (sprays), ointments, creams, or gels are preferred, creams are more preferred, and water-in-oil creams are even more preferred.

[0061] Examples of dosage forms of injections include water-soluble injections, water-insoluble injections, suspension injections, emulsified injections, and injections that are dissolved when used, with water-insoluble injections, suspension injections, and emulsified injections being preferred. The administration route of the injectable drug is not limited, and examples thereof include intradermal injection, subcutaneous injection, intravenous injection, and intramuscular injection, with intradermal injection and intramuscular injection being preferred.

[0062] The skin disease treatment drug may contain additives that are generally used in external medicines or injections, as necessary, within the scope of not impairing the effects of the present invention. Examples of additives used in external medicines for skin, such as pharmaceuticals, include oily ingredients, surfactants (synthetic and natural), moisturizing agents, thickeners, preservatives and germicides, powder ingredients, ultraviolet absorbers, antioxidants, chelating agents, pigments, and fragrances. These ingredients may be used alone or in combination of two or more.

[0063] Examples of oily components include plant-derived oils and fats such as olive oil, jojoba oil, castor oil, soybean oil, rice oil, rice bran oil, palm oil, shea butter, and plant-derived squalane; animal-derived oils and fats such as mink oil; waxes such as beeswax, carnauba wax, rice wax, and lanolin; hydrocarbons such as liquid paraffin, petrolatum, paraffin wax, squalane, and microcrystalline wax; fatty acids such as myristic acid, palmitic acid, stearic acid, oleic acid, and isostearic acid; higher alcohols such as lauryl alcohol, cetanol, and stearyl alcohol; synthetic esters and synthetic triglycerides such as isopropyl myristate, isopropyl palmitate, 2-ethylhexyl glyceride, and higher fatty acid octyldodecyl (such as octyldodecyl stearate), among others, but waxes and hydrocarbons are preferred.

[0064] Examples of the surfactant include nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitol fatty acid esters; anionic surfactants such as fatty acid salts, alkyl sulfates, alkylbenzene sulfonates, polyoxyethylene alkyl ether sulfates, and polyoxyethylene fatty amine sulfates; cationic surfactants such as quaternary ammonium salts and primary to tertiary fatty amine salts; and amphoteric surfactants such as N,N-dimethyl-N-alkyl-N-carboxymethylammoniobetaine. Of these, nonionic surfactants and anionic surfactants are preferred, and nonionic surfactants are more preferred.

[0065] Examples of moisturizing agents include polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, and polyethylene glycol; sugars such as sorbitol, xylitol, and trehalose; and mucopolysaccharides such as hyaluronic acid and its derivatives, and chondroitin and its derivatives. Preferred are polyhydric alcohols, and more preferred is glycerin.

[0066] The skin disease treatment drug may contain active ingredients that are generally used in external medicines or injections, as necessary, within the scope that does not impair the effects of the present invention. Examples of active ingredients used in external medicines for skin, such as pharmaceuticals, include antihistamines, steroid compounds, antiviral drugs, bactericides, urea, vitamins, heparinoids, etc. These ingredients may be used alone or in combination of two or more. The skin disease treatment drug preferably contains a heparinoid.

[0067] The skin disease therapeutic drug can be produced by adding compound (a) according to a method generally used for these preparations. Compound (a) may be added at the beginning of the preparation production process, or at the middle or end of the preparation production process, and the method of addition may be appropriately selected from mixing, kneading, dissolving, immersing, scattering, spraying, coating, etc. according to the form of the preparation.

[0068] The skin disease therapeutic agent is usually applied externally or by injection. The skin disease therapeutic agent is preferably applied externally to the affected area of ​​the skin and its surroundings. The method of external application is not particularly limited, and may be applied by coating or rubbing.

[0069] The dosage and frequency of administration of the skin disease therapeutic drug are not particularly limited and can be determined depending on the type and symptoms of the skin disease. In the case of external application, however, preferably, FTU (Finger Tip Unit, the amount squeezed out from a tube with a diameter of 5 mm and placed on an adult's index finger from the tip to the first joint, approximately 0.5 g) is applied externally to an area equivalent to the size of two palms of an adult's hand once or twice a day. The dosage of the skin disease therapeutic agent per administration, in the case of external application, is preferably 0.5 ng to 25 mg, more preferably 5 ng to 5 mg, further preferably 50 ng to 2.5 mg, and particularly preferably 0.25 mg to 1 mg, of compound (a). The administration period of the skin disease therapeutic drug is not particularly limited and can be determined depending on the type and symptoms of the skin disease, but is preferably 1 to 180 days, more preferably 7 to 120 days, and even more preferably 10 to 60 days.

