Agent for treating skin disease and method for producing compound

Abstract

An embodiment of the present invention relates to an agent for treating skin disease, the agent containing at least one compound (a) selected from the group consisting of compounds represented by formula (I) and compounds represented by formula (II).　An embodiment of the present invention relates to a method for producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione, the method comprising a step for bringing NaH into contact 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.

Description

Skin disease treatment drug and method for producing the compound

[0001] The present disclosure relates to a skin disease treatment drug and a method for producing a compound having a specific structure.

[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 steroid medications of different strengths and / or vitamin D3 medications have been widely used. However, there have not necessarily been many topical medications that can 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, a lower incidence rate compared to 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 adults.

[0004] Although the cause of psoriasis is unknown, it is believed that a genetic predisposition to the onset of psoriasis is the underlying cause, 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 contribute to the onset or aggravation of psoriasis include focal infection, HIV infection, diabetes, metabolic syndrome, drugs (calcium channel blockers, beta-blockers, antimalarials, indomethacin, ACE inhibitors, tetracycline, digoxin, etc.), trauma, pregnancy, stress, etc. (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 topical application of steroid ointments, active vitamin D3 ointments, or combinations thereof, phototherapy (PUVA therapy, narrow band UVB therapy), and combination therapy (topical therapy + phototherapy), and systemic therapies include oral administration of cyclosporine, etretinate, methotrexate, apremilast, JAK inhibitors, herbal medicines, etc., and injection therapy using biological preparations (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 alone, 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, recurrence is common, and there are very few cases of cure. As a result, patients' quality of life declines, and in some cases, they are driven to suicide attempts. If local treatment is ineffective and the rash worsens, they move on to systemic treatment, 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, medication, dental metal allergies, psychological stress, etc. Treatment is by topical therapy using steroid compounds, tacrolimus, etc., oral therapy, and / or 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 is a representative disease of localized pustulosis and, like psoriasis, is generally resistant to treatment. Palmoplantar pustulosis manifests as multiple sterile pustules on both palms and soles or on one side of the body, following a chronic course with repeated remissions and exacerbations. When pustules form, lesions accompanied by erythema and / or scales also appear. The prevalence of palmoplantar pustulosis in Japan is approximately 0.12%, with an estimated 136,000 patients. The average age at onset of palmoplantar pustulosis 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 / or neutrophil migration, contributing to the pathogenesis.

[0011] Treatments for palmoplantar pustulosis include (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 irradiation, granulocyte-monocyte apheresis, and biological agents).

[0012] Treatment of 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 undergoes a pathological process 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 pathology 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, while eczema or dermatitis groups with relatively clear causes or typical clinical manifestations include contact dermatitis, atopic dermatitis, seborrheic dermatitis, infantile seborrheic dermatitis, nummular eczema, autosensitization dermatitis, stasis eczema, asteatotic eczema, and shiitake dermatitis (Non-Patent Document 1).

[0016] Atopic dermatitis and seborrheic dermatitis are skin diseases classified as eczema or dermatitis, among a group of 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 its main lesion, and is subject to repeated exacerbations and remissions. Most patients with atopic dermatitis have a predisposition to atopy. While there is no treatment that can completely cure atopic dermatitis in a short period of time, topical treatments such as steroid compounds, tacrolimus, delgocitinib, and difamilast are used. In recent years, phosphodiesterase 4 (PDE4) inhibitors have also been used in topical treatments. 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, increased pityriasis-like scales appear on the scalp, erythematous plaques appear at the hairline, and erythematous plaques with scales appear 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 strong to weak, and the degree of effectiveness of each for each skin disease has been established in clinical practice. Details of the 25 types of 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 as topical steroids for the treatment of psoriasis. Short-term topical application of strong steroid compounds results in faster improvement of the rash in most cases, but discontinuation of topical application results in recurrence, and repeated resumption of topical application causes thinning of the skin and no recovery. Lowering the strength of the steroid compound proportionally reduces the degree of improvement of the rash and lengthens the time required for improvement, resulting in lower patient satisfaction, so-called compliance, and reduced therapeutic efficacy. Furthermore, topical vitamin D3 drugs alone or in combination with steroid compounds, which are commonly used for the treatment of psoriasis, often have effects comparable to or even superior to those of topical steroid compounds alone, but require long-term topical application, which can cause side effects such as hypercalcemia (e.g., fatigue, lethargy, impaired consciousness, polydipsia, polyuria, shortened QT interval, nausea, vomiting, etc.).

