Therapeutic agent for treating skin diseases and method for producing compound

Abstract

To provide more effective therapeutic agents for skin diseases, and to provide a method for easily producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione.SOLUTION: Provided are a therapeutic agent for treating skin diseases, comprising one or more compounds (a) selected from the group consisting of compounds represented by formula (I) and compounds represented by formula (II). Provided is a method for producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione, comprising 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.SELECTED DRAWING: None

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] Topical medications containing various drugs are used to treat skin diseases, and come in a variety of dosage forms (ointments, creams, lotions, gels, foams, etc.), with topical steroids of different strengths and / or vitamin D3 medications being particularly common. However, there have not necessarily been many topical medications that achieve therapeutic effects more quickly and with smaller doses.

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

[0004] Although the cause of psoriasis is unknown, it is believed to be based on a genetic predisposition to the onset of psoriasis, and psoriasis susceptibility genes such as PSORS1, IL12B, IL23R, and IL23A have been reported. Currently, bone marrow-derived immune cells such as helper T cells and dendritic cells are believed to play a central role in the pathogenesis of psoriasis, and the involvement of IL-12, Th1 cells, IL-23, Th17 cells, etc. is thought to be important in the pathogenesis of psoriasis (Non-Patent Document 1). Factors that contribute to or exacerbate psoriasis include focal infection, HIV infection, diabetes, metabolic syndrome, medications (e.g., calcium channel blockers, beta-blockers, antimalarials, indomethacin, ACE inhibitors, tetracycline, digoxin), trauma, pregnancy, and stress (Non-Patent Document 1, p. 379).

[0005] Symptoms of psoriasis include erythema covered with silvery-white mica-like scales, as well as various other forms of erythema, wax flakes, Auspitz's bloody dew, and Koebner's phenomenon, and are sometimes accompanied by itching. Symptoms tend to improve in the summer, but often go through repeated periods of relief and exacerbation. If the rash spreads within about a year of onset and involves 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 therapies such as steroid ointments, activated vitamin D3 ointments, or combinations thereof, phototherapy (PUVA therapy, narrow-band UVB therapy), and combination therapy (topical therapy plus phototherapy). Systemic therapies include oral therapies such as cyclosporine, etretinate, methotrexate, apremilast, JAK inhibitors, and herbal medicines, as well as injection therapy with biologics (Figure 1). The first-line treatment for psoriasis vulgaris is topical therapy, specifically, topical ointments, creams, or lotions containing steroid compounds, or topical ointments, creams, gels, lotions, or foams containing activated vitamin D3, or the combination of these steroid compounds and activated vitamin D3. The effectiveness of these topical therapies varies depending on the severity of the symptoms, but even if the rash disappears, recurrence is common, and cure is rare. As a result, patients' quality of life declines, and in some cases they are driven to attempt suicide. If local treatment is ineffective and the rash worsens, systemic treatment is started, but in severe cases, even if biological agents are used and the condition improves to the point where the rash disappears, complete recovery is difficult and maintenance treatment is necessary.

[0007] Parapsoriasis is a general term for chronic diseases characterized by multiple keratotic erythema on the trunk and other areas of the body, and is broadly divided into guttate parapsoriasis, plaque parapsoriasis, and lichenoid parapsoriasis. Parapsoriasis is primarily 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 (lacy white spots), and nails. The cause of lichen planus is unknown, but it can be triggered by hepatitis C virus infection, medications, dental metal allergies, psychological stress, and other factors. It is treated with topical or oral steroid compounds or tacrolimus, as well as phototherapy.

[0009] Pustulosis is a skin disease that causes the formation of sterile or non-infectious pustules. Pustules are purulent blisters that 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 (PPP) is a representative localized pustulosis and, like psoriasis, is generally resistant to treatment. It manifests as multiple sterile pustules on one or both palms and soles, following a chronic course with repeated remissions and exacerbations. When pustules form, lesions accompanied by erythema and scale also appear. The prevalence of PPP in Japan is approximately 0.12%, with an estimated 136,000 patients. The average age at onset of PPP is 55.5 years, with a male-to-female ratio of approximately 1:2, with a female predominance. Abnormal activation of the IL-17 signaling pathway is thought to induce inflammation and neutrophil migration, contributing to the pathogenesis.