[0070] The skin disease treatment drug of the present invention is expected to be effective more safely at lower doses and for a shorter period of time than existing topical steroid medications. The skin disease therapeutic drug of the present invention is expected to be effective against psoriasis at a lower dose and for a shorter period of time than existing psoriasis therapeutic drugs, particularly topical steroid medications, and to be effective more safely. The skin disease therapeutic agent of the present invention is expected to be effective against atopic dermatitis at lower doses and for a shorter period of time than existing atopic dermatitis therapeutic agents, particularly topical steroids and topical phosphodiesterase 4 (PDE4) inhibitors, and to be effective more safely. The therapeutic drug for skin diseases of the present invention is expected to be effective against palmoplantar pustulosis at a lower dose and for a shorter period of time than existing therapeutic drugs for palmoplantar pustulosis, particularly topical steroid medications. The skin disease therapeutic agent of the present invention is expected to be effective against eczema at a lower dose and for a shorter period of time than existing eczema therapeutic agents, particularly topical steroid medications, and to be effective more safely.

[0071] The skin disease targeted by the therapeutic drug for skin disease is not particularly limited, and examples of the skin disease include inflammatory keratosis, pustular disease, and diseases causing inflammatory changes. The severity of the skin disease is not particularly limited, but preferably the skin disease is severe enough to be treated with topical steroids. The skin condition may be acute or chronic.

[0072] The inflammatory keratosis is not particularly limited, and examples thereof include psoriasis, parapsoriasis, lichen planus, pityriasis rubra pilaris, lichen linearis, lichen nitidus, and pityriasis rosea of ​​Gibert, but is preferably one or more selected from the group consisting of psoriasis, parapsoriasis, and lichen planus.

[0073] The psoriasis may be any of psoriasis vulgaris, acute guttate psoriasis, erythrodermic psoriasis, psoriasis arthropathy, and pustular psoriasis, but is preferably psoriasis vulgaris. The site where psoriasis develops is not particularly limited and may be the head, hairline, elbows, knees, back, lower back, buttocks, lower legs, pubic area, groin, armpits, palms, soles, etc., but is preferably the head, hairline, back, lower back, or lower legs. The severity of psoriasis is not particularly limited and may be mild, moderate, or severe, but is preferably psoriasis with a PSI total score of 3 to 25 or a PSSI total score of 3 to 42, as described later in the Examples.

[0074] The pustulosis may be any of localized pustulosis, generalized pustulosis, and pyoderma gangrenosum, but is preferably localized pustulosis. Examples of the pustulosis include palmoplantar pustulosis, subcorneal pustulosis, eosinophilic pustular folliculitis, acute generalized pustular bacterial eruption, and infantile acropustulosis, but is preferably palmoplantar pustulosis.

[0075] The group of diseases that cause inflammatory changes can be rephrased as the group of diseases that cause eczema reactions, and examples of these include eczema / dermatitis, bullous pemphigoid, sarcoidosis, granuloma annulare, and alopecia areata. The group of diseases causing inflammatory changes is preferably one or more selected from the group consisting of eczema and dermatitis, more preferably atopic dermatitis and seborrheic dermatitis.

[0076] Eczema / dermatitis can be further classified into eczema / dermatitis with relatively clear causes or typical clinical symptoms, such as atopic dermatitis, seborrheic dermatitis, contact dermatitis, infantile seborrheic dermatitis, nummular eczema, autosensitization dermatitis, stasis eczema, skin deficiency eczema, shiitake dermatitis, insect bites, hand eczema (housewives' eczema), dyshidrotic eczema (dyshidrotic eczema, dyshidrotic eczema), miliaria, and chronic lichen simplex, and other eczema / dermatitis, which may be acute or chronic. The above-mentioned other eczema / dermatitis group includes many eczemas with unknown causes, and can be classified into acute eczema and chronic eczema, which show the symptoms shown in the eczema triangle.

[0077] Atopic dermatitis may be of any severity, but is preferably mild or moderate atopic dermatitis. One of the main factors that aggravate atopic dermatitis is scratching, and if scratching is not performed, the rash will often improve. Therefore, the skin disease treatment drug can be used to treat atopic dermatitis patients who sometimes scratch lightly, and may be used to treat patients with VAS 40 or more, or VAS 60 or more. VAS will be described later.