[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 due to the long-term use period.Since the side effects of topical steroid compounds can also occur in eczema or dermatitis that are not difficult to treat, there is always a need for topical medications that work more quickly.

[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 reacted for 5 hours (Non-Patent Document 2).

[0024] Japanese Patent Application Publication No. 9-151197

[0025] Original article: Kenichi Ueno, edited by Fujio Otsuka and Manabu Fujimoto, Dermatology, 11th edition, Kinpodo Co., Ltd., published in June 2022. Tetsuro Hidaka et al., "Study on Betamethasone: Behavior of Betamethasone in Acids, Alkalis, Light Irradiation, and Oxidizing Agents under Weak Conditions," Pharmaceutical Journal, 1980, 100(1), pp. 72-80.

[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.

[0027] The present inventors have conducted extensive research to solve the above problems. As a result, they have found that the above problems can be solved by having the following configuration, and have completed the present invention. Aspects of the present invention relate to, for example, the following [1] to

[11] . [1] A therapeutic drug 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]

[0029] [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] [3] The therapeutic drug for skin diseases according to [1] or [2], wherein the skin disease is inflammatory keratosis. [4] The therapeutic drug for skin diseases 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 drug for skin diseases according to [1] or [2], wherein the skin disease is pustulosis. [6] The therapeutic drug for skin diseases according to [5], wherein the pustulosis is palmoplantar pustulosis. [7] The therapeutic drug for skin diseases according to [1] or [2], wherein the skin disease is a group of diseases causing inflammatory changes. [8] The therapeutic drug for skin diseases according to [7], wherein the group of diseases causing inflammatory changes is eczema or dermatitis. [9] The therapeutic drug 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 production method according to

[10] , wherein compound (B) is betamethasone dipropionate.

[0031] According to one aspect of the present invention, a more effective therapeutic agent for skin diseases can be provided. The therapeutic agent for skin diseases of one aspect 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 one aspect 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 one aspect 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 one aspect of the present invention is also highly effective against seborrheic dermatitis. The therapeutic agent for skin diseases of one aspect of the present invention is also highly effective against chronic eczema.

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

[0033] Figure 1 is a diagram explaining options for psoriasis treatment, modified from Hajime Iizuka, J Visual Dematol 16(9):850-851, 2017. Figure 2 is a diagram explaining the eczema triangle. Figure 3 is an IR chart of compound (I-1-1). Figure 4 is an IR chart of compound (I-1-1). １ 5 is a H NMR chart of compound (I-1-1). １３ 1C NMR chart. FIG. 6 shows the results of automated single crystal X-ray structural analysis of compound (I-1-1). FIG. 7 shows the results of automated single crystal X-ray structural analysis of compound (I-1-1). FIG. 8 shows a summary of the analytical 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). FIG. 9 shows 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. FIG. 10 shows a photograph of the anterior surface of the lower leg four months after the start of topical application of a cream containing compound (I-1-1) in Example 1. FIG. 11 shows a photograph of the left temporal region before the start of topical application of a cream containing compound (I-1-1) in Example 2. 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] FIG. 13 is a photograph of the frontal hairline before the start of topical application of a cream containing compound (I-1-1) in Example 3. FIG. 14 is a photograph of the frontal hairline 14 days after the start of topical application of a cream containing compound (I-1-1) in Example 3. FIG. 15 is a photograph of the anterior surface of the right lower leg before the start of topical application of a cream containing compound (I-1-1) in Example 4. FIG. 16 is a photograph of the anterior surface of the right lower leg 52 days after the start of topical application of a cream containing compound (I-1-1) in Example 4. FIG. 17 is a photograph of the palms of both hands before the start of topical application of a cream containing compound (I-1-1) in Example 5. FIG. 18 is a photograph of the palms of both hands 3 weeks after the start of topical application of a cream containing compound (I-1-1) in Example 5. FIG. 19 is a photograph of the occipital hairline before the start of topical application of a cream containing compound (I-1-1) in Example 6. Figure 20 is a photograph of the back of the head hairline on day 28 after the start of topical application of a cream containing compound (I-1-1) in Example 6. Figure 21 is a photograph of the both antecubital and popliteal fossae before the start of topical application in Example 7.