[0011] Treatment for palmoplantar pustulosis includes (1) lifestyle guidance (smoking cessation, oral care), (2) elimination of aggravating factors, i.e., treatment of focal infections, specifically treatment of tonsillar lesions, dental 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 for palmoplantar pustulosis is based on the above (1) and (2), and the first choice of symptomatic treatment is topical application of steroid ointment and 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 prevalent is a group of diseases that cause inflammatory changes in the skin known as eczematous reactions. This group of diseases progresses through a pathological condition known as the eczema triangle (Figure 2, Non-Patent Document 1, p. 140), but exhibits common clinical symptoms and histological findings in the acute phase. The etiology and pathogenesis are diverse, with many unknowns. Eczematous reactions account for more than one-third of skin disease patients. The basic features of eczematous reactions are lymphocyte invasion of the epidermis and a spongiotic state, but parakeratosis and acanthosis can also occur. Histological findings can be acute, subacute, or chronic. Most cases are primarily treated with topical steroid compounds, but there is a constant need for topical medications that can provide faster healing.

[0014] Acute eczema presents with a variety of symptoms, such as erythema, pustules, scaling, papules, vesicles, weeping, or crusting, as shown in the eczema triangle. However, the etiology and pathogenesis are diverse, and many aspects remain unknown. When the symptoms of the eczema triangle are present, it is called acute eczema, but when it does not improve 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, scaling, papules, vesicles, weeping, and crusts, are symptoms of eczema whose cause is unclear. On the other hand, the eczema / dermatitis group, which has a relatively clear cause or presents 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 skin diseases classified as eczema and dermatitis, which are a group of diseases that cause inflammatory changes. They 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 undergoes repeated exacerbations and remissions. Most patients with atopic dermatitis have a predisposition to atopy. There is no treatment that can completely cure atopic dermatitis in a short period of time, but topical treatments such as steroid compounds, tacrolimus, delgocitinib, and difamilast are used. In recent years, phosphodiesterase 4 (PDE4) inhibitors have also been used for topical treatment. In addition to oral and dietary treatments, biological agents have also been developed in recent years, and their therapeutic effects have 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 characterized by erythematous plaques accompanied by light brown scales on seborrheic and intertriginous areas (head, face, axillae, genitals, etc.). In adults, symptoms include increased pityriasis-like scales on the scalp, erythematous plaques at the hairline, and erythematous plaques with scales on the eyebrows and nasolabial folds. Erythematous plaques with macerated scales are sometimes seen in the axillae, under the breasts, and genitals. In infants, seborrheic dermatitis may be indistinguishable from atopic dermatitis. Symptoms of seborrheic dermatitis often improve and worsen over a long period of time. The fungus Malassezia has also been implicated as a cause of seborrheic dermatitis. It has been suggested that the inflammation-inducing mechanisms of Malassezia include complement activation 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 for various skin diseases has been established in clinical practice. Details of the 25 steroid compounds will be described later, but they range from very effective to almost ineffective.

[0020] There are over 20 types of steroid compounds commonly used in the treatment of psoriasis. The strongest steroid compounds improve the rash more quickly with short-term application in most cases, but they recur when application is discontinued, and repeated resumption of application causes thinning of the skin, which never recovers. Lowering the strength of the steroid compound reduces the degree of improvement in the rash, prolonging the time required for improvement, lowering patient satisfaction, reducing compliance, and reducing the effectiveness of treatment. 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, polydipsia, polyuria, shortened QT interval, nausea, and vomiting) may occur.