[0078] Seborrheic dermatitis may occur in any area, such as the hairline, behind the ears, eyebrows, nasolabial folds, and sternal area, but is preferably seborrheic dermatitis occurring in the hairline.

[0079] The "treatment" of the aforementioned skin disease therapeutic drugs includes not only curing the disease or symptoms, but also alleviating (alleviating) the disease or symptoms, and preventing the recurrence of the disease or symptoms after the disease or symptoms have been cured.

[0080] The subject to which the skin disease therapeutic agent is administered may be either human or non-human (for example, mammals such as dogs, cats, mice, etc.), but is preferably human.

[0081] The skin disease therapeutic agent of the present invention can be used in combination with other drugs, such as other skin disease therapeutic agents or preventive agents, in topical therapy. When the skin disease therapeutic agent of the present invention is used in combination with other skin disease therapeutic agents or preventive agents, the therapeutic effect of skin disease is more likely to be improved than when the skin disease therapeutic agent of the present invention is used alone. The type of other skin disease therapeutic agent or preventive agent is not limited, and examples thereof include antihistamines, steroid compounds, antiviral drugs, bactericides, urea, vitamins, and heparinoids. The other skin disease therapeutic agent or preventive agent may be used alone or in combination of two or more.

[0082] The therapeutic agent for skin diseases of the present invention may be used in combination with phototherapy (PUVA therapy, narrow band UVB therapy), oral therapy, or injection therapy.

[0083] [Method of producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione] The method for producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione of the present invention includes a step of contacting one or more compounds (B) selected from the group consisting of betamethasone dipropionate, clobetasol propionate, betamethasone butyrate propionate, betamethasone valerate, clobetasone butyrate, and difluprednate with NaH.

[0084] <Compound (B)> Compound (B) is one or more compounds selected from the group consisting of betamethasone dipropionate, clobetasol propionate, betamethasone butyrate propionate, betamethasone valerate, clobetasone butyrate, and difluprednate.

[0085] The compound (B) is not particularly limited, and a compound produced by a known method can be used, or a commercially available product can be used. The amount of compound (B) used is not particularly limited and can be determined according to the desired amount of 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione.

[0086] Compound (B) is preferably one or more compounds selected from the group consisting of betamethasone dipropionate, clobetasol propionate, betamethasone butyrate propionate, betamethasone valerate, and clobetasone butyrate, more preferably one or more compounds selected from the group consisting of betamethasone dipropionate, clobetasol propionate, betamethasone butyrate propionate, and betamethasone valerate, and even more preferably betamethasone dipropionate.

[0087] <nah> NaH is not particularly limited, and may be prepared by a known method or may be a commercially available product. NaH may be used in the form of a pure solid or a dispersion in oil, but is preferably a dispersion in oil. The amount of NaH used is not particularly limited, but can be determined depending on the amount of compound (B), and is preferably a catalytic amount.

[0088] NaH is a strong base (pKa=35) and is widely used to deprive NH, OH, SH, or CH, and is widely used in William's ether synthesis, etc. In the production method of the present invention, NaH deprives the proton of C21 of the steroid skeleton of compound (B), causing a nucleophilic attack within the molecule, and then a unique electron transfer occurs, generating a ketone group at the C17 position. It is presumed that NaH caused a chemically extremely rare and revolutionary reaction in the production method.

[0089] <Contacting step> The method for contacting the compound (B) with NaH is not particularly limited, and any known method can be used. The compound (B) and NaH are usually contacted in an organic solvent. The method for contacting compound (B) with NaH is preferably a method of mixing compound (B) with NaH in an organic solvent, more preferably a method of mixing compound (B) with NaH and then stirring the mixture. Stirring may be performed by a known method, for example, using a stirrer. When compound (B) comes into contact with NaH, the two react to produce 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione.

[0090] The contact temperature may be appropriately determined depending on the solvent used, and is, for example, 1 to 40° C., and preferably room temperature (1 to 30° C.) The contact time is, for example, 0.1 to 15 hours.