[0035] Figure 22 is a photograph of both cubital fossae and both popliteal fossae on day 15 after the start of external application in Example 7. Figure 23 is a photograph of both cubital fossae before the start of external application in Example 8. Figure 24 is a photograph of both cubital fossae on day 14 after the start of external application in Example 8. Figure 25 is a photograph of both thighs before the start of external application in Example 9. Figure 26 is a photograph of both thighs on day 14 after the start of external application in Example 9. Figure 27 is a photograph of both soles before the start of external application in Example 10. Figure 28 is a photograph of both soles on day 29 after the start of external application in Example 10. Figure 29 is a photograph of the medial edge of the right sole before the start of external application in Example 11. Figure 30 is a photograph of the medial edge of the right sole 12 days after the start of external application in Example 11. Figure 31 is a photograph of the sacrum before the start of external application in Example 12. FIG. 32 is a photograph of the sacrum in Example 12, taken six and a half months after the start of external application.

[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 A or more and B or less. For example, the expression "1 to 5%" means 1% or more and 5% or less.

[0037] [Skin disease therapeutic agent] <Compound (a)> The skin disease therapeutic agent of one embodiment of the present invention contains compound (a). The skin disease therapeutic agent of one embodiment of the present invention may contain one type of compound (a), or two or more types of compound (a).

[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]

[0040] [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. ２ is preferably a fluorine atom or a hydrogen atom, more preferably a hydrogen atom. ３ is preferably a methyl group.

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

[0043]

[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 combinations include Compound Nos. 13 to 24. 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]

[0046] Because the effect of the therapeutic drug for skin diseases 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]

[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%, even 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 are obtained, irritation to the skin is low, and the feel in use is good.

[0049] The method for producing compound (a) is not particularly limited, and compound (a) 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 the Presence of Acid, Alkali, Light Irradiation, and Oxidizing Agents Under Weak 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 place.

[0052] Topical steroids have a history dating back to 1952, when Sulzberger developed 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); Diaquat (diflorasone acetate) 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 (hydrocortisone-containing mixed killed bacteria suspension) The structural formula of prednisolone, a representative of commonly used topical steroid medications, is shown in formula (P) below.

[0054]

[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) A double bond between C4 and C5 is essential for enhancing glucocorticoid activity. (4) When C6 and C9 contain halogen atoms, the medicinal effect is further enhanced. (5) It is essential for C11 to have an OH group (hydroxyl group) or a C=O group (ketone group) to exert anti-inflammatory effects. (6) The α-OH group on C17 is important for exerting anti-inflammatory effects. (7) When the OH groups (hydroxyl groups) on C17 and C21 are esterified, affinity to the skin is increased.

[0056] Compound (a) differs significantly in structure from the 25 types of steroid compounds mentioned above in that C17 is a C=O group (ketone group). Considering (6) above, compound (a) would be expected to have reduced affinity to the skin. However, as shown in the examples below, this is not the case. Rather, it has been suggested that if C17 is a C=O group (ketone group), the pharmacological effect is 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 25 types of steroid compounds mentioned above (the largest being Flumeta (mometasone furoate, molecular weight 521.43) and the smallest being 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 transdermal absorption (Maruho Medical Professionals' Site, Topical Medicine Trivia, Chapter 2, Active Ingredients and Transdermal Absorption: Characteristics of Active Ingredients that are Easily Transdermal). This transdermal absorption can also be said to be inversely exponential.

[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 considered to have a therapeutic effect on skin diseases at a lower dose and / or for a shorter period than existing topical steroid medications, without any noticeable side effects, and more safely (mainly, with less possibility of skin thinning).

[0059] <Skin Disease Therapeutic Drug> A skin disease therapeutic drug in one embodiment of the present invention comprises one or more compounds (a) selected from the group consisting of compounds represented by formula (I) and compounds represented by formula (II). The skin disease therapeutic drug in one embodiment of the present invention is not particularly limited in its form and dosage form, as long as it comprises compound (a). Examples of the form of the skin disease therapeutic drug include solid, semisolid, liquid, emulsion, cream, gel, and foam (mousse), and preferably emulsion, cream, gel, or foam (mousse).

[0060] The skin disease therapeutic drug can be an external medicine such as a dermatological drug, eye drops, nasal drops, ear drops, oral medicine, suppository, or injection, but is preferably an external medicine, more preferably an external medicine. The dosage form of the external medicine includes, for example, an external solid preparation such as an external powder; an external liquid preparation such as a liniment or lotion; a spray (spray) such as an aerosol or pump spray; an ointment such as an oily ointment or a water-soluble ointment; a cream (emulsion base) such as an oil-in-water cream or a water-in-oil cream; a gel such as an aqueous gel or an oily gel; a patch such as a cataplasm or tape, but is preferably a spray (spray), an ointment, a cream, or a gel, more preferably a cream, and even more preferably a water-in-oil cream.