[0021] In addition to psoriasis, there are many other skin diseases 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 over a long period of time.Since side effects of topical steroid compounds can also occur in eczema and dermatitis that are not difficult to treat, there is a constant 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 effects of 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione have 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 June 2022 [Non-patent document 2] Tetsuro Hidaka et al., "Study on Betamethasone: Behavior of Betamethasone in Acid, Alkali, Light Irradiation and Oxidizing Agents under Mild Conditions," 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 therapeutic drug for skin diseases according to [1], wherein the compound (a) is a compound represented by the following formula (I-1):

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

[0031] According to the present invention, it is possible to provide a more effective therapeutic agent for skin diseases. The therapeutic agent for skin diseases of the present invention is more effective, particularly for psoriasis vulgaris, than existing topical medications containing steroids and vitamin D3, and is free of the side effects caused by vitamin D. The therapeutic agent for skin diseases of the present invention is equally or more effective, particularly for palmoplantar pustulosis, than existing topical medications containing steroids and vitamin D3, and is free of the side effects caused by vitamin D. The therapeutic agent for skin diseases of the present invention is equally or more effective, particularly for atopic dermatitis, than existing topical medications containing steroids or phosphodiesterase 4 (PDE4) inhibitors. The therapeutic agent for skin diseases of the present invention is also highly effective against seborrheic dermatitis. The therapeutic agent 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 explanation of the drawings]

[0033] [Figure 1] Figure 1 is a diagram explaining psoriasis treatment options, adapted from Hajime Iizuka, J Visual Dematol 16(9):850-851, 2017. [Figure 2] Figure 2 is a diagram illustrating the eczema triangle. [Figure 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). [Figure 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 structural analysis of compound (I-1-1). [Figure 7] FIG. 7 shows the results of automated single-crystal X-ray structural 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 surface of the 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 four 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 in Example 2 before the start of topical application of a cream containing compound (I-1-1). [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 hairline in Example 3 before the start of topical application of a cream containing compound (I-1-1). [Figure 14] FIG. 14 is a photograph of the frontal hairline in Example 3, taken 14 days after the start of topical application of a cream containing compound (I-1-1). [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 in Example 4, taken 52 days after the start of topical application of a cream containing compound (I-1-1). [Figure 17] FIG. 17 is a photograph of both palms in Example 5 before the start of topical application of a cream containing compound (I-1-1). [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 of the head hairline 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 in Example 6 on day 28 after the start of topical application of a cream containing compound (I-1-1). [Figure 21] FIG. 21 shows photographs 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 in Example 7 on the 15th day after the start of external application. [Figure 23] FIG. 23 is a photograph of both cubital fossae in Example 8 before the start of external application. [Figure 24] FIG. 24 shows photographs of both cubital fossae in Example 8 on the 14th day after the start of external application. [Figure 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 in Example 9 on the 14th day after the start of external application. [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 in Example 10, taken 29 days after the start of external application. [Figure 29] FIG. 29 is a photograph of the medial edge of the right plantar surface in Example 11 before the start of external application. [Figure 30] FIG. 30 is a photograph of the medial edge of the right plantar surface in Example 11, taken 12 days after the start of external application. [Figure 31] FIG. 31 is a photograph of the sacrum area before the start of external application in Example 12. [Figure 32] FIG. 32 is a photograph of the sacrum in Example 12, taken six and a half months after the start of external application. DETAILED DESCRIPTION OF THE INVENTION

[0036] Next, the present invention will be described in detail. Note that, unless otherwise specified, the expression "A to B" regarding a numerical range means that it is equal to or greater than A and equal to or less than B. For example, the expression "1 to 5%" means that it is equal to or greater than 1% and equal to or less than 5%.