[0091] The organic solvent is not particularly limited and any known organic solvent can be used, but is preferably a polar solvent. Examples of polar solvents include tetrahydrofuran (THF), dioxane, acetonitrile, and dimethylsulfoxide (DMSO). The polar solvent is preferably one or more organic solvents selected from the group consisting of tetrahydrofuran (THF) and dioxane, and more preferably tetrahydrofuran (THF). The purity of the organic solvent is not particularly limited, but the higher the purity, the more preferable, and the purity is more preferably 95% or higher. The organic solvent may be used after distillation or may not be used after distillation. Even if a non-distilled organic solvent is used, the production method of the present invention can produce 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione by reacting compound (B) with NaH. The amount of the organic solvent used is not particularly limited, but can be determined depending on the amount of compound (B), and is preferably an amount that completely dissolves compound (B).

[0092] The environment in which the step of contacting compound (B) with NaH is carried out is not particularly limited, and it may be carried out in a gas phase, and does not necessarily have to be under nitrogen.

[0093] According to the above-mentioned preparation method, 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione can be easily prepared in a short time at a temperature close to room temperature.In addition, since compound (B) is a generally available compound, the above-mentioned preparation method is suitable for industrial use.

[0094] The present inventors predict that when one or more compounds selected from the group consisting of dexamethasone propionate, mometasone furoate, dexamethasone valerate, diflucortolone valerate, alclometasone propionate, dexamethasone, deprodone propionate, hydrocortisone butyrate propionate, prednisolone valerate acetate, hydrocortisone butyrate, prednisolone, and hydrocortisone butyrate are contacted with NaH, the two react to produce 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione and / or its related compounds (analogs). EXAMPLES

[0095] <Production Example 1: Preparation of compound (I-1-1)> Betamethasone 17,21-dipropionate was manufactured by Tokyo Chemical Industry Co., Ltd. For TLC (Thin Layer Chromatography), a 20 x 20 cm TLC Silicagel 60F254 manufactured by MERCK was used. The developing solvent was n-Hexane-AcOEt (1:1.5), and the detector was an As ONE Handy UV Lamp SUV-4 254 nm. The various spectra were measured using the following models. IR spectrum (infrared absorption spectrum) was measured using JASCO FT / IR-410. 1 H NMR, 13 C NMR was measured using a Varian UNITY INOVA 400 with TMS as the internal standard, and the values ​​were expressed as δ values ​​(ppm). Single crystal automated X-ray structure analysis was performed using a Rigaku VariMax Saturn CCD724α.

[0096] Betamethasone 17,21-dipropionate (203mg) was dissolved in tetrahydrofuran (Tokyo Chemical Industry Co., Ltd.) (4mL), NaH (Fujifilm Wako Pure Chemical Industries, Ltd., Sodium Hydride, in Oil) was added, and the mixture was stirred with a magnetic stirrer for 15 hours. Water was added, and the mixture was extracted with chloroform, washed with water until pH 7, dried by adding sodium sulfate, filtered, the solvent was removed, and the mixture was developed by TLC. The band with Rf (retention factor value) 0.53 was eluted with acetone, and the solvent was removed to obtain 18mg of a white powdery substance (40% yield). The above was carried out at room temperature. The obtained white powdery substance is hereinafter referred to as compound (I-1-1).

[0097] For compound (I-1-1), infrared absorption spectrum, 1 H NMR, and 13 C NMR was measured, and then single crystal automated X-ray structure analysis was performed. The obtained IR chart is shown in Figure 3. 1 H NMR chart is shown in Fig. 4. 13 The C NMR chart is shown in Figure 5, and the results of the automated single crystal X-ray structure analysis are shown in Figures 6 and 7. A summary of all these analysis results and the chemical structural formula (9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione) of compound (I-1-1) determined from them are shown in Figure 8.

[0098] <Production Example 2: Preparation of Compound (b) and Compound (c)> 105 mg of Antebate (betamethasone butyrate ester propionate ester) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in 3.5 mL of tetrahydrofuran (manufactured by Tokyo Chemical Industry Co., Ltd.), a small spoonful of NaH (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., sodium hydride, in oil) was added, and the mixture was stirred with a magnetic stirrer for 15 hours, after which water was added, the mixture was extracted with chloroform, washed with water until the pH reached 7, sodium sulfate was added for drying, and the mixture was filtered, the solvent was removed, and the mixture was developed by TLC (n-hexane: ethyl acetate = 1: 3). The two bands around Rf 0.41 were eluted with acetone, the solvent was removed, and 5 mg of a white powdery substance was obtained. The above was carried out at room temperature. The obtained white powdery substance is presumed to be a mixture of two types of compounds (b) and (c). Compound (b) and compound (c) are suspected to be 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione or a related compound.