[0061] The dosage form of the injection drug may be, for example, a water-soluble injection drug, a water-insoluble injection drug, a suspension injection drug, an emulsified injection drug, or an injection drug that is dissolved before use, with water-insoluble injection drug, a suspension injection drug, or an emulsified injection drug being preferred. The route of administration of the injection drug is not limited, and may be, for example, an intradermal injection, a subcutaneous injection, an intravenous injection, or an 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, as long as they do not impair the effects of the present invention. Examples of additives used in topical skin preparations, such as pharmaceuticals, include oily components, surfactants (synthetic and natural), moisturizing agents, thickeners, antiseptics 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-ethylhexyl glyceride, 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 therapeutic agent can be appropriately blended with active ingredients typically used in topical or injectable drugs, as needed, within the scope of not impairing the effects of the present invention. 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. It is preferable that the skin disease therapeutic agent contain 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, immersing, 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 agent are not particularly limited and can be determined depending on the type and symptoms of the skin disease. For external use, preferably, FTU (Finger Tip Unit, the amount squeezed out of a 5 mm caliber tube and placed on an adult's index finger from the tip to the first joint, approximately 0.5 g) is applied to an area equivalent to two palms of an adult's hand once or twice a day. For external use, the dosage of the skin disease therapeutic agent per administration is preferably 0.5 ng to 25 mg, more preferably 5 ng to 5 mg, even 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 agent is not particularly limited and can be determined depending on the type and symptoms of the skin disease. However, it is preferably 1 day to 180 days, more preferably 7 days to 120 days, and even more preferably 10 days to 60 days.

[0070] The skin disease therapeutic agent of one embodiment of the present invention is expected to be effective at a lower dose and / or for a lower duration than existing topical steroid medications. The skin disease therapeutic agent of one embodiment of the present invention is expected to be effective against psoriasis at a lower dose and / or for a lower duration than existing psoriasis therapeutic agents, particularly topical steroid medications. The skin disease therapeutic agent of one embodiment of the present invention is expected to be effective against atopic dermatitis at a lower dose and / or for a lower duration than existing atopic dermatitis therapeutic agents, particularly topical steroid medications and topical phosphodiesterase 4 (PDE4) inhibitor medications. The skin disease therapeutic agent of one embodiment of the present invention is expected to be effective against palmoplantar pustulosis at a lower dose and / or for a lower duration than existing palmoplantar pustulosis therapeutic agents, particularly topical steroid medications. The skin disease therapeutic agent of one embodiment of the present invention is expected to be effective against eczema at a lower dose and / or for a lower duration than existing eczema therapeutic agents, particularly topical steroid medications.

[0071] The skin disease targeted by the therapeutic drug for skin disease is not particularly limited, but 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 a severity that is usually treated with a topical steroid. The skin disease 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, psoriatic arthritis, and pustular psoriasis, but is preferably psoriasis vulgaris. The site of psoriasis onset is not particularly limited and may be the head, hairline, elbows, knees, back, lower back, buttocks, lower legs, pubic area, groin, axillae, 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 below 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 causing inflammatory changes can be rephrased as the group of diseases causing eczema reactions, and examples thereof include eczema or 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 or dermatitis, more preferably atopic dermatitis and seborrheic dermatitis.

[0076] Eczema or dermatitis can be further classified into eczema or dermatitis with a relatively clear cause or typical clinical features, such as atopic dermatitis, seborrheic dermatitis, contact dermatitis, infantile seborrheic dermatitis, nummular eczema, autosensitization dermatitis, stasis eczema, asteatotic eczema, shiitake dermatitis, insect bites, hand eczema (housewife's eczema), dyshidrotic eczema (dyshidrotic eczema, dyshidrotic eczema), miliaria, and lichen simplex chronicus, and other eczema or dermatitis, which may be acute or chronic. The other eczema or dermatitis group includes many eczemas with unknown causes, and can be classified into acute eczema and chronic eczema, which show the features 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 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 of 40 or more, or a VAS of 60 or more. 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 the context of the therapeutic agents 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 a human or a non-human (for example, a mammal such as a dog, cat, or mouse), but is preferably a human.