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

[0042] The compound represented by formula (I) includes compounds represented by X shown in Table 1 below. 1 , X 2 , and X 3Examples of the compounds include Compounds Nos. 1 to 12 having the combination of the following:

[0043] [Table 1]

[0044] The compound represented by formula (II) includes compounds represented by X shown in Table 2 below. 1 , X 2 , and X 3 Examples of the compounds include Compounds Nos. 13 to 24 having the following combinations: 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] Because the effect of the skin disease treatment drug is enhanced, 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 %, still more 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 can be obtained, 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 it can be produced by a known method. 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 Hidaka Tetsuro et al., "Study on Betamethasone: Behavior of Betamethasone in Acid, Alkali, Light Irradiation, and Oxidizing Agents Under Mild Conditions," Pharmaceutical Journal, 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] In consideration of the stability to light, compound (a) is preferably stored in a light-shielded location.

[0052] Topical steroids have a history of being developed by Sulzberger in 1952 with the development 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 25 types listed below are currently in common use, all of which share a common chemical structure. Group I (Strongest): Dermovate (clobetasol propionate ester), Diaquat (diflorasone acetate ester) Group II (very strong): Flumeta (mometasone furoate), Antebate (betamethasone butyrate propionate), Topsym (fluocinonide), Rinderon DP (betamethasone dipropionate), Visderm (amcinonide), Nerisona, Texmetene (diflucortolone valerate), Pandel (hydrocortisone butyrate propionate), Myser (difluprednate)

[0053] Group III (strong): Boala (dexamethasone valerate), Betnebate, Rinderon V, Rinderon 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), Kindavate (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 commonly used topical steroid, is shown below in formula (P).

[0054] [ka]

[0055] The 25 types of topical steroids currently in common use share the following common molecular structural characteristics 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) differs significantly in structure from the 25 steroid compounds mentioned above in that C17 is a C=O group (ketone group). Considering (6) above, compound (a) would be expected to have a lower affinity for the skin. However, as shown in the Examples below, this is not the case. Rather, it has been suggested that a C=O group (ketone group) at C17 enhances the pharmacological effect. 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 25 steroid compounds mentioned above (the largest being flumethasone furoate, molecular weight 521.43, and the smallest being teracortril (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 greater its transdermal absorption (Maruho Medical Professionals' Site, Topical Ointment Trivia, Chapter 2, Active Ingredients and Transdermal Absorption: Characteristics of Active Ingredients that are Easily Transdermal). This transdermal absorption can also be said to have an inverse exponential relationship.

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

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

[0059] <Skin disease treatment drug> The therapeutic agent for skin diseases of the present invention comprises one or more compounds (a) selected from the group consisting of the compounds represented by the formula (I) and the compounds represented by the formula (II). The properties and dosage forms of the therapeutic drug for skin diseases of the present invention are not particularly limited as 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 preferably an emulsion, cream, gel, or foam (mousse).

[0060] The therapeutic agent for skin diseases 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 preferred, and an external medicine is more preferred. Examples of dosage forms for topical medications include solid topical preparations such as topical powders; liquid topical preparations such as liniments and lotions; sprays (atomized preparations) such as aerosols and pump sprays; ointments such as oily ointments and water-soluble ointments; creams (emulsion-based preparations) 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. Sprays (atomized preparations), 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 before use, with water-insoluble injections, suspension injections, and emulsified injections being preferred. The route of administration of the injection 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 can be appropriately blended with additives typically used in topical or injectable drugs, as needed, within the scope of not impairing the effects of the present invention. Examples of additives used in topical skin preparations, such as pharmaceuticals, include oily components, surfactants (synthetic and natural), moisturizers, thickeners, preservatives and disinfectants, powder components, UV absorbers, antioxidants, chelating agents, pigments, and fragrances. These components can 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-ethylhexylglyceride, and higher fatty acid octyldodecyl (e.g., octyldodecyl stearate), among others, with waxes and hydrocarbons being preferred.

[0064] Examples of surfactants 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, with polyhydric alcohols being preferred, and glycerin being more preferred.