[0099] The following examples were carried out after the effects and side effects were fully explained to the patients (subjects) and their written consent was obtained.

[0100] (Preparation of cream) A predetermined amount of compound (I-1-1) was added to Hirudoid Soft Ointment 0.3% (manufactured by Maruho Co., Ltd.) and thoroughly mixed until homogenous, to obtain a cream containing compound (I-1-1). Hirudoid Soft Ointment 0.3% is a water-in-oil cream containing 3.0 mg of a heparinoid as an active ingredient per 1 g, and containing the following additives: glycerin, squalane, light liquid paraffin, paraffin, microcrystalline wax, white petrolatum, white beeswax, glycerin fatty acid ester, dibutylhydroxytoluene, sodium edetate hydrate, methyl parahydroxybenzoate, and propyl parahydroxybenzoate.

[0101] (PSI score) The severity of local symptoms of psoriasis other than on the scalp was evaluated using the PSI (Psosiasis Severity Index) score. The PSI score is an index that scores the severity of erythema, infiltration / thickening, and scaling, and is a useful index for evaluating the efficacy of treatment for specific skin lesions of psoriasis vulgaris. The severity of erythema, infiltration / thickening, and scaling was scored according to the criteria in Table 3 below.

[0102] [Table 3]

[0103] The total PSI score was calculated from the scores of erythema, infiltration / thickening, and scaling according to the following formula (A). PSI total score = PSI erythema score + PSI infiltration / thickening score + PSI scaling score ...Formula (A) In general, a PSI total score of 5 or less is mild, greater than 5 but less than 20 is moderate, and greater than 20 is severe.

[0104] (PSSI) The severity of local symptoms of scalp psoriasis was evaluated using the Psoriasis Scalp Severity Index (PSSI) score. The PSSI score is an index that can independently evaluate each skin finding of erythema, infiltration / thickening, and scale, which are the main symptoms of scalp psoriasis vulgaris, and can also evaluate the extent of the lesion. The PSSI score was determined by comparing clinical observations (findings) with "Psoriasis Vulgaris Case Photographs by Evaluation Index" provided by Maruho Co., Ltd. These photographs of psoriasis vulgaris cases show different severity of skin findings and different lesion areas, and each has a PSSI score written on it. This is a common evaluation tool for easily determining the PSSI score in clinical practice. The written PSSI score was calculated using the following method.

[0105] The severity of each skin finding on the scalp (erythema, infiltration / thickening, scale) and the area of ​​psoriasis vulgaris lesions on the scalp relative to the scalp area (%) were scored, and these were applied to a formula to calculate the PSSI score. The severity of erythema, infiltration / thickening, and scale were scored according to the criteria in Table 4 below.

[0106] [Table 4]

[0107] The PSSI total score was calculated from the scores for erythema, infiltration / thickening, and scaling using the following formula (B). PSSI total score = (erythema score + infiltration / thickening score + scaling score) × lesion extent score ··· formula (B)

[0108] <Example 1> (Profile of Subject 1) A 79-year-old man developed psoriasis on his extremities 3 years ago. He had been prescribed Otezla tablets and Dovobet ointment at another hospital for 1.5 years. However, the scales and erythema did not disappear, and palm-sized skin rashes remained on the front of both lower legs. He was then treated for about 7 months with oral cyclosporine capsules (4 capsules of 25 mg, twice a day) and topical Dovobet Foam (manufactured by Leo Pharma Co., Ltd.) (appropriate amount, once a day). However, the scales and erythema on the front of both lower legs did not disappear.

[0109] (Administration of Compound (I-1-1) to Subject 1) Topical application of Dovobet foam was discontinued, and oral cyclosporine was continued at the same dose. 5 g of cream containing 2.9 mg of compound (I-1-1) was prescribed and applied topically to the affected area in an FTU (Finger Tip Unit, approximately 0.5 g) amount once a day.

[0110] (result) The total PSI score before the start of topical application of compound (I-1-1) was 20. A photograph of the anterior lower leg is shown in FIG. 9. Four months after the start of topical application, the total PSI score was 3. A photograph of the anterior lower leg is shown in FIG. 10. Severe psoriasis improved to milder severity by topical application of a cream containing (I-1-1). No side effects were observed.