[0081] The skin disease therapeutic agent of one embodiment of the present invention can be used in topical therapy in combination with other drugs, for example, other skin disease therapeutic or preventive drugs. When the skin disease therapeutic agent of one embodiment 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 one embodiment 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 according to one embodiment of the present invention may be used in combination with phototherapy (PUVA therapy, narrow band UVB therapy), oral therapy, or injection therapy.

[0083] One aspect of the present invention is a method for treating a skin disease in a patient, as described below. Item 1-1. A method for treating a skin disease in a patient, comprising administering to the patient an effective amount of one or more compounds (a) selected from the group consisting of the compounds represented by formula (I) and the compounds represented by formula (II). [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.] Item 1-2. The method of Item 1-1, wherein the compound (a) is a compound represented by formula (I-1). Item 1-3. The method of Item 1-1 or 1-2, wherein the skin disease is inflammatory keratosis. Item 1-4. The method of Item 1-3, wherein the inflammatory keratosis is one or more selected from the group consisting of psoriasis, parapsoriasis, and lichen planus. Item 1-5. The method of Item 1-1 or 1-2, wherein the skin disease is pustulosis. Item 1-6. The method of Item 1-5, wherein the pustulosis is palmoplantar pustulosis. Item 1-7. The method of Item 1-1 or 1-2, wherein the skin disease is a group of diseases causing inflammatory changes. Item 1-8. The method of Item 1-7, wherein the group of diseases causing inflammatory changes is eczema / dermatitis. Item 1-9. Item 8. The method according to Item 1, wherein the disease causing inflammatory changes is one or more selected from the group consisting of atopic dermatitis and seborrheic dermatitis.

[0084] One aspect of the present invention is the following compound (a) for use in the treatment of skin diseases. Item 2-1. One or more compounds (a) selected from the group consisting of compounds represented by formula (I) and compounds represented by formula (II) for use in the treatment of skin diseases. [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 ３is a methyl group or a hydrogen atom.] Item 2-2. Compound (a) according to Item 2-1, wherein the compound (a) is a compound represented by formula (I-1). Item 2-3. Compound (a) according to Item 2-1 or 2-2, wherein the skin disease is inflammatory keratosis. Item 2-4. Compound (a) according to Item 2-3, wherein the inflammatory keratosis is one or more selected from the group consisting of psoriasis, parapsoriasis, and lichen planus. Item 2-5. Compound (a) according to Item 2-1 or 2-2, wherein the skin disease is pustulosis. Item 2-6. Compound (a) according to Item 2-5, wherein the pustulosis is palmoplantar pustulosis. Item 2-7. Compound (a) according to Item 2-1 or 2-2, wherein the skin disease is a group of diseases causing inflammatory changes. Item 2-8. Compound (a) according to Item 2-7, wherein the group of diseases causing inflammatory changes is eczema / dermatitis. Item 2-9. Item 8. Compound (a) according to Item 2-7, wherein the disease causing inflammatory changes is one or more selected from the group consisting of atopic dermatitis and seborrheic dermatitis.

[0085] One aspect of the present invention is the use of one or more compounds (a) selected from the group consisting of compounds represented by formula (I) and compounds represented by formula (II) for treating a skin disease. Another aspect of the present invention is the use of one or more compounds (a) selected from the group consisting of compounds represented by formula (I) and compounds represented by formula (II) in the manufacture of a therapeutic agent for a skin disease.

[0086] [Method for Producing 9α-Fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione] One aspect of the present invention is a method for producing 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione, which comprises the 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.

[0087] <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.

[0088] 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.

[0089] 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.

[0090] <NaH> NaH is not particularly limited, and can be produced by a known method, or a commercially available product can be used. NaH can be used as 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.

[0091] NaH is a strong base (pKa = 35) and is widely used to deprive NH, OH, SH, or CH of a proton, and is widely used in William's ether synthesis, etc. In the production method of one embodiment 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 then 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.

[0092] <Contacting Step> The method for contacting compound (B) with NaH is not particularly limited, and known methods 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. Stirring can be performed by known methods, for example, using a stirrer. When compound (B) and NaH are contacted, they react with each other, and 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione can be produced.

[0093] 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.), and the contact time is, for example, 0.1 to 15 hours.