[0066] The skin disease treatment drug can be appropriately blended with active ingredients typically used in topical or injectable drugs as needed, as long as the effects of the present invention are not impaired. Examples of active ingredients used in topical skin preparations, such as pharmaceuticals, include antihistamines, steroid compounds, antiviral drugs, disinfectants, urea, vitamins, and heparinoids. 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, middle or end of the production process of the preparation, and the method of addition may be selected from mixing, kneading, dissolving, immersion, sprinkling, spraying, coating, etc., depending on 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 surrounding area. The method of external application is not particularly limited, and may be by application 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, an FTU (Finger Tip Unit, the amount squeezed out from a 5 mm diameter tube 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 single dose of the skin disease therapeutic drug, in the case of external use, is preferably 0.5 ng to 25 mg, more preferably 5 ng to 5 mg, still more 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 safer and more effective at lower doses and for a shorter period of time than existing topical steroid medications. The skin disease therapeutic agent 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 agents, particularly topical steroid medications, and to be more safe. The skin disease therapeutic agent of the present invention is expected to be effective against atopic dermatitis at lower doses and for a shorter duration than existing atopic dermatitis therapeutic agents, particularly topical steroids and topical phosphodiesterase 4 (PDE4) inhibitors, and to be more safe. 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, and to be effective more safely. The skin disease treatment drug 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 treatment drugs, particularly topical steroid medications, and to be safer.

[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, pustulosis, and diseases that cause inflammatory changes. The severity of the skin disease is not particularly limited, but preferably it is a skin disease of such severity that it is usually treated with a topical steroid. 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] Psoriasis may be any of psoriasis vulgaris, acute guttate psoriasis, erythrodermic psoriasis, psoriatic arthritis, and pustular psoriasis, but is preferably psoriasis vulgaris. The site where psoriasis occurs is not particularly limited and may be the head, hairline, elbows, knees, back, lower back, buttocks, lower legs, pubic area, groin, armpits, palms, soles of the feet, 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 pustulosis include palmoplantar pustulosis, subcorneal pustulosis, eosinophilic pustular folliculitis, acute generalized pustular bacterial exanthema, 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 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 manifestations, 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 lichen simplex chronicus, and other eczema / dermatitis, which may be acute or chronic. The above-mentioned group of other eczema / dermatitis includes many types of eczema whose causes are unclear, and can be classified into acute eczema and chronic eczema, which show the images shown in the eczema triangle.

[0077] Atopic dermatitis may be of any severity, but is preferably mild or moderate. One of the main factors that worsen atopic dermatitis is scratching, and the rash often improves if scratching is avoided. Therefore, the skin disease therapeutic drug can be used to treat, for example, patients with atopic dermatitis who occasionally resort to light scratching, and may also be used to treat patients with a VAS score of 40 or higher, or a VAS score of 60 or higher. VAS will be described later.

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

[0079] The term "treatment" in relation to the aforementioned therapeutic drugs for skin diseases includes not only curing the disease or symptoms, but also alleviating (relieving) the disease or symptoms, and preventing the recurrence of the disease or symptoms after they 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 topical therapy in combination with other drugs, such as other skin disease therapeutic or preventive drugs. When the skin disease therapeutic agent of the present invention is used in combination with other skin disease therapeutic or preventive drugs, the therapeutic effect of the skin disease is likely to be higher than when the skin disease therapeutic agent of the present invention is used alone. The type of other skin disease therapeutic or preventive drug is not limited, and examples include antihistamines, steroid compounds, antivirals, disinfectants, urea, vitamins, and heparinoids. The other skin disease therapeutic or preventive drugs 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 of the present invention for producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione includes a step of contacting NaH with one or more compounds (B) selected from the group consisting of betamethasone dipropionate, clobetasol propionate, betamethasone butyrate propionate, betamethasone valerate, clobetasone butyrate, and difluprednate.