[0111] <Example 2> (Profile of Subject 2) A 61-year-old man developed psoriasis on the left side of his head several years ago. Since then, he had been using various topical steroids (Dermovate scalp lotion, Comclo shampoo, Antebate lotion, etc.) and his condition had repeatedly improved and worsened.

[0112] (Administration of Compound (I-1-1) to Subject 2) The use of topical steroids that had been used up until then was discontinued, and 10 g of a cream containing 5.8 mg of compound (I-1-1) was prescribed, with treatment being performed by applying an amount equivalent to FTU once a day.

[0113] (result) The PSSI total score before the start of topical application of compound (I-1-1) was 16, and the PSSI total score 28 days after the start of topical application was 8. Figure 11 shows a photograph of the left temporal region before topical application of compound (I-1-1), and Figure 12 shows a photograph 28 days after topical application. Moderate psoriasis improved to mild by topical application of a cream containing compound (I-1-1). No side effects were observed.

[0114] <Example 3> (Profile of Subject 3) A 48-year-old woman was diagnosed with psoriasis for the first time. She had noticed symptoms two months before her first visit. A scaly erythema measuring 2 cm in area and 8 cm in length had appeared at the hairline of her forehead.

[0115] (Administration of Compound (I-1-1) to Subject 3) 5 g of cream containing 2.9 mg of compound (I-1-1) was prescribed for the right half of the lesion, and 15 g of Dovobet Gel (manufactured by Leo Pharma Co., Ltd.) was prescribed for the left half, and treatment was performed by applying the FTU amount to each lesion once a day.

[0116] (result) Before starting topical application of compound (I-1-1) Right Left PSSI total score 27 27 14th day after starting topical use PSSI total score 0 2 A photograph of the frontal hairline before the start of application of compound (I-1-1) is shown in Figure 13, and a photograph 14 days after the start of application is shown in Figure 14. The right side, where the cream containing compound (I-1-1) was applied, was evaluated as a successful treatment. No side effects were observed.

[0117] <Example 4> (Profile of Subject 4) A 50-year-old man had been undergoing treatment for psoriasis (on the head, back, and lower back) for the past 20 years. Five or six years ago, the disease spread to the nails of all the fingers, and he had been treating the condition with cyclosporine, dovobet foam, etc. A scaly erythema remained only on the anterior surface of the right lower leg.

[0118] (Administration of Compound (I-1-1) to Subject 4) After discontinuing the use of cyclosporine, dovobet foam, etc., the patient was treated by applying 10 g of a cream containing 11 mg of compound (I-1-1) in an amount equivalent to FTU once a day to the affected area on the front of the right lower leg.

[0119] (result) PSI total score before starting topical application of compound (I-1-1) 15 PSI total score on the 52nd day after starting topical treatment: 7 A photograph of the right lower leg anterior surface before the start of application of compound (I-1-1) is shown in Figure 15, and a photograph of the right lower leg anterior surface 52 days after the start of application is shown in Figure 16. Moderate psoriasis was improved to mild as a result of application of a cream containing compound (I-1-1). No side effects were observed.

[0120] <Example 5> (Profile of Subject 5) A 42-year-old man with palmoplantar pustulosis. Two years ago, small pustules accompanied by erythema started appearing on the palms of both hands. He had only visited another hospital once. At the first visit, there was pale pink erythema all over the palms of both hands, and the right palm had more scales than the left palm, but no blisters or pustules were seen on either palm.

[0121] (Administration of Compound (I-1-1) to Subject 5) Treatment was performed by applying 7 g of cream containing 8.1 mg of compound (I-1-1) to the right palm and applying a FTU equivalent amount of Dovobet ointment (manufactured by Leo Pharma Co., Ltd.) to the left palm once a day before going to bed.

[0122] (result) After 3 weeks, the erythema and scales on the right palm improved concentrically compared to the left palm, and the itching on the right palm disappeared, clearly showing a difference between the left and right palms. Figure 17 shows a photograph of both palms before the start of topical application of compound (I-1-1), and Figure 18 shows a photograph three weeks after the start of topical application. The improvement effect of the cream containing compound (I-1-1) was confirmed. No side effects were observed.

[0123] <Example 6> (Profile of Subject 6) A 54-year-old woman with seborrheic dermatitis at the back of her head and hairline that had been present for the past 10 years. The condition had been difficult to treat from the beginning, and she had visited several dermatologists, where she had been prescribed various steroid lotions, including Dovobet gel, but none of these worked.