[0094] 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, more preferably tetrahydrofuran (THF). The purity of the organic solvent is not particularly limited, but a higher purity is preferable, more preferably 95% or higher. The organic solvent may be used after distillation or without distillation. In one embodiment of the production method of the present invention, even when an undistilled organic solvent is used, compound (B) and NaH can react to produce 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione. The amount of the organic solvent used is not particularly limited and can be determined depending on the amount of compound (B), and is preferably an amount that completely dissolves compound (B).

[0095] 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.

[0096] According to the above-described production method, 9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione can be easily produced in a short time at a temperature near room temperature. Furthermore, since compound (B) is a generally available compound, the above-described production method is suitable for industrial use.

[0097] 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.

[0098] <Production Example 1: Preparation of Compound (I-1-1)> Betamethasone 17,21-dipropionate (betamethasone dipropionate ester) manufactured by Tokyo Chemical Industry Co., Ltd. was used. 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 As ONE Handy UV Lamp SUV-4 254 nm. Various spectra were measured using the following models. IR spectrum (infrared absorption spectrum) was measured using a JASCO FT / IR-410, １ H NMR, １３ C NMR was measured using a Varian UNITY INOVA 400 instrument with TMS as the internal standard, and the values ​​are shown as δ values ​​(ppm). Single crystal automated X-ray structure analysis was performed using a Rigaku VariMax Saturn CCD724α.

[0099] 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 using a magnetic stirrer. Water was then added, the mixture was extracted with chloroform, washed with water until the pH reached 7, and dried by adding sodium sulfate. The mixture was then filtered, the solvent was 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, yielding 18 mg of a white powdery substance (yield 40%). The above procedure was carried out at room temperature. The resulting white powdery substance is hereinafter referred to as compound (I-1-1).

[0100] For compound (I-1-1), infrared absorption spectrum, １ H NMR, and １３ C NMR was measured, and further, automatic single crystal X-ray structure analysis was performed. The obtained IR chart is shown in Figure 3. １ 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.

[0101] Production Example 2: Preparation of Compounds (b) and (c) 105 mg of Antebate (betamethasone butyrate propionate) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in 3.5 mL of tetrahydrofuran (manufactured by Tokyo Chemical Industry Co., Ltd.), and one small spoonful of NaH (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., sodium hydride in oil) was added. After stirring for 15 hours with a magnetic stirrer, water was added, the solution was extracted with chloroform, washed with water until the pH reached 7, dried by adding 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 powdery substance. The above procedures were carried out at room temperature. The resulting white powdery substance is presumed to be a mixture of two types of 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.

[0102] 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.

[0103] (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 uniform, 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 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.

[0104] (PSI Score) The severity of local symptoms of psoriasis other than on the scalp was evaluated using the PSI (Psosis 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 therapeutic effect on specific skin eruptions of psoriasis vulgaris. The severity of erythema, infiltration / thickening, and scaling was scored according to the criteria in Table 3 below.

[0105]

[0106] The PSI total score was calculated from the scores for erythema, infiltration / thickening, and scale according to the following formula (A): PSI total score = PSI erythema score + PSI infiltration / thickening score + PSI scale score Formula (A) Generally, a PSI total score of 5 or less indicates mild disease, greater than 5 but less than 20 indicates moderate disease, and 20 or more indicates severe disease.

[0107] (PSSI) The severity of local symptoms of scalp psoriasis was evaluated using the PSSI (Psoriasis Scalp Severity Index) score. The PSSI score is an index that independently evaluates each of the skin findings of scalp psoriasis vulgaris, which are the main symptoms of scalp psoriasis vulgaris: erythema, infiltration / thickening, and scaling, and can also evaluate the extent of the lesion. The PSSI score was determined by comparing clinical observations (findings) with the "Psoriasis Vulgaris Case Photographs by Evaluation Index" provided by Maruho Co., Ltd. These psoriasis vulgaris case photographs are photographs of multiple psoriasis vulgaris cases with different severity of each skin finding and lesion area, each with a PSSI score written on it, and are a common evaluation tool for easily determining PSSI scores in clinical practice. The written PSSI scores were calculated using the following method.

[0108] The severity of each skin finding on the scalp (erythema, infiltration / thickening, scale) and the lesion area of ​​psoriasis vulgaris 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 was scored according to the criteria in Table 4 below.

[0109]

[0110] The PSSI total score was calculated from the scores for erythema, infiltration / thickening, and scale using the following formula (B): PSSI total score = (erythema score + infiltration / thickening score + scale score) × lesion extent score Formula (B)

[0111] Example 1 (Profile of Subject 1) A 79-year-old male 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. Therefore, treatment was 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) for approximately 7 months. However, the scales and erythema on the anterior surface of both lower legs remained.