[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 compounds produced by known methods can be used, or commercially available products can be used. The amount of compound (B) used is not particularly limited and can be determined depending on 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> The NaH is not particularly limited, and may be prepared by a known method or may be a commercially available product. The 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 at C21 of the steroid skeleton of compound (B), causing a nucleophilic attack within the molecule, which is presumed to result in a unique electron transfer, generating a ketone group at the C17 position. NaH is presumed to have caused a chemically extremely rare and groundbreaking reaction in the production method.

[0089] <Contacting step> The method for contacting compound (B) with NaH is not particularly limited, and any known method can be used. 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 can 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, but is, for example, 1 to 40° C., 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 a polar solvent is preferred. Examples of polar solvents include tetrahydrofuran (THF), dioxane, acetonitrile, and dimethyl sulfoxide (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 better, and more preferably 95% or higher. The organic solvent may be used after distillation or without distillation. Even when an undistilled 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 allows compound (B) to be completely dissolved.

[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 production method, 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione can be easily produced at around room temperature in a short time. Furthermore, since compound (B) is a generally available compound, the above-mentioned production 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 brought into contact with NaH, the two react to produce 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione and / or a related compound (analog) thereof. [Example]

[0095] <Production Example 1: Preparation of Compound (I-1-1)> Betamethasone 17,21-dipropionate was manufactured by Tokyo Chemical Industry Co., Ltd. Thin layer chromatography (TLC) was performed using a 20 x 20 cm TLC Silicagel 60F254 column manufactured by Merck. The developing solvent was n-Hexane-AcOEt (1:1.5), and the detector was an As One Handy UV Lamp SUV-4 at 254 nm. The various spectra were measured using the following instruments. 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] 203 mg of betamethasone 17,21-dipropionate was dissolved in 4 mL of tetrahydrofuran (Tokyo Chemical Industry Co., Ltd.), a small spoonful of NaH (Fujifilm Wako Pure Chemical Industries, Ltd., sodium hydride in oil) was added, and the mixture was stirred for 15 hours on a magnetic stirrer. Water was then added, the mixture was extracted with chloroform, washed with water until the pH reached 7, and dried with sodium sulfate. The mixture was then filtered, the solvent removed, and the mixture was developed by TLC. The band with an Rf (retention factor value) of 0.53 was eluted with acetone, and the solvent was removed to obtain 18 mg of a white powder (40% yield). This procedure was carried out at room temperature. The resulting white powder 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 structural analysis was performed. The resulting IR chart is shown in Figure 3. 1 The H NMR chart is shown in Figure 4. 13 The C NMR chart is shown in Figure 5, and the results of automated single-crystal X-ray structural analysis are shown in Figures 6 and 7. A summary of all these analytical results and the chemical structural formula of compound (I-1-1) (9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione) 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 propionate) (Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in 3.5 mL of tetrahydrofuran (Tokyo Chemical Industry Co., Ltd.), and one small spoonful of NaH (Fujifilm Wako Pure Chemical Industries, Ltd., sodium hydride in oil) was added. After stirring for 15 hours on a magnetic stirrer, water was added, the mixture was extracted with chloroform, washed with water until the pH reached 7, dried with sodium sulfate, filtered, the solvent removed, and developed by TLC (n-hexane:ethyl acetate = 1:3). Two bands around Rf 0.41 were eluted with acetone, and the solvent was removed to obtain 5 mg of a white powder. This procedure was carried out at room temperature. The resulting white powder is presumed to be a mixture of two compounds, compound (b) and compound (c). Compound (b) and compound (c) are presumed to be 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione or a related compound thereof.

[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% (Maruho Co., Ltd.) and mixed thoroughly until homogeneous, 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 heparinoid as an active ingredient per 1 g, and containing 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 as additives.

[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 effectiveness of treatment for specific skin lesions in 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 for erythema, infiltration / thickening, and scaling using 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 considered mild, a score greater than 5 but less than 20 is considered moderate, and a score of 20 or more is considered severe.