[0124] (Administration of Compound (I-1-1) to Subject 6) A cream containing 5 mg of compound (I-1-1) (10 g) was prescribed, and treatment was performed by topically applying an amount equivalent to FTU once a day.

[0125] (result) After 28 days, all the scales and erythema had disappeared and healed. Figure 19 shows a photograph of the hairline at the back of the head before the start of topical application of compound (I-1-1), and Figure 20 shows a photograph 28 days after the start of topical application. The improvement effect of the cream containing compound (I-1-1) was confirmed. No side effects were observed.

[0126] <Example 7> (Profile of Subject 7) A 23-year-old man developed atopic dermatitis 4 years ago, presenting with itchy erythema and dry skin on his face, limbs, and trunk. He had been prescribed various topical medications at other hospitals.

[0127] (Administration of Compound (I-1-1) to Subject 7) 5 g of cream containing 3.2 mg of compound (I-1-1) was prescribed for the left cubital fossa and left popliteal fossa, and a mixture of 20 g of Antebate ointment and 20 g of Hirudoid soft cream was prescribed for the right cubital fossa and right popliteal fossa. Treatment was performed by applying the equivalent amount of FTU once a day before going to bed.

[0128] (result) After 15 days, the itching in the left cubital fossa and the left popliteal fossa disappeared, and the erythema in the left cubital fossa and the left popliteal fossa was also improved compared to the right cubital fossa and the right popliteal fossa, and a clear difference was observed between the left and right sides. Figure 21 shows a photograph of both cubital fossas and both popliteal fossas at the start of topical medication, and Figure 22 shows a photograph on the 15th day after topical medication was started. It was confirmed that the therapeutic effect of the cream containing compound (I-1-1) was greater than that of a mixture of Antebate ointment and Hirudoid soft cream (1:1). No side effects were observed.

[0129] <Example 8> (Profile of Subject 8) A 22-year-old man developed atopic dermatitis almost all over his body two years ago, but left it untreated.

[0130] (Administration of Compound (I-1-1) to Subject 8) A cream containing 8 mg of compound (I-1-1) (12.5 g) was prescribed for the left cubital fossa, and 20 g of 1% Moisert ointment was prescribed for the right cubital fossa. The cream containing compound (I-1-1) was applied once a day, and the Moisert ointment 1% was applied twice a day in an amount equivalent to FTU before going to bed. The VAS (Visual Analogue Scale) at the start of application was 40 for both cubital fossae.

[0131] The VAS is one of the methods for assessing itching in atopic dermatitis. The patient evaluates the degree of itching and indicates the number on a scale ranging from 0 to 100 mm. 100 (mm) represents the worst imaginable itching, and 0 (mm) represents no itching.

[0132] (result) After 14 days, itching, erythema, etc. improved in both cubital fossae, but the tendency of erythema to disappear was more pronounced in the left cubital fossa, where a cream containing compound (I-1-1) was used, than in the right cubital fossa, where Moisert ointment was used. The VAS improved to 20 in both cubital fossae. Photographs of both cubital fossae at the start of application of the topical medication are shown in Figure 23, and photographs 14 days after the start of application are shown in Figure 24. It was confirmed that the therapeutic effect of the cream containing compound (I-1-1) was equal to or greater than that of Moisert ointment. No side effects were observed.

[0133] <Example 9> (Profile of Subject 9) A 14-year-old boy. His atopic dermatitis had worsened over the past 2-3 years, causing itchy red spots and dry skin on his face and limbs. He had been receiving treatment at another hospital using topical and oral steroids, but the condition was intractable.

[0134] (Administration of Compound (I-1-1) to Subject 9) A cream containing 9.6 mg of compound (I-1-1) was administered in 15 g to the right thigh, and an antebet ointment in 30 g to the left thigh, with each administered once a day before bedtime in an amount equivalent to FTU. The VAS score at the start of administration was 80 for both thighs.

[0135] (result) After 14 days, the right thigh, where the cream containing compound (I-1-1) was used, improved to a level similar to that of the left thigh, where Antebate ointment was used, and the erythema and dry skin disappeared, there was no difference in itching between the left and right thighs, and the VAS improved to 38 on both thighs. Figure 25 shows a photograph at the start of topical medication, and Figure 26 shows a photograph 14 days after the start of topical medication. It was confirmed that the cream containing compound (I-1-1) had almost the same effect as Antebate ointment. No side effects were observed.