[0112] (Administration of Compound (I-1-1) to Subject 1) After discontinuing the topical application of Dovobet Foam, the subject continued to take the same amount of oral cyclosporine, and was prescribed 5 g of a cream containing 2.9 mg of Compound (I-1-1), which was applied topically to the affected area in an FTU amount (Finger Tip Unit, approximately 0.5 g) once a day.

[0113] (Results) 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 Figure 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 Figure 10. Severe psoriasis improved to milder symptoms by topical application of a cream containing (I-1-1). No side effects were observed.

[0114] Example 2 (Profile of Subject 2) A 61-year-old male developed psoriasis on the left side of his head several years ago. Since then, he had experienced repeated relief and exacerbation of his condition with the topical application of various steroids (Dermovate scalp lotion, Comclo shampoo, Antebate lotion, etc.).

[0115] (Administration of Compound (I-1-1) to Subject 2) The use of the topical steroid preparation 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, and treatment was performed by topically applying an amount equivalent to FTU once a day.

[0116] (Results) 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.

[0117] Example 3 (Profile of Subject 3) A 48-year-old woman was a patient who had developed psoriasis for the first time. She noticed symptoms two months before her first consultation. A scaly erythema appeared at the front of her head at the hairline, measuring 2 cm in area and 8 cm in length.

[0118] (Administration of compound (I-1-1) to subject 3) 5 g of cream containing 2.9 mg of compound (I-1-1) was prescribed to the right half of the lesion, and 15 g of Dovobet gel (manufactured by Leo Pharma Co., Ltd.) was prescribed to the left half, and treatment was performed by applying the amount of FTU topically to each lesion once a day.

[0119] (result) A photograph of the frontal hairline area before the start of topical application of compound (I-1-1) is shown in Figure 13, and a photograph taken 14 days after the start of topical application is shown in Figure 14. The right side, where the cream containing compound (I-1-1) was applied topically, was evaluated as a successful treatment. No side effects were observed.

[0120] Example 4 (Profile of Subject 4) A 50-year-old male. He had been undergoing treatment for psoriasis (head, back, and lower back) for the past 20 years. Five or six years ago, the disease spread to the nails of all his fingers and toes, and he had been treating it with cyclosporine, dovobet foam, etc. Scale-covered erythema remained only on the anterior surface of his right lower leg.

[0121] (Administration of Compound (I-1-1) to Subject 4) After discontinuing the use of cyclosporine, dovobet foam, etc., treatment was performed by topically 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.

[0122] (Results) PSI total score before the start of topical application of compound (I-1-1): 15 PSI total score on day 52 after the start of topical application: 7 A photograph of the anterior right lower leg before the start of topical application of compound (I-1-1) is shown in Figure 15, and a photograph on day 52 after the start of topical application is shown in Figure 16. Moderate psoriasis improved to mild as a result of topical application of a cream containing compound (I-1-1). No side effects were observed.

[0123] Example 5 (Profile of Subject 5) A 42-year-old male patient with palmoplantar pustulosis. Two years ago, small pustules accompanied by erythema began to appear frequently on the palms of both hands. The patient had only visited another hospital once. At the initial visit, pale pink erythema was observed over the entire palms of both hands, and the right palm had more scales than the left palm, but no blisters or pustules were observed on either palm.

[0124] (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 in an amount equivalent to FTU once a day before going to bed.

[0125] (Results) 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.

[0126] Example 6 (Profile of Subject 6) A 54-year-old woman. The patient is thought to have developed seborrheic dermatitis at the back of the head and hairline 10 years ago. The condition was intractable from the beginning, and she visited several dermatologists, receiving prescriptions for various steroid lotions, including Dovobet gel, but none of these worked at all.

[0127] (Administration of Compound (I-1-1) to Subject 6) 10 g of a cream containing 5 mg of compound (I-1-1) was prescribed, and treatment was carried out by topically applying an amount equivalent to FTU once a day.

[0128] (Results) After 28 days, all of the scales and erythema had disappeared and the patient was cured. 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.

[0129] Example 7 (Profile of Subject 7) A 23-year-old male developed atopic dermatitis four years ago, presenting with itchy erythema and dry skin on the face, limbs, and trunk. He had been prescribed various topical medications at other hospitals.