[0104] (PSSI) The severity of local symptoms of scalp psoriasis was assessed using the Psoriasis Scalp Severity Index (PSSI) score. The PSSI score is an index that can independently evaluate each of the skin findings of scalp plaque psoriasis (erythema, infiltration / thickening, and scaling), and also assess 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 multiple cases of psoriasis vulgaris with different severity of skin findings and lesion area, each with a written PSSI score, making this a common assessment tool for easily determining PSSI scores in clinical practice. The written PSSI scores were calculated using the following method.

[0105] The severity of each scalp skin finding (erythema, infiltration / thickening, scaling) 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 scaling was 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 rashes remained on the anterior surface of both lower legs. He was then switched to oral cyclosporine capsules (four 25 mg capsules twice daily) and topical Dovobet Foam (manufactured by Leo Pharma Co., Ltd.) (appropriate amount once daily), and continued treatment for approximately 7 months. However, the scales and erythema on the anterior surface of both lower legs remained.

[0109] (Administration of Compound (I-1-1) to Subject 1) The topical application of Dovobet Foam was discontinued, and the oral administration of cyclosporine was continued at the same dose. 5 g of cream containing 2.9 mg of compound (I-1-1) was prescribed, and treatment was performed by applying an FTU amount (Finger Tip Unit, approximately 0.5 g) to the affected area once a day.

[0110] (result) The total PSI score before starting topical application of compound (I-1-1) was 20. A photograph of the anterior lower leg is shown in Figure 9. Four months after starting topical application, the total PSI score was 3. A photograph of the anterior lower leg is shown in Figure 10. Severe psoriasis improved to milder severity with 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 repeatedly experienced relief and exacerbation after using various topical steroids (Dermovate scalp lotion, Comclo shampoo, Antebate lotion, etc.).

[0112] (Administration of Compound (I-1-1) to Subject 2) The patient was discontinued from the topical steroid medication that had been used up until then, and was prescribed 10 g of a cream containing 5.8 mg of compound (I-1-1), which was applied topically in 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 the start of topical application of compound (I-1-1), and Figure 12 shows a photograph 28 days after the start of 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 consultation. A scaly, erythematous plaque measuring 2 cm in area and 8 cm in length 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 topically 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 Figure 13 shows a photograph of the frontal hairline area before the start of topical application of compound (I-1-1), and Figure 14 shows a photograph 14 days after the start of topical application. 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 (head, back, and lower back) for the past 20 years. Five or six years ago, the condition spread to the nails of all his fingers and toes, and he had been treating it with cyclosporine and dovobet foam. A scaly erythema remained only on the anterior surface of his right lower leg.

[0118] (Administration of Compound (I-1-1) to Subject 4) After discontinuing the use of cyclosporine, dovobet foam, etc., treatment was performed 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 of topical application: 7 Figure 15 shows a photograph of the anterior right lower leg before the start of topical application of compound (I-1-1), and Figure 16 shows a photograph 52 days after the start of topical application. The moderate psoriasis improved to mild as a result of topical 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 (PPP) developed multiple small pustules accompanied by erythema on the palms of both hands two years ago. He had only visited another hospital once. At the initial consultation, pale pink erythema was present on the entire palms of both hands, and the right palm had more scales than the left, but no blisters or pustules were observed 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 Dovobet ointment (manufactured by Leo Pharma Co., Ltd.) to the left palm once a day before going to bed in an amount equivalent to FTU.

[0122] (result) After three 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 demonstrating a difference between the left and right palms. Photographs of both palms before the start of topical application of compound (I-1-1) are shown in Figure 17, and photographs three weeks after the start of topical application are shown in Figure 18. 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 was diagnosed with seborrheic dermatitis at the back of her head and hairline 10 years ago. Her condition had been intractable from the start, and she had visited several dermatologists, receiving treatments including various steroid lotions and even Dovobet gel, but none of these worked.