[0136] <Example 10> (Profile of Subject 10) A 64-year-old woman had developed palmoplantar pustulosis several months ago, with multiple erythema, small blisters, and scales on the soles of both feet. Since her first visit, she had been using 30g of a mixed topical medication of vitamin D and a very strong steroid, but her condition was worsening.

[0137] (Administration of Compound (I-1-1) to Subject 10) A cream containing 9 mg of compound (I-1-1) was prescribed in an amount of 14 g for the soles of both feet, and the patient was treated by applying an amount equivalent to FTU once a day before going to bed.

[0138] (result) After 29 days, the erythema, small blisters, and scales on both soles of the feet were significantly reduced. Photographs taken at the start of application are shown in Figure 27, and photographs taken 29 days after application are shown in Figure 28. It was confirmed that the cream containing compound (I-1-1) was more effective than the previously used topical mixture of vitamin D and very strong steroid. No side effects were observed.

[0139] <Example 11> (Profile of Subject 11) A 32-year-old woman had been diagnosed with palmoplantar pustulosis at another hospital for the past two years, and had been prescribed vitamin D ointment, very strong steroid ointment, and heparinoid cream on the palms and edges of the feet, but there had been little improvement.

[0140] (Administration of Compound (I-1-1) to Subject 11) A cream containing 9.6 mg of compound (I-1-1) was prescribed in an amount of 15 g for the medial edge of the right plantar region, and the patient was treated by applying an amount equivalent to FTU once a day before going to bed.

[0141] (result) After 12 days, although some new erythematous lesions were found, the erythema, scales, and blisters were not noticeable overall, and the therapeutic effect was confirmed. Figure 29 shows a photograph at the start of application, and Figure 30 shows a photograph on the 12th day after the start of application. No side effects were observed.

[0142] <Example 12> (Profile of Subject 12) A 74-year-old man. Two or three months before his first visit, he noticed mild lateral tenderness in the sacral region and two pale pink, slightly thickened lesions measuring about 1 or 2 cm in diameter. When he touched them with his fingers, scale-like material peeled off. He visited the hospital because the lesions were showing a tendency to grow. He was diagnosed with chronic eczema.

[0143] (Administration of Compound (I-1-1) to Subject 12) A 5g cream containing 3mg of compound (I-1-1) was prescribed for the affected area, and the patient was given an FTU equivalent amount to apply once a day before going to bed. One month later, 20g of the same cream was prescribed.

[0144] (result) After 4 or 5 months, the lesions were completely cured. Photographs taken at the start of application are shown in Figure 31, and 6 and a half months after application are shown in Figure 32. No side effects were observed.< / nah>

Claims

1. A therapeutic agent for skin diseases, comprising one or more compounds (a) selected from the group consisting of compounds represented by the following formula (I) and compounds represented by the following formula (II): 【Chemistry 1】 【Chemistry 2】 [In formula (I) and formula (II), X 1 is a fluorine atom or a chlorine atom, and X 2 is a fluorine atom, a chlorine atom or a hydrogen atom, and X 3 is a methyl group or a hydrogen atom.

2. The method for treating a skin disease according to claim 1, wherein the compound (a) is a compound represented by the following formula (I-1): 【Chemistry 3】

3. The drug for treating a skin disease according to claim 1 or 2, wherein the skin disease is inflammatory keratosis.

4. The method of claim 3, wherein the inflammatory keratosis is one or more selected from the group consisting of psoriasis, parapsoriasis, and lichen planus.

5. The method of claim 1 or 2, wherein the skin disease is pustulosis.

6. The drug for treating skin diseases according to claim 5, wherein the pustulosis is palmoplantar pustulosis.

7. The drug for treating a skin disease according to claim 1 or 2, wherein the skin disease is a group of diseases that cause inflammatory changes.

8. The drug for treating skin diseases according to claim 7, wherein the disease group causing inflammatory changes is a group of eczema and dermatitis.

9. The drug for treating skin diseases according to claim 7, wherein the disease causing inflammatory changes is one or more selected from the group consisting of atopic dermatitis and seborrheic dermatitis.

10. A method for producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione, comprising a step of contacting one or more compounds (B) selected from the group consisting of betamethasone dipropionate, clobetasol propionate, betamethasone butyrate propionate, betamethasone valerate, clobetasone butyrate, and difluprednate with NaH.

11. The method according to claim 10, wherein the compound (B) is betamethasone dipropionate.

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