[0130] (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, and treatment was performed by applying an amount equivalent to FTU externally once a day before going to bed.

[0131] (Results) After 15 days, the itching in the left cubital fossa and left popliteal fossa disappeared, and the erythema in the left cubital fossa and left popliteal fossa was also less severe than that in the right cubital fossa and right popliteal fossa, with a clear difference between the left and right sides being observed. Photographs of both cubital fossas and both popliteal fossas at the start of topical application are shown in Figure 21, and photographs taken 15 days after the start of 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.

[0132] Example 8 (Profile of Subject 8) A 22-year-old male developed atopic dermatitis almost all over his body two years ago, but left it untreated.

[0133] (Administration of compound (I-1-1) to subject 8) 12.5 g of cream containing 8 mg of compound (I-1-1) was prescribed for the left cubital fossa, and 20 g of 1% Moisert ointment was prescribed for the right cubital fossa. Treatment was performed by applying the cream containing compound (I-1-1) once a day and the 1% Moisert ointment twice a day in an amount equivalent to FTU before going to bed. The VAS (Visual Analogue Scale) at the start of topical application was 40 for both cubital fossae.

[0134] 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.

[0135] (Results) 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. 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.

[0136] Example 9 (Profile of Subject 9) A 14-year-old male. His atopic dermatitis had worsened for more than two or three years, causing severe itchy erythema and dry skin on his face and limbs. He had been treated at another hospital with topical and oral steroids, but the condition was intractable.

[0137] (Administration of compound (I-1-1) to subject 9) 15 g of a cream containing 9.6 mg of compound (I-1-1) was prescribed for the right thigh, and 30 g of Antebate ointment was prescribed for the left thigh, and treatment was performed by applying an amount equivalent to FTU to each subject once a day before going to bed. The VAS at the start of topical application was 80 for both thighs.

[0138] (Results) 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, with the erythema and dry skin disappearing, no difference in itching between the left and right thighs, and the VAS score 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 an effect similar to that of Antebate ointment. No side effects were observed.

[0139] Example 10 (Profile of Subject 10) A 64-year-old woman had developed palmoplantar pustulosis several months earlier, with numerous erythema, small blisters, and scales on the soles of both feet. Since her initial consultation, she had been using 30 g of a topical mixture of vitamin D and very strong steroids, but her condition was worsening.

[0140] (Administration of Compound (I-1-1) to Subject 10) 14 g of a cream containing 9 mg of compound (I-1-1) was prescribed for the soles of both feet, and treatment was carried out by applying an amount equivalent to FTU externally once a day before going to bed.

[0141] (Results) After 29 days, the erythema, small blisters, and scales on both soles were significantly reduced. 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 very strong steroid. No side effects were observed.

[0142] 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 little improvement was observed.

[0143] (Administration of Compound (I-1-1) to Subject 11) 15 g of cream containing 9.6 mg of compound (I-1-1) was prescribed to the medial edge of the right sole, and treatment was performed by applying externally an amount equivalent to FTU once a day before going to bed.

[0144] (Results) After 12 days, although some new erythematous plaques had appeared, overall erythema, scales, and blisters were not noticeable, confirming the therapeutic effect. Figure 29 shows a photograph taken at the start of topical application, and Figure 30 shows a photograph taken 12 days after the start of topical application. No side effects were observed.

[0145] Example 12 (Profile of Subject 12) A 74-year-old male. 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 approximately 1 or 2 cm in diameter. When touched with the fingers, scale-like material peeled off. The lesions were showing a tendency to grow larger, so he visited the hospital. He was diagnosed with chronic eczema.

[0146] (Administration of Compound (I-1-1) to Subject 12) 5 g of a cream containing 3 mg of Compound (I-1-1) was prescribed to the affected area, and treatment was performed by applying an amount equivalent to FTU once a day before going to bed. One month later, 20 g of the same cream was additionally prescribed.

[0147] (Results) After 4-5 months, the lesions were completely cured. Figure 31 shows a photograph at the start of topical application, and Figure 32 shows a photograph 6.5 months after the start of topical application. No side effects were observed.

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): [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):

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

4. The skin disease treatment drug according to claim 3, wherein the inflammatory keratosis is one or more selected from the group consisting of psoriasis, parapsoriasis, and lichen planus.

5. A skin disease treatment drug according to claim 1 or 2, wherein the skin disease is pustulosis.

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

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

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

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

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