[0124] (Administration of Compound (I-1-1) to Subject 6) A 10 g cream containing 5 mg of compound (I-1-1) 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 area at the back of the head at the hairline before the start of topical application of compound (I-1-1), and Figure 20 shows a photograph taken 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) 5g of cream containing 3.2mg of compound (I-1-1) was prescribed for the left cubital fossa and left popliteal fossa, and a mixture of 20g of Antebate ointment and 20g of Hirudoid soft cream was prescribed for the right cubital fossa and right popliteal fossa. Treatment was performed by applying an amount equivalent to FTU once a day before going to bed.

[0128] (result) After 15 days, the itching in the left cubital and popliteal fossae disappeared, and the erythema in the left cubital and popliteal fossae was also less severe than in the right cubital and popliteal fossae, with a clear difference between the left and right sides. Photographs of the cubital and popliteal fossae at the start of topical application are shown in Figure 21, and photographs on the 15th day after topical application are shown in Figure 22. 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) 12.5g of cream containing 8mg of compound (I-1-1) was prescribed for the left cubital fossa, and 20g 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 1% Moisert ointment was applied twice a day, in an amount equivalent to an 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 a method for assessing itching in atopic dermatitis. Patients rate the severity of itching and indicate 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 for 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. Figure 23 shows photographs of both cubital fossae at the start of topical application, and Figure 24 shows photographs 14 days after the start of topical application. 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 two or three years, causing itchy red spots and dry skin on his face and limbs. He had been treated with topical and oral steroids at another hospital, but the condition was intractable.

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

[0135] (result) After 14 days, the right thigh, on which the cream containing compound (I-1-1) had been used, had improved to a level similar to that of the left thigh, on which Antebate ointment had been used; the erythema and dry skin had disappeared, there was no difference in itching between the left and right thighs, and the VAS score had improved to 38 on both thighs. Figure 25 shows a photograph taken at the start of topical application, and Figure 26 shows a photograph taken 14 days after the start of topical application. 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 presented with palmoplantar pustulosis, with numerous erythema, small blisters, and scales on the soles of both feet a few months earlier. Since her initial consultation, she had been using 30g of a topical mixture of vitamin D and a very strong steroid, but her condition had been 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 treatment was performed by applying an amount equivalent to FTU externally once a day before going to bed.

[0138] (result) After 29 days, the erythema, small blisters, and scales on both soles of the feet had significantly decreased. Photographs taken at the start of topical application are shown in Figure 27, and photographs taken 29 days after the start of topical 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 a 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 her feet, but there had been little improvement.

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

[0141] (result) After 12 days, although some new erythematous plaques had appeared, the erythema, scales, and blisters were generally not noticeable, confirming the effectiveness of the treatment. Figure 29 shows a photograph taken at the start of application, and Figure 30 shows a photograph taken 12 days 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 tenderness in the sacral region and two pale pink, slightly thickened lesions, each about 1 or 2 cm in diameter. When touched with the fingers, scale-like material peeled off. The lesions were growing larger, so he visited the hospital. He was diagnosed with chronic eczema.

[0143] (Administration of Compound (I-1-1) to Subject 12) 5g of cream containing 3mg of compound (I-1-1) was prescribed for the affected area, and treatment was performed by applying the equivalent amount of FTU 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 had completely healed. Photographs taken at the start of topical application are shown in Figure 31, and photographs taken 6.5 months after the start of topical 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): 【Chemical 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 therapeutic agent for skin diseases according to claim 1, wherein the compound (a) is a compound represented by the following formula (I-1): 【Chemistry 3】

3. The skin disease therapeutic agent 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 skin disease therapeutic drug according to claim 1 or 2, wherein the skin disease is pustulosis.

6. The skin disease therapeutic drug according to claim 5, wherein the pustulosis is palmoplantar pustulosis.

7. The therapeutic agent for skin diseases according to claim 1 or 2, wherein the skin diseases are a group of diseases that cause inflammatory changes.

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

9. The therapeutic agent for skin diseases according to claim 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 claim 10, wherein the compound (B) is betamethasone dipropionate.

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